Autopsy & Case Reports by Editora Cubo

ISSN 2236-1960

v.3, n.4, out./dez. 2013

Autopsy and Case Reports 2013; 3(4): 1-3

Editorial

Medical education Geraldo Brasileiro Filhoa Brasileiro Filho G. Medicial education [editorial]. Autopsy Case Rep [Internet]. 2013; 3(4): 1-3. http://dx.doi.org/10.4322/ acr.2013.032

Over the years, producing good physicians has been a huge challenge worldwide. Over the last two decades, this issue has gained notorious interest in Brazil, due to the uncontrolled expansion of medical schools, many of which are unable to adequately prepare students for professional practice. In any community, good healthcare professionals are essential to promote health, prevent illness, and cure or rehabilitate patients. People do not easily tolerate failures or errors in medical practice, so it is understandable that society continuously demands excellent skills and competence among physicians. In this context, the irreplaceable role of qualified medical schools emerges. Medical education, which is a continuous process, comprises three stages: undergraduation, post-graduation, and continuous education. The first two stages have an established duration, while the latter, by definition, is endless. Undergraduation and post-graduation, as in any area of teaching and learning, are based on the combination of four essential elements: pedagogical projects, physical structures, teachers, and students. It is vital that these four components are present simultaneously and work together. Well-conceived educational projects, adequate physical infrastructure, and good teachers are not enough; one cannot expect competent professionals if the students are not minimally qualified to assimilate the theoretical knowledge and practical skills required. Therefore, one of our major contemporary challenges is to ameliorate the training of students during their elementary and secondary education to improve the

quality of medical education in the future. Without well-prepared students, higher education cannot achieve its goal. This has indeed been a justified concern. One of the most important requirements in every professional training process is the acquisition of a competence set (knowledge, skills, and attitudes), which is essential for the professional to do their job properly. In medicine, many general and specific competences are required. Therefore, the educational project, the laboratory infrastructure, the health facilities, and the teachers should be well articulated to enable the acquisition of these competencies. Besides the essential technical and scientific skills, it is still expected that physicians be prepared to practice with humanism, ethics, and professionalism.1 The knowledge that doctors need to acquire is notoriously enormous.2 Although they are necessary for good training, biological components alone are not enough to prepare competent professionals. Reasonable training in philosophy, anthropology, sociology, literature, and other content of the social sciences is absolutely essential for future doctors to understand the insertion of the person in their families and communities. Neglecting the fact that individuals continuously interact with and take part in the social environment is a serious mistake that should not be made in good medical schools. Much has been debated about the objectives, content, and methodology of medical training. Although it is possible to develop good professionals by different ways of teaching and learning, some principles are adopted worldwide.

Departamento de Anatomia Patológica e Medicina Legal - Faculdade de Medicina - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil.

Copyright © 2013 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

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Brasileiro Filho G.

A solid scientific basis on the origin, development, and evolution of diseases is absolutely essential to rationally guide the prophylactic, therapeutic, and diagnostic procedures. Therefore, the basic principles of structure and function of cells, tissues, organs, and systems, are the firmest pillar on which medical training stands. Understanding how different internal and external injuries interact with individual defense and adaptation mechanisms in the process of illness development is essential to intervention or treatment. Due to the extraordinary and rapid advances of knowledge in health sciences during the last few decades, many diseases can now be faced with a reasonable chance of treatment success, which has resulted in a tremendous increase in expectancy and quality of life for many people, who, even in the recent past, would have died prematurely or lived in conditions of great suffering. The gains brought by these conquests are well known and undeniable.

believing that their technical and scientific knowledge is sufficient to form disciples. Even worse, they almost always seek to replicate with their students the experiences they had when they were students.

Medical education can benefit from scientific progress in many ways. On one side, technically qualified teachers with a reasonable scientific background act more effectively with their patients and communities; on the other, they can induce scientific thinking in their students and encourage them to adopt scientific attitudes. Although many people consider research to be something done only in sophisticated laboratories and with animal experiments, scientific activities can be undertaken in any medical activity. As is well known, considerable knowledge progress can be achieved solely based on meticulous clinical observations. Thus, medical schools need to continually stimulate their students in their curiosity and desire to explore the natural environment, in which we, as human beings, are all involved. Therefore, it is expected that teachers have, beyond the competencies related to their tasks, scientific attitudes in daily and sometimes trivial situations, so the students can realize the importance of putting the scientific way of thinking into practice.

In Brazil, medical education is heterogeneous in several aspects. Besides the asymmetric geographical distribution, which in a certain way reflects the socioeconomic conditions and uneven development in the vast Brazilian territory, the quality of medical education varies greatly among different institutions. It is well known that the uncontrolled expansion of medical schools in the last 20 years has widely contributed to this reality. Without effective conditions to evaluate and monitor medical faculties, the Brazilian State failed to regulate the national system. Despite strong evidence of the inability to prepare good doctors, due to varied shortages many medical schools continue to graduate thousands of doctors every year without the required and desired qualifications. From what is expected regarding quality, many schools could not have been authorized to function, while several others should have been closed! In this context, the pivotal role of evaluations of institutions and courses emerges. Well-planned and carefully conducted periodic assessments represent a strong guarantee for minimum training quality. An emblematic example is the evaluation of post-graduation programs. Based on well-defined strategy, and counting on experienced evaluators, post-graduation courses in Brazil are an example of uncontested achievement. The success is such that several other countries have adopted the Brazilian model. Apart from providing a strong stimulus for better improvement, this assessment system does not allow unqualified courses to go further and form masters or doctors without minimum conditions. If a similar evaluation system had been applied in

The challenges imposed on the training process, and consequently for the medical schools, are great. One of them involves the necessity of counting on qualified, dedicated, and numerous teaching staff. By the way, this has been a big challenge for most medical faculties, as indicated by the few available evaluations of medical courses. Although well trained in their professional practice areas, the majority of teachers do not have the necessary training to teach.3 Therefore, they ignore and do not apply the basic pedagogical principles,

There have been several attempts to break with the traditional model of teaching and learning, which is based on the predominant role of the teacher. In this setting, much of the time the student stays as a mere spectator and information receiver, which is not always perceived critically. Another relevant issue is the correct appropriation of scientific progress on the complex learning process.4 Concerned with this reality, many schools around the world, including Brazil, adopted the studentcentered teaching method in which the student becomes responsible by his learning process. In this setting, the method called â&#x20AC;&#x153;problem-based learningâ&#x20AC;? (PBL) was well accepted in this country and is now adopted in many Brazilian medical schools.

