Consenso diagnostico riñon adulto by Diego J

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Rev Esp Patol. 2015;48(2):90---96

Patología R E V I S TA

E S PA Ñ O L A

D E

www.elsevier.es/patologia

REVIEW

The International Society of Urological Pathology Consensus Conference regarding the classiﬁcation, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors Antonio Lopez-Beltran a,∗ , Brett Delahunt b , John R. Srigley c , Lars Egevad d , Rodolfo Montironi e a

Department of Pathology and Surgery, Cordoba University Medical School, Spain Department of Pathology and Molecular Medicine, Wellington School of Medicine, University of Otago, Wellington New Zealand c Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada d Department of Oncology-Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden e Institute of Pathological Anatomy and Histology, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy b

Received 17 August 2014; accepted 12 September 2014 Available online 15 November 2014

KEYWORDS Renal cell carcinoma; ISUP; Classiﬁcation

∗

Abstract The International Society of Urological Pathology (ISUP) 2012 Consensus Conference has made recommendations regarding the classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. There was consensus that five entities should be recognized as new tumor entities: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell papillary RCC, MiT family translocation RCC (in particular t(6;11) RCC) and hereditary leiomyomatosis-associated RCC. In addition, three rare epithelial carcinomas were considered emerging or provisional entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK-translocation RCC. There were also a number of suggested modifications to existing WHO 2004 categories with the new classification to be known as the ISUP Vancouver Classification. Tumor morphotype, sarcomatoid/rhabdoid differentiation and tumor necrosis were identified as significant prognostic parameters for RCC. The ISUP Grading System was accepted with grades 1---3 of clear cell and papillary RCC being based upon nucleolar prominence, while extreme nuclear pleomorphism, or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed that chromophobe RCC should not be graded. Consensus guidelines were formulated for specimen handling and it was agreed that renal sinus invasion is present when the tumor is in direct contact with

Corresponding author. E-mail address: em1lobea@uco.es (A. Lopez-Beltran).

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The International Society of Urological Pathology Consensus Conference

fat or the loose connective tissue of the sinus, or if there is involvement of endothelial lined spaces within the renal sinus, regardless of size. The role of biomarkers in the diagnosis and assessment of prognosis of renal tumors was considered and panels of immunohistochemical markers were identiﬁed for use in speciﬁc differential diagnostic scenarios. © 2014 SEAP y SEC. Published by Elsevier España, S.L.U. All rights reserved.

PALABRAS CLAVE Carcinoma de células renales; ISUP; Clasiﬁcación

Encuentro de consenso de la Sociedad Internacional de Uropatología acerca de la clasificación, factores de pronóstico, estadificación y valoración inmunohistoquímica y molecular de los tumores renales del adulto Resumen La conferencia de consenso organizada por la Sociedad Internacional de Patología Urológica (ISUP) en 2012 ha hecho recomendaciones en relación con la clasificación, los factores pronósticos y la estadificación, y con la determinación de parámetros inmunohistoquímicos y moleculares en el estudio de tumores renales en el adulto. El consenso alcanzado reconoce 5 nuevas entidades tumorales: carcinoma renal tubuloquístico, carcinoma renal asociado con enfermedad renal quística adquirida, carcinoma renal papilar de células claras, familia de carcinomas renales asociados con translocación MiT (particularmente los tumores t(6;11), y carcinomas renales asociados con leiomiomatosis hereditaria. Tres formas raras de carcinoma han sido propuestas como entidades emergentes o provisionales: carcinoma renal de tipo tiroideo, carcinoma renal asociado con deficiencia de succinato dehidrogenasa B, y carcinoma renal asociado con translocación de ALK. El consenso también incluye la propuesta de modificación de la clasificación actualmente en vigor conocida como clasificación de la Organización Mundial de la Salud del 2004 de los tumores renales, generando una nueva clasificación conocida como Clasificación ISUP Vancouver de los tumores renales. Se reconocen el tipo histológico, y la presencia de diferenciación sarcomatoide/rabdoide, y/o necrosis, como parámetros pronósticos relevantes. El sistema de gradación ISUP se aceptó con grados 1---3 basados en la prominencia nucleolar de los carcinomas de células claras y papilares. La presencia de pleomorfismo nuclear extremo o de áreas sarcomatoides/rabdoides se definen como ISUP grado 4. También fue acordado que el carcinoma de tipo cromófobo no debe gradarse. Igualmente, se establecieron guías para la manipulación de muestras, incluyendo un acuerdo expreso que establece invasión del seno renal cuando el tumor está en contacto directo con la grasa o tejido conectivo del seno renal, o bien si se observa invasión de espacios vasculares tapizados por endotelio presentes en el seno renal, con independencia de su tama˜ no. El papel de diferentes biomarcadores en el diagnóstico y pronóstico de los tumores renales fue también discutido, emergiendo paneles específicos para diferentes escenarios, en particular en el área de diagnóstico diferencial. © 2014 SEAP y SEC. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.

