JBR 2013-3 by office

WETTEREN 1

P 702083

Volume 96 Page 109-187 May-June

Bimonthly

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2013

DIAGNOSTIC AND INTERVENTIONAL IMAGING, RELATED IMAGING SCIENCES, AND CONTINUING EDUCATION

ORGANE DE LA SOCIETE ROYALE BELGE DE RADIOLOGIE (SRBR) ORGAAN VAN DE KONINKLIJKE BELGISCHE VERENIGING VOOR RADIOLOGIE (KBVR) 00a-Couv-2013.indd 1

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Subscribers’ information The JBR-BTR is published 6 times a year. Subscription of members of the Belgian Society of Radiology are included in membership dues and are handled by the Society. Non-members’ subscriptions are available from the ARSMB-KVBMG. The rate is valid to date and can be amended without notice according to fluctuation of printing and material costs. Annual subscriptions or single issue orders should be made promptly. The publishers cannot guarantee supply of back issues. Change of address must be notified 60 days in advance. RATES: Annual Belgium 150 € Other Countries 175 € All amounts are net and include postal and handling charges.

Single issue 38 € 44 €

You are kindly invited to address all your correspondence to Mrs A. Hirsch and execute all payments to ARSMBKVBMG (see below).

Instructies voor abonnees Het JBR-BTR geeft 6 nummers uit per jaar. Het tarief is vatbaar voor wijzigingen zonder voorafgaand bericht, in verhouding tot de evolutie van de papierprijzen en loonkosten in de grafische nijverheid. Het abonnement van de leden van de Koninklijke Vereniging voor Radiologie is begrepen in de bijdrage van het lidgeld. De abonnementen van niet-leden zijn te onderschrijven bij de KVBMG. Jaarabonnementen of bestellingen van losse nummers moet zo snel mogelijk gebeuren, de uitgever waarborgt de levering van de vorige nummers niet voor de abonnementen die te laat werden onderschreven. De adresveranderingen moeten 60 dagen te voren gemeld worden. TARIEF: Jaarlijks Belgie 175 € Andere landen 200 € Verzendingskosten zijn inbegrepen.

Aflevering 42 € 49 €

U wordt vriendelijk verzocht alle briefwisseling te richten aan Mevr. A. Hirsch en alle betalingen te verrichten op het banknummer van ARSMB-KVBMG (zie hieronder).

Instructions aux abonnés Le JBR-BTR publie 6 fascicules par an. Les tarifs sont susceptibles de modifications sans préavis, en fonction de l’évolution des prix du marché du papier et des travaux d’impression. Le prix de l’abonnement des membres de la Société Royale de Radiologie est inclus dans le montant de la cotisation. L’abonnement d’un non-membre est à souscrire auprès de l’ARSMB. La souscription d’abonnement ou la commande de numéro isolé doit être exécutée rapidement, l’éditeur ne pouvant pas garantir la livraison d’éditions passées. Les changements d’adresse doivent être signalés 60 jours à l’avance. TARIF: Belgique Autres pays Envoi et port inclus.

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Nous vous prions d’adresser toute correspondance à Mme A. Hirsch et d’effectuer tout paiement au compte de l’ARSMB-KVBMG (voir ci-dessous).

Koninklijke Vereniging van de Belgische Medische Wetenschappelijke Genootschappen – (KVBMG), vzw W. Churchill-laan 11/30, B-1180 Brussel, België tel.: (02) 374 25 55 fax: (02) 374 96 28

Association Royale des Sociétés Scientifiques Médicales Belges – (ARSMB), asbl avenue W. Churchill 11/30, B-1180 Bruxelles, Belgique tél.: (02) 374 25 55 fax: (02) 374 96 28

Webaddress: http://www.ulb.ac.be/medecine/loce/amb.htm E-mail: jbr-btr@skynet.be Bank Account: Post Office Account Fortis: 210-0251210-32 Giro: 000-0273502-59 IBAN: BE 90210025121032 IBAN: BE 84000027350259 BIC: GE BABEBB36A BIC: BPOTBEB1

JBR-BTR  96/3  2013 Journal Belge de  Belgisch Tijdschrift voor  RADIOLOGIE

Founded in 1907 A bimonthly journal devoted to diagnostic and interventional imaging, related imaging sciences, and continuing education Contents LUNG CANCER IMAGING IN 2012: UPDATES AND INNOVATIONS, TERVUREN, 12.11.12 Editorial B. Ghaye, E. Coche. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 The new classification of lung adenocarcinomas: implications for pathologists and radiologists B. Weynand, J. Cohen, M. Delos, C. Fervaille, M. Michoud, M.C. Nollevaux, E. Reymond, G.R. Ferretti. . . . . . 112 Update in non small- cell lung cancer staging R.A. Salgado, A. Snoeckx, M. Spinhoven, B. Op de Beeck, B. Corthouts, P.M. Parizel. . . . . . . . . . . . . . . . . . . . . 118 Invasive staging of the mediastinum W. De Wever, J. Coolen, J. Verschakelen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Whole body PET-CT: M staging in non small- cell lung cancer F.-X Hanin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Contribution of MRI in lung cancer staging A. Khalil, T. Bouhela, M.-F. Carette. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Percutaneous ablation of malignant thoracic tumors B. Ghaye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 4D PET-CT guided radiation therapy X. Geets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Dosimetry: which dose for screening, diagnosis and follow-up ? D. Tack, H. Salame. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Screening for lung cancer by imaging: the NELSON study M. Oudkerk, M.A. Heuvelmans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 RECIST and beyond E. Coche. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Assessment of lung tumor response by perfusion CT E. Coche. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

SPECIAL ARTICLE A midline sagittal brain view depicted in da Vinci’s “Saint Jerome in the wilderness” M.M. Valença, M. de F. V. Vasco Aragao, M. Castillo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

LETTERS TO THE EDITOR Peritoneal carcinomatosis and prostatic cancer : a rare manifestation of the disease with an impact on management M. Ghaddab, E. Danse, J.P. Machiels, A. Dragean, L. Annet, B. Tombal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Variations of the hepatic artery B. Karaman, V. Akgun, S. Celikkanat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

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IMAGES IN CLINICAL RADIOLOGY Duodenal duplication cyst complicated by haemorrhage C. Ruivo, C. Antunes, L. Curvo-Semedo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Pelvic girdle enthesitis in spondyloarthritis C. Van Langenhove, L. Jans, L. Van Praet, P. Carron, D. Elewaut, F. Van Den Bosch, K. Verstraete. . . . . . . . . . 181 Active and structural lesions of the sacro-iliac joints in spondyloarthritis L. Coeman, L. Jans, L. Van Praet, P. Carron, D. Elewaut, F. Van Den Bosch, K. Verstraete. . . . . . . . . . . . . . . . . 182 Leiomyosarcoma of the great saphenous vein C. Werbrouck, J. Marrannes, P. Gellens, B. Van Hoslbeeck, E. Laridon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Pseudomyxoma peritonei due to mucinous adenocarcinoma of the appendix S. Idjuski, I. Turkalj, K. Petrovic, F.M. Vanhoenacker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Skull base bone hyperpneumatization E.J. Houet, L.M. Kouokam, A.L. Nchimi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Congenital azygos pseudocontinuity with right lower intercostal vein M.A. Houbart, Th. Couvreur, L. GĂŠrard, A. Georgiopoulos, B. Desprechins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Corrected announcement from the Museum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Forthcoming Courses and Meetings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Instructions to Authors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii Subscribers information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . cii Advertising index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

u The terms used for indexation of subjects were developed by the Radiological Society of North America (RSNA) over a period of years. Their use here is by permission of the RSNA. The terms may not be used in any other index, print or electronic, except by specific permission of RSNA. uu Indexed in Index Medicus and in Zentralblatt Radiologie. Evaluated for Medline User, EMBASE and CANCERNET. Abstracted in Excerpta Medica Journals.

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Editor: J. Pringot Assosiated Editors: B. Ghaye, E. Coche

Royal Belgian Society of Radiology: Http://www.rbrs.org President: R. Hermans

Consulting Co-Editor: M. Castillo (USA)

Vice-President: D. Henroteaux

Managing Editors: P. Seynaeve

Past-President: J.F. De Wispelaere

Editorial Board: F. Avni, L. Breysem, N. Buls, B. Coulier, B. Daenen, E. Danse, H. Degryse, P. Demaerel, B. Ghaye, J. Gielen, P. Habibollahi, N. Hottat, M. Laureys, F. Lecouvet, M. Lemmerling, B. Lubicz, J.F. Monville, T. Mulkens, J.F. Nisolle, B. Op de Beeck, R. Oyen, S. Pans, V.P. Parashar (USA), P. Parizel, P. Peene, H. Rigauts, N. Sadeghi, P. Simoni, S. Sintzoff Jr, A. Snoeckx, J. Struyven, H. Thierens, P. Van Dyck, F. Vanhoenacker, Ph. Van Hover, J. Verschakelen, K. Verstraete.

General Secretaries: M. Lemort, J. Verschakelen Meeting Secretaries: M. Spinhoven, Y. Lefebvre Treasurers: D. Brisbois, A. Van Steen Coordinator of continuing education: G. Villeirs Coordinators of professional defence: C. Delcour, D. Bielen Webmasters: J. de Mey, J. Struyven

Sections of the Royal Belgian Radiological Society (SRBR-KBVR): Abdominal and digestive imaging

B. Op de Beeck, E. Danse

Bone and joints

J.F. Nisolle, M. Shahabpour

Breast imaging

M. Mortier, S. Murgo

Cardiac imaging

R. Salgado, O. Ghekière

Cardiovascular and interventional radiology

S. Heye, D. Henroteaux

Chest radiology

B. Ghaye, W. De Wever

Head and neck radiology

J. Widelec, R. Hermans

Neuroradiology

M. Lemmerling, L. Tshibanda

Pediatric radiology

B. Desprechins, L. Breysem

For addresses and particulars, see website at http://www.rbrs.org

Instructions to authors The purpose of The Belgian Journal of Radiology is the publication of articles dealing with diagnostic radiology and related imaging techniques, therapeutic radiology, allied sciences and continuing education. All — new and revised — manuscripts and correspondence should be addressed to JBR-BTR Editorial Office, Avenue W. Churchill 11/30, B-1180 Bruxelles, tel.: 02-374 25 55, fax: 32-2-374 96 28. Please note that the following instructions are based on the “Uniform Requirements for manuscripts Submitted to Biomedical Journals” adopted by the International Committee of Medical Journal Editors (Radiology, 1980,135: 239-243). It should however be noted that presentation modifications may be introduced by the Editorial Office in order to conform with the JBR-BTR personal style. Authors should specify to which of the following headings their manuscript is intended: Original Article, Review Article, Case Report, Pictorial Essay, Continuing Education, Technical Note, Book Review, Opinion, Letter to the Editor, Comment, Meeting News, in Memoriam, News. Authors should consider the following remarks and submit their manuscripts accordingly. All articles must contain substantive and specific scientific material. – Original articles are articles dealing with one specific area of Radiology or allied science related through the personal experience of the author. – Review articles are special articles reporting the experience of the author considered in

–

the general perspective of the literature over the topic. Case reports are short descriptions of a particular case providing a message directly linked to an individual patient investigated. No more than one case should be described in detail and clinical description should be kept to a minimum. Case reports should invest the usual headings of articles but should focus on the particular radiologic procedure that contributed to the diagnosis. References should be present, though limited in number. Tables and acknowledgements are usually omitted. Pictorial essays are articles presenting information through illustrations and legends. The presentation remarks stated in the paragraph dealing with case reports apply to pictorial essays. Continuing education articles are designed in accordance with the general guidelines for articles published in the JBR-BTR in particular they are divided into introduction, material and methods, results, discussion, references, and are provided with an abstract. However, papers addressing the continuing education may have only additionnally to their contents an introduction (stating the aim of the article and providing any background information useful to understand why the topic is relevant, and describing the subtopics covered by the study), references, and an abstract. Tables should be limited to a maximum of one table per 6 pages of manuscript. Illustrations should also be limited to a maximum of one illustration (1010 cm)

(possibly made up of different parts) per 3 pages of manuscript. All the material should be made available to the JBR- BTR editorial office (2 copies of the manuscript with 2 sets of illustrations) with the corresponding diskette though there will not be peer review. – Images in Clinical Radiology are short (max. 1 typed page) case reports designed to illustrate with max. 3 figures a specific entity. The report should not include abstract nor discussion but consist of a synthetic description of the clinical and radiological features as well as the final diagnosis and one major reference. Technical notes are short descriptions of a specific technique, procedure or equipment of interest to radiologists. Technical notes may originate from radiologists having experience of the item presented or from commercial firms (these should contact the Editorial Office to obtain specific guidelines for publication). The manuscript length should be inferior to 1 typed page, original language should be English, the manuscript may be accompanied by maximum 1 b/w figure, and include one major reference. – Book reviews should be limited to one typed page, mention full references of the book, including number of pages, of illustrations (when available), and price. The author should specify to whom the book is intended and give a personal appreciation. They will be published with the initial letters of the signature. (continued on next page)

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– Opinion articles are special articles dealing with controversial topics of specific concern to radiologists. They may include tables and figures, and must provide a references list. – Letters to the Editor and their replies present objective and useful criticism over an article published in one of the lest four issues of the JBR-BTR. They will be published with the name and address of the author. References are necessary, tables and figures are accepted but acknowledgements are not appropriate. – Meeting news are reports of national or international congresses, symposia and meetings of radiology. Full references of the meeting, including date, place and summary of the main topics should be mentioned. Text should be kept to major facts. Figures, tables, references and acknowledgements should not be included. – In memoriams and News are essentially dealt with in the Editorial Office. Contributions may however be submitted under the form of letters addressed to the Editorial Office which will check the adequacy of the information.

General Guidelines for Papers Manuscript Requirements Send 3 copies of the manuscript, including tables and figures (1 original set + 2 copies of the text and 2 original sets + 1 copy of the illustrations) and the corresponding diskette (see below Instructions for Electronic Manuscript Submission). In keeping with sound environmental and economic principles, the JBR-BTR encourages all authors to submit manuscripts printed on both sides of the page. The practice not only will save paper but also will reduce the price of postage required to mail the manuscript. Note that failure to provide an electronic version of manuscript will result in costs to be charged to the author. The original set should mention the personal references of the author. The copies should be nameless (including the figures). Each section of the manuscript begins on a new page in the following order: titre page running title page + key-words, abstract, text, acknowledgements, references, tables and captions for illustrations. Use English or one of the national languages. In the latter case, an English version of the titre, abstract, key-words, legends must necessarily be provided. Note that the author will be charged the costs of translation. Submitted manuscripts may not be covered by a previous copyright. The author will be held responsible for any litigation that might possebly ensue. Manuscripts will be submitted to a review Committee whose decision is final. Authors are usually notified within eight weeks as to the acceptability of their paper. Instructions for Electronic Manuscript Submission

Please send an electronic version of your manuscript either a floppy disk or a CD-rom in conjunction with the traditional paper version or separately as an e-mail with attachments to JBR-BTR@skynet.be. Please follow the general instructions on style/ arrangements and, in particular, the reference style as given in the present “Instructions to Authors”. Note, however, that while the paper version of the manuscript must be presented in the traditional double spaced format, the electronic version will be typeset and should not contain any extraneous instructions. For exemple: use hard carriage returns only at the end of paragraphs and display lines (e.g. titles, subheadings); do not use an extra hard return between paragraphs; do not use tabs or extra space at the start of a paragraph or for list entries; do not indent runover lines in references; turn off line spacing; turn off hyphen-

ation and justification; do not specify pages breaks, page numbers, or headers; do not specify typeface. Care should be taken to correctly enter “one“ (1) and longer case “el“ (l), as well as “zero” (O) and capital “o“ (O). Illustrations and tables will be handled conventionally. However, figures and table legends should be included at the end of the electronic file. Nonstandard characters (Greek letters, mathematical symbols, etc.) should be coded consistently throughout the text. Please make a list of such characters and provide a listing of the codes used. Note that disks and CD-roms will not be returned to authors. Title – Keep it short and relevant. – Title must be followed by the surname(s) and first name(s) (for computer processing purposes, 2 initial letters only will be admitted) of all authors. – The position held by the authors, their academic degrees, the name of the institution to which they belong and/or from which the article originates and the name of the department Head (if required) must be indicated at the bottom of the first page. – The titIe in the national language of the text should be noted after the key-words. – A running title in English should be provided on a separate page. – Two copies of a blind titre page are included, giving only the titre (without the authors names) for use in the review process. Abstract and Key-words Written in English exclusively, the abstract should head the manuscript and summarize the aim, the methods, results and conclusions. It should not exceed 200 words for major papers and 100 words for the other studies. No abbreviation or references are used in the abstract. Three to six key-words from the terms used in the JBR-BTR Subject Index (and/or the most recent three-year cumulative index of Radiology) should be listed. Text The text should be clearly divided in the following sections: introduction, material and methods, results, discussion and conclusion. Abbreviations should be defined in an explanatory note before being used as such. The definitive text should be typed on one side only of a standard size (A4) typewriting paper, in doublespacing throughout and have at least 3 cm margins. The manuscript should not be longer than 16 typewritten pages, including references and summary for a major paper unless otherwise agreed by the Editor (one typewritten page is equivalent to approximately 250 words) and no longer than 6 typewritten pages for the other types of work. Specific guest editorials Specific guest editorials are invited papers written by selected distinguished specialists. They should summarize in concise the stase of the art in one specific field of medical imaging or related sciences in no more than 8 typewritten pages, including either 1 table or illustration (drawing or graph). The bibliography should not exceed 12-15 recent and/or fundamental references. References References should be numbered consecutively in the order in which they appear in the text. Their number should be kept down to 20 for major papers and 8 for case reports and other papers.

They should be given as follows: a) abridged titles of periodicals should conform to those in the Index Medicus. All authors are listed when six or fewer; when seven or more authors, the first three are listed, followed by “et al.”. Ex.: Bomsel F., Couchard M., Henry E.: Respiratory distress in the newborn. J Belge Radiol, 1980, 63: 89-107. b) in the case of books, references should indicate: the authors of the chapter, the title of the chapter, the title of the book, the editor(s), publisher, edition, city, year and specific pages. – Ex.: Isengrin P.: Radiologie stomacale. 3e édition, Arscia, Bruxelies, 1974, p. 22. – Ex.: Weinstein L., Swartz M.N.: Pathogenic properties of invading microorganisms. In: Pathologic physiology: mechanisms of disease. Edited by Sodeman W.A. Jr, Sodeman W.A., Cds. Printed by Saunders, Philadelphia, 1974, pp. 457-472. Quote the name and address of the author to whom the reprints will be sent, at the end of the references. Corresponding author and Reprints The name and address of the corresponding author to should be mentioned affer the references. 25 reprints, are offered free by the JBR-BTR. Tables Tables should be presented on a separate page and numbered in Roman numerals in the order in which they are cited in the text. They should have an English title and legend. Abbreviations should be defined in a foot note. Only commonly admitted measurement standards should be used. Figures and Legends Illustrations should be restricted to the minimum required to show the essentiel features described in the paper. They must be mentioned in the text. Two complete unmounted sets of original figures in labeled envelopes should be provided. All figure parts relating to one patient should have the same figure number. Use capital letters A, B, C, in the ieft longer corner to distinguish figures from one set. Figures should be marked on the back with an arabic numeral indicating the sequence in which they are to be referred to, with a lightly pencilled “top“ indicating their topside and the name of the first author. Never use ink on front or back of any figure. For uniformity purposes, points of interest should be showed on the figures with removable (Letraset) arrows or/and letters, or should be indicated on an accompanying photocopy of the figures, in order to enable our services to use their own characters. Images should be uniform in size and magnification. 1. Radiographs Cost and number: depending on the length of the manuscript (a total of 2 to 6 times 14 ⫻ 15 cm is availabie free of charge). Presentation: glossy prints, no larger than 18/24 cm. It is advisable for films to be centered on the zone of major interest and they should be grouped. Arrows should indicate the important points. 2. Photographs and drawings Four-colour illustrations will be printed at the expense of the authors. Drawing and graphs should be of professional quality. They should illustrate — not duplicate — data given in the text. Legends are typed separately and preceded by the number of the corresponding illustration. Note that illustrations will not be returned to authors.

(*) Pr J. PRINGOT, Avenue W. Churchill 11/30, B-1180 Bruxelles, Belgique (tél.: 02-374.25.55, fax: 02-374.96.28, e-mail: JBR-BTR@skynet.be).

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JBR–BTR, 2013, 96: 109-111.

LUNG CANCER IMAGING IN 2012: UPDATES AND INNOVATIONS* Editorial1

The idea of editing a special issueof the Belgian Journal of Radiology arose rapidly during the successful meeting in Ter vuren on the 10th of November 2012. This meeting “Lung Cancer Imaging in 2012: updates and innovations ” was held in the magnificent venue of the Palace of the Colonies built in 1897 by the King of Belgium Leopold the second. During this one-day symposium, Belgian and interna tionally-renowned experts pre sented the most significant and recent advances in lung cancer imaging. Lung cancer is one of the most common malignancies world wide and remains a leading cause of mortality. Hopefully researchis evolving rapidly in this area with many recent and important innovations in the fields of pathology, imaging and treatment. Consequently, radiologists have to adapt their interpretation of chest CT/MR/PET-CT to the recent refinements of the technology and guidelines. The earlier the diag nosis the better the survival. Radiologists have therefore a prominent role to play to detect lung cancer as early as possible, and thus decrease the mortality related to this life-threatening disease. Indeed surgery is the treatment of choice for stage I and II NSCLC, with survival of 75 and 50%, respectively. Recurrence rate is lower in case of lobec tomy / pneumonectomy than in sub-lobar resection. For stage IIIa, survival after a classic multi disciplinary treatment does not exceed 10-15%. Stage IIIb is not surgical and combined radiochemotherapy results in a survival of less than 5%. Chemotherapy alone is used in stage IV with a mediansurvival of 8 months (1, 2). A new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adeno carcinoma has been recently proposed (3). Various recent studies have presented correlations between histologic findings of lung adenocarcinoma and the

pattern of ground-glass and non-solid pulmonary nodules on CT. Moreover, serial CT imaging has demonstrated stepwise progression of these nodulesin a subset of patients, characterized by increasein size and density of ground glass nodules and development of a solid component (4). The seventh edition of the lung cancer TNM stag ing has provided major refinements over the pre vious version (5, 6). This new edition provides more accurate TNM descriptors (most changes concern the T and the M) and stage groups resulting in betterpatient grouping in terms of survival and prognosis. Moreover, use of new staging tech niques often lead to better accuracy and stage migration, PET-CT often upstaging disease. Impor tant advances in nodal staging have also resulted from minimally invasive guided sampling under endobronchial and endoesophageal ultrasound (7, 8). Besides increasing the accuracy in N and M stag ing over CT, FDG PET may further refine prognosis of the patient by providing metabolical information from the primary tumor (9, 10). MRI is emerging as the only ionizing radiation-free technique that enables non-invasive whole-body assessment. Besidesproviding high soft tissue contrast with high spatial resolution (i.e. for superior sulcus

*Meeting organized by B. Ghaye and E. Coche held in Tervuren on November 10th, 2012. 1. B. G. and E. C., Department of Medical Imaging, Cliniques Universitaires St-Luc, Brussels, Belgium.

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tumor), MR further improves lung cancer work-up thanks to functional exploration using MR spectroscopy, perfusion and diffusion-weighted images (DWI) (11, 12). The future will let us know if PETCT and MR are complementary or competitive techniques for whole-body imaging in lung cancer. Refinements in lung cancer therapy have also evolved rapidly. While new systemic drug therapy based on genetic analysis provide encouraging early results, non-resectable tumors may benefit from advances of radiation therapy and the more recent advent of percutaneous ablative therapy. New high precision radiotherapy modalities, such as intensity modulated radiation therapy, image-guided radiotherapy and stereotactic body radiation therapy, may offer better local control of the tumor together with lower toxicities to the sensitive intra-thoracic organs (13, 14). By the turn of the millennium, percutaneous ablation of primary or secondary malignant disease in the thorax has been increasingly performed using various types of energies. Early results of percutaneous ablation treatment of stage I and II lung cancer appear to be comparable to those of surgery. The post-ablation survival data are not yet mature as the technique is still too . The position of percutaneous ablation in recent the therapeutic armamentarium for lung cancer remainsto be defined (15). It is interesting to note that, rather than competing, ablation and radio therapy may have synergistic effects and prove to be complementary (16). CT radiation dose has to be carefully selected and recent data reinforce the ALARA (As Low As Reasonable Achievable) principle to be applied on any CT technique, and in particular for screening, diagnosis and follow-up examinations (17, 18). Indeed, the dose has to be on the one hand minimal in screening examination, which is applied by definition on a healthy population, and on the other hand high enough to enable high-quality images in a diagnosis CT examination. During follow-up, the delivered radiation dose can be decreased becausesuch examination will be interpreted by comparison with the reference high-quality diag nosis examination. With the development of low-dose CT techniques, there has been a resurgent interest in screening for lung cancer. The most recent studies published in this field support the fact that lungcancer screening may be used as an efficient tool in a high-risk population of smokers to detect early lung cancer (19, 20). A recent paper published in the New England Journal of Medicine has demon-

strated a 20% decrease in lung-cancer r elated mortality in the cohort of subjects screened by low-dose CT compared to the arm-control group screened by chest radiograph (19). However, we need to be very cautious before spreading screening in the public policy recommendations. We need to rigorously analyse the cost-effectiveness of low-dose CT screening and the consequences of additional radiationand of the many false positive results encounteredduring the screening and follow-up process. Logistic and financial data will probably be the major limitations of this method of screening and need to be taken into account. Response to therapy is routinely evaluated on CT by two-dimensional measurements as recommended by the RECIST group (21). This method suffers from many limitations mainly due to the inter- and intra-observer variability. Furthermore, in the vast majority of cases morphologic criteria are unable to document early changes in patients responding to therapy. For those reasons, some researchers have proposed to evaluate lung tumors with volumetric segmentation combined with functional data provided by FDG-PET and density measurementsof the tumor. Some studies have suggested that perfusion CT might have potential utility in the assessment of patients undergoing chemotherapy and radiation therapy (22). Some parameters like blood flow, blood volume, and permeabilityvalues are different in responding and non-responding patients. Some discrepancies betweenperfusion measurements and RECIST evaluation are observed. Further studies are needed to clearly define the potential role of perfusion CT in the work-up of lung tumors. Professor Pierre Bodart, Professor of Radiology and foundator of the current Medical Imaging Unit at the Cliniques Universitaires St-Luc in Brussels, died on June 27th 2012. He was an extraordinary man with a great sense of humanity and respect of patients. His field of expertise was the gastrointestinalimaging but he was involved in many facetsof radiology. He was the mentor of many Belgianradiologists. During this symposium, we took the opportunity to pay tribute to this e xceptional man. Finally, we would like to address our grateful thanks to Professor Jacques Pringot, Editor-inchief of the Belgian Journal of Radiology, to have given the opportunity to edit this special issue summarizingthe key points of our symposium on “Lung Cancer Imaging in 2012: updates and innovations”.

Benoît Ghaye and Emmanuel Coche

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EDITORIAL

References 1. Rose S.C., Thistlethwaite P.A., Sewell P.E., Vance R.B.: Lung cancer and radiofrequency ablation. J Vasc Interv Radiol, 2006, 17: 927-951. 2. Jemal A., Murray T., Ward E., et al.: Cancer statistics, 2005. CA Cancer J Clin, 2005, 55: 10-30. 3. Travis W.D., Brambilla E., Noguchi M., et al.: IASLC/ ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol, 2011, 6: 244-285. 4. Naidich D.P., Bankier A.A., M acMahon H., et al.: Recommendationsfor the Management of Subsolid Pulmonary Nodules Detected at CT: A Statement from the Fleischner Society. Radiology, 2013, 266: 304317. 5. UyBico S.J., Wu C.C., Suh R.D., Le N.H., Brown K., Krishnam M.S.: Lung cancer staging essentials: the new TNM staging system and potential imaging pit falls. Radiographics, 2010, 30: 1163-1181. 6. Cogen A., Dockx Y., Cheung K.J., Meulemans E., Lau wers P., Nia P.S., Hendriks J.M., Van Schil P.E.: TNMclassification for lung cancer: from the 7th to the 8th edition. Acta Chir Belg, 2011, 111: 389-392. 7. Gu P., Zhao Y.Z., Jiang L.Y., et al.: E ndobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer, 2009, 45: 1389-1396. 8. Micames C.G., McCrory D.C., Pavey D.A., et al.: Endo scopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic reviewand metaanalysis. Chest, 2007, 131: 539-548. 9. Abramyuk A., Appold S., Zöphel K., Hietschold V., Abolmaali N.: Quantitative modifica Baumann M., tions of TNM staging, clinical staging and therapeutic intent by FDG-PET/CT in patients with non small cell lung cancer scheduled for radiotherapy--a retrospec tive study. Lung Cancer, 2012, 78: 148-152. 10. Agarwal M., Brahmanday G., Bajaj S.K., Ravikrishnan K.P., Wong C.Y.: Revisiting the prognostic value of preoperative (18)F-fluoro-2-deoxyglucose ((18)F-FDG) positron emission tomography (PET) in early-stage (I & II) non-small cell lung cancers (NSCLC). Eur J Nucl Med Mol Imaging, 2010, 37: 691-698. 11. Biederer J., Beer M., Hirsch W., Wild J., Fabel M., PuderbachM., Van Beek EJ.: MRI of the lung (2/3).

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Why … when … how? Insights Imaging, 2012, 3: 355371. 12. Biederer J., Mirsadraee S., Beer M., Molinari F., Hintze C., Bauman G., Both M., Van Beek E.J., Wild J., Puderbach M.: MRI of the lung (3/3)-current applica tions and future perspectives. Insights Imaging, 2012, 3: 373-386. 13. Heinzerling J.H., Kavanagh B., Timmerman R.D.: Ste reotactic ablative radiation therapy for primary lung tumors. Cancer J, 2011, 17: 28-32. 14. McCloskey P., Balduyck B., Van Schil P.E., Faivre-Finn C., O’Brien M.: Radical treatment of non-small cell lung cancer during the last 5 years. Eur J Cancer, 2013; 49: 1555-1564. 15. Dupuy D.E.: Image-guided thermal ablation of lung malignancies. Radiology, 2011, 260: 633-655. 16. Grieco C.A., Simon C.J., Mayo-Smith W.W., et al.: Percutaneousimage-guided thermal ablation and radiationtherapy : outcomes of combined treatment for 41 patients with inoperable stage I/II non-smallcell lung cancer. J Vasc Interv Radiol, 2006, 17: 11171124. 17. Bankier A.A., Tack D.: Dose reduction strategies for thoracic multidetector computed tomography: background, current issues, and recommendations. J Thorac Imaging, 2010, 25: 278-288. 18. Molinari F., Tack D.M., Boiselle B., Ngo L., MuellerMang C., L itmanovitch D., Bankier A.A.: Radiation dose management in thoracic CT: an international survey. Diagn Interv Radiol, 2013; 19: 201-207. 19. The National Lung Screening Trial Research Team: Reduced lung-cancer mortality with low-dose com puted tomographic screening. N Engl J Med, 2011, 365: 395-409. Ru Zhao Y., Xie X., de Koning H.J., Mali W.P., 20. VliegenthartR., Oudkerk M.: NELSON lung cancer screening study. Cancer Imaging, 2011, 11: S7984. 21. Eisenhauer E.A., Therasse P., B ogaerts J., et al.: New response evaluation criteria in solid tumors: revised RECIST guidelines (version 1.1). Eur J Cancer, 2009, 45: 228-247. 22. Tacelli N., Remy-Jardin M., Copin M.C., et al.: Assess ment of non-small cell lung cancer perfusion : patho logic-CT correlation in 15 patients. Radiology, 2010, 257: 863-871.

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THE NEW CLASSIFICATION OF LUNG ADENOCARCINOMAS: IMPLICATIONS FOR PATHOLOGISTS AND RADIOLOGISTS* B. Weynand1, J. Cohen2, M. Delos1, C. Fervaille1, M. Michoud2, M.C. Nollevaux1, E. Reymond2, G.R. Ferretti2 The present manuscript is a summary of two lectures which were given respectively by B. Weynand and G.R. Ferretti. The new classification of lung adenocarcinomas has changed the view of the radiologists and the pathologists espe cially regarding the former bronchiolo-alveolar carcinoma (BAC). The aim of this paper is to correlate radiological and histopathological images according to the 2011 classification for lung adenocarcinoma proposed by the Interna tional Association for the Study of Lung cancer, the American Thoracic Society and the European Respiratory Society and to draw attention to the way these lesions can be approached preoperatively. Key-word: Lung neoplasms.

Lung cancer is very frequent, being the second most frequent tumour in men and the third most frequent in women in Belgium with a very high mortality rate (1). Adenocarcinoma is nowadays the most often diagnosed subtype representing between 35 and 40% of all lung cancers (2). Subtyping may be difficult especially on small specimen such as cytological material from endobronchial ultrasound guided fine needle aspiration (EBUS) and small biopsy fragments, representing 85% of the available diagnostic material. Yet, treatment strategies have changed dramatically over the last decade asking for a precise diagnosis. In February 2011, the International Association for the Study of Lung cancer, the American Thoracic S ociety and the European Respiratory Society published a multidisciplinary classification of lung adenocarcinoma involving chest physicians, oncologists, thoracic surgeons, pathologists, molecular biologists and radiologists (3). It is also well known that there is a close relationship between pathological and CT findings especially for adenocarcinomas which tend to be peripheral lesions (4). Therefore, it seemed interesting to detail the new classification of adenocarcinoma which has been largely accepted by pathologists on insisting on the CT/ histopathological correlations. The new classification of lung adeno carcinoma: pathological aspects In the new classification (3), a istinction was made between the d reporting of small tissue fragments and cytology and resection specimen. The most important changes which have been implemented concern bronchiolo-alveolar carcinoma

(BAC). In the 2004 WHO classification (5), the only distinction used for these tumours was their cell composition, namely mucinous, non-mucinous and mixed BAC. Although it was considered to be of rather good prognosis, this could not always be verified, because its definition was not straightforward and a matter of debate between pathologists. In the new classification, the term BAC has been discarded and replaced by different entities from non-invasive to frankly invasive tumours with different outcomes. Preinvasive lesions Atypical adenomatous hyperplasia (AAH) is an entity which has been recognized in the early nineties as being a precursor lesion of adenocarcinoma (6). It is by definition a small lesion measuring less than 5 mm. Usually it is an incidental finding on resection specimen in the vicinity of a larger tumour, not detected before surgery. It is characterized by atypical hyperplastic pneumocytes lining preexisting alveolar septae without any sign of invasion (Fig. 1A,B). Adenocarcinoma in situ (AIS), which can be nonmucinous or mucinous, is first defined by its size, less than 3 cm. It is rare, representing 3 to 4% of all non small cell carcinomas (NSCLC). It has a 100% 5 year survival. By definition, no invasion is described neither of stroma, vessels nor of pleura, although septal widening is frequent (Fig. 1C,D). Invasive tumours Minimally invasive adenocarcinoma (MIA) measures also less than 3 cm, but in contrast to AIS, it harbors an invasive area measuring less than

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Department of Pathology, CHU Mont-Godinne, UCL, Belgium, 2. Department of Radiology, CHU Grenoble, France.

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5 mm composed of any subtype of adenocarcinoma beside lepidic aspect (see further). No invasion of blood vessels, lymphatics or pleura is seen and necrotic areas are not present. It is usually a solitary and discrete tumour, but synchronous tumours can occur. Most of the tumour shows tumour cells growing along alveolar walls centered on a small area of consolidation where infiltrating tumour cells are recognized (Fig. 1E,F). Again, a near 100% 5-year survival is associated with this tumour. Beside the classical forms of invasive adenocarcinomas, such as acinar, papillary, micropapillary and solid tumours, which present radiologically as solid nodules, two other forms are newly described. Lepidic predominant adenocarcinoma is on the contrary to MIA associated with invasion of blood vessels, lymphatics or pleura and/or necrosis and/or an infiltrative area of more than 5 mm. It is exclusively composed of nonmucinous tumour cells (Fig. 1I, J,K). It is associated with a 90% 5-year survival. Finally, invasive mucinous adenocarcinoma is the last category considered here. It measures more than 3 cm with an invasive area of more than 5 mm. Usually, this tumour is composed of multiple nodules which lack circumscription and shows a miliary spread towards the adjacent lung parenchyma. The tumour is composed of mucinous cells growing along alveoli secreting an abundant amount of mucus filling alveoli (Fig 1G,H). Because of size and multiplicity of localization it is considered to harbor an infiltrating area. CT/ histopathological correlations: radiological aspects Radiological definitions The increasing use of thoracic high resolution multidetector CT

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Fig. 1. — A,B: AAH. A: small area of septal widening lined by a few atypical pneumocytes (H&E, bar = 100 µm), B: higher magnification highlighting the atypical pneumocytes (H&E, bar = 10 µm); c,d: AIS. C: larger area of septal widening without invasion (H&E, bar = 5 mm), D: on higher magnification, the enlarged septae are lined by tumour cells (H&E, bar = 50 µm), E,F: MIA. E: low magnification showing whole lesion with a fibrous scar on the left (H&E, bar = 5 mm), F: on higher magnification, a few neoplastic glands are identified in the fibrous area (H&E, bar = 20 µm); G,H: invasive mucinous adenocarcinoma, numerous mucin secreting tumour cells grow along preexisting alveolar septae (H&E, bar = 20 µm); I,J,K: invasive lepidic adenocarcinoma. I: high magnification of lepidic aspect of the tumour (H&E, bar = 20 µm), J: low magnification of whole lesion showing a fibrous area in lower center with a neoplastic glandular infiltration and a periphery characterized by a lepidic growth pattern (H&E, bar = 5 mm), K: invasive acinar adenocarcinoma in the fibrous scar (H&E, bar = 20 µm).