Medical education

medical undergraduate courses, there is no doubt that the Brazilian medical training system would be much better than it is today. Another important principle is that the teaching and learning process in medicine should be essentially practical, be developed in teaching laboratories, and above all, be in the different places where doctors work. In other words, learning the profession takes place mostly in conjunction with the student, the teacher, and the patient. For good medical practice, alongside the many activities in out-patients’ clinics, health units, emergency services, and hospitals where these three participants take part, the important role or continuing education stands out. With the rapid technical and scientific progress nowadays, it is absolutely essential that all doctors keep reasonably up to date with the continued advances in the medical field. With the current facility to get technical and scientific information generated throughout the world, it becomes easier to track the daily advances and adopt innovative and more effective practices.

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contributing to the dissemination of good quality scientific information, and is a source of ongoing knowledge for both medical students and medical professionals. The editorial profile of Autopsy & Case Reports is based on the description of clinical cases with autopsy findings, representing a huge potential to help medical learning. Therefore, it is of paramount importance that this periodical becomes widespread and acts as a permanent source of updated information, which is just as useful and valuable for future doctors as for those who are already in the profession. This is another good reason to recognize its important educational role, which, besides filling a gap in Brazilian medical literature, represents a real and valuable instrument for training. At the same time, it is necessary that the academic community consider this journal as an effective vehicle for disseminating its anatomoclinical studies, favoring the consolidation and continued growth of the journal. In my opinion, the success of the journal will largely contribute to the improvement of medical education not only in Brazil but also around the world.

Among the several ways to keep professionally updated, especially in terms of diagnosis and treatment, the physician can count on clinicopathological conferences, in which clinical studies are correlated with the morphological findings obtained from biopsies or autopsies.5 As recognized worldwide, these conferences are one of the most effective ways to continue medical education.

REFERENCES 1.

Cohen JJ. Professionalism in medical education, an American perspective: from evidence to accountability. Med Educ. 2006;40:607-17. PMid:16836532. http://dx.doi.org/10.1111/ j.1365-2929.2006.02512.x

Fitzgerald FT. Curiosity. Ann Intern Med. 1999;130:70-2. PMid:9890857. http://dx.doi.org/10.7326/0003-4819-1301-199901050-00015

In fact, medicine became truly scientific when our ancestors had the curiosity and interest to know what went on in the cells, tissues, organs, and systems of people when they got sick and died. Anatomical findings and pathophysiological disorders produced by lesions give the basis for understanding signs and symptoms and to achieve a clinical diagnosis.

Perim GL, Abdalla IG, Aguilar-da-Silva RH, Lampert JB, Stella RCR, Costa NMSC. Desenvolvimento docente e a formação de médicos. Rev Bras Educ Med. 2009;33(Supl 1):70-82. Portuguese. http://dx.doi.org/10.1590/S010055022009000500008

Bleakley A. Broadening conceptions of learning in medical education: the message from teamworking. Med Educ. 2006;40:150-7. PMid:16451243. http://dx.doi.org/10.1111/ j.1365-2929.2005.02371.x

In this particular issue, the Autopsy & Case Reports journal has a singular role in

Rocha LOS. Sessões anatomoclínicas: valor pedagógico Lato Sensu. Belo Horizonte: Coopmed; 2010. 502 p. Portuguese.

Correspondence: Geraldo Brasileiro Filho Departamento de Anatomia Patológica e Medicina Legal - Faculdade de Medicina - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil. E-mail: gbrasil@medicina.ufmg.br

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Article Artigo Infective endocarditis: a history of the development of its understanding Stephen A. Gellera Geller SA. Infective endocarditis: a history of the development of its understanding. Autopsy Case Rep [Internet]. 2013; 3(4): 5-12. http://dx.doi.org/10.4322/acr.2013.033

ABSTRACT Inflammation of the inner layer of the heart, especially the valvular endothelium, chordae tendinae and mural endocardium was first recognized almost 350 years ago. Over the years it has had many names, but is now generally designated infective endocarditis (IE) and has an associated infectious agent. A sterile vegetative process can also affect the valves and is usually referred to as Libman-Sacks endocarditis. The developments of medical science that allowed for our understanding of this entity included refinement of the autopsy, medical microscopy, microbiology, and in recent years, molecular studies. Some observations were misleading but clarification particularly followed the reports of Morgagni, Osler and Libman. As understanding of the pathobiology of infective endocarditis grew so did the effectiveness of therapy. This paper provides a detailed history of the development of the concept of Infective endocarditis citing many key morphological observations and concludes with brief comments about current concepts of pathogenesis as well as a few remarks about therapy. Keywords: Endocarditis/diagnosis; Endocarditis/history. Endocarditis is the inflammation of the inner layer of the heart, usually involving the heart valves, both native and prosthetic. Other cardiac structures including the chordae tendinae, the mural endocardium, the sinuses of Valsalva and the interventricular septum can also be involved. The typical lesion of endocarditis is the vegetation, which in its earliest stages, consists of fibrin and platelets with no or few inflammatory cells. This beginning vegetation, characteristic of coagulopathic states, is known as non-bacterial thrombotic endocarditis or endocardiosis (NBTE). These uncomplicated histopathologic features are also typical of the vegetations of acute rheumatic fever1 and systemic lupus erythematosus, also known as Libman-Sacks endocarditis.2 a

When infectious agents and inflammatory cells supervene the term “infective” or “infectious” endocarditis is applied. Bacteria are most often the cause, but fungi can also be seen, particularly in immunodeficient (e.g., AIDS) or immunosuppressed (e.g., post-chemotherapy or post-transplantation) patients. For many years the terms “acute bacterial endocarditis” (ABE) and “subacute bacterial endocarditis” (SBE) were applied but, with the increasing recognition of a variety of causative organisms and their variable clinical presentations, the term “infective endocarditis” has come to be the standard. Staphylococci or streptococci were often identified in the “acute” cases, typically affecting a chronically damaged (e.g., calcific aortic stenosis) or congenitally deformed (e.g., bicuspid aortic) valve.