Introduction

Consensus conference organization

The International Society of Urological Pathology (ISUP) acts as the international reference organization for urological pathology. Since its establishment in 1992, the Society has convened consensus conferences that have provided international guidelines for the classification of bladder tumors, Gleason grading of prostatic carcinoma, and the handling and staging of radical prostatectomy specimens.1 In 2012 the Society sought consensus on a variety of issues relating to recent advances in the field of renal neoplasia and this resulted in the formulation of a contemporary classification of renal tumors, the recognition of valid prognostic factors for renal cell carcinoma (RCC), including the establishment of guidelines for grading of these tumors, recommendations for specimen handling and staging and the development of panels of immunohistochemical stains to facilitate identification of tumor morphotypes.2---5

As is customary for consensus conferences coordinated by the ISUP, the organization of the conference was overseen by a steering committee, formed by experts in the process of consensus. Four key topics were identiﬁed by the steering group and working groups were assigned to each of these.6 1. 2. 3. 4.

classiﬁcation of renal tumors prognostic factors specimen handling and tumor staging immunohistochemical and molecular markers

Each working group had access to all relevant published data, including the recently publish renal tumor survey results from the European Network of Uropathoogy.7 Their task was to design a survey to canvas current opinion and identify speciﬁc areas of controversy. The completed

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92 survey consisted of 87 multiple choice questions as well as the possibility of adding comments if desired. The survey was circulated to all members of the ISUP in October 2011, with a cut-off date for return of replies by 20 November 2011. Replies were received from 206 members (North America 55%, Europe 26%, Australia and New Zealand 7%, Asia 7%, South America 4% and Middle East 1%). Working group participants and those members of the Society who had returned the survey by the cut-off date were invited to participate in the formal consensus conference in Vancouver, Canada on 17 March 2012 in conjunction with the Annual Scientiﬁc Meeting of the United States Academy of Pathology. The conference was attended by 133 voting delegates from 29 countries (North America 57%, Europe 23%, Australia and New Zealand 8%, Asia 6%, South America 4.5% and the Middle East 1.5%). The conference was divided into four sections, with the members of each working group presenting a comprehensive review of the literature and the results of the survey. A series of questions was then put to the meeting with a formal ballot being taken electronically. A majority of 65% of voting delegates was taken as a consensus in accordance with the established practice of the ISUP.8 A total of 63 questions were considered at the meeting and, of these, a consensus was achieved in 42 (67%).

The Vancouver classification of renal neoplasia During the consensus conference eight forms of renal neoplasia were proposed for recognition and of these five were considered to be sufficiently well defined to be included in the revised classification (Table 1). The remaining three tumors were designated as new and emerging entities. In addition to this, recommendations were made concerning refinements to tumor categories included within the 2004 World Health Organization (WHO) Renal Tumor Classification.