(HR-MDCT) in clinical practice and for lung cancer screening purposes have allowed performing correlations between histopathological presentation of adenocarcinoma and radiological patterns. Three types of pulmonary nodules (by definition rounded or irregular opacity ≤ 30 mm in diameter) are defined on HRMDCT (7):

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1. subsolid nodules that include a. Nonsolid nodules (Fig. 1, 2) also called pure ground-glass nodules), which are spherical or oval pulmonary nodules of hazy increase of lung attenuation, with preservation of vascular structure visualization. b. Part-solid nodules (Fig. 3, 4) also called mixed ground-glass

nodules) that have a nonsolid component containing tissue density (or solid) component(s) with soft tissue density completely obscuring the lung parenchyma and the contour of the vessels with which it is in contact. Solid component can be either located centrally, peripherally or forming several islets (8).

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2. Solid nodules (Fig. 5, 6) which are focal areas of increased attenuation of lung parenchyma that obscure any normal structure such as v essels without any ground glass opacity. Although close but imperfect correlations exist between HR MDCT patterns of pulmonary nodules and pathology of adenocarcinoma, radiologist should remember that all these patterns may also be caused by benign conditions such as infectious pneumonia, organizing pneumonia, localized area of fibrosis and inflammation (9, 10). CT/histopathological (Table I)

correlation

Atypical adenomatous hyper plasia (AAH) always appears as nonsolid nodule (11). AAH is a pure GGO nodule measuring ≤ 5 mm, but can exceed 10 mm. AAH can be solitary but is often multiple and bilateral. Adenocarcinoma in situ (AIS), usually appears on HR-MDCT as a pure GGO nodule > 5 mm, but may present as a part solid or rarely as a solid nodule. Part solid or solid presentations have been correlated to alveolar collapse (12) or rare mucinous types. A recent case report showed that gravity may increase artificially the density of pure GGO nodules located in the posterior lung

zones transforming the GGO presentation into a solid one. CT in prone position is suitable in order to demonstrate the GGO pattern (13). Criteria have been studied in order to differentiate AIS from AAH within GGO nodules: AIS tends to present with a bubble like pattern and a higher attenuation, diameter is larger (> 5 mm) than AAH. However, these criteria suffer many exceptions and there is an overlap among imaging patterns of AAH, AIS, and MIA. MIA has been described more recently and extensive correlations are lacking. However, the majority of MIA is nonmucinous and appears as part solid GGO nodule, with a solid portion of less than 5 mm (14). Mucinous MIA is very rare and may appear as solid nodules. Invasive adenocarcinomas are not always solid nodules and their CT appearance is related to their histopathological pattern. Invasive adeno carcinoma with predominant lepidic pattern tends to present as part solid nodule or solid nodule but rarely as pure GGO nodule. There is a correlation between the solid part of the nodule being the invasive component at histology and the GGO being the lepidic component. Tumour aggressiveness increases as the solid part becomes more prominent in the nodule, resulting in a reduction in tumour volume doubling time, an increase in frequency of lymph node

Fig. 2. — AAH in a 52-year-old woman presenting as a pure ground glass opacity nodule, 7-mm in diameter in the right upper lobe.

metastases and vascular invasion, and an increase in risk of local recurrence (15, 16, 17). In clinical practice, radiologists should estimate the relative proportion of the solid part in a mixed GGO as it showed a prognostic value. Other types of invasive ADC more often present as solid nodules and are associated with a more severe prognosis. Invasive mucinous adenocarcinoma (Fig. 7) has replaced the term “mucinous BAC”. The HR MDCT presentation of these tumours can be

Table I. — 2011 IASLC/ATS/ERS classification of lung adenocarcinoma in resection specimens. IASLC/ATS/ERS classification Preinvasive lesions

Minimally invasive lesions Invasive lesions

Variants of invasive lesions

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Former denomination (WHO 2004) AAH

HRCT usual pattern

Adenocarcinoma in situ (AIS) (≤ 30 mm)

Solitary BAC

Minimally invasive adenocarcinoma (MIA) (≤ 30 mm lepidic predominant with invasion (≤ 5 mm) Lepidic predominant

ADC mixed subtype with predominant BAC pattern

Pure GGO ≤ 30 mm (Rarely part solid GGO or solid) Pure GGO Part solid GGO solid

Atypical adenomatous hyperplasia (AAH)

Acinar predominant Papillary predominant Micropapillary predominant Solid predominant Invasive mucinous ADC Colloid Fetal Enteric

Pure GGO ≤ 5 mm

Nonmucinous BAC with invasion > 5 mm

Part solid GGO Solid

Mucinous BAC

Part solid GGO / solid Consolidation

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A Fig. 5. — Invasive acinar adenocarcinoma in a 61-year-old man smoker. Partly solid nodule, 25-mm in diameter, in the left upper lobe. Notice the air-bronchogram and the retraction of the main fissure.

B Fig. 3. — AIS in a 66-year-old woman presenting as a pure ground glass opacity nodule, 9.5-mm in diameter in the right lower lobe. A: HR CT. B: 3D volume assessment of the lesion estimated at 447mm3.

very different from one patient to another as it comprises chronic pulmonary consolidations with air bronchogram and angiogram, mutifocal unilateral or bilateral consolidations, nodules, or masses of solid, non solid or sub solid appearance, that have a bronchogenic distribution (18). CT technical considerations Detection and characterization of lung nodules is optimized by using HR-MDCT as compared to conventional slice by slice CT or helical CT with thick collimation and should therefore be used in clinical practice (19). Low dose technique is adapted to detect pulmonary nodules while reducing patient’s exposure to radiation. However, dose length product associated with HR MDCT can vary considerably according to the patient’s morphology, the technology of acquisition and the use of iterative reconstruction. Therefore, no recommended value can be formulated but the principle of ALARA (As Low As Reasonably Achievable) should be respected. Contrast media

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B Fig. 4. — 66-year-old woman former smoker presenting with 2 pulmonary nodules in the right upper lobe. Treatment consisted in right upper lobectomy. A: pure GGO nodule, 13-mm in diameter, identified histologically as nonmucinous AIS. B: mixed nodule, 9-mm in diameter, with GGO < 10% surrounding the solid part, related to nonmucinous AIS with centrally located fibrosis responsible for the solid pattern at CT.

injection is not useful to detect or characterize pulmonary nodules in clinical practice but it is useful to establish the extent of the tumour (N and M of the TNM classification). Follow-up of small pulmonary nodules should be optimally performed with the same CT scan unit and same exam protocol in order to reduce technical variations that may increase the level of errors in measurement, density evaluation, and volume calculation of nodules. Standardization of acquisition parameters is mandatory to follow pulmonary nodules. Evolution of the nodules Repeated CT scans have allowed assessment of the natural history of nonsolid and part solid nodules as compared to solid ones. Three types of morphological development for

Fig. 6. — Invasive papillary ADC, T1aN0 in the right upper lobe in a 54 -year-old man smoker. CT shows solid nodule with irregular and speculated contours.

malignant nonsolid nodules were described in a small series (20): increase in size of the nonsolid area (n = 5); reduction in size of the nonsolid area coupled with appearance of a solid component (n = 2); stable dimension of the nodule but progression from non-solid to a part-solid nodule (n = 1). The doubling time of malignant solid nodules is usually between 30 and 400 days. Doubling time of preinvasive or invasive nonsolid or partsolid nodules is longer and has been

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C B

calculated at 813 +/- 375 days for nonsolid nodules, 457 +/- 260 days for part-solid nodules, and only 149 +/- 125 days for solid nodules (21). Because of the long doubling times, prolonged surveillance of nonsolid and part-solid nodules is recommended; this goes against the concept of 2-year nodule stability implying that a nodule is benign (22). Transthoracic biopsy: implications for radiologists Image guided percutaneous needle biopsy is a valuable technique to provide cytological or histological samples allowing for tissue characterization, as well as immunohistochemical and molecular analysis, when indicated. Such variety of analysis permits classifying precisely lung tumours into small cell carcinoma or non small cell carcinoma, and the new classification emphasizes that NSCLC be classified into precise subtypes such as adenocarcinoma or squamous cell carcinoma. In case of metastatic adenocarcinoma, genotyping the tumour opens the way to personalized therapy using new drugs, such as tyrosine kinase inhibitors in case of epidermal growth factor receptor (EGFR) mutation. Due to the increasing demand of tissue for performing all these analysis, radiologists should be aware that they should provide as much tissue as possible from transthoracic biopsies

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Fig. 7. — CT of invasive mucinous ADC in a 65-year-old man presenting with persistent consolidation of the right lower lobe. A: axial and B: sagittal CT images show pulmonary consolidation with air bronchogram within the right lower lobe. Note the presence of a small ground glass nodule within the right middle lobe. C: axial CT one year after combined right lower and middle lobectomy shows bilateral areas of pulmonary consolidation with air bronchogram due to lepidic spreading of the ADC.

and preserve the specimen according to multidisciplinary group recommendations in order to optimize the use of these samples (23). However, due to the heterogeneity of subsolid nodule, the diagnosis of AIS and MIA requires that the entire lesion be analyzed by the pathologist on a surgical resection, therefore transthoracic biopsy is not recommended in these nodules. PET evaluation of subsolid pulmo nary nodules PET is not recommended in order to characterize pure GGO nodules as it has demonstrated a low sensitivity to depict AIS or MIA, related to the low metabolism of preinvasive or minimally invasive adenocarcinoma with lepidic pattern. Moreover, these tumours are localized and are not associated with node or distant metastases. On the contrary PET is indicated in part solid nodules in which the solid portion is > 10 mm, according to the recently published guideline of the Fleischner society (24). Recommendations for managing non solid nodules After the propositions of Godoy and Naidich (19), the Fleischner society recently published recommendations adapted to the specific situation related to the discovery of

subsolid nodules, completing the 2005 recommendations for solid nodules (24). Specific recommendations for pathologists and radiologists pro posed by the IASLC/ATS/ERS clas sification of lung adenocarcino ma (3) 1. the term bronchiolo-alveolar carcinoma (BAC) should be avoided to describe a pure GGO or part-solid nodule with < 50% GGO. These tumours should be classified as AAH, AIS, MIA, although precise correlations between CT and pathology for MIA are lacking. 2. invasive adenocarcinoma appears usually as a solid nodule, as a part solid nodule or infrequently as pure GGO 3. morphological criteria are associated with well differentiated localized stage IA adenocarcinoma and longer volume doubling time when cystic or bubble like lucencies are present within a pure GGO nodule. 4. the presence of spiculation or peribronchovascular thickening around the nodule is associated with vascular invasion and lymph node involvement and poorer prognosis. 5. small peripheral adenocarcinomas with a nonsolid component of over 50% on CT present significantly less lymph node metastases or vascular invasion than those with a nonsolid component of less than 10%.

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The nonsolid proportion influences patients survival as it was significantly superior in patients presenting a nodule with a nonsolid component of > 50% compared to those with a nonsolid component of < 50%. 6. As size is a very important criterion for the differential diagnosis of all these lesions, it is critical that it is recorded correctly, on thin-section CTs. Therefore, pathologists and radiologists are advised to record not only the total area of the tumour, including the ground-glass compo nent, but also the solid part, separately. This will help in identifying in the future if invasive size predicts prognosis better than total size. In conclusion, in order to standardize terminology, the new IASLC/ ATS/ERS classification of lung adenocarcinoma should be used by all the specialists involved in lung cancer care because it results from a multidisciplinary approach and takes into account the most recent developments in the field of clinical, histopathological, molecular, radiological and surgical research. With better knowledge of the CT/histopathological correlations, pretreatment d iagnosis will be more and more a ccurate. References 1. Belgian Cancer Registry data. Available at www.Kankerregister.org. 2. SEER cancer statistics review, 19752008. Available at http://seer.cancer. gov/. 3. Travis W.D., Brambilla E., Noguchi M., et al.: IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol, 2011, 6: 244-285. 4. Suzuki K., Kusumoto M., Watanabe S., et al.: Radiologic classification of small adenocarcinoma of the lung: radiologic-pathologic correlation and its prognostic impact. Ann Thorac Surg, 2006, 81: 413-419.

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5. Travis W.D., Brambilla E., MullerHermelink H.K., et al. Pathology and Genetic. Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press, 2004. 6. Nakahara R., Yokose T., Nagai K., et al.: Atypical adenomatous hyperplasia of the lung: a clincopathological study of 118 cases including cases with multiple atypical adenomatous hyperplasia. Thorax, 2001, 56: 302305. D.M., Bankier A.A., 7. Hansell MacMahon H., McLoud T.C., Muller N.L., Remy J.: Fleischner Society: glossary of terms for thoracic imaging. Radiology, 2008, 246: 697722. 8. Nakazono T., Sakao Y., Yamaguchi K., Imai S., Kumazoe H., Kudo S.: Subtypes of peripheral adenocarcinoma of the lung: differentiation by thinsection CT. Eur Radiol, 2005, 15: 15631568. 9. Kim H.Y., Shim Y.M., Lee K.S., Han J., Yi C.A., Kim Y.K.: Persistent pulmonary nodular ground-glass opacity at thin-section CT: histopathologic comparisons. Radiology, 2007, 245: 26775. 10. Felix L., Serra-Tosio G., Lantuejoul S., et al.: CT characteristics of resolving ground-glass opacities in a lung cancer screening program. Eur J Radiol, 2011, 77: 410-6. 11. Kawakami S., Sone S., Takashima S., et al.: Atypical adenomatous hyperplasia of the lung: correlation between high-resolution CT findings and histopathologic features. Eur Radiol, 2001, 11: 811-814. 12. Yang Z.G., Sone S., Takashima S., et al.: High-resolution CT analysis of small peripheral lung adenocarcinoma revealed on screening helical CT. Am J Roentgenol, 2001, 176: 13991407. 13. Ferretti G.R., Arbib F., Roux J.F., et al.: Effect of lung volume and gravity on the attenuation and size of a pure ground glass nodule. J Thorac Imaging, 2012, 27: W15-17. 14. Austin J.H.M., Garg K., Aberle D., et al.: Radiologic implications of the 2011 classification of adenocarcinoma of the lung. Radiology 2012 [Epub ahead of print]

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15. Noguchi M., Morikawa A., K awasaki M., et al.: Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995, 75: 28442852. 16. Kawakami S., Sone S., Takashima S., Li F., Yang Z.G., Maruyama Y., Honda T., Hasegawa M., Wang J.C.: Atypical adenomatous hyperplasia of the lung: correlation between highresolution CT findings and histopathologic features. Eur Radiol, 2001, 11: 811-814. 17. Aoki T., Tomoda Y., Watanabe H., Nakata H., Kasai T., Hashimoto H., Kodate M., Osaki T., Yasumoto K.: Peripheral lung adenocarcinoma: correlation of thin-section CT findings with histologic prognostic factors and survival. Radiology, 2001, 220: 803809. 18. Wislez M., Massiani M.A., Milleron B., et al.: Clinical characteristics of pneumonic-type adenocarcinoma of the lung. Chest, 2003, 123: 1868-1877. 19. Godoy M.C.B., Naidich D.P.: Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management. Radiology, 2009, 253: 606-622. 20. Kakinuma R., Ohmatsu H., Kaneko M., Kusumoto M., Yoshida J., Nakai K., et al.: Progression of focal pure groundglass opacity detected by low dose helical computed tomography screening for lung cancer. J Comput Assist Tomogr, 2004, 28: 17-23. 21. Hasegawa M., Sone S., Takashima S., et al.: Growth rate of small lung cancers detected on mass CT screening. Br J Radiol, 2000, 73: 1252-1259. 22. Yankelevitz D.F., Henschke C.I.: Does 2-year stability imply that pulmonary nodules are benign? Am J Roent genol 1997, 168: 325-328. 23. Travis W.D., Brambilla E., Noguchi M., et al.: Diagnosis of lung cancer in small biopsies and cytology. Arch Pathol Lab Med, 2012, 136: 1-17 24. Naidich D.P., Bankier A.A., MacMahon H., et al.: Recommenda tions for the Management of Subsolid Pulmonary Nodules Detected at CT: A Statement from the Fleischner Society. Radiology, 2012 Oct 15. [Epub ahead of print].

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UPDATE IN NON SMALL-CELL LUNG CANCER STAGING* R.A. Salgado, A. Snoeckx, M. Spinhoven, B. Op de Beeck, B. Corthouts, P.M. Parizel1 Significant progress has been made with the introduction of the TNM-7 staging system for non-small cell lung cancer (NSCLC). Constituting the first major revision in 12 years, the seventh edition of NSCLC TNM (TNM-7) is based on the recommendations from the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project of 2007. This new TNM iteration includes a subset analysis on SCLC and carcinoid tumors. A thorough understanding of its principles by the radiologist is helpful to increase efficiency and to improve com munication with the referring clinicians. Key-word: Lung neoplasms, staging.

Lung cancer is a well-known devastating disease, representing the most common cancer-related death in males, and responsible for more than 1.4 million deaths in 2008 (1). With almost all subtypes expressing a significant initial clinically silent period, only 25% of the patients are eventually considered potential surgical candidates at the time of diagnosis (2). In order to provide the best standard of care for each individual patient, a correct disease staging at the time of diagnosis remains the best predictor of survival. Essentially, a staging system is needed to group different patients according to their disease progression, establish a comprehensive evaluation for a standardized treatment strategy for a particular disease stage, and provide guidance on prognosis and further disease evolution. In order for staging systems to be practically implementable, they must be accurate, uncomplicated and easy reproducible. The best-known and widely implemented staging system for non-small cell lung cancer (NSCLC) is the TNM-system, based on information regarding the primary tumor (T), nodal status (N) and the characteristics of metastatic disease (M). Using different disease prescriptors, patients are grouped according to the biological behavior of the tumor, and stratified accordingly along different treatment lines. The TNM staging system provides as such a standardized nomenclature for exchange of information in both a clinical and research setting. TNM 1-6 staging system: history and contemporary criticism The initial steps to set up a clinically implementable staging system were taken by Pierre Denoix in 1942

and 1952. The TNM lung cancer staging system originates from proposals made by Mountain et al. in 1973 (3). Ever since its introduction, the TNM system has been continuously refined with up to six editions until 2009 by the TNM Prognostic Factors Project of the International Union Against Cancer (IUAC) as more data became available. While these iterations of the TNM staging system have proven to be an excellent tool in clinical practice and scientific research, they are not without their criticism on different levels. The data used as a foundation in the TNM system was mostly collected from a single center (M.D. Anderson Cancer center, Houston, Texas, USA), and consisted of 2155 cases of histologically proven adenocarcinoma. This relatively small database, acquired from surgically staged patients, resulted in some cases in TNM data subsets containing too few cases for proper analysis (4). Furthermore, while there was some internal validation, the TNM data was not subjected to any external validation. Another more pointing criticism was that the grouping of patients in different disease stages, based on the implementation of the existing descriptors, was far from perfect in earlier editions of the TNM system. In an ideal system, the stratification of patients according to their disease stage would create different groups who are strictly discriminated from each other by their specific prognosis and survival rates (Fig. 1A). As such, each stage group has its specific disease progression properties, allowing optimization of different treatment plans targeted to a specific disease stage. Unfortunately, it has been shown that significant overlap in cumulative survival exists be-

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Dept. of Radiology, Antwerp University Hospital, Edegem, Belgium.

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tween groups, often complicating a comparison between different disease stages (Fig. 1B) (5-7). More specifically, little difference in survival was encountered between disease stage IB and IIA, IIA and IIB and between IIIB and IV (6). The prevalence of the different histological subtypes of NSCLC has also changed over time (8). In the original TNM staging database, 30% of the contained cases were adenocarcinoma, 58% of squamous cell carcinoma and 12% of unspecified subtypes. However, a more recent survey by the Surveillance, Epidemiology and End Results (SEER) program based on data collected between 2002 and 2006 showed a changing prevalence of the different subtypes: the presence of adenocarcinoma increased to 43%, with a decrease to 23% of squamous cell carcinoma and 34% share of unspecified subtypes. Therefore, the stage grouping and prognostic information derived from the original TNM database had now an outdated histologic disease distribution. Furthermore, the rising incidence of lung cancer in females has just recently started to reach a plateau phase after two decades of rise (9), reflecting a changing sex distribution which was yet unaccounted for. New diagnostic imaging techniques have also an increasing impact on the accuracy of staging. More specifically, the introduction of 2(fluorine-18) fluoro-2-deoxy-D-glucose positron emission tomography (PET) and PET-CT systems in clinical practice have added a metabolic dimension to the previously solely morphological detection of tumoral presence and spread using CT and plain chest film (Fig. 2 A,B), consequently often upstaging disease. Furthermore, advances in conventional CT technology with an ever increasing spatial resolution and multiplanar capabilities have further contributed to an improved overall evaluation. Finally, contemporary

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B Fig. 1. — In an ideal staging system, patients would be according to their disease stage grouped in several disease stages, which do not overlap with each other in terms of treatment plans, prognosis and overall survival (A). However, this stratification proved imperfect in previous editions of the TNM-system, with several groups having overlapping survival curves (B). Adapted from reference (4).

staging tools like endoscopic ultrasonography (US), endo-bronchial US, endoscopic US-guided fine needle aspiration and endobronchial US-guided transbronchial needle aspiration have further pushed minimally invasive tumor staging to new frontiers (10) . As such, these new staging techniques often lead to better accuracy of the initial staging, frequently upstaging patients as compared with older imaging techniques and consequently leading to stage migration in a significant number of patients (1). This is especially true in patients who have clinically silent advanced disease. When these patients consequently migrate from an early disease stage to a more advanced disease group, this can lead to an

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B Fig. 2. — A patient with a primary lung carcinoma in the right lung (not shown). The axial CT view shows no morphologically abnormal lymph nodes (A). However, the PET examination (B) reveals at the same anatomic level abnormal uptake in two lymphnodes (arrows), indicating mediastinal and hilar adenopathy and as such upstaging the stage of disease.

improved survival rate in both groups. This well-known effect has been termed the “Will Rogers”- phenomenon, and its existence must always be considered when evaluating and interpreting results from staging systems (11). Up to TNM-6, only one size cut-off of 3 cm was used to distinguish between T1 and T2 tumors. However, different survival rates in tumor of various sizes have been reported (1215). This is more specifically the case for tumors smaller than 2 cm and for tumors larger than 5-7 cm. This implicates that by using only a single size threshold for stratification of patients based on tumor size, the resulting discrimination will not take into account the different possible survival rates.

Finally, advances in (surgical) treatment techniques have led to more potentially resectable tumors. If adaptations to the staging system are not made to reflect this improved treatment options, in some cases this can potentially lead to unnecessarily ‘upstaging’ of potentially resectable tumors (16, 17). TNM-7 In order to address these mentioned and other shortcomings, a major revision on the TNM system was introduced in 2009. Constituting the first major revision in 12 years, the seventh edition of NSCLC TNM (TNM-7) was based on the recommendations from the International Association for the Study of Lung

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Fig. 3. — The size prescriptor has been further refined to better indicate the different survival characteristics of tumors of different sizes. Note that the 3 cm size cut-off remains the discriminating factor between T1 and T2, and that tumors larger than 7 cm are now considered T3 tumors.

Fig. 4. — TNM-7, a distinction is made whether tumoral nodules are within the same or different lobe as the primary tumor. Furthermore, metastatic disease has been further refined into introthoracic or extrathoracic spread, the latter having the worst prognosis.

Cancer (IASLC) Lung Cancer Staging Project of 2007. This new TNM iteration also includes a subset analysis on SCLC and carcinoid tumors (1820). The gathered database encompasses initially more than 100.000 cases assembled during 1990-2000 in a multicentric, international fashion. A stable staging algorithm was used, with both internal and external validation (21). While the data was predominantly acquired from surgical staging information, contribution of non-surgical treatment modalities like radio- and chemotherapy was also included. One of the main goals of this new TNM system was to achieve better grouping of patients according to their disease stage in order to provide a better stratified prognosis. To accomplish this, more accurate TNM prescriptors and stage groups were introduced. The changes mostly affected the descriptors for size and location of the primary tumor (T) and the classification of metastatic disease (M). To better reflect different survival rates between tumors of different

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sizes, additional size cut-offs were introduced (2, 20). While the 3 cm threshold remains the discriminating factor to distinguish between a T1 and T2 tumor, both these prescriptors were further refined to include tumors of more specific size-ranges (Fig. 3). Further data analysis also indicated that tumors with a size equal or larger than 7 cm had a survival comparable with T3 tumors, and were consequently reclassified as T3. As such, it became the first time that size was used as a discriminator between T2 en T3. As previously stated, evolving treatment practices allow to extend the range of potentially resectable tumors compared with previous generations. While a tumor invading the great vessels or mediastinum remains a T4 tumor, recent data has shown that a primary lung tumor with adjacent nodules in the same lobe has a more favorable prognosis similar to a T3 tumor. Therefore, this type of tumor presentation has been reclassified as T3, providing another example of better stratification between tumors that were considered before as similar (Fig. 4).

When further exploring the impact of concomitant lung nodules outside the primary tumor, it becomes clear that patients with ipsilateral nodules in a different lobe than the primary lesion have a better prognosis that patients with nodules in the contralateral lung. Consequently, these patients are now reclassified as T4 instead of M1 (Fig. 4). The characterization of metastatic disease has also been further refined. One of the new key concepts is the distinction between intra- or extrathoracic metastatic disease. A T4 tumor with nodules in the ipsilateral lung but outside the lobe of the primary lesion has a median survival of 13 months. Even so, this is still more favorable than the presence of a malignant pleural/pericardial dissemination or nodules in the contralateral lung, both which are associated with a median survival of 8 months. Metastatic disease outside the lung has the worst prognosis with a median survival of 5 months. To make the distinction between intra- or extrathoracic disease, the M prescriptor has been further divided in M1a and M1b indicating intra- or extrathoracic metastatic disease (Fig. 4) (21). No further distinction is made between single or multiple sites of involvement. M-stage still precludes surgery. The modification of the nodal stage (N) prescriptor has been more modest, with no major changes. The validity of the existing prescriptors has been further confirmed. Efforts also have been centered at the reconciliation of the Naruke and MDATS nodal map. TNM-7 introduces in this respect six nodal zones, with the hilar and peripheral zone indicating N1 status with the others zones corresponding to N2 disease. A new international lymph node map is current being developed, but has not yet been presented at the time of this writing (22). Finally, while there appears to be small differences in tumoral behavior in the presence of skip metastases, data subsets are still too small to make formal recommendations in this respect. Consequences of TNM-7 TNM-7 does not introduce new subcategories to the current stage divisions. However, the effects of changed T and M prescriptors, and the impact of the new T1 and T2 subclassifications have led to a changed survival profile in some cases. As an example, a T2N1M0 disease corresponded with a IIB stage in previous

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A Fig. 6. — Slow growing tumor in de left lung with multiple bilateral small nodules, formerly known as mucinous bronchioloalveolar carcinoma. This rare type of tumor exhibits a much slower growth than a classical invasive adenocarcinoma. As such, they often have different survival rates than other tumors included in the TNM-database, the question remaining to what extend traditional results are applicable to this rare subtype of lung cancer.

B Fig. 5. — The conventional CT image shows a large heterogeneous mass extending anteriorly from the right hilus (A). Based on this image, it is unclear which part of this mass represents tumoral tissue, and which mass component is solely retro- obstructive atelectasis or other associated non-neoplastic changes. The PET image at the same level (B) additionally r eveals an extensive uptake in the right hilus, indicating the site of the primary tumor (arrow). However, this type of image is yet no validated for exact tumor measurement to be used in staging systems.

staging systems. In TNM-7, this has now to be further refined using the mentioned subclassifications. As such, a patient with a previously determined IIB stage will, depending on the T2 subclassification status, migrate to a lesser stage IIA (T2aN1M0), or will stay at IIB if the criteria for a T2b prescriptor are met. The end result of stage migration secondary to the changed TNM prescriptors is that 10 subsets have been downstaged, and conversely 7 stages are upstaged (9). The clinical significance is that, since the boundary for surgery is set around stage IIA-B, the number of patients with potentially resectable tumors changes.

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Issues or limitations Despite the advances made in TNM-7, many limitations and restrictions remain. While it is not the aim of this overview to provide a complete coverage of this topic, some important remarks deserve to be mentioned. Despite the significant advances in CT technology, it remains an imaging modality which is not often optimal for discrimination between different tissues. This is especially an issue when tumoral tissue is surrounded by atelectasis or other tissues with similar density, making the primary tumor indistinguishable

from non-tumoral tissues (Fig. 5A). Consequently, the determination of tumor size is not always straightforward and sometimes performed with a significant margin of error. While PET-CT has a clear advantage in this respect, it has not been yet validated to serve as a tool for exact tumor sizing (Fig. 5B). Furthermore, the impact of the multiplanar capabilities of modern CT systems allowing measurements in a different plane than the standard axial view has not yet included in any staging database. Finally, questions remain on how to correctly approach infiltrative tumors with no clear boundaries, and/ or tumor subtypes with a slow growing nature which probably have a more favorable prognosis (Fig. 6). It is also unclear if the number of contralateral or extrathoracic metastasis has an objective impact on survival. Conclusion It is evident that a significant rogress has been made with the p introduction of the TNM-7 staging system for NSCLC. While some questions remain, it remains the principal keystone for lung cancer staging. A thorough understanding of its principles and implication by the radiologist will increase its participation in the staging process, and improve the communication with referring clinicians.

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References 1. Mirsadraee S., Oswal D., Alizadeh Y., Caulo A., van Beek E., Jr.: The 7th lung cancer TNM classification and staging system: Review of the changes and implications. World J Radiol, 2012, 4: 128-134. 2. Rami-Porta R., Crowley J.J., Goldstraw P.: The revised TNM staging system for lung cancer. Ann Thorac Cardiovac Surg, 2009, 15: 4-9. 3. Mountain C.F., Carr D.T., Anderson W.A.: A system for the clinical staging of lung cancer. AJR, 1974, 120: 130-138. 4. Goldstraw P., Crowley J., Chansky K., et al.: The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol, 2007, 2: 706-714. 5. Pfannschmidt J., Muley T., Bulzebruck H., Hoffmann H., Dienemann H.: Prognostic assess ment after surgical resection for nonsmall cell lung cancer: experiences in 2083 patients. Lung Cancer, 2007, 55: 371-377. 6. Naruke T., Tsuchiya R., Kondo H., Asamura H.: Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience. Ann Thorac Surg, 2001, 71: 1759-1764. 7. Goya T., Asamura H., Yoshimura H., et al.: Prognosis of 6644 resected nonsmall cell lung cancers in Japan: a Japanese lung cancer registry study. Lung Cancer, 2005, 50: 227-234. 8. Wynder E.L., Muscat J.E.: The changing epidemiology of smoking and lung cancer histology. Environmental Health Perspectives, 1995, 103 Suppl 8: 143-148. 9. Nair A., Klusmann M.J., Jogeesvaran K.H., Grubnic S.,

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JBR–BTR, 2013, 96 (3) Green S.J., Vlahos I.: Revisions to the TNM staging of non-small cell lung cancer: rationale, clinicoradiologic implications, and persistent limitations. Radiographics, 2011, 31: 215238. 10. Gomez M., Silvestri G.A.: Endobronchial ultrasound for the diagnosis and staging of lung cancer. Proceedings of the American Thoracic Society, 2009, 6: 180-186. 11. Feinstein A.R., Sosin D.M., Wells C.K.: The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. New Engl J Med, 1985, 312: 1604-1608. 12. Flieder D.B., Port J.L., Korst R.J., et al.: Tumor size is a determinant of stage distribution in t1 non-small cell lung cancer. Chest, 2005, 128: 23042308. 13. Asamura H., Goya T., Koshiishi Y., Sohara Y., Tsuchiya R., Miyaoka E.: How should the TNM staging system for lung cancer be revised? A simulation based on the Japanese Lung Cancer Registry populations. J Thorac Cardiovasc Surg, 2006, 132: 316-319. 14. Takeda S., Fukai S., Komatsu H., Nemoto E., Nakamura K., Murakami M.: Impact of large tumor size on survival after resection of pathologically node negative (pN0) non-small cell lung cancer. Ann Thorac Surg, 2005, 79: 1142-1146. 15. Lopez-Encuentra A., Duque-Medina J.L., Rami-Porta R., de la Camara A.G., Ferrando P.: Staging in lung cancer: is 3 cm a prognostic threshold in pathologic stage I non-small cell lung cancer? A multicenter study of 1,020 patients. Chest, 2002, 121: 15151520. 16. Oliaro A., Filosso P.L., Cavallo A., et al.: The significance of intrapulmonary metastasis in non-small cell lung cancer: upstaging or downstaging? A re-appraisal for the next TNM staging

system. Eur J Cardio-Thorac Surg, 2008, 34: 438-443. 17. Urschel J.D., Urschel D.M., Anderson T.M., Antkowiak J.G., Takita H.: Prognostic implications of pulmonary satellite nodules: are the 1997 staging revisions appropriate? Lung Cancer, 1998, 21: 83-87. 18. Vallieres E., Shepherd F.A., Crowley J., et al.: The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol, 2009, 4: 1049-1059. 19. Shepherd F.A., Crowley J., Van Houtte P., et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol, 2007, 2: 1067-1077. 20. Rami-Porta R., Ball D., Crowley J., et al.: The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol, 2007, 2: 593-602. 21. Postmus P.E., Brambilla E., Chansky K., et al.: The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol, 2007, 2: 686-693. 22. Rusch VW., Asamura H., Watanabe H., Giroux D.J., Rami-Porta R., Goldstraw P.: The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol, 2009, 4: 568-577.

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Invasive staging of the mediastinum* W. De Wever, J. Coolen, J. Verschakelen1 Staging of patients with lung cancer provides accurate information on the extent of disease and guides the choice of treatment. Non-invasive imaging techniques are safe, however these imaging techniques have limited accuracy in detection of mediastinal lymph node metastases. The American College of Chest Physicians guidelines for lung can cer staging recommend that patients with abnormal lymph nodes on CT or PET, or centrally located tumors without mediastinal LNs, should undergo invasive staging. Mediastinal nodal sampling has traditionally been performed by cervical mediastinoscopy. However, with the development of endoscopic needle aspiration techniques such as endo bronchial ultrasound (EBUS) to guide transbronchial needle aspiration (TBNA) and endoscopic ultrasound (EUS), the diagnostic algorithm for lung cancer is changing. Key-word: Mediastinum, CT.

Correct staging of patients with lung cancer provides accurate information on the extent of disease, guides choice of treatment, gives an idea about prognosis and is necessary for comparison of studies. In patients with non-small cell lung cancer (NSCLC), surgical resection of the tumor is the treatment of choice in the absence of metastatic mediastinal lymph nodes (LN). Combined modality treatment is indicated for patients with mediastinal nodal metastases. CT, fluorodeoxyglucose PET (FDG-PET) and PET-CT are noninvasive imaging techniques to detect mediastinal metastases. Although CT and PET are safe, these imaging techniques have limited accuracy in detection of mediastinal LN metastases with positive predictive value

(PPV) of only 56% to 79%, and negative predictive value (NPV) of 83% to 93% (1) (Table I). Tissue confirmation is usually recommended when there are abnormal findings with these non-invasive imaging modalities (2, 3). The American College of Chest Physicians (ACCP) guidelines for lung cancer staging recommend to limit the impact of false-positive results, that paand false-negative tients with abnormal LNs on CT or PET, or centrally located tumors without mediastinal LNs, should undergo invasive staging (4). Mediastinal nodal sampling has traditionally been performed by c ervical mediastinoscopy or anterior mediastinotomy (5). However, with the development of endoscopic n eedle aspiration techniques such as endobronchial

ultrasound (EBUS) to guide transbronchial needle aspiration (TBNA) and endoscopic ultrasound (EUS) with needle aspiration (NA), the diagnostic algorithm for lung cancer is changing. In this paper we will give an overview of the possible staging techniques for invasive mediastinal staging. Primary mediastinal invasive lymph node staging Mediastinoscopy Mediastinoscopy has traditionally been the gold standard for invasive mediastinal staging of patients with potentially operable lung cancer. Different forms of mediastinoscopy have been described. Cervical

Table I. — Sensitivities (%) and negative predictive values (%) for different invasive staging modalities in different studies and meta-analysis. Study Toloza (1) Toloza (11)

Medford (19)

Ernst (24) Yasufuku (25) Annema (26) Mateu-Navarro (21) Van Schil (27) De Leyn (22)

Staging technique CT PET Blind TBNA EUS-FNA Mediastinoscopy Cervical mediastinoscopy Conventional TBNA EBUS-TBNA EUS-FNA EBUS Cervical mediastinoscopy EBUS Cervical mediastinoscopy Surgical staging Endosonography and surgical staging Remediastinoscopy Remediastinoscopy Remediastinoscopy

Sensitivity 57 84 76 88 81 78-81 76-78 88-93 84-88 87 68 76.9 84.6 79 94 70 73 29

Negative predictive value 83 93 71 77 91 91 71-72 76 77-81 78 59 85.9 90.4 86 93 75 52

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Department of Radiology, University Hospitals Leuven, Belgium.