Department of Pathology and Laboratory Medicine – Weill Medical College of Cornell University – New York/NY – EUA.

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These forms of endocarditis were often destructive and many of the earliest descriptions of endocarditis highlighted the ulcero-necrotic behavior of the infection. Streptococcus viridans was recognized as the prototypic organism of subacute bacterial endocarditis3 which, characteristically, affected damaged and fibrotic valves of chronic rheumatic fever and which, also characteristically, usually took four to six months from diagnosis to death. The final illness of Gustav Mahler (1860-1911), the great conductor and composer, exemplifies this illness.4,5 Mahler had well-documented childhood rheumatic fever. His endocarditis developed while he was conductor of the New York Philharmonic Orchestra. Emanuel Libman (1872-1946), the brilliant physician who had studied with Theodor Escherich (18571911) and was himself an expert microbiologist, as well as a superb pianist, advised Mahler of his prognosis, allowing Mahler time to return to his beloved Vienna where he died approximately six months after consulting with Libman. Although endocarditis almost certainly occurred throughout the ages, there is no documentation of cardiac valvular/endothelial inflammation until Lazare Rivière (1589-1655) described,6-8 in 1646 (Table 1), a patient presenting with palpitations and irregular pulse who died after a relatively short course. At autopsy, “round carbuncles” were found in the left ventricle, resembling a “cluster of hazelnuts” and filling up the “opening of the aorta.” His description also suggested that the aortic valve was “hardened”.8 Although not unequivocally evocative of endocarditis, Laennec credited this report as the first account of aortic valve disease with vegetations of endocarditis.9 Rivière, who introduced the teaching of chemistry at Montpellier, was an advocate of the medicinal uses of antimony.10 De sedibus, et causis morborum per anatomen indagatis (the sites and causes of disease by anatomic investigations) is, along with Andreas Vesalius’ (1514-1564) 1543 De humani corporis fabrica libri septem (the structure of the human body in seen books), William Harvey’s (1578-1657) 1628 Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (an anatomical study of the motion of the heart and blood in animals) and James Watson’s and Francis Crick’s (1916-2004) 1953 paper on the structure of DNA,11 one of the four most important and influential publications in the history of medicine. This great

Geller SA.

work of Giovanni Battista Morgagni (1682-1771) (Figure 1) set the firm foundation for the practice of medicine by establishing clinical and pathologic correlations as the basis for the understanding of disease.12 In Section II of De sedibus … Morgagni described chronic rheumatic valvulitis with aortic valve endocarditis, correlated in great detail with the clinical course of the patient with the findings at autopsy. Both Giovanni Maria Lancisi (16541720) and Raymond de Vieussens (1641-1715) described lesions likely representing aortic valve infective endocarditis prior to Morgagni7, but neither the descriptive details nor the clinical correlations are as clear. Jean-Nicolas Corvisart (1755-1821) provided the first description of mitral valve endocarditis and introduced the term “vegetation,” alluding to soft valvular excrescences easily detached from the valves.13 The lesions reminded Corvisart of syphilitic warts and he incorrectly concluded that the cardiac lesions were another manifestation of that disease, even suggesting that anti-venereal treatment might be useful if the diagnosis could be established.7 Corvisart was physician to Napoleon. Every case dying on

Figure 1 – Giovanni Battista Morgagni (1682-1771). Dr. Stephen A Geller private collection.

Infective endocarditis: a history of the development of its understanding

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Table 1 – Key figures in the history of the pathology of endocarditis Year

Author Key publication

1674

Lazare Riviére (1589-1655) Opera Medica Universa

1771

Giovanni Battista Morgagni (1682-1771) De sedibus, et causis morborum per anatomen indagatis

1806

Jean-Nicolas Corvisart (1755-1821) Essai sur les maladies et les lésions organiques du Coeur et des gros vaisseaux

1815

Joseph Hodgson (1788-1869) On the Diseases of Arteries and Veins

1826

René-Theophile Hyacinthe Laennec (1781-1826) Traité des maladies des poumons et du coeur

1824

Jean Baptiste Bouillaud (1796-1881) Traité clinique des maladies du coeur

1852

William Senhouse Kirkes (1823-1864) On the effects which may result from the separation of fibrinous deposits from the valves or interior of the left side of the heart, and their mixture with the systemic blood On the effects which may result from the detachment of fibrinous deposits from the right valves of the heart

1869

Emanuel Fredrik Hagbarth Winge (1827-1894) [Mycosis endocardii] (Norwegian)

1870

Samuel Wilks (1824-1911) Capillary embolism or arterial pyaemia

1872

Hjalmar Heiberg (1837-1897) Ein Fall von Endocarditis ulcerosa puerperalis mit Pilzhildungen in Herzen (Mycoses endocardia)

1878

Edwin Klebs (1834-1913) Weitere Beiträge zur Enststehungsceshichte der endocarditis

1884

Byrom Bramwell (1847-1931) Diseases of the Heart and Thoracic Aorta

18851909

William Osler (1849-1919) On some points in the etiology and pathology of ulcerative endocarditis Galstonian lectures on malignant endocarditis Endocarditis infectieuses chroniques Chronic infectious endocarditis

1903

Hugo Schottmuller (1867-1936) Die Artunterscheidung der fur den Menschen pathogenen Streptokokken Munchen

1910

Max Friedrich Löhlein (1877-1921) Uber hamorrhagische Nierenaffectionen bei chronischer ulceroser Endocarditis