Table 1 New and emerging renal cell carcinomas (RCCs) and novel concepts identiﬁed at the 2012 ISUP Consensus Conference. New tumor entities Acquired cystic disease associated RCC Clear cell (tubulo) papillary RCC Hereditary leiomoyomatosis syndrome associated RCC MiT family translocation RCC (including t(6:11) RCC) Tubulocystic RCC Emerging tumor entities ALK-translocation RCC Succinate dehydrogenase B deﬁciency associated RCC Thyroid-like follicular RCC Novel concepts Multilocular cystic renal cell neoplasm of low malignant potential Hybrid oncocytic/chromophobe tumors Epitheloid angiomyolipoma: low/intermediate/high risk Cystic nephroma/mixed epithelial and stromal tumor of kidney

A. Lopez-Beltran et al.

New renal tumor entities A variety of morphotypes of RCC occur in patients with end-stage kidneys and in particular those with acquired cystic disease. Acquired cystic disease-associated RCC is a new morphotype characteristically seen in these kidneys, with the incidence increasing in patients having long-term dialysis.9 These tumors occur as nodules in the walls of acquired cysts and have a variety of histological patterns, with tumor cells showing prominent vacuolation resulting in a cribriform architecture. Oxalic acid crystals are almost always present. These tumors show a variety of genetic changes, with gains in chromosomes 1, 2, 3, 6, 7, 16 and Y being reported. Stage for stage these tumors appear to behave more aggressively than other RCC subtypes. Originally described as clear cell papillary RCC, clear cell (tubulo) papillary RCC occurs both sporadically and in association with acquired renal cystic disease.10 These tumors are well circumscribed and are often encapsulated. On microscopy they have a variable morphology with a tubular, cystic and/or papillary architecture. Tumor cells have a clear cytoplasm, exhibit positive immunoexpression of cytokeratin 7 and have a characteristic pattern of carbonic anhydrase IX staining. Genetically, mutations of the VHL gene or gains of chromosomes 7 and 17, typical of clear cell and papillary RCC respectively, are not seen. Although follow up of these tumors is limited, no cases of metastatic disease have been reported. While hereditary leiomyomatosis-associated RCC is included in the 2004 WHO classification, it was considered as a variant of type 2 papillary RCC.11 However, it has been recognized that they have a characteristic morphology and are now considered a unique morphotype of RCC.12 They are part of the hereditary leiomyomatosis RCC syndrome. This is autosomal dominant and is associated with germline mutations in the fumarate hydratase gene, sited at chromosome 1q42. The syndrome is characterized by cutaneous and uterine leimoyomas and one third of patients develop RCC. The renal tumors have a papillary, alveolar, solid or tubular architecture with the characteristic features being a large nucleus and a prominent nucleolus, with a clear peripheral halo. They behave aggressively and have a poor prognosis compared to other hereditary forms of RCC or clear cell and papillary morphotypes. Xp11 translocation RCC is included as a specific morphotype of RCC in the 2004 WHO renal tumor classification. These tumors have a breakpoint that involves the TFE3 transcription factor gene at Xp11.2. Tumors with fusion to one of a number of genes (ASPL, PRCC, NonO, PSF and CLTC) have been reported. A small group of translocation RCCs varies from this genetic profile. These show Alpha-TFEB gene fusion, resulting from t(6;11)(p21;q12) and are designated t(6,11) translocation RCC.13 At the meeting there was consensus that along with Xp11 translocation RCC, t(6,11) translocation RCC should be considered under the designation Microphthalmia Transcription Factor (MiT) Family Translocation RCC. These tumors most commonly occur in young adults and have a variety of morphologic patterns. Most typically these tumors are biphasic, consisting of large and small epithelioid cells. The small epithelioid cells form nests of rosettes clustered around basement membrane

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The International Society of Urological Pathology Consensus Conference material. These tumors express melanocytic antigens and are rarely positive for epithelial markers. The behavior of these tumors is yet to be fully characterized, although 10% of the 30 reported cases have developed fatal metastatic disease. Tubulocystic RCC had been previously described under various names and were considered a low grade variant of collecting duct carcinoma. Macroscopically, tubulocystic RCC is well circumscribed, having the appearance of complex multilocular ﬂuid ﬁlled cysts.14 Histologically, these tumors consist of tubules and cysts showing varying degrees of dilatation. The tumor cells have eosinophilic cytoplasm and typically have a large irregular nucleus and prominent nucleolus. While these tumors were originally thought to be of collecting duct origin, limited studies indicate gene expression similar to papillary RCC, with gains of chromosomes 7 and 17, and loss of Y being commonplace. While four cases of metastatic disease have been reported, most tumors are pT1-2 at diagnosis and appear to have an excellent prognosis.