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Table II. — Access to different lymph nodes with different staging techniques. Technique

LN stations

Cervical mediastinoscopy EUS-FNA EBUS-TBNA VATS left

8-9

+ +/+ -

+ + + -

+ + -

+ + + -

(+/-) +

+ + + -

+ +

+R +/+ -

+ -

EUS-FNA: Endo-oesophageal ultrasound with fine needle aspiration. EBUS-TBNA: Endobronchial ultrasound with trans bronchial needle aspiration. VATS: Video-assisted thoracoscopic surgery.

ediastinoscopy is the most comm monly used. More recently, videomediastinoscopy is introduced (5). Other modified techniques are mediastinal lymphadenectomy through a cervicotomy approach (VAMLA, v ideo-assisted mediastinoscopic lymphadenectomy (6) -TEMLA, trans cervical extended mediastinal lymphadenectomy (7)). Cervical mediastinoscopy is a surgical open biopsy technique usually performed in an operating theatre under general anaesthesia. An incision is made just above the suprasternal notch and the mediastinoscope is inserted adjacent to the trachea to view and biopsy the accessible mediastinal nodes. Cervical mediastinoscopy has a reported morbidity (e.g. arrhythmia, haemorrhage and recurrent laryngeal nerve injury) and mortality rate of 2% and 0.08% respectively (8, 9). An advantage of mediastinoscopy over TBNA is the performing of a more complete mediastinal mapping, including contralateral LN stations (5). According to the LN map proposed by Mountain and Dresler (10) the following LN stations can be evaluated by cervical mediastinoscopy: the highest mediastinal LN station (level 1), the right and left superior paratracheal LN stations (level 2 right, level 2 left), the right and left inferior paratracheal LN stations (level 4 right, level 4 left) and the subcarinal LN station (level 7) (5) (Table II). Sensitivity of cervical mediastinoscopy varied between 72% and 89%, with an average of 81% with a NPV of 91% 11 (Table I). The results of the suboptimal sensitivity can partly be explained by the fact that some LN stations (levels 5, 6, posterior part of level 7 and levels 8 and 9) are not accessible by cervical mediastinoscopy. Video mediastinoscopy allows better visualization and a more complete dissection of nodal tissue than cervical mediastinoscopy (4). A re-

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cent retrospective analysis of the two techniques revealed a lower incidence of recurrent laryngeal nerve palsies and postoperative bleeding with video mediastinoscopy. The number of nodes sampled was also higher with video mediastinoscopy. Existing studies show a higher sensitivity for video mediastinoscopy (86-93%) over the conventional version (81%) (8). Transbrochial needle aspiration TBNA has been shown to be safe and useful in patients with enlarged mediastinal LNs. Conventional TBNA has been long established as a minimally invasive method for diagnosing and staging patients with bulky subcarinal and paratracheal LNs at the same time as fibreoptic bronchoscopy. TBNA is performed under local anaesthesia with sedation as required as a day case procedure in the endoscopy suite. It is a well-tolerated procedure with no additional risks to a standard fibreoptic bronchoscopy. In reality, it is most often used to sample nodes at station 7. Stations 2 and 4 can also be sampled but these are technically more challenging due to the required angulation of the scope. Studies have reported sensitivity rates of 43-83% and positive predictive values of 89100% (12) (Table I). The negative predictive value is low and does not obviate the requirement for further surgical staging. A potential limitation of mediastinal lymph node staging with TBNA is the blind character of this technique. Numerous papers confirm the safety of the procedure. The rare complications reported are: pneumothorax, pneumomediastinum, haemomediastinum, bacteraemia and pericarditis. One of the major complications of TBNA is the possible severe damage to the working channel of the scope (13).

Endo-oesophageal ultrasound with fine needle aspiration Endo-oesophageal ultrasound (EUS) is a relatively new method first described in 1991 (14). The procedure is performed under local anaesthetic and conscious sedation. EUS and endo-oesophageal ultrasound with fine needle aspiration (EUSFNA) are safe, simple and highly accurate in detecting and confirming nodal metastases and have been increasingly used for staging of potentially resectable NSCLC. EUS can visualise the posterior and inferior nodal stations 9, 8, 7 and 5 and also sometimes level 4 but cannot image anterior mediastinal nodes because of the interposition of the trachea (Table II). The left lobe of the liver and the left adrenal gland can also be studied and sampled for metastases if abnormalities are found with non-invasive imaging techniques. Morbidity from this technique is almost nihil and even patients with poor lung function tolerate it well. Visual assessment of mediastinal lymphnodes by EUS gave for various observers sensitivities of 54-75%, specificities of 71-98%, PPV of 4677% and NPV of 85-93% (15) (Table I). Characteristics of lymph nodes indicating possible malignancy are hypo echoic core, sharp edges, round shape and a long axis diameter > 10 mm (15). Signs of benignancy are a hyperechoic core (fat), central calcification, ill-defined edges, a long and narrow shape and a long axis diameter up to 1 cm (16, 17). Endobronchial ultrasound - TBNA Endobronchial ultrasound (EBUS) is a procedure similar to conventional TBNA: it is a day case procedure using local anaesthesia and sedation with a similar gauge needle, sampling handling technique using four passes per node and similar or superior safety profile. There are, however, a

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Restaging of the mediastinum

EUS: Endo-oesophageal ultrasound EBUS: Endobronchial ultrasound FNA: fine needle aspiration TBNA: trans bronchial needle aspiration N0: patients with a peripheral tumor with FDG uptake and with LN < 1 cm on CT and/or no FDG uptake in the mediastinum. If PET or PET/CT is negative, mediastinoscopy is still indicated in central tumors, tumors with low FDG uptake, tumors with LN > = 1.6 cm and / or PET N1 disease. Fig. 1. — The proposed diagnostic algorithm for invasive mediastinal staging when PET or PET/CT is available adapted from P. De Leyn (5).

few differences. The patient is intubated orally from behind due to the larger external diameter of the EBUS bronchoscope (6.9 versus 4.95.1 mm in a standard fibroscopic bronchoscope). In general, a lineartype ultrasound probe is most commonly used for real-time imaging (8). EBUS-TBNA is a relatively quick, safe, minimally invasive and a day case procedure under conscious sedation performable by pulmonologists (18). Pneumomediastinum, pneumothorax and haemomediastinum can occur very rarely, but a postprocedure chest radiograph is not usually needed. Major vessel puncture is less likely because of real-time sampling. Infectious complications have rarely been reported, and bacteraemia is usually asymptomatic and clinically insignificant (19). EBUS-TBNA has access to all the mediastinal lymph node stations accessible by mediastinoscopy. EBUSTBNA can provide histology of the

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superior mediastinal LNs (levels 2 and 4, right and left) and the subcarinal LNs (level 7). Additionally, the hilar (station 10) and intrapulmonary nodal stations can be biopsied with TBNA (Table II). The nodes are directly visualised and sampled in realtime reducing the chances of major vessel puncture, and a larger tissue core is obtained. The negative predictive value of EBUS-TBNA is lower than for mediastinoscopy. This is the reason that patients with a high pretest probability of lung cancer with a negative EBUS-TBNA currently still need a mediastinoscopy. A recent meta-analysis reported an impressive pooled sensitivity of 93% (Table I) (20). Fig. 1 shows the proposed algorithm to follow primary mediastinal staging when PET or PET/CT scan is available. Proposition is based on the guidelines from the European Society of Thoracic Surgeons for preoperative lymph node staging for NSCLC (5).

Recent studies suggest that mainly patients with initial stage IIIA or IIIB and mediastinal downstaging will benefit from surgical resection. As a consequence, mediastinal restaging after induction therapy is required for selection of patients likely to benefit from surgical resection. Repeat mediastinoscopy offers the advantage of providing histological evidence of response after induction therapy. However repeat mediastinoscopy is technically more difficult than the first procedure. The sensitivity to detect residual mediastinal disease is about 70% (21). In a prospective study, evaluating the accuracy of re-mediastinoscopy and PET-CT in restaging the mediastinum after videomediastinoscopy proven N2 disease in 30 patients, De Leyn et al. concluded that, after a thoroughly performed initial videomediastinoscopy, repeat videomediastinoscopy was technically feasible but inaccurate due to severe adhesions and fibrosis. The sensitivity to detect residual positive mediastinal LNs was only 29%, with an accuracy of 60% (22). The degree of adhesions and mediastinal fibrosis is mainly secondary to preinduction mediastinoscopy rather than to induction treatment itself (22). An alternative, less invasive test to restage the mediastinum after induction chemotherapy is EBUS-TBNA or EUS-FNA. Annema et al. reported results in 19 patients with proven N2 disease which were restaged by EUS after induction chemotherapy. Diagnostic accuracy in this study was 83% (23). Conclusion The ACCP guidelines for lung cancer staging recommend that patients with abnormal LNs on CT or PET, or centrally located tumors without mediastinal LNs, should undergo invasive staging. Mediastinal nodal sampling has traditionally been performed by cervical mediastinoscopy. EBUS-TBNA and EUS-FNA are new techniques that provide cytohistological diagnosis and are minimally invasive techniques. They can be complementary to surgical invasive staging techniques. Their specificity is high, but their NPV is low. For this reason an invasive surgical technique is indicated if they yield negative results. However, if fine needle aspiration is positive, this result may be valid as proof of N2 or N3 disease.

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References 1. Toloza E.M., Harpole L., McCrory D.C.: Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest, 2003, 123: 137S146S. 2. Silvestri G.A., Gould M.K., Margolis M.L., et al.: Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest, 2007, 132: 178S-201S. 3. Cerfolio R.J., Ojha B., Bryant A.S., et al.: The role of FDG-PET scan in staging patients with nonsmall cell carcinoma. Ann Thorac Surg, 2003, 76: 861-866. 4. Detterbeck F.C., Jantz M.A., Wallace M., et al.: Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest, 2007, 132: 202S-220S. 5. De Leyn P., Lardinois D., Van Schil P.E., et al.: ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg, 2007, 32: 1-8. 6. Hurtgen M., Friedel G, Toomes H, et al.: Radical video-assisted mediastinoscopic lymphadenectomy (VAMLA) – technique and first results. Eur J Cardiothorac Surg, 2002, 21: 348-351. 7. Kuzdzal J., Zielinski M., Papla B., et al.: Transcervical extended mediastinal lymphadenectomy – the new operative technique and early results in lung cancer staging. Eur J Cardiothorac Surg, 2005, 27: 384-390; discussion 390. 8. Medford A.R., Bennett J.A., Free C.M., et al.: Mediastinal staging procedures in lung cancer: EBUS, TBNA and mediastinoscopy. Curr Opin Pulm Med, 2009, 15: 334-342. 9. Khoo K.L., Ho K.Y.: Endoscopic mediastinal staging of lung cancer. Respir Med, 2011, 105: 515-518.

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JBR–BTR, 2013, 96 (3) 10. Mountain C.F., Dresler C.M.: Regional lymph node classification for lung cancer staging. Chest, 1997, 111: 1718-1723. 11. Toloza E.M., Harpole L., Detterbeck F., et al.: Invasive staging of non-small cell lung cancer: a review of the current evidence. Chest, 2003, 123: 157S166S. 12. Utz J.P., Patel A.M., Edell E.S.: The role of transcarinal needle aspiration in the staging of bronchogenic carcinoma. Chest, 1993, 104: 1012-1016. 13. Dasgupta A., Mehta A.C.: Transbronchial needle aspiration. An underused diagnostic technique. Clin Chest Med, 1999, 20: 39-51. 14. Schuder G., Isringhaus H., Kubale B., et al.: Endoscopic ultrasonography of the mediastinum in the diagnosis of bronchial carcinoma. Thorac Cardiovasc Surg, 1991, 39: 299-303. 15. Micames C.G., McCrory D.C., Pavey D.A., et al.: Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis. Chest, 2007, 131: 539-548. 16. Fritscher-Ravens A., Sriram P.V., Bobrowski C., et al.: Mediastinal lymphadenopathy in patients with or without previous malignancy: EUSFNA-based differential cytodiagnosis in 153 patients. Am J Gastroenterol, 2000, 95: 2278-2284. 17. Chang K.J., Erickson R.A., Nguyen P.: Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration of the left adrenal gland. Gastrointest Endosc, 1996, 44: 568-572. 18. Herth F.J., Eberhardt R., Vilmann P., et al.: Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax, 2006, 61: 795798. 19. Medford A.R.: Endobronchial ultrasound: what is it and when should it be used? Clin Med, 2010, 10: 458-463.

20. Gu P., Zhao Y.Z., Jiang L.Y., et al.: ultrasound-guided Endobronchial trans bronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer, 2009, 45: 1389-1396. 21. Mateu-Navarro M., Rami-Porta R., Bastus-Piulats R., et al.: Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg, 2000, 70: 391-395. 22. De Leyn P., Stroobants S., De Wever W., et al.: Prospective comparative study of integrated positron emission tomography-computed tomography scan compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy-proven stage IIIA-N2 Non-small-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol, 2006, 24: 3333-3339. 23. Annema J.T., Veselic M., Versteegh M.I., et al.: Mediastinal restaging: EUS-FNA offers a new perspective. Lung Cancer, 2003, 42: 311-318. 24. Ernst A., Anantham D., Eberhardt R., et al.: Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol, 2008, 3: 577-582. 25. Yasufuku K., Chiyo M., Koh E., et al.: Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer, 2005, 50: 347-354. 26. Annema J.T., van Meerbeeck J.P., Rintoul R.C., et al.: Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA, 2010, 304: 22452252. 27. Van Schil P., van der Schoot J., Poniewierski J., et al.: Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer. Lung Cancer, 2002, 37: 281-285.

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WHOLE BODY PET-CT: M STAGING IN NON SMALL-CELL LUNG CANCER* F.-X. Hanin1 FDG PET has been used for years in the diagnosis and recurrence of non small cell lung cancer (NSCLC). It has an important impact on patient management, and its coupling with CT for immediate fusion allows immediate localiza tion and characterization of uptake. This article reviews the role of FDG PET-CT in the staging of NSCLC for the detec tion of metastatic disease. Key-words: Lung neoplasms, CT – Lung neoplasms, emission CT (ECT).

The Belgian cancer registry estimates the newly diagnosed cases of lung cancer in 2009 at 7572 in Belgium (2077 females and 5495 males). It represents the third incidence of cancer after breast and colon cancers, but remains the first cause of (1). Accurate cancer-related death staging of cancer prior to therapy is critical to patient management. In this field, FDG PET represents a noninvasive metabolic imaging procedure allowing both nodal and distant metastatic staging, and as such, is recommended by the 2007 ACCP guidelines as first staging procedure when NSCLC is diagnosed, for both mediastinal and distant metastases detection (2, 3). Nuclear medicine imaging is based on the tracer principle, defined by Hevesy (4) as the in vivo use of a very small amount of radioactive isotopes showing identical chemical properties as biological compounds to analyze a particular metabolic pathway. PET imaging is based on positron-emitters such as 18F, 15O or 82 Rb, among others. The annihilation of the positron emitted leads to the emission of two 180°-sided 511 kev photons, detected by a full crystal ring (5). Radiochemistry and radiopharmacy both represents an important prerequisite to molecular imaging, as they allow the incorporation of the positron emitter in a chemical structure suitable for injection and further, to the analysis of a precise physiological pathway. Integrated in glucose (as 18F-fluorodeoxyglucose, FDG), fluorine-18 allows the metabolic imaging of increased glucose metabolism (6) – or its reduction or absence (in therapy monitoring, in cysts or in particular epilepsy indications). Current PET-CT cameras show a typical resolution (full-width at halfmaximum, FWHM) of about 5 mm (79). There is an ongoing research on crystals or semi-conductor detectors

to improve both sensitivity and time resolution, the last showing great importance for time-of-flight imaging (10-12). The main advantage of PET-CT cameras compared to single PET detection is the instantaneous fusion with anatomical data, leading towards better spatial localization of hot spots, increasing specificity (13). In addition, the density map offered by CT images can be used for attenuation correction after little adaptations related to the difference in energy between 511 kev radiation from annihilation, and X-rays (14). On the clinical side, the effect of FDG PET-CT imaging on NSCLC patient management is widely documented in the literature. An interesting and recent study by Gregory et al. (15) considered the change in treatment planning induced by FDG PET-CT and its effect on a 5-year survival period. In 42.3% of the 168 cases, a change of treatment modality or curative intent was induced by FDG imaging. Furthermore, FDG PET-CT staging was highly predictive of Overall Survival (OS). Another study evaluated at 34% the change in therapy planning related to M-staging from FDG PET-CT data compared to (16) Finally, conventional imaging FDG PET-CT imaging leads also to a reduction of futile thoracotomies (17) compared to conventional imaging. Global sensitivity and specificity In a recent meta-analysis including 13 studies and 2873 patients, sensitivity and specificity of PET-CT in the detection of extrathoracic metastases were estimated respectively to 77 and 95% (18). These numbers include the detection of brain metastases, were there is a known lack of sensitivity du to the high physiological uptake of FDG in the cerebral cortex. PET-CT sensitivity for the detection of brain metastases is about

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Nuclear Medicine Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

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27% with a very high specificity of 98%. (19). Therefore, when combining PET-CT with MRI for the detection of brain metastases, the global sensitivity for the detection of extra thoracic metastases from NSCLC rises to 84% according to Lee et al. (20). Cost-effectiveness Alongside with the clinical efficiency of PET-CT in the staging of NSCLC, the cost-effectiveness from an economical point of view has to be discussed (21). An interesting study from Sogaard et al. (22) analyses the potential economical spare by the reduction of futile thoracotomies and subsequent morbidity. Although, if the cost-effectiveness remains an important point from a payer’s perspective, the societal cost as further discussed by Schreyogg and colleagues (23), should also be taken into account. Finally, there is an increasing amount of publications from China (18, 24), where an increased incidence of NSCLC is expected in the next years due to the high prevalence of smoking (25). Primary diagnosis and M staging Whole-body PET-CT allows the staging of NSCLC in one procedure: the size of the primary, the involvement of mediastinal nodes and extra-thoracic spread assessment naturally leads to a TNM staging. However, as T staging relies more on size and anatomical relation with mediastinum or chest wall, a high resolution CT or in some cases chest MRI are better suited to a precise T staging. The metabolical information given by the primary (intensity of uptake) was investigated as a prognosis factor of survival in stage I and II NSCLC (26, 27). In addition, the assessment of global tumor burden (using metabolic tumor volume, MTV) was also investigated as prognosis factor (28-31). The involvement of mediastinal node metastasis (N staging) is detailed elsewhere in this issue of the

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Fig. 1. — Primary staging of a right lung mass in a 66 year-old patient. A. Maximal Intensity projection (MIP) of whole-body 18FFDG-PET showing the primary lung tumor in the right superior lobe, and both right hilar and right mediastinal invaded lymph nodes. The analysis of the lumbar region reveals a high uptake of FDG in the right part the body of the third lumbar vertebrae; a small focus is also noted in the region of the right coxa (arrows). B. Axial fusion PET-CT revealing a high focus of FDG in L3, raising suspicion for metastatic disease. C. T1-weighted MR image of the lumbar spine shows a large area of low signal intensity resulting from a marrow replacement in L3 (thick arrow), and other small areas in L1 (thin arrow) and in the right coxal bone (not shown). The TNM staging according to AJCC 7th edition was T2a (tumor larger than 3 cm) N2 (homolateral mediastinum invasion) M1b (bone metastases).

Belgian Journal of Radiology, and will therefore not be discussed. M1a: pleural effusion According to the 7th edition of the AJCC cancer staging manual (32), and since January 1, 2010, pleural effusion is considered as M1a staging. Pleural effusion in FDG PET-CT can be assessed by the maximal Standardized Uptake Value (SUVmax) of pleural lesions, but a ratio to the SUVmax value of the primary was reported to be the best predictive factor of malignancy (33). It must be kept in mind that pleural inflammatory disease is a well known false positive, in particular after talc

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pleurodesis (even years after the procedure). This particularly illustrates the increase in specificity of hybrid imaging, as higher density of the high-uptaking pleural lesion (calcifications) is in favor of benign inflammatory process (34).

ity and specificity at respectively 93,9% and 98,9%, for a global accuracy of 97,8% (35). Figure 1 illustrates the high FDG uptake in metastatic bone lesions.

M1b: bone

The assessment of adrenal involvement is a challenge, since the prevalence of incidental discovered lesions (“Incidentalomas”) is estimated at autopsy ranging from 1.4% to 2.9% (36). In lung cancer patients in particular, this issue remains important as adrenals are common site of secondary lesions (37). Therefore, several authors have investigated potential parameters to distinguish

A recent meta analysis from Wu and colleagues pooled Six studies involving 1894 patients for the assessment of bone metastases, estimating the sensitivity at 91% and a 98% specificity (18). The most recent included in this meta-analysis is a study from Liu et al. including 362 patients and estimating sensitiv-

M1b: adrenals

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Fig. 2. — Coronal (A) and sagital (B) maximal intensity projections of FDG PET in a 36 years old patient referred for staging of squamous cell carcinoma of the right lung. In addition to the right hilar lesion, the whole-body analysis reveals multiple foci of uptake. C & D. The PET-CT fusion reveals the muscle location of the lesions (thin arrows), in addition to some bone lesions (not shown). Notice the primary right hilar lesion (thick arrow, D).

benign from malignant lesions (3845). A study from Sweden about 534 patients (41) estimated that about only one fourth to one half of the adrenal lesion in cancer patients are actually from malignant origin. Authors recommend using dedicated adrenal imaging with CT attenuation measurements including washout, and biological testing for primary adrenal lesions. Other authors recommend the use of lesionto-liver SUVmax ratio, as it appears to be more discriminating than SUVmax alone (40, 44). The interpretation of increased uptake in the remaining adrenal gland after adrenalectomy has to be performed carefully, as physiological increase in FDG uptake might be seen in the remaining adrenal gland (46). M1b: other - second malignancy In rare cases, PET can discover nusual sites of metastases, such as u muscle metastasis (47). Figure 2 shows a rare case of widespread muscle and bone metastases from lung primary in a 36 years-old patient. Another incidental finding in addition to adrenal incidentalomas is

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the fortuitous discovery of another primary. This is not as rare as expected, as lung cancer shares its main risk factor (smoking) with other malignancies – head and neck squamous cell carcinoma, or esophageal carcinoma, among others. Lin and Ambati (48) estimate the prevalence of such unexpected primary between 1,2 and 4,2%, which as expected has high impact on patient management. Figure 3 shows a head and neck squamous cell carcinoma discovered by PET performed for the staging of lung cancer. Recurrence There is at the time no clear guidelines consensus for the timeline of FDG PET-CT to be performed after surgery for the detection of recurrence in asymptomatic patients. However, there is a clear role for PET as recently summarized and investigated by Toba and colleagues (49). This group from Japan estimated sensitivity and specificity at 94,4 and 97,6%, respectively, in a 101 patients cohort. These patients were elected for surgery, with a pathological stage ranging from 0 to IIIa. The authors

conclude to the usefulness of PET-CT in this indication, but requiring larger studies especially from the costeffectiveness point of view. Future: PET-MRI? In the last decade, all manufacturers of PET scanners moved to the hybrid PET-CT camera: there is on the market no more PET-alone available camera. This trend in hybrid imaging leads the major actors in industry to develop SPECT-CT scanners for monophotonic imaging, and beyond, PET-MRI. Technically, this integration must overcome many issues, mainly du to the magnetic field, by removing photomultiplier tubes in favor of semi-conductor detectors. This solution is not perfect, as it must compromise on both PET and MRI detection quality. Another option is to separate both the MRI and PET gantries, at the cost of a longer time examination, one of the gantries remaining unused. In addition, further research is required to maintain a high quality for attenua(50), in order to tion correction maintain the semi-quantitative information of PET.

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Fig. 3. — 60-year-old woman referred for PET-CT in the context of a left hilar mass. In addition to the primary directly invading the left hilum, (thin white arrow), an intense FDG uptake is noticed in both adrenal glands. The metabolic staging of the lung cancer concludes to a stage IV (M1b). In addition to the lung cancer, a clear focus of uptake in the right part of the floor of the mouth, associated with a lymph node in left level II cervical area, revealed a primary head and neck squamous cell carcinoma.

There is at the time no clinical data available to assess both usefulness and cost-effectiveness of PETMRI in NSCLC patients.

Acknowledgements

Conclusion

References

PET-CT in NSCLC patients is a cost-effective and powerful tool in TNM staging, and in the detection of recurrence. It has to be coupled to brain MRI in the staging process due to its low sensitivity in brain metastases detection. Further studies a still required to evaluate the optimal timing of imaging after surgery, and the role of PET-CT in therapy response assessment. PET-MRI remains at the time in an early phase in development and no valid clinical data is yet available to evaluate its potential role in patient management.

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The author thanks J. Malghem for the comment of the MRI figure.

1. Belgian Cancer Registry. 2009 Incidence rates of cancer in Belgium. Downloaded from http://www.kankerregister.org/ on October, 1, 2012. 2. Silvestri G.A., Gould M.K., Margolis M.L., Tanoue L.T., McCrory D., Toloza E., et al.: Noninvasive staging of nonsmall cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest, 2007, 132 (3 Suppl): 178S-201S. 3. Cerfolio R.J., Bryant A.S.: The role of integrated positron emission tomo graphy-computerized tomography in evaluating and staging patients with non-small cell lung cancer. Semin

Thorac Cardiovasc Surg, 2007, 19: 192-200. 4. Gest H.: The early history of (32) P as a radioactive tracer in biochemical research: A personal memoir. Biochem Mol Biol Educ, 2005, 33: 159-164. 5. Turkington T.G.: PET Imaging Basics. In: Clinical PET-CT in Radiology Integrated Imaging in Oncology. Edited by Shreve P., Townsend D. Printed by Springer, New York, 2011, pp. 21-37. 6. Ambrosini V., Nicolini S., Caroli P., Nanni C., Massaro A., Marzola M.C., et al.: PET/CT imaging in different types of lung cancer: an overview. Eur J Radiol, 2012, 81: 988-1001. 7. Sathiakumar C., Som S., Eberl S., Lin P.: NEMA NU 2-2001 performance testing of a Philips Gemini GXL PET/ CT scanner. Australas Phys Eng Sci Med, 2010, 33: 199-209. 8. Surti S., Kuhn A., Werner M.E., Perkins A.E., Kolthammer J., Karp J.S.: Performance of Philips Gemini TF PET/CT scanner with special consideration for its time-of-flight imaging capabilities. J Nucl Med, 2007, 48: 471-480. 9. Teras M., Tolvanen T., Johansson J.J., Williams J.J., Knuuti J.: Performance of the new generation of whole-body PET/CT scanners: Discovery STE and Discovery VCT. Eur J Nucl Med Mol Imaging, 2007, 34: 1683-1692. 10. Schaart D.R., Seifert S., Vinke R., van Dam HT., Dendooven P., Lohner H., et al.: LaBr (3): Ce and SiPMs for time-offlight PET: achieving 100 ps coincidence resolving time. Phys Med Biol, 2010, 55: N179-189. 11. van Elmbt L., Vandenberghe S., Walrand S., Pauwels S., Jamar F.: Comparison of yttrium-90 quantitative imaging by TOF and non-TOF PET in a phantom of liver selective internal radiotherapy. Phys Med Biol, 2011, 56: 6759-6777. 12. Kwon S.I., Lee J.S., Yoon H.S., Ito M., Ko G.B., Choi J.Y., et al.: Development of small-animal PET prototype using silicon photomultiplier (SiPM): initial results of phantom and animal imaging studies. J Nucl Med, 2011, 52: 572-579. 13. Lardinois D., Weder W., Hany T.F., Kamel E.M., Korom S., Seifert B., et al.: Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med, 2003, 348: 2500-2507. 14. Bunyaviroch T., Turkington T.G., Wong T.Z., Wilson J.W., Colsher J.G., Coleman R.E.: Quantitative effects of contrast enhanced CT attenuation correction on PET SUV measurements. Mol Imaging Biol, 2008, 10: 107-113. 15. Gregory D.L., Hicks R.J., Hogg A., Binns D.S., Shum P.L., Milner A., et al.: Effect of PET/CT on management of patients with non-small cell lung cancer: results of a prospective study with 5-year survival data. J Nucl Med, 2012, 53: 1007-1015. 16. Abramyuk A., Appold S., Zophel K., V., Baumann M., Hietschold

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bolmaali N.: Quantitative modificaA tions of TNM staging, clinical staging and therapeutic intent by FDG-PET/CT in patients with non small cell lung cancer scheduled for radiotherapy - A retrospective study. Lung Cancer, 2012, 78 (2): 148-152. 17. Fischer B., Lassen U., Mortensen J., Larsen S., Loft A., Bertelsen A., et al.: Preoperative staging of lung cancer with combined PET-CT. N Engl J Med, 2009, 361: 32-39. 18. Wu Y., Li P., Zhang H., Shi Y., Wu H., Zhang J., et al.: Diagnostic value of fluorine 18 fluorodeoxygluclose positron emission tomography/computed tomography for the detection of metastases in non-small-cell lung cancer patients. Int J Cancer, 2013, 132 (2): E37-47. 19. Kruger S., Mottaghy F.M., Buck A.K., Maschke S., Kley H., Frechen D., et al.: Brain metastasis in lung cancer. Comparison of cerebral MRI and 18FFDG-PET/CT for diagnosis in the initial staging. Nuklearmedizin, 2011, 50: 101-106. 20. Lee H.Y., Lee K.S., Kim B.T., Cho Y.S., Lee E.J., Yi C.A., et al.: Diagnostic efficacy of PET/CT plus brain MR imaging for detection of extrathoracic metastases in patients with lung adenocarcinoma. J Korean Med Sci, 2009, 24: 1132-1138. 21. Mac Manus M.P., Hicks R.J.: How can we tell if PET imaging for cancer is cost effective? Lancet Oncol, 2010, 11: 711-712. 22. Sogaard R., Fischer B.M., Mortensen J., Hojgaard L., Lassen U.: Preoperative staging of lung cancer with PET/CT: cost-effectiveness evaluation alongside a randomized controlled trial. Eur J Nucl Med Mol Imaging, 2011, 38: 802-809. 23. Schreyogg J., Weller J., Stargardt T., Herrmann K., Bluemel C., Dechow T., et al.: Cost-effectiveness of hybrid PET/CT for staging of non-small cell lung cancer. J Nucl Med, 2010, 51: 1668-1675. 24. Wang Y.T., Huang G.: Is FDG PET/CT cost-effective for pre-operation staging of potentially operative non-small cell lung cancer? - From Chinese healthcare system perspective. Eur J Radiol, 2012, 81: e903-e909. 25. Alberg A.J., Brock M.V., Samet J.M.: Epidemiology of lung cancer: looking to the future. J Clin Oncol, 2005, 23: 3175-3185. 26. Agarwal M., Brahmanday G., Bajaj S.K., Ravikrishnan K.P., Wong C.Y.: Revisiting the prognostic value of preoperative (18)F-fluoro-2-deoxyglucose ( (18)F-FDG) positron emission tomography (PET) in early-stage (I & II) non-small cell lung cancers (NSCLC). Eur J Nucl Med Mol Imaging, 2010, 37: 691-698. 27. Hanin F.X., Lonneux M., Cornet J., Noirhomme P., Coulon C., Distexhe J., et al.: Prognostic value of FDG uptake in early stage non-small cell lung

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M STAGING OF NSCLC WITH PET-CT — HANIN cancer. Eur J Cardiothorac Surg, 2008, 33: 819-823. Zhang H., Wroblewski K., 28. Appelbaum D., Pu Y.: Independent prognostic value of whole-body metabolic tumor burden from FDG-PET in non-small cell lung cancer. Int J Comput Assist Radiol Surg, 2013, 8 (2): 181-191. 29. Oh J.R., Seo J.H., Chong A., Min J.J., Song H.C., Kim Y.C., et al.: Wholebody metabolic tumour volume of 18F-FDG PET/CT improves the prediction of prognosis in small cell lung cancer. Eur J Nucl Med Mol Imaging, 2012, 39: 925-935. 30. Kim K., Kim SJ., Kim I.J., Kim Y.S., Pak K., Kim H.: Prognostic value of volumetric parameters measured by F-18 FDG PET/CT in surgically resected non-small-cell lung cancer. Nucl Med Commun, 2012, 33: 613-620. Liao S., Penney B.C., Zhang H., 31. Suzuki K., Pu Y.: Prognostic value of the quantitative metabolic volumetric measurement on 18F-FDG PET/CT in Stage IV nonsurgical small-cell lung cancer. Acad Radiol, 2012, 19: 69-77. 32. Edge S.B., Byrd D.R., Compton C.C., Fritz A.G., Greene F.L., Trotti A.: AJCC Cancer Staging Manual, 7th edition Springer, 2010 33. Kim B.S., Kim I.J., Kim S.J., Pak K., Kim K.: Predictive value of F-18 FDG PET/CT for malignant pleural effusion in non-small cell lung cancer patients. Onkologie, 2011, 34: 298-303. 34. Nguyen N.C., Tran I., Hueser C.N., Oliver D., Farghaly H.R., Osman M.M.: F-18 FDG PET/CT characterization of talc pleurodesis-induced pleural changes over time: a retrospective study. Clin Nucl Med, 2009, 34: 886890. 35. Liu N., Ma L., Zhou W., Pang Q., Hu M., Shi F., et al.: Bone metastasis in patients with non-small cell lung cancer: the diagnostic role of F-18 FDG PET/CT. Eur J Radiol, 2010, 74: 231-235. 36. Aron D., Terzolo M., Cawood T.J.: Adrenal incidentalomas. Best Pract Res Clin Endocrinol Metab, 2012, 26: 69-82. 37. Stenbygaard L.E., Sorensen J.B., Larsen H., Dombernowsky P.: Metastatic pattern in non-resectable nonsmall cell lung cancer. Acta Oncol, 1999, 38: 993-998. 38. Blake M.A., Slattery J.M., Kalra M.K., Halpern E.F., Fischman A.J., Mueller P.R., et al.: Adrenal lesions: characterization with fused PET/CT image in patients with proved or suspected malignancy – initial experience. Radiology, 2006, 238: 970-977. 39. Chong S., Lee K.S., Kim H.Y., Kim Y.K., Kim B.T., Chung M.J., et al.: Integrated PET-CT for the characterization of adrenal gland lesions in cancer patients: diagnostic efficacy and interpretation pitfalls. Radiographics, 2006, 26: 1811-1824.

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40. Gratz S., Kemke B., Kaiser W., Heinis J., Behr T.M., Hoffken H.: Incidental non-secreting adrenal masses in cancer patients: intra- individual comparison of 18F-fluorodeoxyglucose positron emission tomography/computed tomography with computed tomography and shift magnetic resonance imaging. J Int Med Res, 2010, 38: 633-644. 41. Hammarstedt L., Muth A., Sigurjonsdottir H.A., Almqvist E., Wangberg B., Hellstrom M.: Adrenal lesions in patients with extra-adrenal malignancy – benign or malignant? Acta Oncol, 2012, 51: 215-221. 42. Jana S., Zhang T., Milstein D.M., Isasi C.R., Blaufox M.D.: FDG-PET and CT characterization of adrenal lesions in cancer patients. Eur J Nucl Med Mol Imaging, 2006, 33: 29-35. 43. Quint L.E.: Staging non-small cell lung cancer. Cancer Imaging, 2007, 7: 148-159. 44. Xu B., Gao J., Cui L., Wang H., Guan Z., Yao S., et al.: Characterization of adrenal metastatic cancer using FDG PET/CT. Neoplasma, 2012, 59: 92-99. 45. Zubeldia J., Abou-Zied M., Nabi H. 12. Patterns of Adrenal Gland Involvement from Lung Cancer Shown by 18F-Fluorodeoxyglucose Positron Emission Tomography Compared to Computed Tomography and Magnetic Resonance Imaging. Clin Positron Imaging, 2000, 3: 166. 46. S., Deandreis D., Leboulleux Escourrou C., Al Ghuzlan A., Bidault F., Auperin A., et al.: Fluorodesoxyglucose uptake in the remaining adrenal glands during the followup of patients with adrenocortical carcinoma: do not consider it as malignancy. Eur J Endocrinol, 2011, 164: 89-94. 47. Yilmaz M., Elboga U., Celen Z., Isik F., Tutar E.: Multiple muscle metastases from lung cancer detected by FDG PET/ CT. Clin Nucl Med, 2011, 36: 245247. 48. Lin M., Ambati C.: The management impact of clinically significant incidental lesions detected on staging FDG PET-CT in patients with nonsmall cell lung cancer (NSCLC): an analysis of 649 cases. Lung Cancer, 2012, 76: 344-349. 49. Toba H., Sakiyama S., Otsuka H., Kawakami Y., Takizawa H., Kenzaki K., et al.: 18F-fluorodeoxyglucose positron emission tomography/computed tomography is useful in postoperative follow-up of asymptomatic nonsmall-cell lung cancer patients. Interact Cardiovasc Thorac Surg, 2012, 15 (5): 859-864. 50. Kim J.H., Lee J.S., Song I.C., Lee D.S.: Comparison of Segmentation-Based Attenuation Correction Methods for PET/MRI: Evaluation of Bone and Liver Standardized Uptake Value with Oncologic PET/CT Data. J Nucl Med, 2012, 53 (12): 1878-1882.

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CONTRIBUTION OF MRI IN LUNG CANCER STAGING* A. Khalil1,2, T. Bouhela1, M.-F. Carette1,3 Major advances in the WB-MRI in the initial evaluation and follow-up of patients with lung cancer have been per formed in recent years. Multicentric studies using different magnet systems are necessary to confirm these promising results. Key-word: Lung neoplasms, MR.

Lung cancer is the leading cause of cancer-related death worldwide, with a dismal 5-year survival rate of 15% (1). It accounts for 12.2% of all new cases of cancer in Europe in 2008 (1) and 14% of all new cases of cancer in the USA in 2011 (2). Accurate staging is mandatory to select the most appropriate therapy and to determine prognosis. The two advanced imaging methods used for this staging were CT-scan and 18F-FDG PET/CT. However, both technics had some limitations. Limitations of 18F-FDG PET/CT are particularly limited spatial resolution (3) and low specificity in distinguishing malignant nodule or lymphadeno pathy from inflammatory changes, resulting in a considerable number of false-positive findings (4). The 18 F-FDG PET/CT is not recommended for brain staging. Moreover, PET/CT is associated with a considerable radiation burden to patients and medical personnel. Limitations of CT-scan are the use of morphological (aspect and size of the nodule, size of the small diameter of the lymphadenopathy) data without functional or biological information. Magnetic resonance imaging (MRI) is currently the only technique that enables non-invasive wholebody assessment without ionizing radiation. Another strength of MRI is its capability to create high soft tissue contrast without external contrast agents and with high spatial resolution. Currently, MRI is recommended in the assessment of lung cancer extension to the lung apices (superior sulcus or Pancoast-Tobias tumor), to the spinal cord, and to the cardiac cavity. For metastases issues, MRI is also recommended for its high sensitivity and specificity for brain, bone, liver and adrenal metastases diagnosis. Recent advances in

Fig. 1. — Left superior sulcus tumor. A: Multidetector CT-scan’s sagittal reformatting shows the tumor invades the first (R1) and second (R2) ribs. The vascular structures, subclavian artery (SCA) and the subclavian vein (SCV), are not invaded by the tumor. B, C, D: Sagittal T1-weighted MR image of the left superior sulcus show tumor extension into T1-2 neurovertebral foramen (*). Radiologist is more confident with MRI for extension evaluation of the tumors within the superior sulcus. Abbreviations: AS: Anterior scalene muscle, PS: Posterior scalene muscle.