1910

Emanuel Libman (1872-1946) The etiology of subacute infective endocarditis

1912

George Baehr (1887-1978) Glomerular lesions of subacute bacterial endocarditis

Corvisart’s wards was autopsied14 and his book, Essai sur les maladies et les lésions organiques du coeur et des gros vaisseaux, is one of the classic texts of cardiac literature.10 Although best known for his studies of aneurysms, excellent illustrations of fungating as well as ulcerating/perforating aortic valve endocarditis were provided by Joseph Hodgson (1788-1869) in his 1815 book On the Diseases of Arteries and Veins.15 He used the term “fungus” to

describe “wart-like excrescences” occurring in an 18-year-old patient who also had abscess formation at the aortic root. This report was also the first to document peripheral embolization, later described in greater detail almost a century later by Löhlein and Baehr.16,17 A towering figure in the history of medicine, René-Theophile Hyacinthe Laennec (1781-1826) provided physicians with the first and, for the next two centuries, the most important aid to studying

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cardiac disease when he invented the stethoscope.9 In addition to many detailed studies of diseases of the heart valves he reported on a number of patients with infective endocarditis. Laennec noted that several of his endocarditis patients had no history of syphilis and he doubted that association proposed by his teacher Corvisart. Laennec described two forms of vegetations (verrucal and globular), suggesting that the globular form represented thrombus formation, a hypothesis eventually confirmed by others.7,8 Renowned as “the last of the great bloodletters,” Jean Baptiste Bouillaud (1796-1881) was, nonetheless, a fine physician who recognized the connection between rheumatic fever and heart disease and also recognized the value of digitalis as the “opium of the heart”.10,18 In his 1824 monograph, Traité cliniques des maladies du coeur et des gros vaisseaux, written with René-JosephHyacinthe Bertin (1757-1828)10,19, and a year later in his own book, Traité Clinique des maladies du Coeur, he introduced the terms “endocardium” and “endocarditis.” He described the various stages of endocarditis, from acute, early inflammatory changes with edema as well as suppurative cases to a second period of organization of the inflammatory process and, in the patients who survived, fibrotic valvular change with ultimate calcification and ossification, noting the regurgitation was associated with valvular retraction. His acute lesions correlate with both acute rheumatic valvulitis and, in those examples of suppuration, acute infective endocarditis. William Senhouse Kirkes (1823-1864) described a number of cases of infective endocarditis with peripheral embolization, emphasizing both systemic signs and symptoms.20 He greatly expanded the understanding of the embolic potential of vegetations of both the left and right heart valves. He particularly emphasized the effects of relatively large systemic emboli. William Osler would later acknowledge a debt to Kirkes for his lucid studies. Others, who studied infectious endocarditis, both before and after Kirkes, included Jean-Martin Charcot (1825-1893), Alfred Vulpian (1826-1887), Rudolf Virchow (1821-1902), Karl von Rokitansky (1804-1878) and others.7,8 It may be that both Virchow and Rokitansky recognized, but incorrectly interpreted, bacteria as “small granulations” in the vegetations they studied.7 The earliest suggestion that microbials were the cause of an endocarditis came from Emanuel Fredrik Hagbarth Winge (1827-1894), a student

Geller SA.

of Rudolf Virchow. Winge suggested that “parasitic particles” could penetrate the skin to enter the circulatory system and be disseminated to the cardiac valves, although the basis of his conclusion is not clear.7,21 The experimental injection of material from vegetation did not cause the death of a rabbit.7 Sir Samuel Wilks (1824-1911), the great physician at Guy’s Hospital, London, cited the work of Kirkes but concentrated his attention on the effects of embolic vegetations when they involved the small vessels of organs.22 He postulated that the systemic effects of “arterial pyemia” were usually the cause of death in patients with infective endocarditis, rather than the valvular vegetations themselves and emphasized that infective endocarditis should always be considered as a possible diagnosis in patients with fevers of unknown origin. He also suggested scarlet fever as the cause of the local valvular lesions.7 Three years after Winge a countryman, Hjalmar Heiberg (1837-1897) described a 22-yearold postpartum woman who became critically ill ten days after delivery and died a few weeks later. He described chains of cocci within the vegetation23,24 although his original interpretation of them was incorrect. Theodor Albrecht Edwin Klebs (18241913), also a student of Virchow, was a pioneering microbiologist who determined the etiology of diphtheria (Corynebacterium diphtheriae) and for whom the genus Klebsiella was named. In 1878 he proposed that all cases of endocarditis were due to an infectious organism.25 Other students of microbial organisms, including Louis Pasteur (1822-1895) and Robert Koch (1843-1910), helped develop microbiology as a distinct and increasingly sophisticated specialty and, although only peripherally involved with the study of endocarditis, certainly contributed to its understanding. Pasteur advocated newer approaches to obtaining blood cultures, including obtaining samples from various sites, evidence of his understanding of the vascular dissemination of infectious agents. Although the 1884 monograph by Sir Byrom Bramwell (1847-1931)26 provided little in the way of new information, it does offer a comprehensive, highly readable review of the information available at the time of its writing. There are outstanding and highly accurate illustrations of the macroand microscopic features of the various forms of endocarditis, which he described in considerable

Infective endocarditis: a history of the development of its understanding

detail. By the time of publication of Bramwell’s book, Gram staining for bacteria had become available and he noted their presence in both the vegetations and in the embolized material. Bramwell was one of the first to emphasize that left-sided valves were more often involved than right. He also highlighted the various ways, in which infective endocarditis presents, nothing that death was inevitable. One of the greatest physicians of all time, and one of the four principal founding physicians of the Johns Hopkins School of Medicine, Sir William Osler (1849-1919) (Figure 2) was a brilliant diagnostician, pathologist, writer and lecturer. He expanded greatly the understanding of the clinical manifestations and the pathology of infectious endocarditis.27 His Gulstonian lectures, emphasizing clinical-pathologic correlations, were based on his personal experience with more than 200 patients.28 He recommended simplification of the relatively complex classifications previously used, advocating that endocarditis be clinically distinguished as simple, with few or slight symptoms, and malignant, in which there were prominent, often destructive valvular lesions, and severe constitutional disturbances.27-30 He also emphasized that “sclerotic or malformed” valves were more prone to endocarditis. He pointed

Figure 2 – William Osler (1849-1919). (William Osler Photo Collection - image CUS_044-004_P – McGill Osler Library).