Emerging and provisional tumor morphotypes Following the identiﬁcation of a variant of RCC resembling well differentiated follicular carcinoma of the thyroid gland, fourteen further cases have been reported in the literature. Designated thyroid-like follicular RCC, these tumors are tan brown, homogenous and well circumscribed. Microscopically they consist of tumor follicles of varying size containing dense eosinophilic colloid-like material.15 The genetics and immunohistochemical expression of these tumors are, as yet, not fully characterized although thyroid follicular cell markers, thyroglobulin and TTF-1 are negative. The majority of cases reported to date have shown an indolent behavior, although metastases to lymph nodes in two cases and a single case with pulmonary metastases have been reported. A fusion of the anaplastic lymphoma kinase (ALK) gene with the gene for the cytoskeletal protein vinculin (VCL) resulting from the translocation t(2:10)(p23;q22) has been reported in two tumors. VCL-ALK translocation RCC appear to have a characteristic appearance, consisting of cells with a polygonal to spindled morphology.16 While these two cases were associated with sickle cell trait, two further RCCs showing ALK fusion with different partner genes have been described, although neither of these showed a sickle cell association. More recently two additional cases of RCC demonstrating ALK fusion have been reported; however, in these cases the fusion partner is unknown. The third tumor designated an emerging RCC entity is Succinate Dehydrogenase B mutation associated RCC.17 These tumors are seen in patients within germline Succinate Dehydrogenase B mutation, which is associated with a syndrome characterized by pheochromocytoma, paraganglioma and type 2 gastrointestinal stromal tumors. Microscopically these tumors are characterized by the presence of compact nests of eosinophilic polygonal cells. Cytoplasmic vacuoles and pale eosinophilic cytoplasmic inclusions are commonly seen and these represent giant mitochondria. Less than ten cases have been reported to date and follow-up is limited. Of note, sarcomatoid change was identiﬁed in two patients

with metastatic disease, one of whom died of tumor related causes.

New concepts relating to recognized tumor types Multilocular clear cell RCC is recognized as a subtype of clear cell RCC and like clear cell RCC shows loss of heterozygosity at chromosome 3p. These tumors are characterized by the presence of multiple cysts lined by clear cells which exhibit low grade pleomorphism.18 Multiple follow-up studies have shown these tumors to have an excellent prognosis with no reports of either metastatic disease or tumor related deaths. In view of this favorable outcome, there was consensus that these tumors be re-designated as multilocular cystic renal cell neoplasms of low malignant potential. It is recognized that rare tumors consist of a mixture of cells having the morphologic features of oncoytoma and chromophobe RCC. Known as hybrid oncocytic/ chromophobe tumors (HOCT), these occur sporadically, as part of renal oncocytosis and in association with the BirtHogg-Dubé syndrome. Three variants are recognized: (1) a mixture of typical oncocytoma and chromophobe RCC cells, (2) scattered chromophobe cells displaying perinuclear halos and occasional binucleation in an otherwise classical oncocytoma, and (3) large vacuolated eosinophilic cells showing a mild to moderate degree of nuclear pleomorphism arranged in a nested oncocytoma-like pattern.19 These tumors show various genetic profiles that differ from both oncocytoma and chromophobe RCC. HOCT appears to behave in a benign fashion. Epithelial angiomyolipoma is recognized as having malignant potential, although it appears that not all of these tumors behave in this manner. There was consensus that these tumors should be divided on the basis of presence or absence of morphologic atypia. There was also near consensus (64%) that tumors be divided into low, intermediate and high risk groups, rather than simply classified as benign/malignant, based on the number of recognized malignant criteria present (metastases, necrosis, size >7 cm, extra-renal extension, renal vein infiltration and carcinomalike growth pattern).20 Mixed epithelial stromal tumor of kidney and cystic nephroma are benign tumors having both stromal and epithelial components. Although these tumors are classified separately in the 2004 WHO Renal Tumor Classification, they share similarities in clinical presentation and morphology. In addition both tumors show positive expression of estrogen and progesterone receptors and have a similar gene expression profile. In view of this there was consensus that these two tumors should be considered variants of the same neoplasm.