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Radiology Department, Tenon Hospital, Paris, 2. CNRS UMR 7241/INSERM U1050, Early Development and Pathologies Center for Interdisciplinary Research in Biology, Collège de France, Paris, 3. University of Pierre et Marie Curie, Paris VI, Paris, France.

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A Fig. 2. — Left superior lung adenocarcinoma with chest pain. A: Axial enhance CT-scan obtained with soft tissue window shows a probable extension of the tumor (T) into the T3-4 neurovertebral foramen (*). B, C: unenhanced (B) and enhanced (C) axial T1-weighted MR image at the same level as (A) helps confirm that the mass (T) extends into the T3-4 neurovertebral foramen (*).

MRI are made around the tumor functional exploration including a whole body exploration. This functional exploration focuses on the specific cellular and vascular architecture of tumors using MRI spectroscopy, perfusion MRI and diffusion-weighted images (DWI). The image contrast of DWI is based on the diffusion properties of water molecules and reflects tissue parameters like cellular density especially in tumor and tissue architecture (5). In the last few years, DWI has been investigated successfully in many fields of oncology (6). In this review we present the contribution of MRI in lung cancer staging including the validated indications and the current development especially with DWI. Validated indication of MRI in lung cancer staging In the initial staging, MRI is the gold standard in the detection of brain metastases and the chest wall invasion especially of the superior sulcus tumor (7). It is also recommended in cases of suspected vertebral or epidural localization and in

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the characterization of suspected lesions of liver and adrenal. Superior sulcus tumor MRI advantages in the evaluation of superior sulcus tumor and determining their resectability include multiplanar capabilities, superior contrast resolution (compared with the other modalities), and lack of ionizing radiation (Fig. 1). MRI is superior to CT in the visualization of tumor extension to the chest wall, extending into the foramina and spinal canal, and the involvement of the brachial plexus (8-11). Although tumor invasion of these structures can be inferred scan data in many cases, MRI allows direct representation of participation and thus improve reader confidence (10). Disadvantages of MRI include its limited availability compared to that of CT, as well as longer time image acquisition and increased sensitivity to motion artifacts and patient claustrophobia. There have been a limited number of prospective studies, conducted in the late 1980s and early 1990s, with small number of patients in which the relative merits of CT and MR imaging of the superior sulcus were

compared (10-12). MRI in all these studies was superior to CT for the assessment of brachial plexus invasion related to the multiplanar MR imaging and contrast resolution. No data are available comparing multidetector CT and MR (7). MR imaging of superior sulcus tumors is performed by using a protocol described by Bruzzi et al. (7) using a modification of a previous protocol described by Demondion et al. (13, 14). This protocol includes axial, sagittal, and coronal T1weighted sequences and sagittal T2weighted sequence. To optimize sensitivity for the small structures in the thoracic inlet, such as the brachial plexus nerve roots and trunks, imaging is performed by using a neurovascular neck coil. T1-weighted sequences are acquired by using thin section (3.0 mm) with a minimal gap (< 0.3 mm) and both cardiac gating and respiratory triggering are used to minimize motion and pulsation artifact. Sagittal T1-weighted sequences provide the most detailed anatomic information and should be performed first in case imaging has to be interrupted or aborted, because the sagittal images alone may provide sufficient diagnostic information.

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A B Fig. 3. — A 58-year-old patient with lower left lobe non-small cell lung cancer. A: Coronal reformatting of axial STIR weighted images shows the spinal metastasis (arrow), the lower left lobe tumor (arrowhead) and the left pleural effusion. B, C: Coronal (B) and sagittal (C) reformatting of axial diffusion-weighted images (b = 1000 sec/mm2) show with a more marked way the abnormality of signal intensity of the spinal and the left lower lobe tumor. D: Sagittal T1-weighted image of the lumbar spine shows clearly the L1 spine involvement by the metastasis of the nonsmall lung cancer.

Indications of contrast medium are in patients in whom vascular invasion or intraforaminal extension is suspected to be present (Fig. 2); in patients who have undergone neoadjuvant therapy before a planned resection, in whom posttreatment fibrosis may result in blurring of the intermuscular fat planes and difficulty in visualizing the primary tumor; and in patients in whom a recurrence is suspected after definitive treatment (7). Brain metastases MRI of the brain is more sensitive and may be more specific for metastases than CT (15, 16). Cerebral metastases occur commonly in lung cancer, particularly from poorly differentiated tumors and adenocarcinoma. MRI with contrast enhancement is the image technique of

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D C

choice (17). It has particular advantages in showing lesions in the posterior fossa and adjacent to the skull. Given its overall higher sensitivity, MRI is therefore currently preferred over CT when screening patients with lung cancer for brain metastases. Liver metastases MR imaging with gadolinium chelates offers an accurate non-radiation based imaging test for detection of liver metastases (18). Liver specific MR contrast agents (hepatobiliary and reticuloendothelial agents) offer greater lesion-to-liver contrast than the conventional extracellular agents (gadolinium chelates). Liver specific MR contrast agents may be used in selected clinical situations when the goal is to achieve the highest detection rate for liver focal lesions, for

example, when a patient is being evaluated for curative liver resection (19). The diagnostic performance of DWI is equal to that of Gd-MRI. DWI alone can be used in patients where gadolinium contrast administration is not allowed. Combination of Gd-MRI and DWI significantly increases diagnostic accuracy (20). Bone metastases MRI is both sensitive and specific for diagnosing skeletal metastases (Fig. 3), and previous limitations have been overcome with the introduction of whole-body MRI (21, 22). Adrenal metastases The discovery of an adrenal gland mass more than 5 cm in the context of lung cancer most often corresponds to a metastatic lesion, except

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Fig. 4. — Bilateral adrenal adenomas in patient with lung cancer. A: Axial gradient-echo T1-weighted in-phase image shows a ilateral mass of adrenal gland (arrows) in high signal intensity. B: Axial gradient-echo T1-weighted out-phase image shows a b strongly decreased signal intensity (arrows) of both adrenal masses related to the presence of a fat component. C, D: Axial diffusion-weighted images (b = 1000 sec/mm2) with inverted grey scale (C) shows a persistence of signal (arrows) on both adrenal glands. The mean ADC value (D) of the left adrenal mass is 1.42 10-9 mm2/sec.

myelolipoma and adrenal cyst, the characteristics of their content, with fat for first and liquid for the second, are easily identified. The problem is especially for small lesions less than 3 cm and having a density enhancement after injection. In most cases, insofar as it is an initial assessment, no previous review is available. The problem of finding these adrenal lesions can be studied by the structural approach in differentiating benign and malignant lesions on the basis of the presence or absence of intracytoplasmic lipids. In benign lesions, lipids are observed, whereas in malignant lesions, the cells containing them are destroyed (Fig. 4). Chemical shift MRI uses a technique based on hydrogen and fat protons, which resonate at different frequencies. By using different time parameters during the same MRI examination, it is possible to identify lipid-rich adenomas. These adenomas show signal loss on outof-phase imaging, as opposed to im-

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aging when the protons are in phase. In contrast, nonadenomas do not show signal loss on out-of-phase imaging (23). Recent studies have shown that 60 to 89 percent of lesions measuring between 10 and 30 HU on unenhanced CT can be characterized using chemical shift MRI (24,25). Current development of MR in lung cancer Powered by tremendous advances in image quality over the past few years, diffusion-weighted imaging with or without background signal suppression has drawn strong interest from the radiologic community and major MR vendors. DW imaging is increasingly used in the thorax, particularly in lung nodules and masses, with promising results for lung nodule lesion detection and characterization. DW imaging can be easily implemented in clinical proto-

cols, as it can be performed relatively quickly (as short as two breath-hold acquisitions or during free breathing or with respiratory triggering) and does not require contrast agent injection, which makes it attractive in patients with decreased renal function, who cannot receive gadolinium-based contrast agents. This recent development of DW leads to other promising opportunities than the detection and characterization of pulmonary lesions, such as the initial staging of lung cancer with the TNM staging and to monitor treatment. Tissues characterization Tissue characterization in lung nodule or mass, likes other organs, stays a challenge even with the development of 18F-FDG PET/CT and the kinetic contrast enhancement using CT or MR. Some DWI MR studies focus on tumor detection and characterization of lung nodules or

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Table I. — Sensitivity, specificity, and accuracy of diffusion-weighted imaging on the diagnosis of lung nodules or masses. Authors

Year

MRI System

Study design

N° of patients

Nodules Malign / Benign

b s/mm2

Cutoff

Mori et al. (27)

2008

Achieva

Prospective

114

106/34

0 / 1000

1.1

0.7 (0.6-0.79)

Intera

Retrospective Consecutive

36/18

0 / 1000

0.89 0.61 0.80 (0.74-0.97) (0.36-0.83) (0.69-0.90)

Satoh et al. 2008 (30)

Sensibility Specificity (95% CI) (95% CI)

Accuracy (95% CI)

0.97 0.76 (0.84-1.00) (0.69-0.84)

Ohba et al. (29)

2009

Achieva

Retrospective Consecutive

110

96/28

0 / 1000

1.2

0.84 0.93 0.78 (0.74-0.91) (0.68-1.00) (0.71-0.85)

Uto et al. (33)

2009

Signa

Prospective

18/10

0 / 1000

0.834

0.72 0.10 0.5 (0.47-0.90) (0.00-0.45) (0.42-0.68)

Liu et al. (26)

2010

TwinSpeed Infinity

Retrospective Consecutive

54/12

0 / 500

1.4

0.83 0.74 0.7 (0.69-0.92) (0.45-0.92) (0.59-0.81)

Ohba et al. (28)

2011

Achieva (1.5T)

Prospective

58/18

0 / 1000

0.91 0.94 0.92 (0.84-0.99) (0.83-1.00) (0.86-0.98)

Ohba et al. (28)

2011

Achieva (3T)

Prospective

58/18

0 / 1000

1.85

0.90 0.94 0.91 (0.82-0.98) (0.83-1.00) (0.85-0.97)

Tondo et al. (32)

2011

Achieva

Retrospective

30/4

0 / 500 / 1000

1.25

0.90 1.00 0.91 (0.73-0.98) (0.40-1.00) (0.82-1.00)

Sommer et 2012 al. (31)

Avanto

Prospective

28 / 3

0 / 800

0.93 (0.84-1.00)

masses (26-33) (Table I). MR is as accurate as 18F-FDG PET/CT for nodule or masses characterization (Fig. 5). MR is more specific comparing to 18FFDG PET/CT in characterization of lung masses or mediastinal lymphadenopathies. In a recent meta-analysis on nodule or mass characterization Wu et al, confirm this assessment on showing that DWI is useful for differentiation between malignant and benign pulmonary nodules with pooled sensitivity of 0.84 and specificity of 0.84. Large-scale randomized controlled trials are still necessary to assess and confirm its clinical value. A threshold value for malignant/benign lesion classification could not be made based on this study because it is influenced by different b values, bias of patient selection, lesions’ pathological characteristics and ADC measurement. Selection of the threshold value should be determined according to the purpose of examination. A relatively higher threshold value may be recommended to minimize missing malignancy in lung cancer screening. If DWI is appended to other diagnostic method (e.g., computed tomography), a relatively lower threshold value may be recommended to reduce false-positive results.

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To go further in the characterization, Matoba et al. (34) reported the ADC value of lung cancer based on its histological type. This study covers only 30 lesions. ADC values of the means were 2.12+/-0.6 10-3mm2/sec (adenocarcinoma), 1.63+/-0.5 10-3mm2/sec (squamous cell carcinoma), 1.3+/-0.4 10-3mm2/ sec (large cell carcinoma) and 2.09+/0.3 10-3mm2/sec (small cell carcinoma) The value of the ADC adenocarcinomas was significantly higher that of squamous cell carcinomas and large cell carcinomas (p < 0.05). In addition to the value of the ADC well-differentiated adenocarcinomas (2.52+/-0.4 10-3mm2/sec) was significantly higher than that of poorly differentiated adenocarcinoma and squamous cell carcinoma. DWI has its place in some special situations to reduce the failure of transthoracic biopsy for large partially necrotic masses (direct biopsy area to which the cell density is highest, the lowest ADC) and differentiates atelectasis from tumor to show the target biopsy (Fig. 6). In the latter situation the DWI is more accurate than other sequences including T2weighted normal (35). MRI always keeps a place in the characterization of silicotic nodules of patients exposed to silica with no signal on T2-

0.5 (0-0-1.00)

0.89 (0.77-1.00)

weighted and diffusion while these nodules are associated with a high uptake in 18F-FDG PET/CT with SUV value greater than 10. Mediastinal and hilar nodal staging In patients with NSCLC, involvement of the mediastinal lymph nodes is an important prognostic factor because accurate disease staging is needed to limit surgery or multimodality treatment to only of those who might benefit from such treatment (Fig. 7). A recent meta-analysis (36) comparing 18F-FDG PET/CT to DWI showed that DWI has a high specificity for N staging of NSCLC compared with 18F-FDG PET/CT and has the potential to be a reliable alternative noninvasive imaging method for the preoperative staging of mediastinal and hilar lymph node in patients with NSCLC (37-41). However, they believe it is too early to call for broad application of this method in clinical practice. They speculate that additional improvement of the technology will increase its role in the future. Additional, larger, prospective, directly comparative studies involving 18 F-FDG PET/CT would be required to determine the true value of DWI for the diagnosis of lymph node metastasis in patients with NSCLC.

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Fig. 5. — Right upper lobe alveolar nodule in a 58-year-old smoker woman. A: Axial CT-scan on parenchymal window shows the alveolar nodule with spiculated margins. B- Axial TSE T2-weighted Fat sat with the PROPELLER technique image with respiratorygated shows clearly the nodule with high signal intensity and spiculated margins. C, D: Axial diffusion-weighted images (b = 1000 sec/mm2) with inverted grey scale (C) shows higher signal on the periphery. The mean ADC value (D) on the periphery is 1.13 10-9 mm2/sec. E- Fusion of both axial images of the TSE T2-weighted Fat sat with the PROPELLER technique and the diffusionweighted image (b = 1000 sec/mm2) shows the exact location of the high cellular area. F- Trans-thoracic needle biopsy directed toward the highest cell density area diagnoses an adenocarcinoma.

Table II. — Sensitivity, specificity, and accuracy of diffusion-weighted imaging on the mediastinal and hilar nodal staging. Authors

Year

MRI System

Study design

N° of patients

Lymph nodes Malign / Benign

b s/mm2

Cutoff

Sensibility Specificity (95% CI) (95% CI)

Accuracy (95% CI)

Hasegawa et al. (37)

2008

Achieva

Prospective

5/37

0 / 1000

0.8 0.97 (0.68-0.92) (0.92-1.03)

0.95 (0.87-1.02)

Nomori et al. (31, 39)

2008

Intera

Prospective

36/698

0 / 1000

1.6

0.67 (0.52-0.82)

0.99 (0.98-1.0)

0.98 (0.97-0.98)

Nakayama et al. (38)

2010

Avanto

Retrospective

13/54

50 / 1000

0.69 (0.58-0.80)

0.94 (0.88-1.0)

Chen et al. (42)

2010

Avanto

Retrospective Consecutive

97/38

0 / 1000

0.91 0.90 0.9 (0.87-0.95) (0.85-0.96) (0.85-0.96)

Ohno et al. (40)

2011

Achieva

Prospective

250

157/93

0 / 1000

2.5

0.75 (0.7-0.8)

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0.95 (0.93-0.97)

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value and signal intensity can be useful in the differentiation of malignant and benign mediastinal lymph nodes (39). DWI can be used in place of 18F-FDG PET/CT for N staging of NSCLC, especially in hospitals in which MRI examinations can be done but 18F-FDG PET/CT examinations cannot. M staging with Whole body MR including DWI

Fig. 6. — Right upper lobe mass in a 62-year-old woman. A: Axial enhanced CT scan shows the tumor (T) and sub-carinal lymphadenopathies (L). B: Axial T2-weighted TSE image with fat suppression and with the PROPELLER technique and respiratory-gated shows the tumor (T), the lymphadenopathy (L), and probably an obstructive pneumonitis. C: Axial diffusion-weighted images (b = 1000 sec/mm2) with inverse grey scale shows a hyper intense tumor and lymphadenopathy but there is no residual signal for lung collapse and obstructive pneumonia. D: Fusion of both axial images of the TSE T2-weighted Fat sat with the PROPELLER technique and the diffusion-weighted image (b = 1000 sec/mm2) shows the exact location of the high cellular area related to the tumor process.

Nomori et al. (39) reported that the accuracy of N staging in 88 patients was 0.89 with DWI, significantly greater than the value of 0.78 obtained with 18F-FDG PET/CT because of less overstaging in the former. The superiority of DWI can be explained by the observation that not only did DWI give fewer false-positive results for N staging of NSCLC

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than did 18F-FDG PET/CT (39), but also DWI gave fewer false-negative results for N staging of NSCLC than did 18F-FDG PET/CT. 18F-FDG PET/CT is likely to show false positive results when lymph nodes contain inflammation and is likely to show falsenegative results when the lymph nodes contain a small amount of cancer cells. The DWI with an ADC

Ohno et al. (21) prospectively compared whole-body DWI alone, whole-body DWI combined with conventional whole-body MRI, and 18 F-FDG PET/CT for M-stage assessment in 203 NSCLC patients. The final M-stage and metastasis of a given site were determined on the basis of the results of conventional radiologic, 18F-FDG PET/CT, and wholebody MRI examinations and on the basis of pathologic results from endoscopic, CT-guided, or surgical biopsies, as well as on the basis of the results of follow-up examinations performed on every patient for more than 12 mo. The area under the ROC curve of whole-body DWI (0.79) was significantly lower (P < 0.05) than that of 18F-FDG PET/CT (0.89). However, the area under the curve of whole-body DWI combined with conventional whole-body MRI (0.87) was not significantly different from that of 18F-FDG PET/CT. The authors concluded that whole-body MRI with DWI can be used for M-stage assessment in patients with NSCLC with accuracy (area under the curve, 0.87) as good as that of 18F-FDG PET/CT (area under the curve, 0.89). In a more recent study of Chen et al. (42), 62 lesions were considered as metastases based on initial findings, 37 distant metastatic lesions (brain, three; liver, six; adrenal gland, two; and bone, 26) and six lung metastatic lesions were validated by biopsy or radiologic follow-up. A total of 35 distant metastases were detected based on DWI. Three lesions of lung metastases, sized less than 10 mm, were not detected at DWI; there was one false-positive bone lesion with DWI. Meanwhile, 37 distant metastases were detected with 18FFDG PET/CT; five lung metastatic lesions were detected by 18F-FDG PET/CT. Only one lung metastatic lesion was missed and no false-positive result at 18F-FDG PET/CT. DWI was found to be sensitive in osseous metastasis. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for detection of metastasis for DWI

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were 0.9; 0.95; 0.97; 0.83 and 0.92 respectively. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for detection of metastasis for integrated 18F-FDG PET/CT were 0.98, 1; 1; 0.95 and 0.98 respectively.

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Fig. 7. — Left lower lobe non-small cell lung cancer in a 69-year-old patient. A: Axial diffusion-weighted image (b = 1000 sec/mm2) shows a high signal intensity lesion in the left supra clavicular area (arrow). Note artefacts related to this echo-planar imaging (arrowheads). B: Axial STIR T2-weighted image shows a high signal intensity lesion in the left supra clavicular area (arrow). C: Coronal reformatting of axial diffusion-weighted images (b = 1000 sec/mm2) shows clearly the left supra clavicular lymphadenopathy. D, E: A new lecture of axial image (D) and coronal reformatting (E) shows the supra clavicular lymphadenopathy.

Conclusion Major advances in the WB-MRI in the initial evaluation and follow-up of patients with lung cancer have been performed in recent years. Multicentric studies using different mag-

net systems are necessary to confirm these promising results. One thing is certain, for metastatic and lymph node staging, that whole-body MRI with the information obtained by WB-DWI and WB-MRI is greater than the scanner including staging and

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lymph node metastasis. Data comparing MRI whole body PET-CT are rare. The implementation of this technique requires a thorough knowledge of MRI, including the management of artifacts generated by echo-planar sequence. References 1. Ferlay J., Parkin D.M., SteliarovaFoucher E.: Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer, 2010, 46: 765-81. 2. Siegel R., Ward E., Brawley O., Jemal A.: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: a cancer journal for clinicians, 2011, 61: 212-236. 3. Aquino S.L., Kuester L.B., Muse V.V., Halpern E.F., Fischman A.J. Accuracy of transmission CT and FDG-PET in the detection of small pulmonary nodules with integrated PET/CT. Eur J Nucl Med and Mol Imag, 2006, 33: 692-696. 4. Roberts P.F., Follette D.M., von Haag D., Park J.A., Valk P.E., Pounds T.R., et al.: Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg, 2000, 70: 1154-1159. 5. Koh D.M., Collins D.J.: Diffusionweighted MRI in the body: applications and challenges in oncology. AJR, 2007, 188: 1622-1635. 6. Padhani A.R., Koh D.M., Collins D.J.: Whole-body diffusion-weighted MR imaging in cancer: current status and research directions. Radiology, 2011, 261: 700-718. 7. Bruzzi J.F., Komaki R., Walsh G.L., Truong M.T., Gladish G.W., Munden R.F., et al.: Imaging of non-small cell lung cancer of the superior sulcus: part 2: initial staging and assessment of resectability and therapeutic response. Radiographics, 2008, 28: 561572. 8. Takasugi J.E., Rapoport S., Shaw C.: Superior sulcus tumors: the role of imaging. J Thorac Imag., 1989, 4: 4148. 9. Beale R., Slater R., Hennington M., Keagy B.: Pancoast tumor: use of MRI for tumor staging. South Med J, 1992, 85: 1260-1263. 10. Heelan R.T., Demas B.E., Caravelli J.F., Martini N., Bains M.S., McCormack P.M., et al.: Superior sulcus tumors: CT and MR imaging. Radiology, 1989, 170: 637-641. 11. Rapoport S., Blair D.N., M cCarthy S.M., Desser T.S., Hammers L.W., Sostman H.D.: Brachial plexus: correlation of MR imaging with CT and pathologic findings. Radiology, 1988, 167: 161-165. 12. Iezzi A., Magarelli N., Carriero A., Podda P.F., Ciccotosto C., Bonomo L.: Staging of pulmonary apex tumors. Computerized tomography versus magnetic resonance. Radiologia Med, 1994, 88: 24-30. 13. Demondion X., Bacqueville E., Paul C., Duquesnoy B., Hachulla E., Cotten A.: Thoracic outlet: assess-

proceedings(tervuren)(nov.2012).indd 140

JBR–BTR, 2013, 96 (3) ment with MR imaging in asymptomatic and symptomatic populations. Radiology, 2003, 227: 461-468. 14. Demondion X., Boutry N., Drizenko A., Paul C., Francke JP., Cotten A.: Thoracic outlet: anatomic correlation with MR imaging. AJR, 2000, 175: 417-422. 15. Sze G., Shin J., Krol G., Johnson C., Liu D., Deck M.D.: Intraparenchymal brain metastases: MR imaging versus contrast-enhanced CT. Radiology, 1988, 168: 187-194. 16. Yokoi K., Kamiya N., Matsuguma H., Machida S., Hirose T., Mori K., et al.: Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest, 1999, 115: 714-719. 17. Sze G., Johnson C., Kawamura Y., Goldberg S.N., Lange R., Friedland R.J., et al.: Comparison of single- and triple-dose contrast material in the MR screening of brain metastases. AJNR, 1998, 19: 821-828. Namasivayam S., Martin D.R., 18. Saini S.: Imaging of liver metastases: MRI. Cancer Imag, 2007, 7: 2-9. 19. Morana G., Cugini C., Mucelli R.P.: Small liver lesions in oncologic patients: characterization with CT, MRI and contrast-enhanced US. Cancer Imag, 2008, 8 Spec No A: S13213. 20. Kenis C., Deckers F., De Foer B., Van Mieghem F., Van Laere S., Pouillon M.: Diagnosis of liver metastases: can diffusion-weighted imaging (DWI) be used as a stand alone sequence? Eur J Radiol, 2012, 81: 1016-1023. 21. Ohno Y., Koyama H., Onishi Y., Takenaka D., Nogami M., Yoshikawa T., et al.: Non-small cell lung cancer: whole-body MR examination for M-stage assessment – utility for whole-body diffusion weighted imaging compared with integrated FDG PET/CT. Radiology, 2008, 248: 643-654. 22. Takenaka D., Ohno Y., Matsumoto K., Aoyama N., Onishi Y., Koyama H., et al.: Detection of bone metastases in non-small cell lung cancer patients: comparison of whole-body diffusionweighted imaging (DWI), whole-body MR imaging without and with DWI, whole-body FDG-PET/CT, and bone scintigraphy. J Magn Reson Imaging, 2009, 30: 298-308. 23. Israel G.M., Korobkin M., Wang C., Hecht E.N., Krinsky G.A.: Comparison of unenhanced CT and chemical shift MRI in evaluating lipid-rich adrenal adenomas. AJR, 2004, 183: 215-219. 24. Haider M.A., Ghai S., Jhaveri K., Lockwood G.: Chemical shift MR imaging of hyperattenuating (> 10 HU) adrenal masses: does it still have a role? Radiology, 2004, 231: 711-716. 25. Yoh T., Hosono M., Komeya Y., Im S.W., Ashikaga R., Shimono T., et al.: Quantitative evaluation of norcholesterol scintigraphy, CT attenuation value, and chemical-shift MR imaging for characterizing adrenal adenomas. Ann Nucl Med, 2008, 22: 513-519. 26. Liu H., Liu Y., Yu T., Ye N.: Usefulness of diffusion-weighted MR imaging in the evaluation of pulmonary lesions. Eur Radiol, 2010, 20: 807-815.

27. Mori T., Nomori H., Ikeda K., Kawanaka K., Shiraishi S., Katahira K., et al.: Diffusion-weighted magnetic resonance imaging for diagnosing malignant pulmonary nodules/ masses: comparison with positron emission tomography. J Thorac Oncol, 2008, 3: 358-364. 28. Ohba Y., Nomori H., Mori T., S hiraishi K., Namimoto T., Katahira K.: Diffusion-weighted magnetic resonance for pulmonary nodules: 1.5 vs. 3 Tesla. Asian Cardiovascular Thorac Ann, 2011, 19: 108-114. 29. Ohba Y., Nomori H., Mori T., Ikeda K., Shibata H., Kobayashi H., et al.: Is diffusion-weighted magnetic resonance imaging superior to positron emission tomography with fludeoxyglucose F 18 in imaging non-small cell lung cancer? J Thorac Cardiovasc Surg, 2009, 138: 439-445. 30. Satoh S., Kitazume Y., Ohdama S., Kimula Y., Taura S., Endo Y.: Can malignant and benign pulmonary nodules be differentiated with diffusion-weighted MRI? AJR, 2008, 191: 464-470. 31. Sommer G., Wiese M., Winter L., Lenz C., Klarhofer M., Forrer F., et al.: Preoperative staging of non-smallcell lung cancer: comparison of wholebody diffusion-weighted magnetic resonance imaging and (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography. Eur Radiol, 2012, 22: 2859-2867. 32. Tondo F., Saponaro A., Stecco A., Lombardi M., Casadio C., Carriero A.: Role of diffusion-weighted imaging in the differential diagnosis of benign and malignant lesions of the chestmediastinum. Radiologia Med, 2011, 116: 720-733. 33. Uto T., Takehara Y., Nakamura Y., Naito T., Hashimoto D., Inui N., et al.: Higher sensitivity and specificity for diffusion-weighted imaging of malignant lung lesions without apparent diffusion coefficient quantification. Radiology, 2009, 252: 247-254. 34. Matoba M., Tonami H., Kondou T., Yokota H., Higashi K., Toga H., et al.: Lung carcinoma: diffusion-weighted mr imaging--preliminary evaluation with apparent diffusion coefficient. Radiology, 2007, 243: 570-577. 35. Qi L.P., Zhang X.P., Tang L., Li J., Sun Y.S., Zhu G.Y.: Using diffusionweighted MR imaging for tumor detection in the collapsed lung: a preliminary study. Eur Radiol, 2009, 19: 333-341. 36. Wu L.M., Xu J.R., Gu H.Y., Hua J., Chen J., Zhang W., et al.: Preoperative mediastinal and hilar nodal staging with diffusion-weighted magnetic resonance imaging and fluorodeoxyglucose positron emission tomography/computed tomography in patients with non-small-cell lung cancer: Which is better? J Surg Research, 2012, 178: 304-314. I., Boiselle P.M., 37. Hasegawa Kuwabara K., Sawafuji M., S ugiura H.: Mediastinal lymph nodes in patients with non-small cell lung cancer: preliminary experience with diffusionweighted MR imaging. J Thorac Imag, 2008, 23: 157-161.

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38. Nakayama J., Miyasaka K., Omatsu T., Onodera Y., Terae S., Matsuno Y., et al.: Metastases in mediastinal and hilar lymph nodes in patients with non-small cell lung cancer: quantitative assessment with diffusionweighted magnetic resonance imaging and apparent diffusion coefficient. J Comput Assist Tomogr, 2010, 34: 1-8. 39. Nomori H., Mori T., Ikeda K., Kawanaka K., Shiraishi S., Katahira K., et al.: Diffusion-weighted magnetic resonance imaging can be used in

place of positron emission tomography for N staging of non-small cell lung cancer with fewer false-positive results. J Thorac Cardiovasc Surg, 2008, 135: 816-822. 40. Ohno Y., Koyama H., Yoshikawa T., Nishio M., Aoyama N., Onishi Y., et al.: N stage disease in patients with non-small cell lung cancer: efficacy of quantitative and qualitative assessment with STIR turbo spinecho imaging, diffusion-weighted MR imaging, and fluorodeoxyglucose PET/CT. Radiology, 2011, 261: 605-615.

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41. Usuda K., Zhao X.T., Sagawa M., Matoba M., Kuginuki Y., T aniguchi M., et al.: Diffusion-weighted imaging is superior to positron emission tomo graphy in the detection and nodal assessment of lung cancers. Ann Thorac Surg, 2011, 91: 1689-1695. 42. Chen W., Jian W., Li H.T., Li C., Zhang Y.K., Xie B., et al.: Whole-body diffusion-weighted imaging vs. FDGPET for the detection of non-smallcell lung cancer. How do they measure up? Magn Reson Imaging, 2010, 28: 613-620.

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PERCUTANEOUS ABLATION OF MALIGNANT THORACIC TUMORS* B. Ghaye1 Lung cancer is the leading cause of death related to cancer. Fifteen to thirty percent of patients with a localized lung cancer are actually inoperable as they present with poor general condition, limited cardiopulmonary function, or a too high surgical risk. Therefore, minimally invasive treatments are needed and percutaneous ablation seems an attractive option. Thermal ablation can be performed by delivering heat (radiofrequency, microwave, laser) or cold (cryotherapy) through a needle inserted into the tumor under CT guidance. The ideal lesion is less than 2 or 3 cm in diameter. Success of percutaneous thermal ablation appears to be close to those of surgery for localized lung cancer. Nevertheless studies are still needed to definitely assess the role of ablation compared to other emerging techniques, as stereo tactic radiotherapy as well as potential synergy with other treatments. Key-word: Lung neoplasms, therapy.

Lung cancer is the leading cause of death related to cancer and accounted for 29% of cancer deaths in the U.S. in 2009 (1). Eighty percent of lung cancers are non-small cell lung cancer-type (NSCLC). Surgical treatment combining lobectomy or pneumonectomy and hilar and/or mediastinal lymphadenectomy remains the only proven curative treatment of stage I-II NSCLC. However, 15-30% of patients may not benefit from surgery, most often due to poor general condition, comorbid cardiopulmonary disease as insufficient pulmonary reserve, or a high surgical risk (1-5). The lungs are the second most frequent site of metastases of extrapulmonary cancers after the lymphatic system. The lungs are the only site of metastasis in approximately 20% of patients after resection of the primitive neoplastic lesion. When the number of lung metastases is limited, their surgical resection is associated with improved survival (1). Unfortunately, as the same exclusion criteria for surgery mentioned above also apply, alternative therapies must be considered, including external beam radiation therapy with or without chemotherapy, improving modestly survival, often with significant toxicity to the patient (2, 3). Therefore, minimally invasive treatments are needed and percutaneous ablation seems an attractive option. After preliminary studies on the electrochemical polarization of cancers, new percutaneous therapeutic modalities have emerged, including percutaneous brachytherapy (6) and thermal ablation of tumors by radiofrequency (RF) or other sources of energy (7). Thermal ablation is currently used to treat focal

malignant lesions located in the liver, kidney, breast, thyroid, head and neck, chest and bones, acting as a substitute or adjunct to other therapeutic modalities (8). Percutaneous thermal ablation is a technique that seems particularly well suited to treat lung tumors, the insulating effect of air in normal lung tissue surrounding the lesion acting like an oven by concentrating the heat in the target tumor (9). Therefore, for a given level of energy, the ablation volume is wider in the lung than in other soft tissues. Moreover, the normal lung parenchyma heals quickly after a thermal injury, and damage to surrounding healthy lung is consequently minimal (9). Theoretically, the main advantages of percutaneous thermal ablation techniques include: relative sparing of healthy tissue which is important to treat patients with reduced cardiopulmonary reserve, reduced morbidity and mortality, faster recovery and earlier discharge from hospital, lower cost, possibility of outpatient treatment, potential synergy with other treatments, and possibility to repeat ablation sessions on the same lesion (10). Types of energy Thermal ablation of tumors located in the lung, chest wall, pleura or mediastinum has been safely performed under CT guidance, mainly with the RF energy so far. Other energy sources are available, including microwave, cryoablation and laser (2, 7, 10, 11). The type of energy that can be used will depend on the patient, location and nature of the tumor, treatment goal, and operator experience or preference.

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Department of Radiology, Cliniques Universitaires St Luc, Catholic University of Louvain, Brussels, Belgium.

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Radiofrequency The RF energy used in tissue ablation is a sinusoidal current from 400 to 500 kHz issued by an electrode/ needle positioned in the target lesion. The RF ablation (RFA) probe acts as the cathode of an electrical circuit that is closed by dispersive electrodes applied on the patient’s thighs (unipolar system). On a few millimeters around the needle, the ionic agitation resulting from the alternating current produces a resistive heating by friction between the molecules. The heat is then transmitted by thermal conduction to the surrounding tissues, causing coagulation necrosis within 1 to 2 cm. The goal is to increase tissue temperature between 50 and 100°C for 4-6 minutes, which is sufficient to cause irreversible cell damage. In contrast, temperature above 105°C causes boiling, vaporization and carbonization of tissue which, by increasing the impedance, decrease the transmission of energy and thereby the size of the ablated area. Therefore manufacturers had to commercialize various types of RFA devices to overcome this limitation and to increase the size of the ablation zone. Some needle designs allow deployment of the tip into multiple electrodes in a “umbrella” – or “bouquet of flowers” – like mode, allowing a larger volume of thermal injury, which can reach up to 5 cm in dia meter (8) (Fig. 1). Other devices or technical algorithms allow ing larger thermal injury have also been developed, including needles having an internal cooling and allowing RF e nergy administration without reaching 100°C in contact of the needle, pulsed RF energy administration, or injection of saline into the lesion (3, 8) (Fig. 1, 2). When treating a large lesion, it may be necessary to use multiple needles, which had to be a ctivated sequentially rather than

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C F

D s imultaneously, or to reposition sequentially a single needle to encompass treatment of the whole lesion. While hypoxia and low blood flow in the center of a necrotic tumor generally render cells more resistant to radiotherapy and chemotherapy on the one hand, they are responsible for a greater sensitivity to RFA on the other hand, as the dissipation of heat is decreased (12, 13). At the opposite, the presence of vessels around the lesion, particularly when

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Fig. 1. — Examples of devices for percutaneous ablation. A, B: RF ablation system with 1 or 3 straight electrode needles having a shaft internally cooled by chilled fluid (Cool-tip, Valleylab, Tyco Healthcare). C: RF ablation system deployable in a “bouquet of flower”-type. Each of 8-12 side electrodes is provided with a system measuring the temperature of tissues. The size of the ablation zone will depend on the degree of deployment of the side electrodes (Starburst, AngioDynamics Rita). D: RF ablation system with 10 electrode needles deployable to form an “umbrella” of 4 to 5 cm in diameter (LeVeen, Boston Scientifics). (E, F) MW ablation system. Note the different shape of the ablation zone between the devices with 1 or 3 straight antennas (MWA Evident, Covidien).

larger than 3 mm in diameter, or of large caliber bronchi of more than 2 cm, is responsible for local heat dissipation by thermal conductivity (this is called the “heat-sink effect”) that may cause persistence of nonablated tissue and treatment failure (Fig. 3). Patients having pacemaker/defibrillator, or other metallic implants should not be treated with RFA, although this type of energy can theoretically be applied if the implanted device is controlled by a

cardiologist (14, 15). Bipolar systems having two active electrodes inserted into the lesion are now commercially available, overcoming the need for dispersive skin electrodes. Microwave Thermal ablation by microwave (MW) is a more recent technique using an electromagnetic energy from 900 to 2450 MHz frequencies that increases the temperature of tissue by stirring the molecules of water (10)

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C Fig. 2. — Radiofrequency ablation. A: Preablation CT image shows a 14 mm squamous cell lung carcinoma (arrow) in the left upper lobe. B: Perprocedure CT image shows a single straight Cool-tip needle transfixing the lesion (arrow). C: Control CT image obtained at the end of the procedure shows a slight groundglass halo (arrow) of 10 mm thickness around the lesion. Note also a small pneumothorax (arrowhead).

B (Fig. 4). The electromagnetic nature of the MW overcomes the problems due to impedance increase secondary to tissue carbonization that may be observed with RFA, and results in a larger ablation volume and safety margins (16). MW ablation (MWA) is therefore less sensitive to the heatsink effect than RFA, as higher temperature can be reached (up to 150°C), but this may be associated with an increased risk of vascular thrombosis (17). Other advantages of MWA are faster rise of temperature, a more spherical pattern of ablation, ability to activate multiple antennas simultaneously, reduced procedure time, no risk of skin burn on the thighs (no dispersion electrode)

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Fig. 3. — Heat-sink effect. Squamous cell lung carcinoma in the left upper lobe treated with RFA using a Cool-tip needle. Coronal reformat in mediastinal window shows that the margins of ablation are oval in shape. Safety margins at the upper and lower portions of the lesion (long arrows) are flattened and thinner when compared to the internal and lateral margins (arrowheads). This is due to the presence of vessels above and below the lesion, that are responsible for heat loss (heat-sink effect) and potentially resulting in incomplete ablation in those areas.