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to the Gram stain as the best way to identify bacterial cocci, which, in his estimation, were always present. A prolific writer, Osler’s clinical and morphologic descriptions are as valid today as they were then and remain valuable reading. Among other phenomena he clarified and clearly described are the characteristic painful red cutaneous nodules of bacterial endocarditis (“Osler’s nodes”), which were first described by Kirkes.20 Osler was the first to mention the association of platelets and fibrin in the vegetations postulating that they were derived from the blood stream and were not a product of the valve lesions.28 Hugo Schottmuller (1867-1936) was the first to isolate Streptococcus viridans from cases of what was then called chronic or subacute bacterial endocarditis, showing that “ordinary” streptococci produced hemolysis on blood agar plates, whereas the “little bacteria” from endocarditis patients did not.31 Others, including Libman, soon confirmed his 1910 report. 1910 was also the year of publication of Max Löhlein’s report of the hemorrhagic kidney lesions associated with infective endocarditis.16 Although embolic lesions were well known at this time, Löhlein provided a clear description of the histopathology of what came to be called “Löhlein embolic glomerulonephritis”, while also highlighting the renal manifestations of this complication. Emanuel Libman (1872-1946) (Figure 3) was a brilliant physician and was referred to as “the Jewish Osler.” He made invaluable contributions to the knowledge of infective endocarditis and helped refine understanding of the subacute forms of the disease.3,32 As Osler, he was a skilled pathologist as well as a particularly astute diagnostician. His 1909 paper, with Herbert Celler, described 43 patients, including 19 who were autopsied.32 Libman had studied with Theodor Escherich (1857-1911) and was a skilled and highly knowledgeable microbiologist. Importantly, blood cultures were obtained from 36 patients, 35 of whom had an “atypical,” nonhemolytic streptococcus. The paper also reviewed the 2,750 blood cultures made over a ten year period noting that the organism found in subacute bacterial endocarditis, which Libman determined to be identical to the Streptococcus viridans identified by Schottmuller two years previously31, was not found in any other form of endocarditis and that blood culture established the diagnosis. In another paper that year he showed that, despite the fact that bacteria may not be detectable and that healing

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Geller SA.

George Baehr (1887-1978), Libman’s student and then colleague at The Mount Sinai Hospital, New York, expanded on the contributions of Kirkes, Osler, Löhlein and others with comprehensive descriptions of the renal pathology in patients with subacute bacterial endocarditis.17 His 1912 report of morphologic studies of 34 patients, in 25 of whom Streptococcus viridans had been cultured, outlined the progression of the glomerular lesions from epithelial swelling to eventual necrosis and inflammatory cell infiltration. It was the young George Baehr, then a house officer, who was dispatched by Libman to Gustav Mahler’s hospital bed to obtain the blood culture sample from which Streptococcus viridans was isolated.4,7 In another version of the story, Baehr took the Fifth Avenue trolley carrying the necessary paraphernalia the two miles from Mount Sinai to New York’s Plaza Hotel to obtain the specimen.

Figure 3 – Emanuel Libman (1872-1946). Courtesy of Barbara Niss, Archivist, Mount Sinai Medical Center, New York.

can occur in a subgroup of patients with subacute bacterial endocarditis, the prognosis remained grim with patients dying from complications such as embolization to various organs as well as from glomerulonephritis. Although subacute endocarditis is sometimes referred to as “Osler disease” it was Libman who proposed the term. In 1924 Libman, along with Benjamin Sacks (1896-1971), described a previously unrecognized form a vegetative endocarditis from which organisms could not be isolated occurring in patients with systemic lupus erythematosus (SLE).2 This byproduct of a coagulopathy, later shown to be part of the antiphospholipid syndrome, is the same as the endocardial fibrin-platelet vegetation associated with various other coagulopathies and, in the non-SLE patient, is known as nonbacterial thrombotic endocarditis or endocardiosis (NBTE). It was noted that the vegetations could localize on either the atrial or the ventricular surfaces of the valve with extensions from the leaflet to the ventricular endocardium. The Libman-Sachs lesions was distinguished from the endocarditis of acute rheumatic fever, which it histologically resembles, by the absence of clinical evidence for rheumatic fever and, especially, by the absence of Aschoff bodies in the myocardium.2

Two decades later sulfur drugs would prove effective in treating at least a few patients with this dread disease33 to be followed, in another decade, by the highly effective penicillin34 and succeeding antibiotics. Infective endocarditis remains a potentially fatal disorder and establishing the diagnosis can be elusive.35-39 Newer organisms, requiring newer treatments, have been recognized. Controversies about therapy, including medical and surgical approaches, persist.36,40,41 Even the importance of pathology studies of infective endocarditis has come into question42 at the same time that the value of autopsy has been reaffirmed.43 In the last four hundred years this disorder has prompted some of the great writings in medical literature.

REFERENCES 1.

Narula J, Virmani R, Reddy KS, Tandor R. Rheumatic fever. Washington: American Registry of Pathology; 2000.

Libman E, Sacks B. A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med. 1924:33;701-37. http://dx.doi.org/10.1001/archinte.1924.00110300044002

Libman E. A study of the endocardial lesions of subacute bacterial endocarditis. Am J Med Sci. 1912;144:313-27. http://dx.doi.org/10.1097/00000441-191209000-00001

Christy NP, Christy BM, Wood GB. Gustav Mahler and his illnesses. Trans Am Clin Climatol Assoc. 1971;82:200-17. PMid:4934017 PMCid:PMC2441060.