Prognostic markers Of the numerous potential morphological prognostic parameters for renal cell carcinoma, only ﬁve were considered by the consensus conference to be sufﬁciently clinically validated to be reported in routine practice.

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A. Lopez-Beltran et al.

Table 2

The ISUP grading system.a

Grade 1 --- nucleoli inconspicuous or absent of 400× magnification Grade 2 --- nucleoli prominent at 400× magnification Grade 3 --- nucleoli prominent of 100× magnification Grade 4 --- extreme nuclear pleomorphism, tumor giant cells and/or sarcomatoid/rhabdoid change). a

Applies to clear cell and papillary subtypes of renal cell carcinoma.

extreme forms of tumor de-differentiation, the morphotype of the original tumor should be reported. There was also agreement that, for sarcomatoid RCC, a minimum percentage of tumor area was not necessary for diagnostic purposes, although it was agreed that the percentage area of sarcomatoid component within an RCC should be reported. Recent studies have shown tumor necrosis within RCC to be of prognostic significance and this was supported by the conference. It was specified that both macroscopic and microscopic necrosis should be reported and that a percentage of the total area showing necrosis, within an individual tumor, should be specified.

The ISUP grading system

Specimen handling Several grading classifications for RCC have been proposed, being based upon architectural, cytoplasmic and/or nuclear features and of these the Fuhrman classification is in widespread use. The Fuhrman classification is a three tiered system in which nuclear size and shape, as well as nucleolar prominence are assessed simultaneously in order to assign a grade. Much debate has surrounded the utility of the classification and questions have been raised regarding its validity as a prognostic parameter.21 In particular it has been noted that the classification has poor reproducibility, that no recommendations are provided regarding the stratification of grading parameters if these give conflicting results, and that there are conflicting results in studies that correlate Fuhrman grading with overall and disease free survival. Recent studies have shown that, for clear cell and papillary RCC, assessment of nucleolar size alone for grading 1---3 tumors is a more powerful prognostic discriminator. At the consensus conference a grading system based upon nucleolar prominence was proposed and the ISUP Grading System for RCC was recommended as a substitute for Fuhrman grading. The ISUP System has four tiers (Grade 1 --- nucleoli inconspicuous or absent at 400× magnification; Grade 2 --- nucleoli prominent at 400× magnification; Grade 3 --- nucleoli prominent of 100× magnification, and Grade 4 --- extreme nuclear pleomorphism, tumor giant cells and/or sarcomatoid/ rhabdoid change) (Table 2). There was consensus that this grading system was applicable to clear cell and papillary RCC. In the absence of evidence that grading chromophobe RCC was of prognostic value, there was consensus that these tumors should not be graded.

Other prognostic factors There was consensus that for RCCs, tumor morphotype was of prognostic signiﬁcance. In particular it was noted that for all stages, both papillary and chromophobe RCC had a more favorable outcome than clear cell RCC. There was consensus that collecting duct RCC was associated with a poor prognosis and that clear cell (tubulo) papillary RCC had an excellent prognosis, with no instances of metastatic disease being noted in the limited number of cases reported to date. There was also consensus that type 1 papillary RCC was associated with a more favorable outcome than papillary RCC with type 2 morphology. Sarcomatoid and rhabdoid differentiation is recognized as being associated with high rates of tumor recurrence and metastasis.22,23 There was consensus that for these two

The conference provided consensus guidelines for handling of surgical specimens. There was agreement that tumor sampling should follow the model of 1 block per cm of tumor. In cases of multiple tumors, it was agreed that the largest five tumors should be sampled. For the assessment of extrarenal extension of tumor there was consensus that perinephric fat invasion should be reported when tumor was seen touching fat or extending as irregular tongues into perinephric tissue. There was also consensus that tumor in direct contact with renal sinus fat or the loose connective tissue of the sinus or infiltration of endothelial-lined spaces within the renal sinus should be considered as renal sinus invasion (TNM staging category pT3a). There was consensus that renal vein margin positivity required adherent tumor present at the tumor margin microscopically. While it was noted that lymph nodes are found in only <10% of radical nephrectomy specimens, it was recommended that examination of nephrectomy specimens for lymph nodes should be undertaken, but that this should be confined to the renal hilum fat only.