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B Fig. 4. — Microwave ablation. Left lower lobe metastasis from an osteosarcoma of the lower limb. A: The lesion (arrow) is transfixed by the straight MW antenna. B: Control CT image obtained at one month after ablation shows a larger thermolesion when compared to (a). Note small bubble-like lucencies inside the lesion. C. Control CT image obtained at 3 months in mediastinal window and after IV contrast medium administration shows a non enhancing lesion that is smaller compared to B. D. Followup PET-CT images at 6 months show no FDG uptake and no sign of recurrence in the ablation area.

MWA would therefore be an ideal technique in case of lesion that is more than 4 cm in diameter, in contact with vessels larger than 3 mm in diameter, in patients with limited respiratory function, or in case of recurrence after thermal ablation performed by another type of energy (18). Cryoablation

D and less pain when tumor is in contact or located in the chest wall. There is also no interference with electromagnetic waves used in MRI, allowing real-time monitoring of

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treatment efficacy under MR. Interference with pacemakers/defibrillators are also less important provided that the treatment area is more than 5 cm away from the heart.

Cryoablation is tissue ablation using cold, a temperature drop of at least -20 to -25°C being lethal for tissues. Cryoablation provides a wide ablation zone in a short time, through various direct and indirect mechanisms, including protein denaturation, breakdown of extra-and intracellular membranes, and ischemia. The treatment can be monitored in real time under US, CT or MR, through visualization of the ice ball whose outer boundary corresponds to the 0°C isotherm, while the isotherm -20°C is located approximately 5 mm inside the latter (19). However, whereas the ice ball is clearly identifiable in the chest wall or mediastinum on CT, it may be less visible in the lung parenchyma because of the

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nary (22). Advantages over other ablation techniques would be absence of sensitivity to the heat-sink effect, a shorter treatment time and less fibrous scarring (23). High intensity focused ultrasounds are another ablation technique, but not used in the thorax so far. Indications

Fig. 5. — Cryoablation. Cryoablation of a painful metastasis invading the chest wall. The margins of the oval ice ball are perfectly delineated allowing to check the proper covering of the tumor and to control the safety gap with adjacent vulnerable tissues, including the spinal cord. For optimal thermal protection of the spinal cord, thermosensors were inserted into the foramina and insulation of the spinal canal was achieved with epidural CO2 dissection (not shown). Courtesy from Afshin Gangi, University Hospital of Strasbourg, France.

low density of air around the thermolesion (Fig. 5). The anesthetic effect of cold on tissues and nerves is a prominent advantage, making the technique particularly suitable for the treatment of lesions located in the chest wall or close to the pleura (11). Finally, the associated antitumoral immune response would be more important than for other ablation techniques, and preservation of tissue architecture allows better cellular repopulation of healthy peritumoral tissues. However, cryoablation carries an increased risk of bleeding, because it has no cauterization effect on the vessels. When frozen, a lesion is more susceptible to trauma and can fracture. The increased risk of bleeding must be considered in patients with precarious lung function (20). Similar to the heat-sink effect for RF, the technique is susceptible to a cold-sink effect by blood flow through vessels larger than 3 mm in diameter. Though the experience is still limited in the thorax, cryoablation seems a safe technique in case of parietal lesion or peripheral pulmonary lesion (21). Laser Laser interstitial thermotherapy (LITT) delivers a high energy laser ra-

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diation (Nd:YAG laser) into the tumor via optical fibers. The tip of the fibers is terminated by a diffuser that emits laser light on an effective distance of 12 to 15 mm (17). Since heat diffuses slowly towards the periphery of the lesion, an exposure time of 10 to 30 minutes is required, depending on the size of the lesion, to obtain a sufficiently high temperature to induce a coagulation necrosis. The technique is not currently widely used in the thorax despite reported results close to ablation with other types of energy, probably because of the complexity of the procedure and the higher caliber of the material. The main advantages of LITT versus RFA are the independence from tissue impedance, the possibility to monitor the procedure in real time under MR, and less aggression to surrounding tissues. Others Irreversible electroporation is a new non-thermal ablation technique, creating permanent pores in cell membranes, leading to cellular deregulation and apoptosis. It uses a high voltage electric current, requiring general anesthesia and cardiac monitoring. The application of this technique in the lung is still prelimi-

The therapeutic approach to any tumoral lesion must be discussed in multidisciplinary oncologic meetings, the respective roles of each therapy evolving continually according to their own progress. It is important to emphasize that, similar to surgery, ablation provides only a local control of the disease. The main indications for ablation are stage I or II NSCLC and recurrent or limited pulmonary metastatic disease in patients that are inoperable or refuse surgery. In case of NSCLC, surgery should always be offered as firstline, lobectomy with lymph node revision being superior to sub-lobar resection and therefore ipso facto to percutaneous ablation (3). Regarding metastasis, nature of the primary cancer and its local control are important factors to consider. Thus, as for surgery, metastatic colorectal cancer and sarcoma are among the most suited conditions for ablation. The maximal number of metastasis that can be ablated is not strictly defined, varying from three to six according to the majority of the authors. The ideal target lesion for ablation is a lesion measuring less than 3 cm diameter, and not in contact with large vessels or bronchi, mediastinum and chest wall (2, 13, 24-30). More uncommon indications are reported in the literature, including palliation of symptoms such as pain, cough or hemoptysis, recurrent disease in a radiation field, or tumor debulking (2, 3, 14, 28, 31-34) (Fig. 5). Contraindications The contraindications are basically the same as for percutaneous transthoracic biopsy (PTTB). Coagulation disorders must absolutely be controlled. Severely reduced pulmonary reserve (FEV1 < 0.6 L), single lung or pulmonary hypertension are not absolute contraindications (3, 35) (Fig. 6). General anesthesia or deep conscious sedation can solve problems in non-cooperative patients or patients presenting with intractable cough. An acute pneumonia in contact with the tumor must

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Fig. 6. — Tumor ablation in a patient with single lung. MW ablation of a 7 mm squamous cell carcinoma in left lower lobe in a patient who underwent right pneumonectomy for stage IIIa NSCLC several years earlier. Follow-up CT image at 1 month after the procedure shows a target pattern of the thermolesion, showing from center to periphery: the ghost of the tumor, a halo of ground glass representing the safety margins of ablation, and a dense rim of inflammatory tissue. There was neither complication nor recurrence of the treated lesion at follow-up.

be treated before ablation in order to prevent the spread of the thermal injury to non-tumoral lung (2). Ideally, patients with pacemakers / pacemaker should better be treated with cryoablation or MW, which have less interferences than RF on these devices. Procedure Confirmation of the tumoral nature of the target lesion should be obtained before planning the procedure. Whatever the type of energy used, the procedure is usually performed under conscious sedation or general anesthesia, depending on the patient, type of lesion and the choice or experience of the operator (10, 11, 19). At the minimum, the patient is put under oxygen administration with continuous monitoring of cardiorespiratory parameters. When using RF, a minimum of two dispersive electrodes are carefully pasted on the thighs. The parietal pleura is anesthetized and systemic analgesics are administered, as thermal ablation of parietal lesions or close to the pleura can be painful during or after the procedure. When treating a lung tumor close to the pleura, an artificial pneumothorax can be obtained to reduce the pain (36) (Fig. 7). Precautions, technical ease and procedure of the needle/antenna placement are similar to those of

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PTTB (37). When multiple needles are needed to treat the whole lesion, they should all be correctly positioned in the target before applying any power to any needle. Their precise deployment is greatly facilitated by the use of fluoro-CT, and optimal positioning relative to the lesion and non-target organs should be confirmed by MPR views (38). Duration and number of treatment applications depend first on the type of energy system used, and secondly on the size and morphology of the target lesion. The shape of each ablation zone is specific to each device and is generally oval in the axis or perpendicular to the axis of the needle. The criteria for treatment success vary from one system to another, some being based on an abrupt increase of impedance (rolloff), while others are based on the intratumoral temperature (70°C ideally). Similar to surgical margins, it is of utmost important to ablate an area of healthy tissue around the lesion. Systematic margins of 0.8 to 1.0 cm are recommended since microscopic extension around of the lesion cannot be predicted based on CT images. Those margins appear as a rim of ground-glass that corresponds to the combination of coagulation necrosis, inflammation, congestion and pulmonary hemorrhage (Fig. 2, 3, 6, 7 and 8). This rim should be correctly identified in all three di-

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mensions (Fig. 3 and 8). Studies have reported more than 80% of treatment failure when the rim of ground-glass was not identified on control CT (39, 40). When the total area of the thermal injury is four times that of the tumor, the success rate of complete necrosis is 96% whereas it falls to 80% if this proportion is not reached (41). Similarly, when the ablation volume is more than three times the tumor volume, tumor destruction is complete in 83% against 61% when this proportion is not reached (27). If the lesion is in contact or near the mediastinum, particularly when close to vascular structures, a heatsink effect can occur. Contact with vessels larger than 3 mm or large caliber bronchi should encourage the use of MW or cryoablation that are less sensitive to heat-sink effect than RF. When necessary, an iatrogenic pneumothorax can be created to separate the tumor from the heart or great vessels. On the other hand, esophagus, trachea and nerves (mediastinal and parietal, particularly the brachial plexus) are sensitive to thermal ablation, and hydrodissection using glucose fluid or CO2 dissection can be performed to isolate the sensitive structures from the heat source. Finally, skin tissue at the puncture site should always be controlled, as they are also sensitive to thermal damage. When treating a superficial lesion, mechanisms of local cooling or heating depending on the type of energy should be used to protect them. At the end of treatment, some devices allow a cauterization of the intrapulmonary needle tract to reduce the risk of bleeding, pneumothorax, and especially of tumor dissemination. The patient is monitored afterwards in the recovery room. A chest radiograph is obtained 2 to 4 hours after the intervention. Painkillers will be administered on demand, and anti-inflammatory drugs are often administrated to prevent the postablation syndrome. Prophylactic administration of antibiotics is controversial. Depending on the type of anesthesia, patients are discharged from hospital either on the same day, either 24 or 48 hours later. Results Primary tumors Complete ablation rate was around 90% in a review of the literature

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A B Fig. 7. — Sensitive structures isolation. A: Preablation CT image shows a 15 mm adenocarcinoma (arrow) close to the pleura in the left upper lobe. B: Apparition of a self-limited pneumothorax after insertion of the MW antenna. This iatrogenic complication had the benefit of holding the site of ablation off the sensitive parietal pleura and chest wall, and thus protecting against per- and post-procedural pain. Note ground-glass halo surrounding the treated lesion. C: Control CT image obtained at 3 months shows a smaller and denser lesion compared to B, also showing more angular contours. Note a small cavitation in the right part and aerated ghost path positions of the MW antenna in the left part of the lesion.

close to those of surgery, keeping in mind that the majority of the treated patients presents with contraindications to surgery (Table I). Pulmonary metastases

including 17 series (4). Comparison of results across studies is difficult due to the heterogeneity of populations, tumor characteristics, ablation techniques and devices (ablation alone or combined with chemotherapy), and lack of standardization of response criteria and monitoring. Most studies show a significantly inferior rate of complete ablation when

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the tumor exceeds 2 or 3 cm in diameter (2, 3, 13, 24-30, 41, 42). Survival data after ablation are not yet mature, the technique still being too recent. Surgery is the treatment of choice for stage I and II NSCLC with a survival rate of 75% and 50%, respectively. Early results of percutaneous ablation treatment of stage I and II NSCLC appear to be

After surgical resection, survival of patients with pulmonary metastases is 36, 26 and 22% at 5 years, 10 years and 15 years, respectively. In case of incomplete resection, survival drops to 13 and 7% at 5 and 10 years, respectively (43). After percutaneous ablation of pulmonary metastatic lesions, the survival is 64 to 78% at 2 years and 27 to 57% at 5 years (26, 29, 30, 41, 44) (Table II). Results are significantly higher in case of c ombined ablation / chemotherapy than chemotherapy alone (87 versus 33%) (45). The overall results of percutaneous ablation are difficult to compare with those of other therapies, particularly surgery, due to differences in patient population. Indeed, the vast

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B Fig. 8. — Radiofrequency ablation. A. Preablation CT image shows a 12 mm adenocarcinoma (arrow) close to the fissure in the left upper lobe. B. Perprocedure CT image shows a halo of ground-glass thicker than 8 mm surrounding the treated lesion, indicating probable complete necrosis of the lesion. C: Followup CT coronal reformat shows the target-pattern of the ablated zone. Such aspect has to be demonstrated in all 3 dimensions to ensure successful treatment of the lesion.

After ablation, cancer-related survival is the order of 83-93% at 1 year, 68-75% at 2 years and 59-61% at 3 years (25, 47, 48). Prospective controlled studies are still needed to definitely assess the role of ablation. Studies are also needed to investigate the theoretical synergistic effects of combining percutaneous ablation and radiotherapy, including stereotactic radiotherapy (42, 49). For stage I and II tumor, the first studies of such combined treatments reported a survival of 87, 70 and 57% at 1, 2 and 3 years, respectively, that may be superior than after percutaneous ablation alone (2, 13, 28). The addition of chemotherapy to percutaneous ablation seems also to increase survival in patients with NSCLC.

C majority of patients treated with ablation have contraindications to other treatments, which makes the results of ablative therapy even more

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Complications encouraging. Repeated ablations improve local control in patients showing a persistence of viable tumor tissue (2, 25, 46).

Percutaneous ablation procedures are well tolerated in the hands of an experienced operator. Complications are usually minor and major

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Table I. — Percutaneous ablation of NSCLC. Patients

Lesions

Mean size (cm) 2,7 ± 1,3

Akeboshi (24) Grieco (13) De Baère (41)

2004 2006 2006

RF RF* RF

10 37 9

Simon (28) Pennathur (61) Hiraki (62) Lencioni (47) Wolf** (48) Lanuti (42) Ambrogi (25)

2007 2007 2007 2008 2008 2009 2011

RF RF RF RF MW RF RF

75 19 20 33 50 31 57

Global survival (%) 1y 89 87

82 34 59

2,7 2,6 2,4 1,7 3,5 ± 1,6 2 2,6

78 95 90 70 65 85 83

70 76 (18 months) 57 68

74 48 55 78 62

45 47 40

* + Radiotherapy. ** Includes NSCLC and metastases.

Table II. — Percutaneous ablation of lung metastases. Patients

Lesions 41

Mean size (cm)

Akeboshi (24) Yan (30) De Baère* (41)

2004 2006 2006

RF RF RF

21 55 51

2,7 ± 1,3 2,1 ± 1,1 1,7 ± 0,9

Simon (28) Yamakado (29) Wolf** (48) Lencioni (47) Gilliams (26) Rosenberg (44) Pallusière** (56)

2007 2007 2008 2008 2008 2009 2011

RF RF MW RF RF LITT RF

18 71 50 73 37 64 189

28 155 82 150 72 108 350

2,7 2,4 ± 1,3 3,5 ± 1,6 1,7 1,8 2 1,5

Global survival (%) 1y 84 85

64 71 (18 months) 87 78 84 62 65 55 89-92 64-66 81

59 72

57 46 45

44 60

44 51

* Includes nine patients with NSCLC. ** Includes NSCLC and metastases.

complication rate is seen in less than 10% (3, 50, 37). A mortality rate from 0.4 to 2.6% is reported, most often due to bleeding, pulmonary sepsis, ARDS, heart failure, or pulmonary embolism (4, 28, 40, 50). Although the procedure is well tolerated, the patient may present with mild to moderate pain ([2, 38). Cryotherapy has the advantage of being less painful than the techniques using heat when treating peripheral or parietal lesions. Pneumothorax is the most common minor complication (10-50%) (Fig. 2, 7 and 9). Risk factors and prevention are similar to those of PTTB. The rate of chest drainage is also similar to that reported after PTTB (10-30%) (3, 40).

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Post-ablation syndrome, presenting with fever, cough, chills, vomiting and malaise, is reported in up to one third of cases and may last from 1 to 7 days. Treatment is strictly symptomatic. The need for prophylactic antibiotics administrated just before the intervention and during the next 5 days is still controversial. Some authors recommend it particularly in patients with prosthetic heart valve or artificial joints (21). Pneumonia is reported in up to 22% of cases, most often in cases of tumor in a central location, associated with retro-obstructive pneumonia, or in case of underlying chronic lung disease (3, 21). Intraparenchymal hemorrhage is uncommon and more generally due

to the manipulation of the needle than the thermal ablation itself, since it has a cauterizing effect (with the exception of cryotherapy). Minor hemoptysis is reported in 15% of cases; major bleeding is more often reported when treating lesions close to hilum. Pleural effusion, usually of small volume and self-limited, can occur in case of peripheral lesion (40). Larger or long-lasting effusion should suggest a more serious condition as a hemothorax or an empyema. Bronchopleural fistula occurs in less than 1% of procedures but may be difficult to resolve (Fig. 9). Among exceptional complications, gas cerebral embolism (51, 52) and needle-tract tumor seeding must be

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Fig. 9. — Bronchopleural fistula. Patient with past-history of multiple sequential lung metastases from a renal cancer. He underwent serial lobectomy and multiple surgical wedge resections. A few years later, two new metastases were ablated using a Cool-tip RF device. In the recovery room, the patient presented with an episode of carbonarcosis requiring positive pressure ventilation. A bronchopleural fistula developed and was responsible for right pneumothorax and parietal emphysema that took 3 weeks to recover. Control CT image shows the fistula (arrow) between a bronchus and the cavitated treated lesion. Note a small remaining pneumothorax (arrowhead).

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entioned m (53). Micro-emboli of gas, detectable by carotid US, have no neurological impact (3). A careful technique should reduce the risk of tumor dissemination during the procedure (17). Despite a possible transient decrease d uring the first 3 weeks after ablation, the overall respiratory function tested at 3, 6 or 12 months after the intervention shows no degradation (25, 41, 42, 47).

Fig. 10. — Cavitation and linear scar after ablation. A: Control CT image performed 1 month after ablation shows an asymptomatic cavitation after ablation of a squamous cell lung cancer of the left upper lobe. Follow-up was uneventful. B: Control coronal CT coronal reformat obtained at 10 months shows a simple linear scar (arrow). PET-CT showed no FDG uptake (not shown).

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Fig. 11. — Inflammatory reaction around the ablation zone. Patient with past-history of metastatic colo-rectal cancer who underwent multiple wedge resections in both lungs. Recurrence was demonstrated at the site of a pulmonary resection in the right upper lobe and was treated wit Cool-tip RF ablation. Control CT image at 2 months after ablation shows absence of enhancement in the center of the thermolesion, some gas bubbles and regular enhancing peripheral rim corresponding to an inflammatory reaction. The high density structures in the center of the lesion correspond to surgical staples. Further follow-up shows cavitation of the lesion without any recurrence.

Follow-up Early detection of residual or recurrent tumor is crucial for proper management of the patient, possibly resulting in a new session of ablation. Follow-up imaging of ablation is difficult and must be known by all interventional and non-interventional radiologists. Mainly contrast-enhanced CT and PET-CT are used for the follow-up. The lesion size alone is not considered as a reliable criterion of complete necrosis during the first 6-12 months. Consequently RECIST is rarely used after ablation and follow-up evaluation criteria should be adapted to the ablation technique (54). Overablation technique to obtain safety margins and inflammation secondary to thermal injury result in a thermolesion larger than the target tumor (Fig 4, 7 and 8). The maximum size is reached within 24 to 48 hours or during the first week after ablation, although growth in the next few weeks has been reported (55). Subsequently, the lesion re-

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mains stable or decreases in size, but the parameters of shrinking are not established so far (2). Any increase in size after one week and a fortiori 3 or 6 months after ablation should indicate tumor recurrence. While retracting, the lesion shows more angular contours, leaving eventually a linear scar (Fig. 7 and 10). The final sequella may however remain nodular, especially if the target lesion was initially larger than 2 cm, and sometimes even larger than the initial lesion (21, 56). Enhancement after IV injection of contrast medium should also be evaluated, as an area of complete necrosis theoretically shows no contrast uptake. Enhancement greater than 10-15 HU or more than 50% of the enhancement of the target lesion before ablation should be suspicious of recurrence, especially when nodular, central, irregular or eccentric, or in contact with a vessel. Enhancement of inflammatory granulation tissue around the ablation zone can be seen as a peripheral rim during the first 6 months (Fig. 11). Bubble-

like lucencies or cavitation in the lesion, usually asymptomatic and considered as a sign of good prognosis, can be visible in 30 to 50% of cases (Fig. 10 and 11). Cavitation usually disappears after 6-9 months (48, 55, 56). Finally, inflammatory hilar and mediastinal lymphadenopathies may appear during the first 3 months and then regress from 6-month (21). It is important to note that the gradual evolution of the ablation lesion to a fibrous linear scar, cavitation or atelectasis does not exclude the possibility of a subsequent local recurrence, emphasizing the importance of a continuous follow-up (56). CT morphological analysis has limitations as an incomplete treatment may only be depicted after several months of follow-up in some cases (41, 56). MRI could better appreciate an early recurrence thanks to its superior contrast resolution (7, 14, 21). Experimental results of diffusion MRI seem particularly promising by detecting recurrences within 3 days after ablation (57). PET-CT is more sensitive than CT alone in detecting residual tumor or recurrence in oncologic practice (24). The role of PET-CT in the early period after ablation, however, is debated in the literature. While some authors suggest its utility for the early detection of recurrence (12 to 24 hours), false positive results due to local inflammation or lymph nodes that may be found in 10-20% of cases suggest that PET-CT should better be obtained 3 to 6 months after treatment (21, 58, 59) (Fig. 4). Various follow-up algorithms are proposed in the literature. In practice, as an example, CT is often performed at 24 hours, 1 month, and then every 3 months during the first year and every 6 months during the second year. CT will be combined with PET at 3- or 6-month, then every 6 months, or when CT is equivocal. Future Percutaneous ablation is still currently considered as a standalone technique of treatment. The true position of ablation in the complex oncologic armamentarium remains to be defined. Future goals are to evaluate the long-term results of ablation compared to other techniques such as surgery and stereotactic radiotherapy, and to evaluate the association of ablation with other type of treatments, including adjuvant or neoadjuvant chemotherapy, and targeted therapies reducing tumor vascularization (60).

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References 1. Sonntag P.D., Hinshaw J.L., et al.: Thermal ablation of lung tumors. Surg Oncol Clin N Am, 2011, 20: 369387. 2. Lee J.M., Jin G.Y., Goldberg S.N., et al.: Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: preliminary report. Radiology, 2004, 230: 125-134. 3. Rose S.C., Thistlethwaite P.A., Sewell P.E., Vance R.B.: Lung cancer and radiofrequency ablation. J Vasc Interv Radiol, 2006, 17: 927-951. 4. Zhu J.C., Yan T.D., Morris D.L.: A systematic review of radiofrequency ablation for lung tumors. Ann Surg Oncol, 2008, 15: 1765-1774. 5. Dupuy D.E.: Image-guided thermal ablation of lung malignancies. Radiology, 2011, 260: 633-55. 6. Brach B., Buhler C., Hayman M.H., et al.: Percutaneous computed tomography guided fine needle brachytherapy of pulmonary malignancies. Chest, 1994, 106: 268-274. 7. Miao Y., Ni Y., et al.: Radiofrequency ablation for eradication of pulmonary tumor in rabbits. J Surg Res, 2001, 99: 265-271. 8. Gazelle G.S., Goldberg S.N., et al.: Tumor ablation with radio-frequency energy. Radiology, 2000, 217: 633646. 9. Goldberg S.N., Gazelle G.S., Compton C.C., McLoud T.C.: Radio frequency tissue ablation in the rabbit lung: efficacy and complications. Acad Radiol, 1995, 2: 776-784. 10. Simon C.J., Dupuy D.E., et al.: Microwave ablation: principles and applications. RadioGraphics, 2005, 25 (Suppl. 1): S69-83. 11. Erinjeri J.P., Clark T.W.: Cryoablation: mechanism of action and devices. J Vasc Interv Radiol, 2010, 21 (8 Suppl.): S187-191. 12. Dupuy D.E., Mayo-Smith W.W., Abbott G.F., DiPetrillo T.: Clinical applications of radio-frequency tumour ablation in the thorax. RadioGraphics, 2002, 22 (Suppl. 1): S259-S269. 13. Grieco C.A., Simon C.J., MayoSmith W.W., et al.: Percutaneous image-guided thermal ablation and radiation therapy: outcomes of combined treatment for 41 patients with inoperable stage I/II non-small-cell lung cancer. J Vasc Interv Radiol, 2006, 17: 1117-1124. 14. VanSonnenberg E., Shankar S., Morrison P.R., et al.: Radiofrequency ablation of thoracic lesions: part 2, initial clinical experience – technical and multidisciplinary considerations in 30 patients. Am J Roentgenol, 2005, 184: 381-390. 15. Vaughn C., Mychaskiw G., et al.: Massive hemorrhage during radio frequency ablation of a pulmonary neoplasm. Anesth Analg, 2002, 94: 1149-1151. 16. Dupuy D.E.: Microwave ablation compared with radiofrequency ablation in

proceedings(tervuren)(nov.2012).indd 153

lung tissue-is microwave not just for popcorn anymore? Radiology, 2009, 251: 617-618. 17. Vogl T.J., Naguib N.N., Lehnert T., Nour-Eldin N.E.: Radiofrequency, microwave and laser ablation of pulmonary neoplasms: clinical studies and technical considerations--review article. Eur J Radiol, 2011,77: 346-57. 18. Carrafiello G., Lagana D., et al.: Microwave tumors ablation: principles, clinical applications and review of preliminary experiences. Int J Surg, 2008, 6 (Suppl. 1): S65-69. 19. McTaggart R.A., Dupuy D.E.: Thermal ablation of lung tumors. Tech Vasc Interv Radiol, 2007, 10: 102-113. 20. Wang H., Littrup P.J., Duan Y., et al.: Thoracic masses treated with percutaneous cryotherapy: initial experience with more than 200 procedures. Radiology, 2005, 235: 289-298. 21. Sharma A., Moore W.H., Lanuti M., Shepard J.A.: How I do it: radiofrequency ablation and cryoablation of lung tumors. J Thorac Imaging, 2011, 26: 162-174. 22. Joskin J., De Baere T., Tselikas L., et al.: Traitement des métastases pulmonaires par électroporation irréversible: expérience préliminaire. Presented at the Journées Françaises de Radiologie, Paris October 19-23, 2012. 23. Dupuy D.E., Aswad B., Ng T.: Irreversible electroporation in a Swine lung model. Cardiovasc Intervent Radiol, 2011, 34: 391-5. 24. Akeboshi M., Yamakado K., Nakatsuka A., et al.: Percutaneous radiofrequency ablation of lung neoplasms: initial therapeutic response. J Vasc Interv Radiol, 2004, 15: 463-470. 25. Ambrogi M.C., Fanucchi O., Cioni R., et al.: Long-term results of radio frequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study. J Thorac Oncol, 2011, 6: 2044-2051. 26. Gillams A.R., Lees W.R.: Radio frequency ablation of lung metastases: factors influencing success. Eur Radiol, 2008, 18: 672-677. 27. Hiraki T., Sakurai J., Tsuda T., et al.: Risk factors for local progression after percutaneous radiofrequency ablation of lung tumors: evaluation based on a preliminary review of 342 tumors. Cancer, 2006, 107: 2873-2880. 28. Simon C.J., Dupuy D.E., DiPetrillo T.A., et al.: Pulmonary radiofrequency ablation: long-term safety and efficacy in 153 patients. Radiology, 2007, 243: 268-275. 29. Yamakado K., Hase S., Matsuoka T., et al.: Radiofrequency ablation for the treatment of unresectable lung metastases in patients with colorectal cancer: a multicenter study in Japan. J Vasc Interv Radiol, 2007, 18: 393398. 30. Yan T.D., King J., Sjarif A., et al.: Percutaneous radiofrequency ablation of pulmonary metastases from colorectal carcinoma: prognostic determinants for survival. Ann Surg Oncol, 2006, 13: 1529-1537.

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31. Belfiore G., Moggio G., Tedeschi E., et al.: CT-guided radiofrequency ablation: a potential complementary therapy for patients with unresectable primary lung cancer – a preliminary report of 33 patients. Am J Roentgenol, 2004, 183: 1003-1011. 32. Dupuy D.E., Liu D., et al.: Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial. Cancer, 2010, 116: 989-997. 33. Grieco C.A., Simon C.J., et al.: Imageguided percutaneous thermal ablation for the palliative treatment of chest wall masses. Am J Clin Oncol, 2007, 30: 361-367. 34. Kishi K., Nakamura H., Sudo A., Kobayashi K., Yagyu H., Oh-ishi S., Matsuoka T.: Tumor debulking by radiofrequency ablation in hypertrophic pulmonary osteoarthropathy associated with pulmonary carcinoma. Lung Cancer, 2002, 38: 317-20. 35. Hess A., Palussière J., Goyers J.F., et al.: Pulmonary radiofrequency ablation in patients with a single lung: feasibility, efficacy, and tolerance. Radiology, 2011, 258: 635-642. 36. Hiraki T., Gobara H., et al.: Technique for creation of artificial pneumothorax for pain relief during radiofrequency ablation of peripheral lung tumors: report of seven cases. J Vasc Interv Radiol, 2011, 22: 503-506. 37. Suh R.D., Wallace A.B., et al.: Unresectable pulmonary malignancies: CT-guided percutaneous radiofrequency ablation – preliminary results. Radiology, 2003, 229: 821-829. 38. King J., Glenn D., et al.: Percutaneous radiofrequency ablation of pulmonary metastases in patients with colorectal cancer. Br J Surg, 2004, 91: 217-223. 39. Anderson E.M., Lees W.R., Gillams A.R.: Early indicators of treatment success after percutaneous radiofrequency of pulmonary tumors. Cardiovasc Intervent Radiol, 2009, 32: 478-483. 40. Steinke K., Sewell P.E., Dupuy D., et al.: Pulmonary radiofrequency ablation – an international study survey. Anticancer Res, 2004, 24: 339-343. 41. de Baère T., Palussière J., Aupérin A., et al.: Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: prospective evaluation. Radiology, 2006, 240: 587-596. 42. Lanuti M., Sharma A., Digumarthy S.R., et al.: Radiofrequency ablation for treatment of medically inoperable stage I non-small cell lung cancer. J Thorac Cardiovasc Surg, 2009, 137: 160-166. 43. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg, 1997, 113: 37-49. 44. Rosenberg C., Puls R., Hegenscheid K., et al.: Laser ablation of metastatic lesions of the lung: long-term outcome. Am J Roentgenol, 2009, 192: 785-792.

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154 45. Inoue Y., Miki C., Hiro J., et al.: Improved survival using multi-modality therapy in patients with lung metastases from colorectal cancer: a preliminary study. Oncol Rep, 2005, 14: 15711576. 46. Hiraki T., Mimura H., et al.: Repeat radiofrequency ablation for local progression of lung tumors: does it have a role in local tumor control? J Vasc Interv Radiol, 2008, 19: 706-711. 47. Lencioni R., Crocetti L., Cioni R., et al.: Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet O ncol, 2008, 9: 621-628. 48. Wolf F.J., Grand D.J., Machan J.T., et al.: Microwave ablation of lung malignancies: effectiveness, CT findings, and safety in 50 patients. Radiology, 2008, 247: 871-879. 49. Beland M.D., Wasser E.J., MayoSmith W.W., Dupuy D.E.: Primary non-small cell lung cancer: review of frequency, location, and time of recurrence after radiofrequency ablation. Radiology, 2010, 254: 301-307. 50. Kashima M., Yamakado K., et al.: Complications after 1 000 lung radiofrequency ablation sessions in 420 patients: a single center’s experiences. Am J Roentgenol, 2011, 197: W576-580. 51. Jin G.Y., Lee J.M., et al.: Acute cerebral infarction after radiofrequency

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JBR–BTR, 2013, 96 (3) ablation of an atypical carcinoid pulmonary tumor. Am J Roentgenol, 2004, 182: 990-992. ondelinger R.F.: 52. Ghaye B., Bruyère P.J., D Nonfatal systemic air embolism during percutaneous radiofrequency ablation of a pulmonary metastasis. Am J Roentgenol, 2006, 187: W327-8. 53. Hiraki T., Mimura H., et al.: Two cases of needle-tract seeding after percutaneous radiofrequency ablation for lung cancer. J Vasc Interv Radiol, 2009, 20: 415-418. 54. Herrera L.J., Fernando H.C., Perry Y., Gooding W.E., Buenaventura P.O., Christie N.A., Luketich J.D.: Radio frequency ablation of pulmonary malignant tumors in nonsurgical candidates. J Thorac Cardiovasc Surg, 2003,125: 929-37. 55. Bojarski J.D., Dupuy D.E., MayoSmith W.W.: CT imaging findings of pulmonary neoplasms after treatment with radiofrequency ablation: results in 32 tumors. Am J Roentgenol, 2005, 185: 466-71. 56. Palussière J., Marcet B., Descat E., et al.: Lung tumors treated with percutaneous radiofrequency ablation: computed tomography imaging followup. Cardiovasc Intervent Radiol, 2011, 34: 989-997. 57. Okuma T., Matsuoka T., Yamamoto A., et al.: Assessment of early treatment response after CT-guided radiofrequency ablation of unresectable lung

tumours by diffusion-weighted MRI: a pilot study. Br J Radiol, 2009, 82: 989994. 58. D., Leboulleux S., Deandreis Dromain C., et al.: Role of FDG PET/ CT and chest CT in the follow-up of lung lesions treated with radio frequency ablation. Radiology, 2011, 258: 270-276. 59. Yoo D.C., Dupuy D.E., et al.: Radio frequency ablation of medically inoperable stage IA non-small cell lung cancer: are early posttreatment PET findings predictive of treatment outcome? Am J Roentgenol, 2011, 197: 334-340. 60. Gadaleta C.D., Solbiati L., Mattioli V., et al.: Unresectable Lung Malignancy: Combination Therapy with Segmental Pulmonary Arterial Chemoembolization with Drug-eluting Microspheres and Radiofrequency Ablation in 17 Patients. Radiology, 2013, 267: 627-637. 61. Pennathur A., Luketich J.D., Abbas G., et al.: Radiofrequency ablation for the treatment of stage I non-small cell lung cancer in high-risk patients. J Thorac Cardiovasc Surg, 2007, 134: 857-864. 62. Hiraki T., Gobara H., Iishi T., et al.: Percutaneous radiofrequency ablation for clinical stage I non-small cell lung cancer: results in 20 nonsurgical candidates. J Thorac Cardiovasc Surg, 2007, 134: 1306-1312.

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4D PET-CT GUIDED RADIATION THERAPY* X. Geets1 Tremendous technological progress in the field of imaging and computation have been revolutionizing radiotherapy of non-small cell lung cancer (NSCLC). Tumor biology can now be characterized by functional imaging for modifying treatment management and dose delivered in better accordance with the radiobiology of solid tumors and normal tissues. Specific radiation therapy (RT) strategies can further address the tumor motion issue, ensuring optimal tu mor coverage with small safety margins. Key-word: Lung neoplasms, therapy.

Radiation therapy has been long past recognized as one of the main treatment modalities of locally- advanced unresectable non-small cell lung cancer (NSCLC), as well as of early stage tumor in medically inoperable patients. Like surgery, the primary objective of RT is to locally control tumors, which is an essential prerequisite of cancer cure. However, local tumor failure remains high in patients with stage II and III NSCLC, with local progression free survival rates of about 30% (1) when conventional radiotherapy schedules are used (60-66 Gy, daily fraction of 2 Gy). Dose intensification strategies, such as concomitant chemo-radiation, accelerated and dose-escalated schemes have been already shown to improve the tumor control and patient survival rates. Interestingly, the improved survival of stage III NSCLC patients with the concurrent delivery of chemotherapy and RT over sequential delivery is solely due to improved local tumor control (1). It is thus clear that improvement of local control leads to a better survival, even in patients with locally-advanced diseases. This justifies pursuing strategies to increase local tumor control that can be integrated with systemic treatment. Moreover, as most local recurrences have been observed in the primary tumor and not in the involved mediastinal lymph nodes, further clinical research needs to more specifically focus on the primary tumor control. The clinical implementation of dose-intensified protocols however remains problematic. The proximity between the target volumes (TV) and highly sensitive intra-thoracic organs, such as the lungs, spinal cord, oesophagus and heart, may result in

unacceptable short- and long-term toxicities when dose intensification is considered. Therefore, the recent development of new high precision radiation techniques, such as intensity modulated radiation therapy (IMRT), image guided radiotherapy (IGRT) and stereotactic body radiation therapy (SBRT) offers new perspectives. However, high precision RT not only requires sophisticated radiation delivery techniques, but also thorough selection and delineation of TVs. In this regard, functional imaging like positron emission tomography (PET) might advantageously complement morphological computed tomography (CT) for RT planning, by providing unique molecular information about the tumor biology. In addition, accuracy would never be achieved in NSCLC RT without optimally accounting for respiratorycorrelated tumor motion. Indeed, it causes major geometric uncertainties during image acquisition, treatment planning and dose delivery, which have certainly contributed to the poor local control achieved with old RT techniques. It is thus anticipated that adequate motion-related strategies would achieve better outcome in terms of both tumor control and toxicity profile. Thus, this paper will discuss the rational, the practicalities and the potential of modern radiotherapy strategies in NSCLC that appeal to recent imaging technologies like PET and four-dimensional (4D) imaging. PET-guided radiotherapy Nowadays, CT is the reference imaging modality for the treatment planning of NSCLC. It is widely available, conveys essential anatomical

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de recherche expérimentale et clinique, Université Catholique de Louvain, Brussels, Belgium.