Infective endocarditis: a history of the development of its understanding

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Levy D. Gustav Mahler and Emanuel Libman: bacterial endocarditis in 1911. Br Med J (Clin Res Ed). 1986;293:162831. http://dx.doi.org/10.1136/bmj.293.6562.1628

Rivière L. Opera medica universa. Francofurti: J.P. Zubrodt; 1674.

Contrepois A. Towards a history of infective endocarditis. Med Hist. 1996;40:25-54. PMid:8824676 PMCid:PMC1037058. http://dx.doi.org/10.1017/S0025727300060658

23. Ronald A. Perspectives on the history of endocarditis. In: Chan K-L, Embil JM, editors. Endocarditis: diagnosis and management. Berlin: Springer; 2006. p. 1-4. PMid:16553892. http://dx.doi.org/10.1007/978-1-84628-453-3_1

Lazare Riviere (1589-1655). The Mitral Valve [cited 2013 October 30]. Available from: http://themitralvalve.org/ mitralvalve/lazare-riviere.

24. Heiberg J. Ein Fall von Endocarditis ulcerosa puerperalis mit pilzbildungen imherzen (mycosis endocardia). Virchows Arch Path Anat. 1872;56:407-14.

Laennec RTH. De l’auscultation mediate, ou traite du diagnostic des maladies des poumons et du Coeur. Paris: J. A. Brosson & J.S. Chaude; 1819. 2 v. (A treatise on the diseases of the chest. Translated by J. Forbes. London: Underwood; 1821.)

25. Klebs E. Weitere Beiträge zur Enststehungsceshichte der endocarditis. Arch Exp Pathol Pharmacol. 1878;9:52.

10. Castiglione A. A history of medicine. Translated by E. B. Krumbhaar. New York: Alfred A. Knopf; 1941. 11. Watson J, Crick F. A structure for deoxyribose nucleic acid. Nature. 1953;4356:737-8. http://dx.doi.org/10.1038/171737a0 12. Geller SA. Il Bo, the foundations of modern medicine are established. In: Thiene G, Pessina AC, editors. Advances in cardiovascular medicine. Padova: Univ Degli Studi di Padova; 2002. 13. Corvisart JN. Essai sur les maladies et les lesions organique du Coeur et des gros vaisseaux. Paris: Mequigon-Marvis; 1806. (An essay on the organic diseases and lesions of the heart and great vessels. Translated by J. Gates. Boston: Bradford and the Read; 1812.) 14. Acherknecht E. A short history of medicine. New York: Ronald Press; 1955. 15. Hodgson J. A treatise on the diseases or arteries and veins. London: T. Underwood; 1815. 16. Löhlein M. Uber hamorrhagische Nierenaffectionen bei chronischer ulceroser endocarditis. Med Klin. 1910;6:375. 17. Baehr G. The etiology of subacute infective endocarditis. J Exp Med. 1912;15:330-47. PMid:19867526 PMCid:PMC2124924. http://dx.doi.org/10.1084/jem.15.4.330 18. Bouillaud JB. Traite clinique des maladies du coeur. Translated by E. Hausner. Paris: J.B. Bailliere; 1835. 2 v.

21. Winge EF. Mycosis endocardia. J Norsk Mag Laegevid (Forh Norske med. Sels-kab). 1869;23:78-82. 22. Wilkes S. Capillary embolism or arterial pyaemia. Guy’s Hosp Rep. 1870;15:29-35.

26. Bramwell B. Diseases of the heart and thoracic aorta. New York: D. Appleton & Co., Bond Street; 1884. 27. Osler W. On some points in the etiology and pathology of ulcerative endocarditis. J.W. Kolckmann; 1881. v. 1, p. 341-6. 28. Osler W. The Gulstonian lectures on malignant endocarditis. Lancet. 1885;I;415-8;459-64;505-8. http://dx.doi.org/10.1016/ S0140-6736(02)00827-9 29. Osler W. Endocardites infectieuses chroniques. Bull Mem Soc Med Hop Paris. 1908;26:794-6. 30. Osler W. Chronic infectious endocarditis. Quart J Med. 1909;2:219-30. 31. Schottmuller J. Endocarditis lenta. Zugleich ein Beitrag zur Artunterscheidung der pathogenen Streptokokken. Munch med Wschr. 1910;57:617-20, 697-9. 32. Libman E, Celler HL. The etiology of subacute infective endocarditis. Am J Med Sci. 1910;4:516-27. http://dx.doi. org/10.1097/00000441-191010000-00005 33. Seabury JH. Subacute bacterial endocarditis, experiences during the past decade. Arch Intern Med. 1947;79:1-21. http://dx.doi.org/10.1001/archinte.1947.00220070013001 34. Loewe L, Roseblatt P, Greene HJ, Russel M. Combined penicillin and heparin therapy of subacute bacterial endocarditis. Progress report of seven consecutive successfully treated patients. JAMA. 1944;124:44-9. http:// dx.doi.org/10.1001/jama.1944.02850030012003

19. Fye WB. Profiles in cardiology: Rene-Joseph-Hyacinthe Bertin. Clin Cardiol. 1993;16:273-4. PMid:8444005. http:// dx.doi.org/10.1002/clc.4960160323

35. Brunn NE, Habib G, Thuny F, Sogaard P. Cardiac imaging in infectious endocarditis. Eur Heart J. 2013, Jul 30. [Epub ahead of print] PMid:23900698. http://dx.doi.org/10.1093/ eurheartj/eht274

20. Kirkes WS. On some of the prinicipal effects resulting from the detachment of fibrinous deposits from the interior the heart, and their mixture with the circulating blood. Med-chir Trans. 1852;35:281-324. PMid:20895983 PMCid:PMC2104207.

36. Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother.