Diagnostic biomarkers While the morphotype of RCCs is usually discernible on examination of the hemotoxylin and eosin stained section, markers are often useful for confirming diagnosis in difficult cases. The main subtypes of RCC (clear cell, papillary, chromophobe and collecting duct RCC) each have typical immunostaining profiles and as such immunohistochemistry is useful in the diagnosis of these tumors. Immunohistochemistry stains can also be used to distinguish malignant tumors from benign tumors and tumor-like processes or to determine if renal tumors are of metastatic origin.23 At the conference, 87% of respondents reported that they would occasionally resort to immunohistochemistry for the subtyping of renal tumors. The majority of participants adopted a panel approach, with two or three markers being used in combination to resolve diagnostic problems. Differential diagnoses for which the use of immunohistochemistry was considered to be of diagnostic value were (1) renal oncocytoma and chromophobe RCC, (2) clear cell and chromophobe RCC, (3) epithelioid angiomyolipoma and RCC, (4) type 1 papillary RCC and metanephric adenoma, (5) TFE3 and TFEB translocation carcinomas and clear cell RCC, and (6) collecting duct RCC and high grade urothelial carcinoma.23

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The International Society of Urological Pathology Consensus Conference Table 3

Common diagnostic immunomarkers for renal tumors.

Tumor type

Positive expression

Negative expression

Clear cell RCC

vimentin, keratin, EMA, CD10, RCCm, Pax 2/8, CAIX keratin, CK7, AMACR, RCCm E-cadherin, Ksp-cadherin, CD117, EMA, CK, CK7 EMA, p63, CK7, HMWCK, Pax 2, Pax 8 CK7, Pax 2, Pax 8 TFE3, TFEB, CD10, RCCm Ksp-cadherin, CD117, Parvalbumin, S100A1 S100, WT1, CD57 CK7, Pax 2, Pax 8, CD10, Vimentin, AMACR HMB45, melan-A, SMA CK, CK7, CK20, p63, thrombomodulin, uroplakin III

CK7, Ksp-cadherin, parvalbumin

Papillary cell RCC Chromophobe RCC Collecting duct Clear cell (tubulo) papillary RCC Translocation RCC Oncocytoma Metanephric adenoma RCC with sarcomatoid features Angiomyolipoma Urothelial carcinoma

CD117, Ksp-cadherin, parvalbumin, WT1 vim, CAIX, AMACR CD10, RCCm, CK20 AMACR, RCCm CK (often weak) CK7, MOC31, EpCam, EABA, CD82 AMACR, RCCm CK, CD10, RCCm, Pax 2, Pax 8 RCCm, CD10, Pax 2, Pax 8

EABA indicates endogenous avidin-binding activity.

In response to questions in the survey, as well as at the consensus conference, participants were asked to nominate preferred immunomarkers for various diagnostic problems and guidelines were produced (Table 3). In addition to consideration of immunohistochemical markers for the diagnosis of renal neoplasms, the role of genetic studies was considered by the conference. It was agreed that in routine clinical practice these were of limited value. There was strong consensus that ﬂuorescence in situ hybridization should be undertaken to conﬁrm a diagnosis of translocation carcinoma if the diagnosis is suspected morphologically or if the patient is under 30 years of age. Other differential diagnoses where genetic studies were considered valuable were: mucinous tubular spindle carcinoma and papillary RCC with sarcomatoid areas and clear cell (tubulo) papillary RCC and either clear cell or papillary RCC.

Ethical disclosures

Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this study.

Conﬁdentiality of data. The authors declare that no patient data appear in this article.

Right to privacy and informed consent. The authors declare that no patient data appear in this article.

Conﬂict of interests

10.

The authors declare no conﬂict of interests. 11.

References 1. Delahunt B, Srigley JR, Montironi R, Egevad L. Urological pathology comes of age. Pathology. 2012;44:389---90. 2. Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, et al. The International Society of Urological Pathology (ISUP)

12.