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information, and also indicates the electronic density of the tissues used for dose calculation. Nevertheless, it offers poor soft tissue contrast between the primary tumor and the surrounding normal tissues in cases of lung parenchyma changes (i.e. fibrosis, atelectasis, pleural effusion, and pneumonia), contiguity between the primary tumor and mediastinal nodes, and tumor located close to the mediastinum or chest wall. Alternatively, FDG-PET provides higher sensitivity and specificity than CT for the detection of primary tumor and mediastinal nodes, and is now considered as a reference for the clinical staging of NSCLC (2, 3). In the radiotherapy field, FDG-PET has already been shown to significantly modify the size, location and shape of the primary Gross Target Volume (GTV, i.e. the macroscopic disease) (4, 5), and to improve the selection of neoplastic lymph nodes in the target volume (6). FDG-PET thus leads to the opportunity to optimize both the patient selection for a given treatment through a better clinical staging, and the radiotherapy treatment planning through a better identification of the target to be irradiated (7, 8). Even more promising, PET has the potential of identifying tumor subvolumes that are suspected of being radioresistant (high tumor burden, hypoxia…), in which an escalated, non-uniform radiation dose distribution could improve tumor control and patient’s outcome (9-11). This so-called “dose-painting” strategy would possibly solve the issue that uniform dose escalation to the whole tumor would lead to too high doses to the normal tissues, with unacceptable subsequent toxicities. Restrictively boosting the parts of the tumor that show unfavourable responsiveness to radiation should thus reconcile tumor radiobiological imperatives with those related to treatment safety. Any PET tracer identifying a metabolic pathway involved in the

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Fig. 1. — Axial PET images from a patient with a primary lung tumor. On the left panel, the PET image corresponds to the raw image reconstructed with 3D OSEM algorithm (A). The application of the bilateral filter and the deconvolution algorithm restored the gradient intensity as shown on conventional image (B). The gradient image is then generated to depict the gradient intensity peak (C, white arrows), and the tumor contour (red line) is finally generated and transferred to the raw image (D).

radio-resistance process, such as hypoxia, glucose metabolism or tumor proliferation could theoretically be selected for driving dose escalation. In NSCLC, FDG appears as pretty good candidate as demonstrated by the Maastro and NKI groups from The Netherlands: 1) it benefits from a large and long-term clinical experience, 2) it demonstrates a good signalto-noise ratio (SNR), 3) its high uptake areas within the tumor correlate with poor local tumor control and survival (12), 4) the radio-resistant areas can be identified on the basis of the pre-treatment FDG-PET, and 5) highly metabolic areas remain at the same location throughout the course of radiotherapy (13, 14). Although indirect evidences exists about a radiation-dose response relationship in NSCLC, the question however remains whether delivering a higher dose to the most avid FDGuptake areas within the tumor would result in higher local control. This should thus be addressed in welldesigned prospective trials that should adequately deal with specific methodological/technical aspects inherent to PET-guided RT as further described in this paper.

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Delineation of the PET-based target volume The first step consists in identifying and delineating FDG-PET-based targets, which still remains technically complex. At the moment, several delineation methods were suggested relying mainly on either manual contouring or automatic threshold-based segmentation. However, manual delineation is a subjective and non-reproducible approach, while some studies pointed out that the threshold for accurately recovers the actual PET volume substantially differ with the size, shape, heterogeneity and background uptake of the tumor (15), questioning thus the validity of thresholding itself. From a methodological point of view, the use of a straightforward segmentation method such as a threshold-based one is driven by the low quality of PET images, in terms of resolution and statistical noise, compared with others modalities like CT or MRI. In this regard, the use of appropriate image-processing tools like denoising and deblurring techniques can address the noise and resolution issues of the images, so

that a segmentation method that exploit the image gradient information could be used. These tools have been developed in our lab, and are in depth described in (16). Briefly, the segmentation process goes through 3 successive steps (Fig. 1): The denoising step with specific edge-preserving filter aims at attenuating the statistical noise without additional smoothing of the tumor edges. The deblurring step aims at compensating for the blur effects of the scanner point spread function. It relies on an iterative deconvolution algorithm that recovers the ideal image from the blurred one, with stepper intensity gradients between the tumor and the background (Fig. 1 B). The intensity gradient detection on the computed gradient image is then done by means of Watershed and Clustering algorithms, and leads to the accurate identification of the object boundaries (Fig. 1 C,D). This method has been validated on FDG-PET images from phantoms, and from patients with head and neck and lung cancers, using the surgical pathology specimen as the “ground truth” (16, 17). Interestingly, our gradient-based segmentation of FDG-PET images provided a closer estimate of the true tumor volume compared to CT, which systematically overestimated it. This method also proved to outperform the classical threshold-based approaches in terms of accuracy and robustness. Based on these facts, the gradientbased segmentation approach was considered as the reference tool for further FDG-PET-driven dose-escalation protocols. FDG-PET guided dose escalation protocol A pilot study was then designed to address the feasibility and the efficacy of FDG-PET-driven dose boosting in locally-advanced stages II-III NSCLC. In this prospective trial, patients are treated with state of the art concomitant chemo-radiation therapy. A total dose of 62.5 Gy is delivered in 5 weeks to classical target volumes, i.e. the primary tumor and the clinically-positive mediastinal lymph nodes, delineated on a routine contrast-enhanced planning CT. The dose by fraction is then escalated on the FDG-PET volumes delineated with our gradient-based method. The dose escalation is performed with Simultaneous Integrated Boost (SIB) IMRT technique using tomotherapy machine, which allows to

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Fig. 2. — Radiotherapy planning process for FDG-PET-guided dose escalation in NSCLC. First, a combined FDG-PET-CT of the patient immobilized in treatment position is acquired (A). Gross tumor volumes (GTV) from involved lymph node (green contour) and primary tumor (yellow contour) are then manually delineated on the contrast-enhanced CT, while the FDG-avid region (red contour) within the primary tumor is automatically segmented on PET images (B). Margins are then added to these GTVs to account for microscopic extension, tumor motion and setup uncertainties. The dose is finally prescribed to reach 62.5 Gy to CT-based volumes, while being escalated for FDG-PET-based volume up to 80 Gy in this particular case (C).

deliver different dose levels to different targets (CT and PET-based volumes) during the same treatment session (Fig. 2). The dose to the PET volume is individually increased until a set of pre-defined dose-limiting normal tissue constraints is reached for lungs, heart, oesophagus, plexus brachialis and mediastinal structures (18). Thus, all parts of the primary tumor will receive at least 62.5 Gy (CTbased volume), while FDG-avid regions will be escalated to a maximal dose of 125 Gy (25 fractions of 5 Gy). This later dose level has been set to be biologically equivalent to this achieved with a 3 times 18 Gy stereo tactic body radiotherapy (SBRT) scheme used in early stage small NSCLC, which results in local tumor control rates above 85% (19). If needed, this dose is lowered for individual patient to ensure that the dose to normal structures will not exceed the current recommendations. Even in this case, the tumor control probability is expected to be much higher than what we can achieve today. This will be evaluated by the localprogression free survival, while acute and late radiation-induced toxicities will be carefully monitored and reported. RT strategies for respiratory-related tumor motion management Breathing induces a three-dimensional, ellipsoidal-shaped (hysteresis) tumor motion that is often significant, especially in the cranio-caudal direction and for lower lobe tumor. This motion can furthermore vary in amplitude, shape, and baseline when

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transient changes occur in the patient’s breathing pattern. In this context, the use of a conventional freebreathing 3D-CT typically leads to several geometric distortions (image artefacts in tumor shape and position, delineation errors...). To account for these geometric uncertainties, large safety margins are needed, thereby limiting the effectiveness of radiotherapy (20). To reduce geometric uncertainties in CT images, and thus the safety margins, timeresolved four-dimensional CT (4DCT) and PET (4D-PET) techniques have been developed. They serve as a basis of various breathing-related RT strategies. Some aspects of these strategies will be tackled in the following paragraphs. Respiratory audio-video coaching To ensure reliable and reproducible tumor motion and trajectory, an audio-video coaching (AVC) procedure has been developed. It aims at regularizing the patient breathing throughout all imaging and treatment sessions. Prior to any image acquisition, a training session is planned to record and characterize the breathing pattern of each individual patient. The average frequency, the relative duration of the inhalation and exhalation phases, as well as the breathing amplitude, are first determined from the signal acquired in free breathing mode. Then, the respiratory sound that best matched the specific patient’s breathing pattern is selected from a large database and further used for the audio coaching procedure. The breathing amplitude is also constrained by a visual feedback of the respiratory

with video-glasses. Several studies have already pointed out that audioguidance stabilized breathing frequency and improved the external/ internal correlation between the breathing and the tumor (21-23). Combining video feedback with audio-guidance further regularizes the breathing amplitude (24, 25). 4D planning imaging In addition to the contrast- enhanced CT (CE-CT) and conventional FDG-PET used for delineation and dose calculation purposes, respiratory-correlated acquisitions are performed to capture the tumor motion. In this technique, the breathing signal coming from external surrogates (pressure belt, optical scanner, infrared camera...) is used to sort the respiratory-correlated CT or PET images in 10 equally distributed temporal bins, so that the resulting 10 respiratory CT and PET phases may provide an estimate of the tumor motion throughout the breathing cycle. Treatment planning strategies Based on this 4D information, various strategies can be deployed. The respiratory synchronized techniques that intend to either gate the dose delivery at a certain tumor position or track the tumor in real-time are appealing since they minimize the tumor motion contribution in the (26-29). safety margin calculation However, these approaches remain complex to implement, require sophisticated and time-consuming inroom verification procedures, and are technically unfeasible with helical tomotherapy machine. Alternatively,

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deed, a 3D image only represents a snapshot of the tumor motion, from which the tumor position can significantly and systematically diverge from its mean position over the whole breathing cycle. Removing this systematic error ultimately allows a substantial reduction of the safety margins, compared to conventional 3D CT and ITV strategies, margins that are actually close to those obtained with gated radiotherapy. Last but not least, the MidP is a simple method that only involves the reconstruction of a new planning CT, and leaves other treatment planning and delivery aspects unchanged. It does not require any complex 4D treatment planning nor additional verification, and is thus easy to implement in clinical routine. A complete, unique validation of this approach with tomotherapy treatment is on going in our lab, which addresses volumetric, dosimetric and dose delivery aspects with Monte Carlo calculation verification (32).

YES COLOR !

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Fig. 3. — Average planning kV-CT (A,C) and MV-CT (B,D) images of a moving spherical phantom (1 cm amplitude motion in the supero-inferior direction). Although MV-CT presents geometric motion artefacts (red arrows, right upper panel), it shares similar density distribution patterns with the average kV-CT (red and yellow dotted lines). Based on that, the centres of mass (red spheres) are directly used for aligning the tumor on its average position between kV and MV-CT.

margin-based approaches, which are more suitable for tomotherapy treatment, aim at either covering the entire tumor trajectory derived from 4D information (internal target volume, ITV) (30), or at taking advantage of the geometrical time-weighted mean tumor position (MidPosition, MidP) (31). In our setting, the internal motion is first estimated using non-rigid registration between the different 4D-CT or 4D-PET respiratory phases. The calculated deformation maps can then be used to either generate ITV or MidP: For ITV, the gross tumor volume delineated by the experienced physician on CE-CT or automatically segmented on FDG-PET is propagated to the 10 respiratory CT/PET phases. The union of all volumes then leads to the definition of the ITV that covers all tumor positions through the whole breathing cycle. An additional margin is added to the ITV to account for setup errors. For MidP, the deformation maps are used for generating a single 3D-

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CT/PET frame, i.e. the MidP CT or PET, from the 4D dataset. This image is obtained by deforming all features of each frame of the 4D dataset from their position in a certain frame to their time-weighted mean position with the estimated motion. Subsequently, averaging over the respiratory phases of the transformed 4DCT results in the MidP CT or PET. The MidP image comprises thus all the internal structures, including the tumor, in their exact time-weighted mean position of the respiratory motion. The mean time-weighted tumor position is finally extended with an appropriate margin to account for residual uncertainties. The MidP strategy presents several advantages (31). First, as the MidP image corresponds to an averaged image from all transformed frames, it is less noisy (better signalto-noise ratio) than each separate time frame. This may contribute to the reduction of delineation errors. More importantly, the MidP eliminates the systematic error due to 3D sampling or tumor hysteresis. In-

In room imaging and positioning To ensure the adequate positioning of the patient during the treatment delivery, a daily MV-CT is performed at the tomotherapy unit. Classically, the bony anatomy is used to realign the actual patient position from the daily MV-CT with this corresponding to the planning CT (i.e. bony anatomy setup correction protocol). Unfortunately, this procedure does not correct for tumor baseline shifts, i.e. day-to-day variations in the basal position of the tumor due to pattern changes in the tumor motion. Without baseline shift correction, a significant margin extension has to be considered to compensate for. Another approach would thus consist in directly aligning the tumor between the MV-CT and the planning CT (i.e. on-line tumor setup correction protocol). Interestingly, MV-CT may be considered as a (very) slow CT capturing the tumor motion, and thus sharing similarities in density distribution with the average kV-CT from the 4D planning CT (Fig. 3). Thanks to this property, the mass centre of the tumor in its average position can be found out and used to realign both images at the tumor level. This procedure, which should account for the possible geometric motion-related distortion within the MV-CT image, is currently under development and validation using moving phantoms and real patient images.

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Conclusion Tremendous technological progresses in the field of imaging and computation have been revolutionizing radiotherapy of NSCLC. The tumor biology can now be characterized by functional imaging for modifying the way the treatment plan is designed and the dose delivers, in better accordance with the radiobiology of solid tumors and normal tissues. Specific RT strategies can furthermore address the tumor motion issue, ensuring optimal tumor coverage with small safety margins. Although results from prospective trials are still awaited, we can expect that these progresses would translate into better patient’s outcome. References 1. Auperin A., et al.: Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol, 2010, 28: 2181-2890. 2. Cerfolio R.J., et al.: The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer. Ann Thorac Surg, 2004, 78: 10171023. 3. Lardinois D., et al.: Staging of nonsmall-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med, 2003, 348: 2500-2507. 4. Grills I.S., et al.: Clinical implications of defining the gross tumor volume with combination of CT and 18FDGpositron emission tomography in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys, 2007, 67: 709719. 5. Brianzoni E., et al.: Radiotherapy planning: PET/CT scanner performances in the definition of gross tumour volume and clinical target volume. Eur J Nucl Med Mol Imaging, 2005, 32: 1392-1399. 6. van Loon J., et al.: Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys, 2010, 77: 329-336. 7. De Ruysscher D., Kirsch C.M.: PET scans in radiotherapy planning of lung cancer. Radiother Oncol, 2010, 96: 335-338.

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8. De Ruysscher D., et al.: PET scans in radiotherapy planning of lung cancer. Lung Cancer, 2012, 75: 141-145. 9. Bentzen S.M.: Theragnostic imaging for radiation oncology: dose-painting by numbers. Lancet Oncol, 2005, 6: 112-117. 10. Bentzen S.M.: Dose painting and theragnostic imaging: towards the prescription, planning and delivery of biologically targeted dose distributions in external beam radiation oncology. Cancer Treat Res, 2008, 139: 41-62. 11. Bentzen S.M., Gregoire V.: Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin Radiat Oncol, 2011, 21: 101-110. 12. Borst G.R., et al.: Standardised FDG uptake: a prognostic factor for inoperable non-small cell lung cancer. Eur J Cancer, 2005, 41: 1533-1541. 13. Aerts H.J., et al.: Identification of residual metabolic-active areas within individual NSCLC tumours using a pre-radiotherapy (18)Fluorodeoxyglucose-PET-CT scan. Radiother Oncol, 2009, 91: 386-392. 14. van Baardwijk A., et al.: Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients. Radiother Oncol, 2007, 82: 145-152. 15. Lee J.A.: Segmentation of positron emission tomography images: some recommendations for target delineation in radiation oncology. Radiother Oncol, 2010, 96: 302-307. 16. Geets X., et al.: A gradient-based method for segmenting FDG-PET images: methodology and validation. Eur J Nucl Med Mol Imaging, 2007, 34: 1427-1438. 17. Wanet M., et al.: Gradient-based delineation of the primary GTV on FDGPET in non-small cell lung cancer: a comparison with threshold-based approaches, CT and surgical specimens. Radiother Oncol, 2011, 98: 117-125. 18. van Baardwijk A., et al.: Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer. J Clin Oncol, 2010, 28: 1380-1386. 19. Grills I.S., et al.: A collaborative analysis of stereotactic lung radio therapy outcomes for early-stage non-small-cell lung cancer using daily online cone-beam computed tomo graphy image-guided radiotherapy. J Thorac Oncol, 2012. 7: 1382-1393.

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20. Balter J.M., et al.: Uncertainties in CTbased radiation therapy treatment planning associated with patient breathing. Int J Radiat Oncol Biol Phys, 1996, 36: 167-174. 21. Neicu T., et al.: Synchronized moving aperture radiation therapy (SMART): improvement of breathing pattern reproducibility using respiratory coaching. Phys Med Biol, 2006, 51: 617-636. 22. Nakamura M., et al.: Effect of audio coaching on correlation of abdominal displacement with lung tumor motion. Int J Radiat Oncol Biol Phys, 2009, 75: 558-563. 23. Shibata M., et al.: Morphometric and functional correlation of human neuronal somata: pyramidal motor, special sensory and general sensory systems. Okajimas Folia Anat Jpn, 2009, 85: 115-117. 24. George R., et al.: Audio-visual biofeedback for respiratory-gated radiotherapy: impact of audio instruction and audio-visual biofeedback on respiratory-gated radiotherapy. Int J Radiat Oncol Biol Phys, 2006, 65: 924-933. 25. Cossmann P.H.: Video-coaching as biofeedback tool to improve gated treatments: Possibilities and limitations. Z Med Phys, 2012, 22: 224-230. 26. Murphy M.J.: Tracking moving organs in real time. Semin Radiat Oncol, 2004, 14: 91-100. 27. Schweikard A., et al.: Robotic motion compensation for respiratory movement during radiosurgery. Comput Aided Surg, 2000, 5: 263-277. 28. Nishioka S., et al.: Exhale fluctuation in respiratory-gated radiotherapy of the lung: a pitfall of respiratory gating shown in a synchronized internal/external marker recording study. Radiother Oncol, 2008, 86: 69-76. 29. Shirato H., et al.: Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor. Int J Radiat Oncol Biol Phys, 2000, 48: 435-442. 30. Underberg R.W., et al.: Use of maximum intensity projections (MIP) for target volume generation in 4DCT scans for lung cancer. Int J Radiat Oncol Biol Phys, 2005, 63: 253-260. 31. Wolthaus J.W., et al.: Comparison of different strategies to use four- dimensional computed tomography in treatment planning for lung cancer patients. Int J Radiat Oncol Biol Phys, 2008, 70: 1229-1238. 32. Sterpin E., et al.: Helical tomotherapy for SIB and hypo-fractionated treatments in lung carcinomas: a 4D Monte Carlo treatment planning study. Radiother Oncol, 2012, 104: 173.

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DOSIMETRY: WHICH DOSE FOR SCREENING, DIAGNOSIS AND FOLLOW-UP?* D. Tack1, H. Salame1 The question of which dose for screening, diagnosing ad follow-up of pulmonary nodules is a permanent issue for radiologists and radiotherapists. The proposed dose values for 2013 reflect the possibilities of the latest CT genera tions, from 2010 or later and include all technical novelties such as iterative reconstructions, automatic tube potential selection, and latest detectors. As the technology is constantly evolving, these parameters are susceptible to lower every year. Key-words: Lung neoplasms, therapeutic radiology – Lung neoplasms, diagnosis – Dosimetry.

Approximately 570.000 Americans will die from cancer in 2013, corresponding to more than 1500 deaths per day (1). Lung carcinoma is the first cause of death in both genders, surpassing prostate and colorectal cancer in men, and breast and colorectal cancer in women. There is a strong relationship between tumour size at time of diagnosis and the survival rate. The discussion of whether and how to screen for lung cancer is decades old and chest radiographs associated to sputum failed to prove providing a reduction in lung cancer specific mortality (2). The introduction of spiral CT made it technically possible to obtain volumetric data with a lower radiation dose than normally used for diagnostic purposes. In the July issue of the 2011 NEJM, the results of the multicenter North-American National Lung cancer Screening Trial (NLST) were published. This trial had been designed to have a more than 90% power to find a 20% decrease of mortality rate (3, 4). Before being answered, the question proposed as title of this overview requires to address two aspects of the radiation dose, the risk of CT scanning and the way to express the dose used for imaging. Risks of CT scanning Apart from the risks associated with the workup or treatment of false-positive or of indeterminate findings at CT screening, the risk from radiation-induced cancer has been discussed controversially in the literature. Brenner, in particular, has calculated risk estimates for various screening applications of CT, such as lung cancer, colon cancer and fullbody CT screening (5-7). For lung

cancer, for example, the life-time risk of a cancer that is induced by the CT screening exam has been calculated to amount up to 0.85% under unfavorable conditions with an upper 95% confidence interval of as much as 5.5% (5). These numbers have to be weighed against the incidence of screening detected cancers and – more importantly – the actual decrease of cancer-related mortality due to screening. This estimation of the risks related to CT screening and CT diagnosis is controversial because it is based on a linear no threshold dose-response relationship that is a matter of huge debate since years (8). However for the first time ever, one recent article based on epidemiological data demonstrated a direct increase in incidence of cancer after CT scanning (9). This research was conducted on children and young adults undergoing CT examinations of the brain and showed that within a delay of 10 year, a 3.18 fold brain cancer and leukemia risk could be observed after one CT examination obtained at a dose higher than 30 mGy. This risk (about 1/10000) has been considered as not far from the one estimated by the National Council on Radiation Protection (10, 11). Even if not negligible, it is from far much lower than the benefit from CT scanning for diagnosis and for screening, provided that these examinations are indicated. These recent data reinforce the ALARA principle to be applied on any CT technique and in particular for screening, diagnosing and for follow-up of nodules in smokers. The response to the addressed question to define which dose should be deliver for screening, diagnosis and follow-up could thus be very simple: a “low-dose” should be ap-

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Epicura Hospital, Clinique Louis Caty, Baudour, Belgium.

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plied in screening and follow-up and “standard dose” for diagnosis. However, these terms deserve further discussion. Nomenclature for describing the dose from CT scanning In the literature and in the daily practice, the term low-dose CT is often used but rarely well defined. No quantitative definition exists to indicate how low the dose in low-dose CT must be. A given CT examination can, thus, be “low dose” only as compared with an examination with a higher dose, commonly referred to as standard-dose CT. Likewise, however, no precise definition of the term standard dose exists. Any definition of low dose is, therefore, substantially limited by its relativistic foundation (12). In addition, the term low dose suffers from several other important drawbacks. First, the term low dose is subject to considerable variation over time because the technique is rapidly evolving and the general awareness of dose is increasing. Thanks to these positive trends in managing the dose, CT examination protocols that were considered low dose in 2000 are now used as default standard ones. Therefore, at any given point in time, the term low dose is accurate only in the short run (12). In screening, the first studies published on low-dose CT delivered around 1.5 mSv per individual screening examination (13, 14). In 2011, an up to date CT “standard” helical CT protocol delivered 77.7 mGy.cm (around 1.2 mSv) in a western population (15). In comparison, the NLST CT protocols used from 2002 to 2005 were quite heterogeneous and delivered 1.5 to 3.5 mSv in the US (3). Up to date CT technique used for follow-up of CT scanning can be done at an effective dose lower than 1 mSv (16). A second drawback of using the term low-dose is that its meaning is

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Table I. — Dose values proposed in 2013. Screening Diagnosis Follow-up

CTDIvol in mGy 0.5 2.6 <1

DLP in mGy.cm 20 90 < 35

Effective Diameter in cm 29 29 29

SSDE in mGy 0.6 3.2 < 1,2

CTDIvol, DLP, effective diameters and SSDE proposed for screening, diagnosis and follow-up of pulmonary nodules.

subject to considerable variation geographically and individually due to variable awareness and to variable average body size around the world. The first screening on lung cancer was conducted on a Japanese population (12) and delivered the same tube output as that conducted by Henschke et al. in a US population with an average weight of 25 to 30% higher that the Japanese one. Thus, both the image quality and the individual risk were not the same in these two publications. Inter-individual variations also reflect the technological possibilities of CT scanners in these years, that where not equipped with automatic exposure control (AEC) devices. Without AEC, there are considerable image quality differences between individuals who are small and or large. On the other hand, using the same tube output in individuals of various body sizes, the risk of each individual is also very different, being higher in small ones and lower in larger ones. Another drawback of using the term low-dose more extensively in the literature is that this term has lost its implicit significance. Thus, new terms appear such as “extremely low dose” and “ultralow dose” CT, and why not emerging newer terms such as “super-extra-nano-lowdose” (12)? Radiology Editors have thus elaborated a statement for describing the CT dose as follows. First, avoidance of the terms low-dose, and standarddose. Second, avoidance of the use of effective dose. The concept of effective dose is not suited for individual risk calculations and the conversion factors elaborated by the International Commission on Radiological Protection (ICRP) are periodically reassessed and have been changing three times since their introduction (17-23). In particular for chest examinations, the weighting risk factor of the breast has been changes from 5% to 12% between 1990 and 2007. Third, to use of the CT dose descriptors available on the

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CT console and the CT dose reports: the volume computed tomography dose index (CTDIvol), and the doselength product (DLP). These two descriptors describe the tube output respectively in a slice and in the entire scanned region. Fourth, use the effective diameter for description of the patient population. The American Association of Physicists in Medicine Task Group 204 report (24) defines the effective diameter as the square root of the antero-posterior diameter times the transverse dia meter. These diameters can be measured on the scout views and or on axial slices. Fifth, to introduce the size-specific dose estimate (SSDE), a new dose descriptor proposed by the AAPM 204 report, aiming to describe the absorbed dose while taking into account the patient’s individual size as follows: SSDE = f(size) × CTDIvol. To warrant a comprehensive description of their results, authors submitting to scientific Journals are thus proposed to report the above mentioned four parameters: CTDIvol, DLP, effective diameter, and SSDE. CTDIvol and DLP will provide information about scanner radiation output. The effective diameter will provide information about the dimensional characteristics of the study population. SSDE will provide an approximation of the dose absorbed by the individual patient. Which dose for screening, diagnosis and follow-up? Now that the justification of minimizing dose, and the parameters to describe the dose have been clarified, it appears easier to answer the addressed question on which dose for screening, diagnosing ad followup of pulmonary nodules. The actual 2013 dose values proposed are listed in Table I (25). They reflect the possibilities of the latest CT generations, from 2010 or later and include all technical novelties such as iterative reconstructions, automatic tube potential selection, and latest detec-

tors. As the technology is constantly evolving, these parameters are susceptible to lower every year. References 1. http://www.cancer.gov/statistics 2. Detterbeck F.C., Boffa D.J., Tanoue L.T.: The new lung cancer staging system. Chest, 2009, 136: 260271. 3. National Lung Screening Trial Research Team. The national lung screening trial: overview and study design. Radiology, 2011, 258: 243253. 4. Reduced lung-cancer mortality with low-dose computed tomographic screening. The National Lung Screening Trial research team. NEJM, 2011, 365: 395-409. 5. Brenner D.J.: Radiation risks potentially associated with low-dose ct screening of adult smokers for lung cancer. Radiology, 2004, 231: 440-444. 6. Brenner D.J., Georgsson M.A.: Mass screening with CT colonography: should the radiation exposure be of concern? Gastroenterology, 2005, 129: 328-337. 7. Brenner D.J., Elliston C.D.: Estimated radiation risks potentially associated with full-body CT screening. Radiology, 2004, 232: 735-738. 8. Pearce M.S., Salotti J.A., Little M.P., McHugh K., Lee C., Kim K.P., Howe N.L., Ronckers C.M., Rajaraman P., Sir Craft A.W., Parker L., Berrington de González A.: Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet, 2012, 380 (9840): 499-505. 9. Hendee W.R., O’Connor M.K.: Radiation risks of medical imaging: separating fact from fantasy. Radiology, 2012, 264: 312-321. 10. National Council on Radiation Protection and Measurements. Ionizing radiation exposure of the population of the United States. NCRP Report No. 160. Bethesda, Md: National Council on Radiation Protection and Measurements, 2009. 11. Brenner D.J., Hall E.J.: Cancer Risks from CT Scans: Now We Have Data, What Next? Radiology, 2012, 265: 330-331. 12. Bankier A.A., Kressel H.Y.: Through the Looking Glass Revisited: The

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162 Need for More Meaning and Less Drama in the Reporting of Dose and Dose Reduction in CT. Radiology, 2012, 265: 4-8. 13. Sone S., Takashima S., Li F., Yang Z., Honda T., Maruyama Y., Hasegawa M., Yamanda T., Kubo K., Hanamura K., Asakura K.: Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet, 1998, 351: 1242-1245. 14. Henschke C.I., McCauley D.I., Yankelevitz D.F., Naidich D.P., McGuinness G., Miettinen O.S., Libby D.M., Pasmantier M.W., Koizumi J., Altorki N.K., Smith J.P.: Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet, 1999, 354 (9173): 99-105. 15. Bendaoud S., Remy-Jardin M., Wallaert B., Deken V., Duhamel A., Faivre J.B., Remy J.: Sequential versus volumetric computed tomo graphy in the follow-up of chronic

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JBR–BTR, 2013, 96 (3) bronchopulmonary diseases: comparison of diagnostic information and radiation dose in 63 adults. J Thorac Imaging, 2011, 26: 190-195. 16. Bankier A.A., Tack D.: Dose reduction strategies for thoracic multidetector computed tomography: background, current issues, and recommendations. J Thorac Imaging, 2010, 25: 278-288. 17. Mettler F.A. Jr., Huda W., Yoshizumi T.T., Mahesh M.: Effective doses in radiology and diagnostic nuclear medicine: a catalog. Radiology, 2008, 248 (1): 254-263. 18. Martin C.J.: Effective dose: how should it be applied to medical exposures? Br J Radiol, 2007, 80: 639-647. 19. McCollough C.H., Christner J.A., Kofler J.M.: How effective is effective dose as a predictor of radiation risk? AJR, 2010, 194: 890-896. 20. McCollough C.H., Schueler B.A.: Calculation of effective dose. Med Phys, 2000, 27: 828-837.

21. International Commission on Radiological Protection. Recommendations of the ICRP. ICRP Publication 26. Ann ICRP, 1977, 1 (3): 1990 22. Recommendations of the International Commission on Radiological Protection. Ann ICRP, 1991, 21: 1-201. 23. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP, 2007, 37(2-4): 1332. 24. American Association of Physicists in Medicine. Size-Specific dose estimates (SSDE) in pediatric and adult body CT examinations. Task Group 204. College Park, Md: American Association of Physicists in Medicine, 2011. 25. Gevenois P.A., Tack D.: Dose Reduction and Optimization in Computed Tomography of the Chest. In Radiation Dose from Multidetector CT. Springer 2012. ISBN: 978-3-64224534-3 (Print) 978-3-642-24535-0.

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SCREENING FOR LUNG CANCER BY IMAGING: THE NELSON STUDY* M. Oudkerk, M.A. Heuvelmans1 The NELSON trial is the first randomised lung cancer screening trial in which pulmonary nodule management is based on volumetry. This led to considerably less false-positive referrals compared to other lung cancer screening trials, with very high negative predictive values found in the first and second screening rounds. Mortality results are still pending, but the knowledge already gained in the NELSON trial and its side-studies provide valuable information in the field of screening for lung cancer. Key-word: Lung neoplasms, diagnosis.

Lung cancer is a major health problem with no improvement in survival over the last decades. At time of diagnosis, lung cancer is often already in advanced stage, with 5-year survival of no more than 15% (1). Currently, several lung cancer screening trials investigating whether early detection of lung cancer in high-risk individuals will eventually reduce lung cancer mortality are ongoing (2-7). To date, the National Lung Screening Trial (NLST) is the only randomized controlled trial in which a significant lung cancer mortality reduction was found (2). The Dutch-Belgian lung cancer screening trial (Dutch acronym: NELSON study) was launched in September 2003. The NELSON study is an ongoing multicentre randomized controlled multi-detector low-dose computed tomography lung cancer screening trial. The primary object is to investigate whether chest CT screening in year 1, 2, 4 and 6.5 will decrease lung cancer mortality by at least 25% in high-risk (ex-)smokers between 50 and 75 years of age compared to a control group receiving no screening. Secondary end points of the study include estimation of the cost-effectiveness of the screening programme, assessment of the optimal screening interval (1, 2 or 2.5 years), and assessment of the impact on quality of life. In addition, multiple side studies are ongoing. One of the major challenges in lung cancer screening is the high false-positive rate, causing patient anxiety, cost and morbidity associated with unnecessary diagnostic procedures for benign nodules. The NELSON trial is the first large lung cancer screening trial in which the nodule management protocol is based on nodule volume, instead of nodule diameter, and nodule growth, in terms of volume doubling time (VDT) of existing nodules. The final

results will indicate whether a volumetry- and VDT based CT protocol is more efficient in terms of detection rate, morbidity, mortality, recall rate, and cost-effectiveness, compared to other approaches. Methods Participants The NELSON multi-centre trial was approved by the Dutch Minister of Health and the ethics board at each participating centre. All participants provided written informed consent. Participants were recruited based on a questionnaire about health, smoking, cancer history, and other lifestyle and health factors. Included were current or former heavy smokers, with a history of > 15 cigarettes daily for > 25 years or > 10 cigarettes daily for > 30 years and between 50-75 years of age. Exclusion criteria were a moderate or bad self reported health, inability to climb two flights of stairs, body weight ≥ 140 kg, lung cancer less than 5 years ago or still under treatment, current or past renal cancer, melanoma or breast cancer, and chest CT less than 1 year ago (8). In total, 15,822 subjects were included. 7,557 were categorized in the screen group, receiving low-dose chest CTs. Participants in the control group received no screening. Participants in the screen group underwent CT, and depending on the screening round, pulmonary function testing and blood sampling on the same day. After each CT examination, participants completed a quality of life questionnaire. Data acquisition The participants randomized to the screen group were invited to one of the four screening sites (University Hospital Groningen, University

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. University of Groningen, University Medical Center Groningen, Center for Medical Imaging - North East Netherlands, Department of Radiology, Groningen, the Netherlands.

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Hospital Utrecht and Kennemer Gasthuis Haarlem in the Netherlands and University Hospital Gasthuisberg Leuven in Belgium). All lowdose chest CT scans were performed by using 16-detector helical CT scanners Sensation-16, Siemens Medical Systems or, at the screening site in Utrecht, Mx8000 IDT or Brilliance 16P, Philips Medical Systems). Scanning of the entire chest was performed in a caudo-cranial direction, without the use of contrast agents. Depending on body weight (< 50 kg, 50-80 kg, and > 80 kg), the kVp settings were 80-90, 120 and 140 kVp respectively. This corresponds to an effective radiation dose < 1.6 mSv. Data sets of the lung were reconstructed at 1.0-mm slice thickness, with 0.7-mm reconstruction increment. Scans were performed in inspiration after appropriate instruction of the participants, to minimize breathing artefacts. Data acquisition and scanning conditions were standard across screening centres and equal for baseline and repeat screening (9). Volumetric measurements image reading

and

Digital workstations (Leonardo, Siemens Medical Solutions) were used for nodule volumetric analysis. This system detected automatically whether a nodule, marked by a radiologist, was new or had been present previously. After a nodule was marked, a program for semiautomated volume measurements (LungCare, version Somaris/5 VB 10A-W, Siemens Medical Solutions) automatically defined the volume of interest around the nodule. An observer could manually modify the segmentation by increasing or decreasing the volume, if necessary (9). Data generated by the LungCare software were uploaded into the NELSON Management System, which automatically detected whether a nodule was new or present on previous scans. The percentage volume change and VDT of previously detected nodules were calculated

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automatically by the system. For each evaluable nodule, the surface characteristics, location, distance to the pleura, and aspect of the nodule (i.e. solid, nonsolid or partial solid) were entered in the NELSON Management System by a radiologist. All CT images were independently read by first and second readers (double reading) as part of the NELSON protocol (9). The first reading was performed by a reader with experience in reading chest CTs varying from none to more than 20 years; the second reading was performed by two readers, each with 6 years of experience. The second readers were unaware of the conclusions of the first readers. In case of discrepancy, the final decision was made by a third reader (10). Screening strategy At baseline, a test was considered positive if any non-calcified nodule was larger than 500 mm3 (> 9.8-mm diameter). The result was indeterminate if the volume of the largest solid nodule or the solid component of a partially-solid nodule was 50-500 mm3 (4.6-9.8-mm diameter). In case of smaller nodules, the screening was negative (9).

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Indeterminate nodules underwent a 3-month follow-up CT to assess for growth. Growth was defined as volume increase of at least 25%. For growing nodules, the final result was based on their VDT. If a growing lesion had a VDT < 400 days, the final result was positive. Otherwise the baseline result was negative and the participant was invited for the regular second-round examination in year 2. At second-round screening, there were two possibilities: either a nodule was new, and the result was based on nodule size, or a nodule was pre-existing. New indeterminate nodules underwent a 6-weeks follow-up CT. For pre-existing nodules, the second round result was based on their VDT immediately. If both new and existing nodules were present, the nodule with the largest volume or fastest growth determined the result. Again, a VDT < 400 days resulted in a positive screen result. A nodule with VDT > 600 was classified as negative. A VDT of 400-600 days comprised an indeterminate result; then a follow-up CT was made 1 year later. Then, if the VDT was less than 400 days, the final result was positive (Fig. 1), otherwise negative. All participants with a negative secondround result were invited to undergo

the third round examination 2 years after the second round (9). The protocols of the third and fourth-round examinations were comparable to the protocol of the second-round, except for the fact that the fourth-round examination was planned 2.5 years after the thirdround examination. The screening program ended after a positive or negative fourth round result, or, in case of an indeterminate fourthround result, after a positive or negative follow-up CT (Fig. 2). Test positives were referred to a pulmonologist for workup. Workup, staging, and treatment were standardized to (inter-) national guidelines (9, 11). Nodules were classified as benign or malignant based on histological examination. Also, nodules could be classified benign based on stable or decreasing size two years after first detection (12, 13). If lung cancer was diagnosed, the participant was treated and left the screening trial; otherwise the regular next-round CT was scheduled. Results NELSON screen results The results of the first and second screening round were published in

Fig. 1. — Growing malignant lesion in a 65-year-old man. Axial computed tomography (CT) scan (A) shows a nodule (arrow) with a volume of 259 mm3 in the left lower lobe. Three months later (B), the nodule volume increased to 270 mm3 (volume-doubling time [VDT] = 1468 days). One year after baseline CT (C), the nodule volume was 425 mm3 (VDT = 528 days). 28 months after baseline CT (D), the nodule volume was 1132 mm3. The VDT at that time was 289 days. Lobectomy revealed a stage IA adenocarcinoma. M.a.b. = months after baseline.