Autopsy and Case Reports 2013; 3(4): 5-12 2102;67:269-89. PMid:22086858. http://dx.doi.org/10.1093/ jac/dkr450 37. Keynan Y, Singal R, Kumar K, et al. Infective endocarditis in the intensive care unit. Crit Care Clin. 2013;29:923-51. PMid:24094385. http://dx.doi.org/10.1016/j.ccc.2013.06.011 38. Pierce D, Calkins BC, Thornton K. Infectious endocarditis: diagnosis and treatment. Am Fam Physician. 2012;85:98186. PMid:22612050. 39. Yamamoto S, Hosokawa N, Sogi M, et al. Impact of infectious disease service consultation on diagnosis of infective endocarditis. Scand J Infect Dis. 2012;44:270-5. PMid:22176644. http://dx.doi.org/10.3109/00365548.201 1.638317 40. Chirillo F, Scotton P, Rocco F, et al. Management of patients with infective endocarditis by a multidisciplinary

Geller SA. team approach: an operative control. J Cardiovasc Med. 2103;14:659-68. PMid:23907154. http://dx.doi.org/10.2459/ JCM.0b013e32835ec585 41. Sabe MA, Sretstha NK, Menon V. Contemporary drug treatment of infective endocarditis. Am J Cardiovasc Drugs. 2013;13:251-8. PMid:23640269. http://dx.doi.org/10.1007/ s40256-013-0015-6 42. Zauner F, Glück T, Salzberger B, et al. Are histopathologic findings of diagnostic value in native valve endocarditis? Infection. 2013;41:637-43. PMid:23378292. http://dx.doi. org/10.1007/s15010-013-0404-4 43. Fernandez Guerrero ML, Alvarez B, Manzarbeitia F, Renedo G. Infective endocarditis at autopsy: a review of pathologic manifestations and clinical correlates. Medicine. 2012;91:152-64. PMid:22543628. http://dx.doi.org/10.1097/ MD.0b013e31825631ea

Conflict of interest: None Submitted on: 1st November 2013 Accept on: 2nd December 2013 Correspondence: Department of Pathology and Laboratory Medicine Weill Medical College of Cornell University – New York/NY – EUA. E-mail: geller16st@gmail.com

Autopsy and Case Reports 2013; 3(4): 13-22

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Infective endocarditis with left to right intracardiac fistula due to Streptococcus anginosus - a rare complication caused by an even rarer bacterium Robert Forstera, Fernando Peixoto Ferraz de Camposb, Silvana Maria Lovisoloc, Vera Demarchi Aiellod, João Augusto dos Santos Martinese Forster R, Campos FPF, Lovisolo SM, Aiello VD, Martines JAS. Infective endocarditis with left to right intracardiac fistula due to Streptococcus anginosus - a rare complication caused by an even rarer bacterium. Autopsy Case Rep [Internet]. 2013; 3(4): 13-22. http://dx.doi.org/10.4322/acr.2013.034

ABSTRACT Although infective endocarditis (IE) has been described in reports dating from the Renaissance, the diagnosis still challenges and the outcome often surprises. In the course of time, diagnostic criteria have been updated and validated to reduce misdiagnosis. Some risk factors and epidemiology have shown dynamic changes since degenerative valvular disease became more predominant in developed countries, and the mean age of the affected population increased. Despite streptococci have been being well known as etiologic agents, some groups, although rare, have been increasingly reported (e.g., Streptococcus milleri.) Intracardiac complications of IE are common and have a worse prognosis, frequently requiring surgical treatment. We report a case of a middle-aged diabetic man who presented with prolonged fever, weight loss, and ultimately severe dyspnea. IE was diagnosed based on a new valvular regurgitation murmur, a positive blood culture for Streptococcus anginosus, an echocardiographic finding of an aortic valve vegetation, fever, and pulmonary thromboembolism. Despite an appropriate antibiotic regimen, the patient died. Autopsy findings showed vegetation attached to a bicuspid aortic valve with an associated septal abscess and left ventricle and aortic root fistula connecting with the pulmonary artery. A large thrombus was adherent to the pulmonary artery trunk and a pulmonary septic thromboemboli were also identified. Keywords: Endocarditis; Bicuspid Aortic Valve; Streptococcus anginosus; Aorta-pulmonary artery fistula; Pulmonary Embolism; Autopsy. CASE REPORT A 56-year-old male had a 2-month history of recurrent low-grade fever, occasional chills, cough, and progressive shortness of breath. He also described malaise and loss of appetite with an 8 kg

weight loss over the 2 last months. A few days before presentation to the emergency unit, his temperature rose to 39 °C and he had shaking, chills, and diaphoresis. Dyspnea supervened. He had been

Department of Internal Medicine – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. c Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. d Laboratory of Pathology – Instituto do Coração – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. e Diagnostic Imaging Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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Forster R, Campos FPF, Lovisolo SM, Aiello VD, Martines JAS.

treated with a 7-day regimen of levofloxacin and antipyretics for a presumed diagnosis of pneumonia, and studies for tuberculosis were initiated. There was a mild and temporary relief of symptoms. Past medical history included hypertension, uncontrolled type II diabetes mellitus, asthma, and smoking. The patient was unaware of previous heart disease. Approximately 2 months before the onset of symptoms, the patient underwent dental root canal

treatment. On admission showed an ill-appearing, obese (111.5 kg body weight) patient, was conscious and febrile (39.5 °C axillary temperature). Blood pressure was 140/60 mmHg, pulse 112 per minute, respiratory rate 44 per minute. With room air oxygen saturation was 69%. Diffuse expiratory wheezing and bilateral rales were present. The remainder of the examination was unremarkable except for mild lower limb edema. Capillary glucose determination was 330 mg/dL; other laboratory test results were unremarkable. Thoracic plain radiography demonstrated expressive pulmonary congestion and an apparently normal heart silhouette. The ECG showed sinus tachycardia without signs of ischemia, conduction block, or QRS axis deviation.

Figure 1 – Multidetector computed tomography (CT) of the thorax with coronal reconstruction showing diffuse bilateral ground-glass opacities, pulmonary parenchyma consolidation, and interlobular septa thickening.