Vancouver classification of renal neoplasia. Am J Surg Pathol. 2013;37:1469---89. Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J, et al. The International Society of Urological Pathology (ISUP) grading classification for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37:1490---504. Trpkov K, Grignon DJ, Bonsib SM, Amin MB, Billis A, Lopez-Beltran A, et al. Handing and staging of renal cell carcinoma: the International Society of Urological Pathology (ISUP) Consensus Conference recommendations. Am J Surg Pathol. 2013;37:1505---17. Tan PH, Cheng L, Rioux-Leclercq N, Merino MJ, Netto G, Reuter VE, et al. Renal tumors: diagnostic and prognostic markers. Am J Surg Pathol. 2013;37:1518---31. Delahunt B, Egevad L, Montironi R, Srigley JR. International Society of Urological Pathology (ISUP) consensus conference on renal neoplasia: rationale and organization. Am J Surg Pathol. 2013;37:1463---8. Algaba F, Delahunt B, Berney DM, Camparo P, Compérat E, Griffiths D, et al. Handling and reporting of nephrectomy specimens for adult renal tumours: a survey by the European Network of Uropathology (ENUP). J Clin Pathol. 2012;65:106---13. Egevad L, Srigley JR, Delahunt B. International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens: rationale and organization. Mod Pathol. 2011;24:1---5. Tickoo SK, dePeralta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young AN, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumorbearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006;30:141---53. Aydin H, Chen L, Cheng L, Vaziri S, He H, Ganapathi R, et al. Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol. 2010;34:1608---21. Kiuru M, Lehtonen R, Arola J, Salovaara R, Järvinen H, Aittomäki K, et al. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res. 2002;62:4554---7. Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007;31:1578---85.

Document downloaded from http://www.elsevier.es, day 26/06/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

96 13. Argani P, Yonescu R, Morsberger L, Morris K, Netto GJ, Smith N, et al. Molecular confirmation of the t(6;11)(p21;q12) renal cell carcinomas in archival paraffin-embedded material using a break-apart TFEB FISH assay expands its clinciopathologic spectrum. Am J Surg Pathol. 2012;36:1516---26. 14. Zhou M, Yang XJ, Lopez JI, Shah RB, Hes O, Shen SS, et al. Renal tubulocystic carcinoma is closely related to papillary renal cell carcinoma: implications for pathologic classification. Am J Surg Pathol. 2009;33:1840---9. 15. Amin MB, Gupta R, Ondrej H, McKenney JK, Michal M, Young AN, et al. Primary thyroid-like follicular carcinoma of the kidney: report of 6 cases of a histologically distinctive adult renal epithelial neoplasm. Am J Surg Pathol. 2009;33:393---400. 16. Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol. 2011;24:430---42. 17. Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, et al. Renal tumors associated with germline SDHB mutations show distinctive morphology. Am J Surg Pathol. 2011;35:1578---85. 18. Suzigan S, López-Beltrán A, Montironi R, Drut R, Romero A, Hayashi T, et al. Multilocular cystic renal cell carcinoma. A

A. Lopez-Beltran et al.

19.

20.

21.

22.

23.

report of 45 cases of a kidney tumor of low malignant potential. Am J Clin Pathol. 2006;125:217---22. Murakami T, Sano F, Huang Y, Komiya A, Baba M, Osada Y, et al. Identiﬁcation and characterization of Birt-Hogg Dube associated renal carcinoma. J Pathol. 2007;211: 524---31. Nese N, Martignoni G, Fletcher CD, Gupta R, Pan CC, Kim H, et al. Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: a clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratiﬁcation. Am J Surg Pathol. 2011;35:161---76. Sika-Paotonu D, Bethwaite PB, McCredie MR, William Jordan T, Delahunt B. Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma. Am J Surg Pathol. 2006;30:1091---6. Mazzucchelli R, Galosi AB, Scarpelli M, Lopez-Beltran A, Cheng L, Montironi R. Comtemporary update on pathology related issues of the adults renal neoplasms. Anal Quant Cytopathol Histopathol. 2014;36. Lopez-Beltran A, Cheng L, Vidal A, Scarpelli M, Kirkali Z, Blanca A, et al. Pathology of renal cell carcinoma: an update. Anal Quant Cytopathol Histopathol. 2013;35:61---76.