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Fig. 2. — Screening programme

the New England Journal of Medicine in 2009 (7). In the baseline round, 1.6% of the subjects in the screen group had a nodule with volume > 500mm3. 19.2% had at least one indeterminate nodule, for which a three-month follow-up CT was performed. In this follow-up CT, growth was demonstrated in only 5.3% of participants with indeterminate nodules. In total, 196/7,557 participants tested positive (2.6%). In 70/196 participants, malignancy was con firmed; the lung cancer detection rate was 0.9%. Sensitivity of the baseline round screening was 94.6%, the negative predictive value was 99.7%. Only three interval cancers were detected between the first and second screening round. In the second screening round, a total of 7,289 participants underwent screening. The screen result was negative in 92.2% of the participants, indeterminate in 6.6% and positive in 1.2%. After follow-up examinations for indeterminate tested nodules, a total of 128/7,289 participants (1.8%) tested positive. Malignancy was confirmed in 54/118 (45.8%) participants referred for work-up. The lung cancer detection rate was 0.8%. Sensitivity of the second round screening was 96.4%, the negative predictive value was 99.9%. NELSON vs NLST Recently, the American National Lung Cancer Screening trial published a 20% lung cancer mortality reduction in their study group which received 3 annual rounds of low-

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dose CT screening. The control group received 3 annual rounds of chest X-ray screening (2). In the NLST screening rounds, the rate of positive tests, defined as greatest nodule diameter of 4 mm or larger, was 24%. No less than 96.4% comprised false positive results. Volume-based nodule management has been suggested to be more accurate (14, than diameter measurements 15), potentially leading to lower false-positive rates. Therefore, the NELSON trial was the first lung cancer screening trial which based screening interpretation on nodule volumetry and growth in terms of volume doubling time instead of diameters. This strategy yielded a rather low rate of positive screening tests (2.6% in the baseline screening; 1.8% in the second-round screening), while the number of missed lung cancers was low. Additional results of the NELSON study Valuable knowledge about interobserver variability and the optimal image reading protocol of semiautomated volume measurements was obtained in the NELSON trial. Gietema et al. found that interobserver correlation was very high (r = 0.99) in small-to-intermediate size (15-500 mm3) lung nodules (10). It was also found that variability on volume measurements is related to nodule size, morphology and location (16). In a further study (17), a difference in repeatability among three

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reconstruction settings was found. It was shown that volume measurement of pulmonary nodules obtained at 1 mm section thickness combined with a soft kernel was most repeatable. Therefore it was concluded that in case of serial CT studies, consistent reconstruction parameters are essential. Furthermore, compared to single reading, no statistically significant benefit for consensus double reading at baseline screening for lung cancer with the use of a nodule management strategy based solely on semi-automated volumetry was found (18). Therefore, in the fourth screening round image reading was performed by only one reader. At last, the performance of computer aided detection (CAD) was compared to double reading. The false-positive rate was 3.7 per CT for CAD and 0.5 per CT for readers. Excluding small nodules (< 50 mm3), the false-positive rate for CAD decreased to 1.9. The sensitivity of nodule detection by readers for nodules with need of further evaluation could have increased by 18.6% (from 78.1% to 96.7%) if CAD had also been used. However, only one lung cancer missed by readers was detected by CAD (19). Three studies focussed on the work-up of pulmonary nodules. In the first (20), it was shown that conventional white-light bronchoscopy should not be routinely recommended for patients with a positive test result in a lung cancer screening trial. The overall sensitivity was 13.5% and the negative predictive value was 47.6%. In the second study (21), the role of a preoperative positron emission tomography after a conclusive or inconclusive nonsurgical workup was evaluated. It was concluded that a preoperative PET scan in participants with an inconclusive nonsurgical workup is not recommended because of the very low negative predictive value. The third study (22) investigated the complication rate in participants of the screen arm of the NELSON lung cancer screening trial who underwent surgical resection. They found that mortality rates after surgical procedures are lower in the NELSON lung cancer screening trial than those in the nonscreening series. The rate of complications is within the same range as in the non-screening series. A number of studies focussed on the characteristics of lung nodules associated with cancer risk. In solid nodules larger than 50mm3, especially size, and to a lesser extent irregular shape and margin, were found to increase the likelihood of malignancy (13). Although baseline lung

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odule CT density was not predictive n of malignancy, an increase in CT density on follow-up CTs in inter mediate-sized nodules suggested lung cancer (23). Cancers in intermediate-sized (50500 mm3) fast-growing solid nodules, diagnosed at 3-month or 1-year follow-up CT after baseline, were found to be non-spherical and purely intraparenchymal, without attachment to the pleura, vessels or fissures (24). Perifissural nodules, accounting for about 20% of all lung nodules found in lung cancer screening, can show growth rates in the range of malignant nodules. However, none of the perifissural nodules turned out to be malignant after 5.5 years of follow-up. Therefore, recognition of these nodules can reduce unnecessary workup (25). Conclusion The first results of the NELSON study show the value of 3D-based lung nodule management for CT lung cancer screening, with very high negative predictive values found in the first and second screening round. Follow-up of the NELSON study population is ongoing and the mortality results are pending, but the unique methodological features of this randomized trial have already yielded important insights that complement the information gained from NLST. References 1. Janssen-Heijnen M.L., Coebergh J.W.: Trends in incidence and prognosis of the histological subtypes of lung cancer in North America, Australia, New Zealand and Europe. Lung Cancer, 2001, 31: 123-137. 2. National Lung Screening Trial Research Team, Aberle D.R., Adams A.M., Berg C.D., Black W.C., Clapp J.D., et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med, 2011, 4, 365: 395-409. 3. Infante M., Lutman F.R., Cavuto S., Brambilla G., Chiesa G., Passera E., et al.: Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. Lung Cancer, 2008, 59: 355-363. 4. Lopes Pegna A., Picozzi G., Mascalchi M., Maria Carozzi F., Carrozzi L., Comin C., et al.: Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer, 2009, 64: 34-40. 5. Blanchon T., Brechot J.M., Grenier P.A., Ferretti G.R., Lemarie E., Milleron B., et al.: Baseline results of

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JBR–BTR, 2013, 96 (3) the Depiscan study: a French randomized pilot trial of lung cancer screening comparing low dose CT scan (LDCT) and chest X-ray (CXR). Lung Cancer, 2007, 58: 50-58. Gohagan J.K., Marcus P.M., 6. Fagerstrom R.M., Pinsky P.F., Kramer B.S., Prorok P.C., et al.: Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer, 2005, 47: 9-15. 7. van Klaveren R.J., Oudkerk M., Prokop M., Scholten E.T., N ackaerts K., Vernhout R., et al.: Management of lung nodules detected by volume CT scanning. N Engl J Med, 2009, 361: 2221-2229. 8. van Iersel C.A., de Koning H.J., Draisma G., Mali W.P., Scholten E.T., Nackaerts K., et al.: Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the DutchBelgian randomised lung cancer multislice CT screening trial (NELSON). Int J Cancer, 2007, 120: 868-874. 9. Xu D.M., Gietema H., de Koning H., Vernhout R., Nackaerts K., Prokop M., et al.: Nodule management protocol of the NELSON randomised lung cancer screening trial. Lung Cancer, 2006, 54: 177-184. 10. Gietema H.A., Wang Y., Xu D., van Klaveren R.J., de Koning H., Scholten E., et al.: Pulmonary nodules detected at lung cancer screening: interobserver variability of semiautomated volume measurements. Radiology, 2006, 241: 251-257. 11. CBO. Guideline - non-small cell lung carcer: staging and treatment. Alphen aan de Rijn, The Netherlands: Van Zuiden Communications BV, 2004. 12. MacMahon H., Austin J.H., Gamsu G., Herold C.J., Jett J.R., Naidich D.P., et al.: Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology, 2005, 237: 395-400. 13. Xu D.M., van Klaveren R.J., de Bock G.H., Leusveld A., Zhao Y., Wang Y., et al.: Limited value of shape, margin and CT density in the discrimination between benign and malignant screen detected solid pulmonary nodules of the NELSON trial. Eur J Radiol, 2008, 68: 347-352. 14. Yankelevitz D.F., Reeves A.P., Kostis W.J., Zhao B., Henschke C.I.: Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. Radiology, 2000, 217: 251-256. 15. Revel M.P., Bissery A., Bienvenu M., Aycard L., Lefort C., Frija G.: Are twodimensional CT measurements of small noncalcified pulmonary nodules reliable? Radiology, 2004, 231: 453458. 16. Wang Y., van Klaveren R.J., van der Zaag-Loonen H.J., de Bock G.H., Gietema H.A., Xu D.M., et al.: Effect of

nodule characteristics on variability of semiautomated volume measurements in pulmonary nodules detected in a lung cancer screening program. Radiology, 2008, 248: 625631. 17. Wang Y., de Bock G.H., van Klaveren R.J., van Ooyen P., Tukker W., Zhao Y., et al.: Volumetric measurement of pulmonary nodules at low-dose chest CT: effect of reconstruction setting on measurement variability. Eur Radiol, 2010, 20: 11801187. 18. Wang Y., van Klaveren R.J., de Bock G.H., Zhao Y., Vernhout R., Leusveld A., et al.: No benefit for consensus double reading at baseline screening for lung cancer with the use of semiautomated volumetry software. Radiology, 2012, 262: 320326. 19. Zhao Y., de Bock G.H., Vliegenthart R., van Klaveren R.J., Wang Y., Bogoni L., et al.: Performance of computer-aided detection of pulmonary nodules in low-dose CT: comparison with double reading by nodule volume. Eur Radiol, 2012, 22: 2076-2084. 20. van ‘t Westeinde S.C., Horeweg N., Vernhout R.M., Groen H.J., Lammers J.W., Weenink C., et al.: The role of conventional bronchoscopy in the workup of suspicious CT scan screen-detected pulmonary nodules. Chest, 2012, 142: 377-384. 21. Van’t Westeinde S.C., de Koning H.J., F.B., Oudkerk M., Thunnissen Groen H.J., Lammers J.W., et al.: The Role of the (18)F-Fluorodeoxyglucose-Positron Emission Tomography Scan in the Nederlands Leuvens Longkanker Screenings Onderzoek Lung Cancer Screening Trial. J Thorac Oncol, 2011, 6: 1704-1712. 22. Van’t Westeinde S.C., Horeweg N., De Leyn P., Groen H.J., Lammers J.W., Weenink C., et al.: Complications following lung surgery in the DutchBelgian randomized lung cancer screening trial. Eur J Cardiothorac Surg, 2012, 42: 420-429. 23. Xu D.M., van Klaveren R.J., de Bock G.H., Leusveld A.L., D orrius M.D., Zhao Y., et al. Role of baseline nodule density and changes in density and nodule features in the discrimination between benign and malignant solid indeterminate pulmonary nodules. Eur J Radiol, 2009, 70: 492498. 24. Xu D.M., van der Zaag-Loonen H.J., Oudkerk M., Wang Y., Vliegenthart R., Scholten E.T., et al.: Smooth or attached solid indeterminate nodules detected at baseline CT screening in the NELSON study: cancer risk during 1 year of follow-up. Radiology, 2009, 250: 264-272. 25. de Hoop B., van Ginneken B., Gietema H., Prokop M.: Pulmonary Perifissural Nodules on CT Scans: Rapid Growth Is Not a Predictor of Malignancy. Radiology, 2012, 265: 611-616.

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RECIST AND BEYOND* E. Coche1 The role of imaging in the evaluation of tumor response is expanding rapidly. The current response evaluation crite ria in solid tumors (RECIST) based on anatomical changes suffers from many limitations related mainly to the interand intra-observer variability to delineate the tumoral edges. Consequently, there is a need to update and integrate the RECIST criteria beyond the classical anatomical changes with other more sophisticated methods using three- dimensional and functional criteria. The goal of this paper is to review the current criteria of RECIST measurements (RECIST 1.1) with their limitations and to evaluate the emerging solutions available with the new imaging techniques like PET-CT. Key-word: Lung neoplasms, CT.

Quantification of tumor burden by medical imaging is being used with increasing frequency to assess the effectiveness of various anticancer therapies. Anatomic criteria defined as change in tumor size according to the World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumor (RECIST) criteria has long been considered as a surrogate marker of therapeutic efficacy. Recently other tumor parameters, beyond RECIST, including three-dimensional measurements, density changes, and avidity for FDG on PET-CT are considered as promising biomarkers to assess more rapidly the functional response to therapy. The goal of this paper is to review the current criteria of RECIST measurements with their limitations and the emerging solutions available with the new imaging techniques. Classical anatomical markers RECIST criteria Tumor response to therapy has been evaluated in many cancer clinical trials using two-dimensional anatomical criteria. In the late 1970s, the International Union against Cancer and the WHO introduced specific criteria for the codification of tumor response evaluation (1). Unfortunately, bidimensional measurements (i.e. the product of the longest diameter and its longest perpendicular diameter) to assess tumor burden response was found to have limited reproducibility (2). RECIST criteria were developed several years lat-

er (3) in order to provide an easier reproducible method of measurement with the concept that one-dimensional measurements were as informative as bidimensional measurements. Response to treatment was categorized into four main categories: complete response (CR), corresponding to a disappearance of all target lesions; partial response (PR), defined as a ≥ 30% decrease in tumor size from the baseline; progressive disease (PD), defined as a ≥ 20% increase in tumor size; and stable disease (SD), defined as small changes that do not meet the above criteria. RECIST 1.1 criteria New response evaluation criteria were published in 2009 (RECIST 1.1) (4) and include several changes compared to the previous version: the number of target lesions to assess tumour burden for response determination has been reduced from a maximum of ten to a maximum of five in total (and from five to two per organ, maximum). Lymph nodes with a short axis measuring ≥ 15 mm have been included as target lesions and included in the sum calculation of tumour response. New clarifications concerning disease progression has been made in addition to the previous definition of progression disease (20% increase in sum) for small lesions. New lesions documented by FDG-PET can be used as indicator of disease progression in the RECIST 1.1. The main differences between RECIST 1.0 and 1.1 and time point responses are summarized in table I and II respectively (4).

*Meeting “Lung Cancer Imaging in 2012: Updates and innovations”, Tervuren, 10.11.2012. 1. Department of Medical Imaging, Cliniques Universitaires St-Luc, Brussels, Belgium. E-mail: Emmanuel.coche@uclouvain.be

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Limitations and difficulties of RECIST There are many drawbacks with the RECIST criteria. When the tumoral lesion has variable morphology, uni-dimensional measurements may be inaccurate specifically when the lesion length exceeds twice its width (5). Variability of lung tumor measurements represents also an important weakness of the RECIST method and may classify a patient in a wrong category due to those measurements errors. Oxnard et al. (6) determined the inter-measurement variance of CT for primary malignant lung lesions. Thirty patients with non-small cell lung carcinoma underwent nonenhanced CT, exited the scanner and were revaluated on the same scanner after a short delay. Images from both CT acquisitions were measured blindly by three radiologists. The radiologists manually measured the longest diameter of the target lesions on the two different scanners using a standard software. Lesions ranged from 1 to 8 cm in size. The absolute difference between scan measurements of single lesion ranged from 0 to 9 mm, with the greatest difference observed with the largest lesions and the greatest fractional differences observed with the smallest lesions. The potential impact of those measurements errors was simulated using statistical methods and found that aberrant assessments of partial response and progressive disease can occur as a result of measurement variance alone. For example, in this simulation, a 4-cm lesion has a measured range as a result of inter-measurement variance alone as broad as 3.5 to 4.5 cm, corresponding to approximately 12% change. Tumors with irregular edges, confluent or infiltrating boundaries pose the most significant challenges to data extraction and are highly observer dependent. Reliable diameter measurements in

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Table I. — Comparison between RECIST 1.0 and RECIST 1.1. RECIST 1.0

RECIST 1.1

Minimum target lesion size

≥ 10 mm (Spiral CT) ≥ 20 mm (conventional CT, MRI)

≥ 10 mm (CT + MRI) ≥ 15 mm (lymph nodes)

N° of measurable lesions, max per organ

Max 10 5 per organ

Max 5 2 per organ

Measurement

Uni-dimensional Long axis for all lesions

Uni-dimensional Lymph-nodes = short axis

PD definition-Target

20% increase in SOD from Nadir

20% increase in SOD + min 5 mm increase from Nadir

PD definition-Non target

Unequivocal progression

Substantial worsening, tumor burden has increased sufficiently

Lymph node measurements

None

Measured short axis, ≥ 15 mm for target, ≥ 10 mm to < 15 mm for nontarget, < 10 mm non-pathological

CR/PR confirmation

Required

Not required for randomized, controlled phase 3 trials

CR = Complete response PR = Partial response SD = Stable disease PD = Progressive disease NE = Non evaluable SOD = sum of diameters Nadir = The smallest sum on study Modified from reference 4.

Table II. — Time point response: patients with target (± non-target) disease (ref. 4). Target Lesions CR CR CR PR SD Not all evaluated PD Any Any

Non-target lesions CR Non-CR/Non-PD Not evaluated Non-PD or not all evaluated Non-PD or not all evaluated Non-PD Any PD Any

New lesions No No No No No No Yes or No Yes or No Yes

Overall response CR PR PR PR SD NE PD PD PD

CR = Complete response PR = Partial response SD = Stable disease PD = Progressive disease NE = Non evaluable.

“ground glass” opacities (Fig. 1), invasive lepidic carcinoma are especially problematic also, particularly if accompanied by pleural e ffusions. Beyond RECIST Three-dimensional evaluation Recent advances in CT technology, specifically volumetric data ac-

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quisition and image processing, allows volumetric tumor burden quantification (7). Some preliminary studies have supported the use of three-dimensional measurements techniques for assessing tumor size (8). An important theoretical advantage of volumetric measurements is that simply estimating overall tumor in an organ can eliminate the limitation of measuring two target lesions per organ (RECIST crite-

ria). In addition, volumetric measurement might be a better method to measure size changes of lesions that are confluent. Mozley and coworkers (9) have studied patients with lung cancers and have compared the reproducibility between long dia meter and volume measurements. They obtained a lesser variability in volume measurement than one- dimensional measurements and conclude that measurements of change

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Fig. 1. — Limitations of RECIST criteria in semi-solid lesions. 82-year old man with a semi-solid lesion located at the left upper lobe. A. Thin-slice CT performed at baseline revealed a solid lesion surrounded by “ground glass” opacity. Long axis of the whole lesion using RECIST criteria was measured at 40 mm. B. Thin-slice CT performed 6 months after baseline revealed a progression of the solid component. Long axis using RECIST criteria was unchanged. Clinical data were in favour of tumoral progression and the patient was operated. Pathology revealed a bronchial adenocarcinoma, classified pT1bN0.

in tumor volumes are adequately reproducible. Density analysis With the introduction of new cytostatic agents, central necrosis, density changes and cystic changes may occur before tumor shrinkage (Fig. 2). It has been suggested by several groups to include the measurement of density to the RECIST criteria on the basis of typical patterns of change observed in some categories of tumors and treatments. As an example, in gastrointestinal tumors, there is a decrease in tumor size at a lower magnitude and increase in tumor homogeneity and hypoattenuation with the treatment. A group from MD Alderson Cancer Center has suggested modifying the RECIST criteria by defining a 10% decrease in one-dimensional measurement or 15% decrease in density, as measured by Hounsfield units as a partial response (10). PET-CT evaluation The limitations of structural imaging modalities such as CT or MRI for

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accurately evaluating the response of tumors to non-surgical therapies are well known. Changes in tumor dimensions may occur slowly and incompletely. Biological parameters do change earlier, and these changes better reflect the actual tumor response. In this context, FDG-PET-CT imaging has a positive predictive value for N2 disease of 93%, compared to 66% for CT. The negative predictive value of PET is 75%, compared to 53% for CT (11). Moreover, a good metabolic response assessed by FDG-PET-CT is correlated with prolonged survival (12). Again, metabolic imaging is an exquisite method for the early quantitative assessment of the tumoral response (Fig. 3). As early as 2 days after the onset of treatment with gefitinib (an inhibitor of the EGF receptor), a decrease of FDG uptake can be measured by PET (13). This could help the clinician in deciding to discontinue a therapy in non-responding patients. Further studies are needed to better understand how FDG uptake reflects the multiple biological changes induced by these novel therapeutic agents.

Based on the literature supporting the use of 18F-FDG PET to assess early treatment response, quantitative PET criteria have been proposed to be used in clinical trials and possibly in clinical practice. Positron Emission Tomography Response Criteria in Solid Tumor (PERCIST) has been developed a few years ago and described extensively in a special issue of the Journal of Nuclear medicine in 2009 (14). Multimodal integration At present, many patients admitted for lung tumor work-up benefit from a multimodality approach combining a morphologic and functional imaging: MDCT, PET-CT, MR. The current challenge for the radiologist and the clinician resides in the integration of those different imaging modalities for an optimal exploitation of the data produced by the different sources. Many efforts are under way by several companies (Fig. 4: CT platform) to develop intelligent platform combining the different image modalities with fusion tools and different types of co-registration.

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YES COLOR !

C Fig. 2. — Inflammatory and cystic changes inappropriately assessed by RECIST criteria. 53-year old woman with bronchial adenocarcinoma of the left upper lobe. The patient was treated by chemotherapy and tyrosine kinase inhibitors (Sorafenib). A. Spiral CT examination performed at baseline revealed an irregular lesion located at the left upper lobe. B. Spiral CT examination performed 1 month later revealed a significant increase of tumoral long axis probably related to inflammatory changes. C. Spiral CT examination performed 2 months later showed cystic changes. Morphological criteria following RECIST were judged as inappropriate to assess the response to therapy in this case.

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Fig. 3. — Current limitations of morphological markers (RECIST 1.1) to evaluate the response of a tumour to therapy. A 46-year old man with NSCLC (squamous cell tumor) of the right inferior lobe initially staged as cT3N2M0 and treated with chemotherapy (Cisplatine, VP16) and radiotherapy. A. MDCT performed after intravenous contrast medium injection. Axial slice obtained at the level of the subcarina area (December 2010). A large subcarinal (station 7) is observed. Its density is homogeneous. B. MDCT performed after intravenous contrast medium injection. Axial slice obtained at the level of the subcarina area (March 2011). Note an oesophageal stent in relationship with post-radiotherapy esophagitis with severe stenosis. The subcarinal lymphadenopathy has decreased in density. Its short axis has slightly decreased but non significantly following RECIST 1.1. C. 18FDG- PET-CT acquired on December 2010, April 2011 and august 2011 respectively, showing the functional response to the therapy. On april 2011, The subcarinal lymph node has clearly reduced is SUV. Courtesy of Dr F.-X. Hanin, Nuclear Medicine Unit, Cliniques Universitaires St-Luc, Brussels, Belgium.

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Fig. 4. — Integration of multimodality tumoral response. The Multimodality Tumor Tracking application (Philips healthcare, Cleveland, OH, US) offers tools to assist clinicians in monitoring change in disease status including disease progression or assessment of therapy response using sequential PET/CT, SPECT/CT, MR, and CT exams, with automatic segmentation of target lesions and quantified results over time. A. Automatic delineation of the right upper lung tumor (in red) on PET-CT. Display of the SUV below each image at every time point. B. The modality provides an integration of PET-CT and volumetric CT with a table summarizing the different tumor volumes, SUV values at different time points. A schematic representation of the tumoral measurements is provided at the left lower corner of the screen.

References 1. World Health Organization. Who Handbook for Reporting Results of Cancer Treatment. Offset Publication, Geneva, Switzerland, 1979. 2. Park J.O., Lee S.I., Song S.Y., et al.: Measuring response in solid tumors: comparison of RECIST and WHO response criteria. Jpn J Clin Oncol, 2003, 33: 533-537. 3. Therasse P., Arbuck S.G., Eisenhauer E.A., et al.: New guide lines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Nat Cancer Inst, 2000, 92: 205-216. 4. Eisenhauer E.A., Therasse P., Bogaerts J., et al.: New response evaluation criteria in solid tumors: revised RECIST guidelines (version 1.1). Eur J Cancer, 2009, 45: 228247. 5. Spears C.P.: Volume doubling measurement of spherical and ellipsoïdal

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tumors. Med Pediatr Oncol, 1984, 12: 212-217. 6. Oxnard G.R., Zhao B., Sima C., et al.: Variability of lung tumor measurements on repeat computed tomography scans taken within 15 minutes. J Clin Oncol, 2011, 29: 3114-3119. 7. Zeman R.X., Fox S.H., Silverman P.M., et al.: Helical (spiral) CT of the abdomen. Am J Roentgenol, 1993, 160: 719-725. 8. Hopper K.D., Kasales C.J., Eggli K.D., et al.: The impact of 2D versus 3D quantification of tumor bulk determination on current methods of assessing response to treatment. J Comput Assist Tomogr, 1996, 20: 930-937. 9. Mozley P.D., Bendtsen C., Zhao B., et al.: Measurement of tumor volumes improves RECIST-based response assessment in Advanced lung cancer. Translational Oncology, 2012, 5: 1925. 10. Choi H.: Critical issues in response evaluation on computed tomography: lessons from gastrointestinal stromal tumor model. Curr Oncol Rep, 2005, 7: 307-311.

11. De Leyn P., Stroobants S., De Wever W., et al.: Prospective comparative study of integrated positron emission tomography-computed tomography scan compared compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy-proven stage IIIA-N2 Non-small-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol, 2006, 24: 3333-3339. 12. Eschmann S.M., Friedel G., Paulsen F., et al.: Repeat 18F-FDG PET for monitoring neoadjuvant chemotherapy in patients with stage III non-small cell lung cancer. Lung Cancer, 2007, 55: 165-171. 13. Sunaga N., Oriuchi K., Kaira K., et al.: Usefulness of FDG-PET for early prediction of the response to gefitinib in non-small cell lung cancer. Lung Cancer, 2008, 59: 203-210. 14. Wahl R.L., Jacene H., Kasamon Y., Lodge M.A.: From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors. J Nucl Med, 2009, 50: 122S-150S.

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ASSESSMENT OF LUNG TUMOR RESPONSE BY PERFUSION CT* E. Coche1 Perfusion CT permits evaluation of lung cancer angiogenesis and response to therapy by demonstrating alterations in lung tumor vascularity. It is advocated that perfusion CT performed shortly after initiating therapy may provide a better evaluation of physiological changes rather than the conventional size assessment obtained with RECIST. The radiation dose,the volume of contrast medium delivered to the patient and the reproducibility of blood flow para meters remain an issue for this type of investigation. Key-words: Multidetector-row – Computed tomography, lung cancer, perfusion.

Several studies suggested that perfusion CT may be potentially useful in the assessment of patients undergoing chemotherapy, radiation therapy, and laser therapy (1-10). Perfusion CT is a tool which in theory can quantify the real perfusion of tissues by applying mathematical models and dedicated software to calculate the delivery of contrast agent and therefore blood to tissues (9). Perfusion CT is based on three different requirements. The first is the administration of contrast medium, in a small amount at high flow rate in order to get a short and sharp bolus. The second is based on the repetition of CT acquisition on the same volume of interest over time, before and after the intravenous administration of iodinated contrast medium to allow the study of the variation of density with time. The third requirement is the selection of the arterial input. The placement of a region of interest (ROI) on an artery permits to obtain a density-time curve of the selected vessel and is expressed in HU/sec. This graph is then compared to the density-time curve obtained in the tissue being analysed, also obtained by placing a ROI to make the distinction between the amount of contrast medium within vascular structures and the amount of contrast medium present in the interstitium. Therefore, it is now possible to quantify perfusion. Several kinetic models can be used to calculate the distribution of the contrast medium in the intravascular space and in the interstitial compartment. The calculation of perfusion parameters is performed using dedicated softwares. Qualitative analysis consists of the analysis of color maps (Fig. 1) that are automatically generated by soft-

ware for every perfusion parameter: Blood volume, blood flow, mean transit time, permeability-surface area product. The tumoral perfusion can be evaluated on a subjective manner, when the observer visually analyses the heterogeneity of the colors generated on the color map, or in a objective manner, with the graphical representation of the distribution in classes of perfusion values of each voxel in histograms. Respiratory motions are potential factors hampering the reproducibility of perfusion parameters as well as the absolute values of CT-measured parameters. This aspect was evaluated in a study (5) with 11 lung tumor patients using two perfusion CT scanners obtained on a 16-MDCT scanner. The authors found that the absolute values and perfusion parameters in lung tumors were significantly influenced by motion and duration of data acquisition. However, this study included only a small number of patients and did not utilize new-generation CT scanners. The use of a 64- or 320-MDCT scanner can improve misregistration through more extensive coverage (16 cm in a single rotation), while reducing respiratory artefacts. The use of a respiration-gated perfusion CT is another potential solution to misregistration artifacts. Moreover, new perfusion software is currently available in daily practice, thus facilitating the evaluation of perfusion data sets. A crucial issue related to perfusion CT concerns the dose of radiation delivered to the patient and the contrast material, which is potentially toxic for the kidneys. Fraioli et al. (10) measured the radiation dose during perfusion CT at 21,7 mSv ± 1,6 using a 64-detector row dual-source scan-

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ner with a tube voltage at 100 kV and tube current at 120 mAs with an automatic tube current modulation. We have to be aware that the radiation dose delivered during this perfusion CT study is much smaller than those given during radiotherapy for lung cancer. Some experiments were conducted to evaluate (11, 12) the relationship between CT perfusion parameters and differentiation characteristics in lung tumors. Using first-pass perfusion imaging with 64-detector row CT in 45 peripheral lung carcinomas, no significant differences in perfusion parameters were found among different histological subtypes. Xiong et al. (12) found that CT perfusion characteristics, mainly blood flow values, were useful in assessing lung cancer differentiation. In this study, the authors found a decrease in CT perfusion parameters coincided with a decrease in the differentiation grade of lung cancer. Blood flow, blood volume, and peak enhancement intensity values were thus found to be lower in poorly differentiated lung cancer. The authors concluded that CT perfusion imaging may be a potential tool for the evaluation and early identification of tumor angiogenesis in addition to being able to assess tumor grade in vivo. Concerning monitoring therapy, several case studies revealed changes in tumor perfusion parameters in patients with NSCLC who were treated with “non-vascular targeting” agents. Wang et al. (1) found a significant decrease in blood flow and volume in a patient following two cycles of chemo-radiotherapy, while Kiessling et al. (4) described a reduction in tumor perfusion in a patient after two cycles of chemotherapy. The effects of chemotherapy and antiangiogenic agents have also been investigated (7, 10). The effects of angiogenesis and EGFR inhibitors were evaluated in a study including 23 patients with a dual-source CT at baseline and 3 and 6 weeks after

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Fig. 1 (A-F). — Patient addressed for adenocarcinoma of the right upper lobe (RUL). Transverse CT images obtained after injection of contrast medium at the level of the left pulmonary artery at baseline (A) and after 1 cycle of antiangiogenetic therapy (B) showed decrease of the tumor size in the RUL. Functional CT maps of mean blood volume at baseline (C) and after 1 cycle of antiangiogenetic therapy (D) were measured and decreased from 5.4 ± 6.5 mL/100 mL to 4.4 ± 6,1 mL/100 mL respectively. Functional CT maps of mean capillary permeability at baseline (E) and after 1 cycle of antiangiogenetic therapy (F) were measured and decreased from 5.9 ± 6.0 mL/100 mL/min to 3.3 ± 5,02 mL/100 mL/min respectively. Courtesy of Nunzia Tacelli, M.D. and Martine Rémy-Jardin, M.D., Ph.D., C.H.R.U. Lille, Hôpital Calmette, Boulevard du prof. J. Leclercq, 59037 Lille Cedex, France.

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treatment. Mean tumor perfusion decreased significantly from 39.2 mL/100 g/min at baseline to 15.1 mL/100 g/min at week 3 and 9.4 mL/100 g/min at week 6. Tumor perfusion was lower in RECIST responders versus non-responders at week 3 and week 6 respectively. Another experimental investigation performed by Fraioli et al. (10) assessed 45 patients with an unresectable NSCLC > 20 mm. Subjects underwent perfusion CT (64-detector row dual-source CT) at baseline and 40 days after treatment with chemotherapy and angiogenic inhibitors. Some patients also benefited from a follow-up perfusion CT 90 days after therapy. The authors showed that treatment-induced changes in perfusion may be identified using perfusion CT. They found that blood flow, blood volume, and permeability values were lower in responding patients compared with other patients. Discrepancies between perfusion measurements and RECIST evaluation were also observed. In approximately one-third of patients, the size of the lesion was considered stable at the first CT follow-up using RECIST criteria, although vascularisation parameters increased. In contrast, in the patients classified as stable disease based on RECIST, a proportion of subjects showed various changes in perfusion parameters, suggesting a tumor response to therapy. The authors emphasized the fact that

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macroscopic changes in tumor size (RECIST) did not reflect the biological changes induced by therapy. It is thus possible that perfusion CT performed shortly after initiating therapy may be more useful for clinical planning, as it provides a better evaluation of physiological changes rather than the conventional size assessment obtained with RECIST. References 1. Wang J., Wu N., Cham M.D., Song Y.: Tumor response in patients with advanced non-small cell lung cancer: perfusion CT evaluation of chemotherapy and radiation therapy. AJR Am J Roentgenol, 2009, 193 (4): 10901096. 2. Hegenscheid K., Behrendt N., Rosenberg C., et al.: Assessing early vascular changes and treatment response after laser-induced thermotherapy of pulmonary metastases with perfusion CT: initial experience. AJR Am J Roentgenol, 2010, 194: 1116-1123. 3. Fraioli F., Vetere S., Anile M., Venuta F.: Computed tomography perfusion: a new method to evaluate response to therapy in lung cancer. J Thorac Oncol, 2011, 6 (9), 1599-1600. 4. Kiessling F., Boese J., Corvinus C., et al.: Perfusion CT in patients with advanced bronchial carcinomas: a novel chance for characterization and monitoring? Eur Radiol, 2004, 14 (7): 1226-1233. 5. Ng C.S., Chandler A.G., Wie W., et al.: Reproducibility of Perfusion Para meters Obtained From Perfusion CT

in Lung Tumors. AJR Am J Roent genol, 2011, 197 (1): 113-121. 6. Tacelli N., Remy-Jardin M., Copin M.C., et al.: Assessment of non-small cell lung cancer perfusion: pathologic-CT correlation in 15 patients. Radiology, 2010, 257 (3): 863-871. 7. Lind J.S., Meijerink M.R., Dingemans A.M., et al.: Dynamic contrast-enhanced CT in patients treated with sorafenib and erlotinib for nonsmall cell lung cancer: a new method of monitoring treatment? Eur Radiol, 2010, 20 (12): 2890-2898. 8. Bellomi M., Viotti S., Preda L., D’Andrea G., Bonello L., Petralia G.: Perfusion CT in solid body-tumors. Part II: Clinical applications and future developments. Radiol Med, 2010, 115 (6): 858-874. 9. Petralia G., Bonello L., Viotti S., Preda L., d’Andrea G., Bellomi M.: CT perfusion in oncology: how I do it. Cancer Imaging, 2010, 10: 8-19. 10. Fraioli F., Anzidei M., Zaccagna F., et al.: Whole-tumor perfusion CT in patients with advanced adenocarci noma treated with conventional and antiangiogenetic chemotherapy: initial experience. Radiology, 2011, 259 (2): 574-582. 11. Li Y., Yang Z.-G., Chen T.-W., Chen H.-J., Sun J.-Y., Lu Y.-R.: Peripheral lung carcinoma: correla tion of angiogenesis and first-pass perfusion parmeters of 64-detector row CT. Lung cancer, 2010, 61: 44-53. 12. Xiong Z., Liu J.K., Hu C.P., Zhou H., Zhou M.L., Chen W.: Role of immature microvessels in assessing the relationship between CT perfusion characteristics and differentiation grade in lung cancer. Arch Med Res, 2010, 41 (8): 611-617.

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SPECIAL ARTICLE A midline sagittal brain view depicted in da Vinci’s “Saint Jerome in the Wilderness” M.M. Valença1,2, M. de F.V. Vasco Aragão1, M. Castillo3 It is estimated that around the year 1480 Leonardo da Vinci painted Saint Jerome in the Wilderness, representing the saint during his years of retreat in the Syrian dessert where he lived the life of a hermit. One may interpret Leonardo’s Saint Jerome in the Wilderness as St. Jerome practicing self-chastisement with a stone in his right hand, seemingly punching his chest repeatedly. The stone, the lion and a cardinal’s hat are conventionally linked to the saint. A skull was also almost always present with the image of the saint symbolically representing penance. With careful analysis of the painting one can identify the skull which is hidden in an arc represented as a lion’s tail. The image is of a hemicranium (midline sagittal view) showing the intracranial dura, including the falx and tentorium, and venous system with the sinuses and major deep veins. This may have been the first time when the intracranial sinuses and the major deep venous vessels were illustrated. Key-word: Radiology and radiologists, history.

It is estimated that around the year 1480 (1) Leonardo da Vinci (1452-1519), painted Saint Jerome in the Wilderness (tempera and oil on 103x75 cm walnut panel, Vatican Museums, Rome), representing the saint during his 4 years of retreat in the Syrian desert where he lived the life of a hermit. Many other painters have depicted Saint Jerome in their works including Bartolomeo Cavarozzi (1590-1625), Michelangelo Merisi da Caravaggio, 1571-1610), Francisco de Zurbarán (1598-1664), Palma Giovane (1548-1628), Louis Cretey (1635-1702), and Pieter Coecke van Aelst (1502-1556) among others (2). One may interpret Leonardo’s Saint Jerome in the Wilderness as St. Jerome practicing self-chastisement with a stone in his right hand punching his chest repeatedly. A skull, representing penance, almost always accompanied the image of the saint. In Renaissance art the skull also symbolized the transitory nature of life on earth or represented a hermit and his contemplation of death (2, 3). The skull has not been described as portrayed in this painting by da Vinci. After a careful analysis of painting we were able to identify a skull which is hidden in an arc represented as a

lion’s tail (Fig. 1). The image of the skull is actually a mid sagittal view that shows midline structures such as the falx and the tentorium and the venous system with the sinuses and the major deep veins (Figs. 1 and 2) (4). The lower part of the skull was cut laterally in such a way as to show the bone just below the transverse and sigmoid sinuses (Fig. 2). In this painting one can see the anatomical details of the different veins and sinuses, namely straight sinus, great vein of Galen, deep internal cerebral veins, superior vermian vein, superior and inferior sagittal sinuses, transverse sinus, sigmoid sinus, and the basal vein of Rosenthal (Fig. 2) (57). Above the skull an image of a head without the calvarium is seen (Fig. 1). A detail that may be interpreted as a folded scalp is seen in the lower part of the head as in a dissection of a human body designed to explore intracranial contents (Fig. 1). Leonardo da Vinci dissected a series of human cadavers in an attempt to understand superior cognitive functions (i.e. sensus imprensiva, sensus communis, memoria) through the study of intracranial contents (8, 9). His illustrations of the human skull contain an outstanding amount of anatomical details (8-13).

From: 1. Neurology and Neurosurgery Unit, Federal University of Pernambuco, Recife, Brazil, 2. Neurosurgery Unit, Hospital Esperança, Recife, Brazil, 3. Division of Neuroradiology, Division of Neuroradiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Address for correspondence: Dr M.M. Valença, M.D., Neurology and Neurosurgery Unit, Department of Neuropsychiatry, Federal University of Pernambuco, Cidade Universitária, 50670-420 Recife, Pernambuco, Brazil. E-mail: mmvalenca@yahoo.com.br

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He is credited with the first accurate depictions of the frontal sinus, the anterior and middle meningeal arteries and the anterior, middle, and posterior cranial fossae and in addition, he is considered to be the first scientific illustrator in the contemporary sense (10, 13). Charles O’Malley and John Saunders in their introductory text to the book Leonardo on the Human Body state that da Vinci’s earliest anatomical drawings, which have survived to the present day, are thought to date from c. 1487 (8). Rather than experience with real dissections of the human body, they hypothesized that at that time da Vinci was influenced by the works of Avicenna (A.D. 9801037), Claudius Galenus (Galen of Pergamon, A.D. 129-c. 200/c. 216), and Mondino De’Luzzi (c. A.D. 1275-1326) and animal dissections in addition to surface inspections of living human beings (8). It is believed that da Vinci had intended to write a treatise on anatomy in the late 1480s, since in plate 5 (dated 1489) he wrote the sentence “the book on the human figure” (14). It is known that da Vinci’s dissected human corpses at the Santa Maria Nuova Hospital in Florence and later in Milan at the Maggiore Hospital and at the Santo Spirito Hospital in Rome. He also collaborated with the anatomist Marcantonio della Torre (1478-1511) in the years 1510-1511 and it seems that he had access to a convict’s head in the year 1489 (15). Before 1489, little is known as to whether da Vinci actually had the opportunity to dissect human cadavers. It is conceivable that he was able to draw the skull without any direct

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B Fig. 1. — Leonardo da Vinci’s “Saint Jerome in the Wilderness”. A. The image is of a hemicranium (right side opening) showing the structure of the intracranial dura-mater, including the falx and the tentorium, and the venous system with the sinuses and major deep veins. B. Above the depicted skull, the image of a head without the calvarium is seen. The detail interpreted as a folded scalp (black arrow) can be seen in the lower part of the head, as in the dissection of a human body to explore the intracranial content.

bservation of human dissections o because skulls as well as the rest of the skeleton were easy to find in Europe in the second half of the XV century. But, in order to draw the intracranial contents with the deep venous system it must have been necessary to see a newly-dissected body in the first few hours or days after death and avoid putrefaction of the corpse. Moreover, the amount of anatomical detail observed in the painting here assessed representing the complex structure of the various vascular components must be a result of a thorough examination and meticulous dissections. This makes us wonder whether da Vinci had a chance to dissect a brain and its surrounding bony structures prior to

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Fig. 2. — The image is of a hemicranium (right side view) showing the structure of the intracranial dura-mater, including the falx and the tentorium, and the venous system with the sinuses and the major deep veins. A. Part of da Vinci’s “Saint Jerome in the Wilderness” was zoomed in to better show the anatomical details, illustrating the different veins and sinuses, namely (1) superior longitudinal sinus, (2) straight sinus, (3) inferior longitudinal sinus, (4) great vein of Galen, (5) deep internal cerebral vein, (6) vermian superior vein, (7) basal vein of Rosenthal, (8) transverse sinus, and (9) sigmoid sinus. B. A normal midline sagittal CT view of adult shows some of the same anatomic details illustrated by da Vinci in his painting.

conceiving the idea of painting Saint Jerome in the Wilderness. Some experts consider Saint Jerome in the Wilderness to be one of da Vinci’s unfinished works. Thanks to the wealth of detail found in Saint Jerome in the Wilderness we question whether he intended to be this way. Among his paintings Saint Jerome in the Wilderness (together with Adoration of the Magi) is one of the few credited as being unquestionably his own work. Other famous painters, notably Michelangelo, also depicted neuroanatomical structures in their paintings. In the Sistine Chapel, in the panel depicting The Separation of Light and Darkness, he painted a brainstem hidden in God’s

throat (16). Additionally, the panel titled The Creation of Adam can be interpreted as grossly also showing a simple diagram of a midline sagittal view of the skull and brain (17). Since both Michelangelo and da Vinci lived at the same time, anatomic dissections and the brain could have been a shared interest. In conclusion, da Vinci was a distinguished anatomist and a pioneer in the depiction of the intracranial venous sinuses and deep veins. The painting here discussed may be the first time that the intracranial sinuses and major deep venous vessels were illustrated indicating that this finding is of importance in the history of neurovascular anatomy and Renaissance art. This painting may be the

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BRAIN VIEW IN DA VINCI’S PAINTING — VALENC¸A et al

first midline sagittal image of the brain ever painted and it projection is akin to the commonly used views in magnetic resonance imaging or sagittal reformations of CT data. References 1. Feinberg L.J.: The Young Leonardo. Art and Life in Fifteenth-Century in Forence. Cambridge University Press (2011). 2. De Bles M.A.: How to Distinguish The Saint In Art By Their Costumes, Symbols and Attributes. Art Culture Publications/Wynkoop Hallenbeck Crawford Co, New York, (1925). 3. Ferguson G.: Signs and Symbols in Christian Art: With Illustrations from Paintings from the Renaissance, Oxford University Press (1966). 4. http://education.yahoo.com/reference/ gray/subjects/subject/193 (November 29, 2012)

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5. Ono M., Rhoton A.L. Jr., Peace D. & Rodriguez R.J.: Microsurgical anatomy of the deep venous system of the brain. Neurosurgery, 1984, 15: 621-657. 6. Curé J.K., Van Tassel P. & Smith M.T.: Normal and variant anatomy of the dural venous sinuses. Semin Ultrasound CT MR, 1994, 15: 499-519. 7. Schreiber S.J., Stolz E. & Valdueza J.M.: Transcranial ultrasonography of cerebral veins and sinuses. Eur J Ultrasound, 2002, 16: 59-72. 8. O’Malley C.D. & Saunders J.B.C.M.: Leonardo on The Human Body. Dover Publications, New York (1983). 9. Del Maestro R.F.: Leonardo da Vinci: the search for the soul. J Neurosurg, 1998, 89: 874-887. 10. Andrassy R.J. & Hagood C.O. Jr.: Leonardo da Vinci: anatomist and medical illustrator. South Med J, 1976, 69: 787-788. 11. Cavalcanti D.D., Feindel W., Goodrich J.T., Dagi T.F., Prestigiacomo C.J. & Preul M.C.: Anatomy, technology, art, and culture: toward a realistic perspec-

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tive of the brain. Neurosurg Focus, 2009, 27: E2. 12. Tascioglu A.O. & Tascioglu A.B.: Ventricular anatomy: illustrations and concepts from antiquity to Renaissance. Neuroanatomy, 2005, 4: 57-63. 13. Ione A.: Chapter 19: Visual images and neurological illustration. Handb Clin Neurol, 2010, 95: 271-287. 14. Gerrits P.O., Veening J.G.: Leonardo da Vinci’s “A Skull Sectioned”: Skull and dental formula revisited. Clin Anat. 2012, 19. doi: 10.1002/ca.22060. [Epub ahead of print] 15. Turner A.R.: Inventing Leonardo: The Anatomy of a Legend. University of California Press, (1994). 16. Suk I., Tamargo R.J.: Concealed neuro anatomy in Michelangelo’s Separation of Light from Darkness in the Sistine Chapel. Neurosurgery, 2010, 66: 851-861. 17. Meshberger F.L.: An interpretation of Michelangelo’s Creation of Adam based on neuroanatomy. JAMA, 1990, 264: 1837-1841.

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JBR–BTR, 2013, 96: 178-179.

LETTERS TO THE EDITOR Peritoneal carcinomatosis and prostatic cancer: a rare manifestation of the disease with an impact on management M. Ghaddab1, E. Danse1, J.P. Machiels2, A. Dragean1, L. Annet1, B. Tombal3

Dear Editor, As it has been recently noted in two papers published in the JBRTBR (1, 2), prostate cancer is the second cause of male-cancer related death. The role of radiologists is crucial at the early stage of the disease, for local and distant staging, and during the follow up of the patient. We would like to take the opportunity to report on an uncommon case of peritoneal carcinomatosis observed during the long term follow up of a patient having prostate cancer. Based on these findings, there was a need for change of therapy, with a positive impact on the outcome. Our 70 year-old patient has a diagnosis of prostate cancer since 8 years (2003), classified as Gleason 8 after surgery. Since 2009, he is treated with hormonal therapy (goserelin and bicalutamide). In June 2010, He presents asthenia requir-

ing medical advice. The blood tests are showing increased PSA level (from 33 ng/mL (02/09) to 407 ng/mL (06/10), nl < 4.0 ng/ml). An abdominal CT-scan is performed, showing a large amount of ascites in all the abdominal compartments, with tissular nodules closed to the right liver surface (Figs. 1 and 2). These findings were considered as signs of peritoneal carcinomatosis. Based on the clinical data, the PSA level and the imaging findings, chemotherapy is then initiated. Biological and imaging controls were normalized 9 months later, with persistence of a calcified centimetric nodule closed to the liver edge. At the present time, the patient disease is stable. Peritoneal carcinomatosis is frequently in the oncologic evolution of patients with colo-rectal cancer, gastric, pancreatic and gynecologic cancers (3). It has been uncommonly reported in prostate cancers (4-6).

Prostate cancer is frequently related to lymph node invasion, bone metastases and sometimes liver and brain localizations (4, 6, 7). Uncom mon metastases are reported in the eyes, the larynx and the peritoneal cavity (6, 7). When peritoneal carcinomatosis is detected in patients with prostate cancer, it can be an isolated finding or revealing the prostate cancer (6, 7). This can also be detected during surgery without being pre-operatively suspected; it can be also observed at the end stage of the disease (7). When histology of peritoneal nodule is available, it has been showed that neuroendocrine differentiation correlates with a poor prognosis (8). Some CT findings are suggestive of peritoneal carcinomatosis including the presence or ascites (a non specific finding), nodules in the fatty tissue of the peritoneal cavity (omentum, mesenteric roots, Douglas pouch), and nodules adjacent to the liver edge (8, 9). CT scan can help to

Fig. 1. — CT scan of the upper abdomen, after iodine contrast injection, showing perihepatic ascitis and hyperattenuating nodules in the Morison pouch (arrowheads), one of these being calcified (arrow). From: 1. Department of Medical Imaging, 2. Oncology Unit, 3. Urology Unit, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. Address for correspondence: Dr E. Danse, M.D., Ph.D., Dpt of Medical Imaging, St Luc University Hospital, Université Catholique de Louvain, 10 av. Hippocrate, B-1200 Brussels, Belgium. E-mail: Etienne.danse@uclouvain.be

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Fig. 2. — Abdominal CT performed 9 months after chemotherapy showing disappearance of the ascites and the peritoneal nodules, a part the calcified nodule of the Morison pouch (arrow).

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suggest the primary cancer: gynecological, colo-rectal or gastric origin, but with a low sensitivity. Prostate cancer is uncommonly suggested with CT: this is the role of digital rectal examination, blood test and biopsy, with the contribution of MRI. CT can help to suspect prostate cancer when pelvic lymph nodes or/ and bone lesions are detected (ribs, spine, pelvis and hips). In our case, peritoneal carcinomatosis was detected during the follow-up in a patient with an abdominal discomfort and abnormal blood tests. We did not have the histological proof of peritoneal carcino matosis but CT was highly suggestive. The final diagnosis of this complication was conclude based on the positive impact of the change of therapy. As a conclusion, peritoneal carcinomatosis is an uncommon finding in patients with prostate cancer. It can be detected during routine abdominal CT performed during the follow-up of this group of patients.

LETTERS TO THE EDITOR

The CT findings are similar to what is observed in colorectal and gynecologic cancers. References 1. Turkbey B., Basaran C., Boge M., Karcaaltincaba M., Akata D.: Unusual presentation of prostate cancer with generalized lymphadenopathy and unilateral leg edema. JBR-BTR, 2008, 91: 211-213. 2. De Visschere P., Oosterlinck W., De Meerleer G., Villeirs G.: Clinical and imaging tools in the early diagnosis of prostate cancer. JBR-BTR, 2010, 93: 62-70. 3. Glockzin G., Schlitt H.J., Piso P.: Peritoneal carcinomatosis: patients selection, perioperative complications and quality of life related to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. World J Surg Oncol, 2009, 7: 5. 4. Zagouria F., Papaefthimioub M., Chalazonitisc A.N., Antonioud N., Dimopoulosa M.A., Bamiasa A.: Prostate Cancer with Metastasis to the Omentum and Massive Ascites: A Rare Manifestation of a Common

179 Disease. Onkologie, 2009, 32: 758761. 5. Brehmer B., Makris A., Wellmann A., Jakse G.: Solitary peritoneal carcinomatosis in prostate cancer. Aktuelle Urol, 2007, 38: 408-409. 6. Lapoile E., Bellaïche G., Choudat L., Boucard M., El Belachany G., Ley G., Slama J.L.: Ascites associated with prostate cancer metastases: an unusual localisation. Gastroenterol Clin Biol, 2004, 28: 92-94. 7. Rodriguez Alonso A., Dominguez Freire F., Perez Garcia D., Ojea Calvo A., Alonso Rodrigo A., Rodriguez Iglesias B., et al.: Metastasis de adenocarcinoma prostatico en saco herniaro. Aportacio, de un caso. Actas Urol Esp, 1999, 23: 717-719. 8. Wynn S.S., Nagabundi S., Koo J., Chin N.W.: Recurrent prostate carcinoma presenting as omental large cell carcinoma with neuroendocrine differentiation and resulting in bowel obstruction. Arch Pathol Lab Med, 2000, 124: 1074-1076. 9. Pannu H.K., Bristow R.E., Montz F.J., Fishman E.K.: Multidetector CT of peritoneal carcinomatosis from ovarian cancer. Radiographics, 2003, 23: 687-701.

Variations of the Hepatic Artery B. Karaman, V. Akgun, S. Celikkanat1 Dear Sir, We read the article titled as ‘Multidetector CT of hepatic artery pathologies’ by Karaosmanoglu et al. (1), published in JBR–BTR (95: 345-349, 2012) with a great interest. This article will be a useful guide for radiologists in their future experiences. In the paper, MDCT angiography has been referred as a very fast and efficient method in identifying hepatic artery variations and pathologies for radiologists. The Authors conclude that MDCT gives both arterial and venous phase images in almost every plane that allows radiologists to inform the clinicians, more accurately and in a shorter time. The authors identified the hepatic artery variations observed nearly in half of the cases, with Michel’s classification method. This classification system was first described by Michel (2) who dissected 200 cadavers

to determine anatomic variations of hepatic artery in 1955. In the following years few studies describing hepatic artery variations have been published by Vandamme et al. (3) and Suzuki et al. (4) Covey et al. (5). The later literature reported few additional differences compared to Michel et al. (2). The standard hepatic artery anatomy was 61.3% by Covey et al., and 55% in Michel’s original report in 1955. The major difference was frequency of replaced left hepatic artery that was 2.63 times more frequent in Covey et al. (3.8% in 600 patients) compared to that of Michel’s report (10.0% in 200 cadavers). In our institution we have about 50 cases with Y-90 radioembolization. In these cases we embolize gastroduodenal and left gastric arteries. At the fourth week of embolization, we take hepatic angiograms and inject Y-90 substance. These hepatic angiograms indicate a large varia-

From: 1. Gulhane Military Medical Academy, School of Medicine, Department of Radiology, Ankara, Turkey. Address fror correspondence: Dr B. Karaman, M.D., Department of Radiology, Gulhane School of Medicine, Tevfik Saglam St., 06018 Etlik/Ankara, Turkey. E-mail: bulkaraman@yahoo.com

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tion and development of collaterals after the embolization. Additional to interindividual variability, there may be some differences even in the same patients depending of the condition. Therefore MDCT is mandatory for imaging and radiologists should consider this situation. References 1. Karaosmanoglu D., Erol B., Karcaaltincaba M.: Pictorial essay multidetector CT of hepatic artety pathologies. JBR-BTR, 2012, 95: 345-349. 2. Michels N.A.: Blood supply and anatomy of the upper abdominal organs with a descriptive atlas. Philadelphia, Pa: Lippincott, 1955. 3. Vandamme J.P.J., Bonte J., Van der Scheueren G.: A reevaluation of hepatic and cystic arteries: the importance of aberrant hepatic branches. Acta Anat, 1969, 73: 192-209. 4. Suzuki T., Nakayasu A., Kawabe K., et al.: Surgical significance of anatomic variations of the hepatic artery. Am J Surg, 1971, 122: 505-512. 5. Covey A.M., et al.: Variant hepatic arterial anatomy revisited: digital subtraction angiography performed in 600 patients. Radiology, 2002, 224: 542-547.

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IMAGES IN CLINICAL RADIOLOGY Duodenal duplication cyst complicated by hemorrhage C. Ruivo1, C. Antunes1, L. Curvo-Semedo1

A 61-year-old male presented to the hospital with a 5-day history of epigastric pain, vomiting and regurgitation. The physical examination was positive only for upper abdominal tenderness. Laboratory findings were unremarkable. Ultrasound examination was negative for gallstones or biliary dilatation. Abdominal contrast-enhanced CT showed a rim- enhancing cystic structure (mean internal density: 13 HU) (Fig. A, arrowhead) lateral to the lumen of the descending duodenum, which was narrowed and internally displaced (Fig. A, arrow). During hospitalization the patient’s clinical status deteriorated, with worsening of abdominal pain, which granted repetition of the CT. This showed that the peri-duodenal cystic lesion had significantly increased in size, and the contents were now high-attenuating (mean internal density: unenhanced scan – 66 HU, contrast- enhanced scan – 71 HU), in keeping with intra-lesional hemorrhage (Fig. B, asterisk). The lesion was surgically excised. The histopathological study was consistent with a duodenal duplication cyst complicated with hemorrhage due to the presence of ectopic gastric mucosa.

Comment Duodenal duplication cysts represent 4-5% of duplications in the gastrointestinal tract, and are thought to develop due to incomplete recanalization of the foregut during embryological development. They usually arise in the medial wall of the second and third portions of the duodenum, and typically do not communicate with the duodenal lumen. The cyst is generally lined by duodenal mucosa, but gastric mucosa and pancreatic tissue may be present in up to 15% of cases. Most duplication cysts manifest during the first year of life with symptoms of bowel obstruction. They seldom are symptomatic in adulthood, and are usually found incidentally at endoscopy or imaging performed for other reasons. However, they may be clinically silent for many years, and present in the adult usually with symptoms of obstruction or a palpable abdominal mass. If heterotopic gastric mucosa is present in the cyst wall, ulceration may occur, and the cyst may present with bleeding or perforation. Jaundice can occur due to biliary obstruction. Infected duodenal duplication cysts and pancreatitis due to compression or communication with the pancreatic duct have also been described. Rarely, carcinoma may develop inside a duplication cyst. On ultrasound, the lesion is hypo/anechoic and the wall of the cyst has a characteristic bowel wall appearance consisting of an echogenic inner mucosa surrounded by a thin hypoechoic halo of muscular layer; peristaltic waves through the cyst may also be seen. At CT, it usually manifests as a well-circumscribed fluid-filled structure with a thick slightly enhancing wall. Areas of high attenuation within the cyst may be evident, resulting from hemorrhage or proteinaceous material. Pancreatic ductal dilatation due to obstruction may also be noted. Infection may be suspected when the cyst shows a thick enhancing wall or septa and surrounding inflammatory changes. The presence of enhancing solid vegetation or mural nodules should raise concern for malignant transformation. Surgical excision is the treatment of choice, in order to alleviate symptoms, prevent pancreatitis and eliminate the risk of malignant transformation. However, when cyst removal is not possible, subtotal resection and/or internal derivation should be performed. Reference 1. Jayaraman M.V., Mayo-Smith W.W., Movson J.S., Dupuy E.D., Wallach M.T.: CT of the Duodenum: An Overlooked Segment Gets Its Due. Radiographics, 2001, 21: S147-S160.

1. Department of Radiology, Hospitais da Universidade de Coimbra – Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

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IMAGES IN CLINICAL RADIOLOGY Pelvic girdle enthesitis in spondyloarthritis C. Van Langenhove1, L. Jans1, L. Van Praet 2, P. Carron2, D. Elewaut2, F. Van Den Bosch2, K. Verstraete1

A 21-year-old woman was admitted to our hospital for a longstanding history of inflammatory type low back pain. There was no significant medical history. Physical examination revealed pressure pain of superior posterior iliac spines. MRI showed focal bone marrow oedema of the left sacroiliac joint in keeping with acute sacroiliitis (Fig. A). Moreover, bone marrow oedema due to inflammation of pelvic girdle enthesis was demonstrated in the right superior anterior iliac spine (Fig. B) and in the superior posterior iliac spine bilaterally (Fig. C). Diagnosis of spondlyoarthritis with enthesitis was made, treatment with nonsteroidal antiinflammatory drugs was started. Comment

The prevalence of spondylarthritides is estimated 1.5%. Imaging of the sacroiliac joints has an important role in diagnosing, classifying and monitoring spondylarthritides. MRI increasingly gains importance since it detects active inflammatory lesions long before radiographic changes become evident. Enthesitis is a primary clinical feature in spondyloarthritis. The enthesis are any point of attachment of skeletal muscles to the bone and represent a preferred site for inflammatory autoimmune disease to occur. The ASAS criteria for classification of axial spondylarthropathy include ‘enthesitis’: sacroiliitis on imaging (definite radiographic sacroiliitis or acute inflammation on MRI) concomitant with enthesitis classifies as axial spondylarthropathy. In our patient, both sacroiliitis and enthesitis were demonstrated in a single MRI examination, allowing definite diagnosis. MRI features of enthesitis include swelling of the enthesis, peritendinous soft tissue swelling, distension of adjacent bursae and bone marrow oedema near the tendon insertion. Reference 1. Sieper J., Rudwaleit M., Baraliakos X., et al.: The assessment of spondyloarthritis international society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis, 2009, 68: ii1-ii44.

1. Department of Radiology, 2. Department of Rheumatology, Ghent University Hospital, Gent, Belgium.

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IMAGES IN CLINICAL RADIOLOGY Active and structural lesions of the sacroiliac joints in spondyloarthritis L. Coeman1, L. Jans1, L. Van Praet2, P. Carron2, D. Elewaut2, F. Van Den Bosch2, K. Verstaete1

MRI gains importance in early diagnosis of spondyloarthritis as it detects active inflammatory and structural lesions well before radiographic changes become evident. A ‘positive’ MRI with bone marrow oedema of the sacro-iliac joint is a key criterion in current disease classification systems. A 36-year-old male was admitted to our department for morning stiffness and chronic buttock pain. There was no significant medical or family history. MRI of the sacroiliac joints showed active inflammatory as well as structural lesions. T1-weighted MR image (Fig. A) shows structural lesions: erosions and subsequent pseudowidening of the sacroiliac joint (short arrows), subchondral sclerosis (arrowhead) and periarticular fat deposition on the left-hand side (long arrows). No ankylosis was seen. STIR MR image (Fig. B) shows extensive bone marrow oedema on both sides of the right sacroiliac joint (arrows) in keeping with acute sacroiliitis. DNA testing for detection of HLA-B27 was positive. Diagnosis of undifferentiated spondyloarthritis with active and structural lesions was made. TNF-alpha blocker treatment improved patient mobility and relieved the buttock pain. No follow-up imaging was obtained. Comment

Seronegative spondyloarthopathy is a group of joint conditions that are not associated with rheumatoid factors, with prevalence estimated 1.5%. Five subgroups are distinguished: ankylosing spondylitis, reactive arthritis (Reiter’s syndrome), psoriatic arthritis, arthritis associated with inflammatory bowel disease and undifferentiated spondyloarthritis. Sacroiliac joint imaging is important for diagnosing and classifying the disease. MRI sequences include T1-weighted and fat-saturated T2-weighted or STIR images in semicoronal planes along the long axis of the sacrum. There is a growing consensus that there is no role for the use of gadolinium contrast in routine clinical practice. MRI gains importance since it detects active inflammatory lesions long before radiographic changes become evident. Moreover, MRI plays a key role in the ASAS (Assessment of Spondyloarthritis International Society) classification system for this group of joint conditions: a ‘positive’ MRI concurrent with at least 1 clinical sign of the disease allows classification as axial spondyloarthritis. MRI demonstrates active lesions (bone marrow edema, capsulitis, synovitis and enthesitis) as well as structural lesions (erosions, sclerosis, periarticular fat deposition, ankylosis). Of these lesions, only ‘bone marrow edema’ is regarded a definite sign of a ‘positive’ MRI for sacroiliitis. Radiologists should be aware that not all bone marrow oedema reflects sacro-iliitis: differential diagnosis includes sacral insufficiency fracture, tumour, infection (often with extensive soft tissue involvement), degenerative disease and osteitis condensans ilii. References 1. Sieper J., Rudwaleit M., Baraliakos X., et al.: The assessment of spondyloarthritis international society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis, 2009, 68: ii1-ii44. 2. Weber U., Ostergaard M., Lambert R., et al.: The impact of MRI on the clinical management of inflammatory arthritides. Skeletal Radiol, 2011, 40: 1153-1173.

Department of 1. Radiology, 2. Rheumatology, Ghent University Hospital, Ghent, Belgium.

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IMAGES IN CLINICAL RADIOLOGY Leiomyosarcoma of the great saphenous vein C. Werbrouck1, J. Marrannes1, P. Gellens2, B. Van Holsbeeck1, E. Laridon1 A 57-year-old man presented to his general practitioner with a palpable, painless mass in the right groin. There was no swelling of the ipsilateral leg. He was referred for diagnostic imaging. Ultrasound (US) identified a moderate circumscribed, heterogeneous hypoechogenic mass in the right groin, probably in or next to A the distal great saphenous vein, measuring approximately 18 × 25 × 26 mm. Power Doppler revealed a centrally strong vascular signal, with both arterial and venous signals (Fig. A). The origin of the mass was not entirely clear on US and subsequently an MRI and an US-guided puncture were performed. A homogeneous hypo-intense mass on T1 weighted imaging (WI) and slightly heterogeneous hyperintense lesion on T2 WI (Fig. B) was revealed, arising from the great saphenous vein, extending into the subcutaneous fat. The great saphenous vein was at least partially thrombosed, B C D with a thickened wall and a mild surrounding infiltration. There were no susceptibility artefacts on gradient echo. Intravenous injection of gadolinium resulted in a strong enhancement in of the lesion (Fig. C, D). Small superficial veins ran into the lesion. The soft tissues surrounding the mass were edematous. There were multiple, slightly enlarged inguinal lymph most parts nodes. No evidence for invasion of the adjacent inguinal canal or muscular structures was found. These finding were suggestive of a primary, possibly malign, tumor. Puncure of the lesion showed a spindle cell E F mesenchymal proliferation. Total resection of the lesion was performed (Fig. E, F), and anatomopathological examination showed a moderately differentiated intravascular leiomyosarcoma with limited pleiomorphic dedifferentiation (5-10%). A sub sequent CT of the thorax and the abdomen was negative for tumoral spread. Comment Leiomyosarcomas are aggressive soft tissue sarcomas arising from smooth muscle cells, and can be divided in three types according to their site of origin: soft tissue (most common), cutaneous (best prognosis) and vascular (arising from the muscular wall). Although five times more common than arterial leiomyosarcomas, primary venous leiomyosarcomas constitute for less than one in every 100,000 malignant tumours, and only 10% of these originate from the great saphenous vein. The inferior caval vein is the predominant venous location, accounting for almost half of the cases, followed by the pulmonary, renal, common femoral, saphenous, superior mesenteric, and ovarian veins, and superior caval vein. The development can be divided into three stages; nonocclusive stage (asymptomatic or nonspecific symptoms), occlusive stage (ranging from asymptomatic to phlebitis or deep vein thrombosis), and terminal stage (distant metastases, especially in the lungs and liver). Color Doppler US is highly reliable in the early, non occlusive stage. MRI and CT allow visualization of the tumor, determination of the venous origin, and relationship with surrounding structures. Current treatment of choice exists of limb-preserving surgery and adjuvant radiotherapy and/ or chemotherapy (1). Reference 1. Yfadopoulos D., Nikolopoulos D., Novi E., Psaroudakis A.: Primary superficial femoral vein leiomyosarcoma: report of a case. Surg Today, 2011, 41: 1649-1654.

1. Department of Radiology, 2. Department of Surgery, Stedelijk Ziekenhuis Roeselare, Roeselare, Belgium.

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IMAGES IN CLINICAL RADIOLOGY Pseudomyxoma peritonei due to mucinous adeno carcinoma of the appendix S. Idjuski1, I. Turkalj2, K. Petrovic2,3, F.M. Vanhoenacker4,5,6 A 60-year-old man was referred for evaluation of long-standing abdominal pain. CT scan of the abdomen showed a fluid-filled dilated appendix with mural calcifications (Fig. A, asterisk) and intraperitoneal low-attenuation mass like nodular formations (Fig. B, arrows) causing scalloping of liver contour (Fig. A, C, arrowheads). The patient underwent appendectomy and peritonectomy followed by uneventful postoperative recovery. Histopathological examination confirmed the radiological suspicion of pseudomyxoma peritonei (PMP) due to appendiceal mucinous adenocarcinoma.

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Comment PMP is a rare disease characterized by intraperitoneal spread of mucinous fluid producing neoplasms which originates from the appendix or ovaries. Inflammatory changes associated with peritoneal tumor formations can lead to fistula formations and adhesions which can cause chronic bowel obstruction. CT is a useful technique in distinguishing simple ascites from PMP since nodular nature of the mucinous material results in a suggestive finding such as hepatic scalloping. However, absence of scalloping does not rule out PMP. Sometimes septae or rim like calcifications could be identified within mucinous nodules. According to redistribution phenomenon, mucin producing cells only seed at peritoneal sites of relative stasis due to their low capability to adhere to the bowel wall that is in constant peristalsis. Therefore, the pouch of Douglas, both subphrenic spaces, and the surface of the liver and spleen are the most common involved sites. Optimal therapy is considered complete macroscopic tumor removal combined with heated intraperitoneal chemotherapy. The treatment is beneficial in controlling of symptoms, but no absolute cure is common. Reference 1. Lipson J.A., Qayyum A., Avrin D.E., Westphalen A., Yeh B.M., Coakley F.V.: CT and MRI of hepatic contour abnormalities. AJR Am J Roentgenol, 2005, 184: 75-81.

1. Emergency Centre, 2. Centre of Radiology, 3. Faculty of Medicine, Univer sity of Novi Sad, Novi Sad, Serbia, 4. Department of Radiology, AZ Sint-Maarten DuffelMechelen, Mechelen, 5. Department of Radiology, Antwerp University Hospital, Edegem, 6. University of Ghent, Faculty of Medicine and Health sciences, Ghent.

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JBR–BTR, 2013, 96: 185.

IMAGES IN CLINICAL RADIOLOGY Skull base bone hyperpneumatization E.J. Houet1, L.M. Kouokam2, A.L. Nchimi3 A 50-year-old male with a long standing history of compulsive Valsalva maneuvers, complaining of episodes of vertigo underwent head computed tomography. Axial CT slices at the level of the skull base (Fig. A) and the first cervical vertebrae (Fig. B) shows an extensive unusual pneumatization of both the body and lateral processes of the first cervical vertebrae (arrows), with air pouches dissecting planes between bone cortex and the periosteum around the occipital bone and the lateral processes of the first cervical vertebrae (arrowheads). These pneumatoceles cause no compression to the central nervous system and the cranial nerves.

Comment

Extent of temporal bone pneumatization varies greatly between individuals. There may be accessory sites of pneumatization caused by unlimited migration of air cells into the zygomatic and styloid processes of the temporal bone during embryogenesis. Pneumatization of the occiptal the bone and cervical vertebrae is very uncommon. Since the first description in 1940, only 12 other cases have been reported so far in the literature (1). Although anecdotic cases of posttraumatic cervico-occipital bone pneumatization via direct communication of the bones with air-containing structures have been reported (1), the vast majority of cases are caused by repetition of Valsalva maneuvers. Long term compulsive repetition of Valsalva maneuver cause hypertension in middle ear and induce diffuse bone loss by microfractures of the mastoid cavity. The bone erosion may lead to the formation of an indirect communication between Eustachian tube, the mastoid cells and through the synovial joints. In general, the main clinical manifestation of skull base hyperB pneumatization is a palpable mass under the scalp, due to a pneumatocele. Neurological disorders may occur by compression of the nervous system when the pneumatocele points toward the subdural space. In our case, the vertigo was likely caused by pressure sensitivity during Valsalva maneuvers. Soon after the patient was advised to control his compulsive Valsalva maneuvers, the symptoms improved but the psychiatric disorder went later out of control and the patient lost to follow-up. References 1. Petritsch B., Goltz J.P., Hahn D., Wendel F.: Extensive craniocervical bone pneumatization. Diagn Interv Radiol, 2011, 17: 308-310.

1. Department of Radiology, CHU Liege, Liege, Belgium, 2. Radiologist, Medical Imaging Unit, Centre Hospitalier de l’Ardenne, Belgium, 3. Department of Thoracic and Cardiovascular Imaging, CHU Liège, Liege, Belgium.

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JBR–BTR, 2013, 96: 186.

IMAGES IN CLINICAL RADIOLOGY Congenital azygos pseudocontinuity with right lower intercostal vein M.A. Houbart, Th. Couvreur, L. Gérard, A. Georgiopoulos, B. Desprechins1

We report the case of a neonate born at 384/7 weeks of gestation with median birth weight and size and in the 75th percentile for head circumference. Routine pregnancy follow up allowed the antenatal discovery of azygos continuation with absence of the inferior vena cava. Within the framework of a polymalformative assessment a low dose thoraco-abdominal angioscanner showed a complete absence of the supra renal and retrohepatic segments of the inferior vena cava (Fig. D, white arrow) while a substitute collateral circulation was provided by a dilated right intercostal vein (Fig. C), white arrow which appeared to be in continuity with the supradiaphragmatic azygos vein. The arch of the azygos vein was also dilated (Fig. A, B, white arrow). Comment

Absence of the retrohepatic segment of the inferior vena cava with azygos continuation is a rare congenital anomaly with a current prevalence of 0,6% (1). In order of frequency, it represents the second most common systemic venous return anomaly, after persistent left superior vena cava (1). Once frequently associated with severe congenital heart diseases, as well as polysplenia and asplenia, it is nowadays, since the advent of cross-sectional imaging, incidentally diagnosed in asymptomatic patients (1). Azygos continuation and absence of the inferior vena cava can be diagnosed using classic imaging techniques such as radiography, ultrasound, CTscanner and MRI. The aforementioned techniques will reveal absence of the retro-hepatic segment of the inferior vena cava and drainage of the hepatic veins into a short inferior vena cava segment, or directly into the right atrium. They will also demonstrate a blind-ended inferior vena cava at its cranial margin at level of renal pedicle, as well as an azygos vein of practically equal calibre to that of the aorta, in the classic forms. In our case, only the supradiaphragmatic segment of the azygos vein and its arch appear dilated, and communicate with a dilated right intercostal vein, which in turn communicates with the right renal vein. Also, we notice a hypoplastic infradiaphragmatic azygos vein associated with an increased (left) hemiazygos vein calibre. Congenital vascular anatomical variations, and in particular, inferior vena cava and azygos venous system congenital variations with azygos continuation are important to recognize and describe in order to avoid any diagnostic errors in the supradiaphragmatic and mediastinum region. Preoperative assessment of the cardiovascular surgical patient requires an adequate knowledge of vascular anatomical variations and malformations. The prognosis of azygos continuation depends on associated cardiac anomalies. Reference 1. Edward Bass A., Redwine M., Kramer L., Huynh P., Harris J.: Spectrum of Congenital Anomalies of the Inferior Vena Cava: Cross-sectional Imaging Findings. RadioGraphics, 2000, 20: 639-652.

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1. Dpt of Pediatrics Imaging, University of Liège, Liège, Belgium.

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Forthc. courses-96(3)_Opmaak 1 28/06/13 10:19 Pagina 1

JBR–BTR, 2013, 96: 187.

FORTHCOMING COURSES AND MEETINGS NATIONAL MEETINGS 12-13.09.13 ATELIER DE COLONOSCOPIE VIRTUELLE Liège, Clinique St Joseph Information: anne-marie.mandic@chc.be 04.10.13 RBRS Cardiovascular and Interventional Radiology Organization and information: Dr S. Grijseels

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