The diagnosis of sepsis due to pulmonary infection was made and treatment with ceftriaxone plus clarithromycin and non-invasive respiratory support was started. Episodes of sudden respiratory worsening ensued, and the appearance of a diastolic parasternal murmur was detected. On hospital day three, blood cultures grew Gram-positive cocci, subsequently identified as Streptococcus anginosus (microbial identification system VITEK® 2 Compact, bioMerieux). Doppler echocardiography showed enlarged left cardiac chambers, left ventricle hypertrophy, left ventricle ejection fraction of 71%, and a thickened aortic valve with a vegetation as well as mild to moderate aortic insufficiency. Thoracic computed tomography (CT) showed diffuse and bilateral ground-glass

Figure 2 – Multidetector CT of the thorax. A – Coronal reformation. The presence of filling defects in the upper lobar and interlobar branches of the right pulmonary artery is evident (arrows); B – The axial plane showing filling defects in the trunk (yellow arrow) and right pulmonary artery branches (white arrow).

Infective endocarditis with left to right intracardiac...

opacity suggestive of pulmonary parenchyma consolidation with interlobular septa thickening (Figure 1). Laminar atelectasis in both lung bases and mediastinal lymphadenomegaly were present. Intraluminal filling defects of the pulmonary artery trunk, and of the segmental and subsegmental branches of the right pulmonary artery were

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detected (Figure 2). In the sagittal reconstruction, a filling defect communicating the aortic root and the pulmonary artery trunk was observed (Figure 3). Abdominal imaging showed an enlarged spleen with peripheral wedge-shaped hypoenhancing images in the spleen indicative of multiple infarctions (Figure 4). The antibiotic regimen was changed to penicillin and gentamycin, but the patient died soon after due to complete atrioventricular (AV) block followed by AV dissociation and asystole, unresponsive to advanced cardiovascular life support maneuvers.

AUTOPSY FINDINGS The external examination was unremarkable except for obesity.

Figure 3 – Multidetector CT of the thorax, sagittal reformation, showing the intraluminal filling defect in the pulmonary artery trunk communicating with the aortic root (yellow arrow).

The brain weighed 1398 g (reference value (RV): 1400 g) and showed an 8.0 long cm right temporo-parietal superficial hemorrhagic area, which, on section surface, was limited to the subdural space and meningeal surface.

Figure 4 – Multidetector CT of the abdomen. A and B – Coronal reformation showing multiple hypo-enhancing areas in the subcapsular splenic region (arrows), compatible with infarctions.

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Forster R, Campos FPF, Lovisolo SM, Aiello VD, Martines JAS.

Mild bilateral pleural serosanguineous effusion was present. The lungs were congested with increased volume and weight. The right lung weighed 1240 g (RV: 350-450 g) and the left weighed 927 g (RV: 250-350 g). A subpleural peripheral yellowish wedge-shaped infarct was present in the right lung, confirmed microscopically to be an ischemic infarction with pulmonary parenchyma necrosis (Figures 5A and 5B). Multiple thromboemboli of segmental branches were present in the pulmonary artery system (Figure 5C). Both the infarction and the thrombi showed Gram-positive cocci (BrownHopps modified Gram method) (Figure 5D). Many alveolar spaces were filled with polymorphonuclear leukocytes and fibrin and surrounded by areas of organization as well as pulmonary edema.

opening orifice in the left ventricle and a cleftshaped fistula connecting the aortic root with the right posterior sinus of the pulmonary valve and the pulmonary artery trunk were found (Figures 6A and 6D; 8A and 8B, 9A and 9B). The left-to-right heart fistulous path was partially obliterated by a large 3.0 cm thrombus adherent to the pulmonary valve cusp (Figures 6A and C). The histologic examination of the aortic valve vegetation (Figures 7B and 7C) and the thrombus into the pulmonary valve cusp showed many Gram-positive cocci (Figure 7D).

The heart weighed 477 g (RV: 350g). A firm white 1.5 cm yellow and friable vegetation was attached to a bicuspid aortic valve (Figures 6B and 7A) with an adjacent septal abscess, a subvalvar

The spleen was greatly enlarged (721 g; RV: 150 g), and was soft with scattered small, yellowish nodules throughout the parenchyma and a larger area of necrosis, The liver was congested and weighed 2880 g (RV: 1500 g). On microscopy, congestion and moderate macrovesicular steatosis were observed. Both kidneys were enlarged, and showed acute tubular necrosis. The remaining organs and tissues did not have significant alterations.

Figure 5 – Photomicrography of the lung. A – Ischemic infarction with necrosis of the pulmonary parenchyma (HE, 10X); B – The ischemic area of the lung with evidence of Gram-positive cocci by Brown-Hopps staining (BH, 4X); C – Thromboembolism of the pulmonary artery subsegmental branches (HE, 10X); D – The presence of Gram-positive cocci into the thrombosed pulmonary blood vessels (BH, 10X).

Infective endocarditis with left to right intracardiac...

Autopsy and Case Reports 2013; 3(4): 13-22

Figure 6 – Gross view of the opened right (A) and left (B) ventricular outflow tracts A shows a large 3.0 cm thrombus filling the right posterior sinus of the pulmonary valve, partially obliterating the left-to-right heart fistulous path (white arrow); In B note the vegetation on the distorted but originally bicuspid aortic valve (white arrow), the cleft-shaped organizing fistula connecting the aortic root with the pulmonary valve (black arrow), and the orifice of the fistula opening in the left ventricle, below the valve (arrow head); C – Photomicrography of the organizing pulmonary valve cusp thrombus with granulation tissue (HE, 20X); D – Photomicrography of the cleft-shaped organizing fistula (black arrow) (HE, 4X).

Figure 7 – A – Photomicrography of the aortic valve vegetation (HE, 1.25X); B and C – The presence of Gram-positive cocci by Brown-Hopps staining (BH, 1.25X, in B) (BH, 40X in C); D – Photomicrography of the pulmonary valve cusp thrombus with Gram-positive cocci (BH, 20X).

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Forster R, Campos FPF, Lovisolo SM, Aiello VD, Martines JAS.

Figure 8 – Gross view of the longitudinal cross-section of the heart through the right ventricular outflow tract. Panels A and B are complementary sections. Compare with the sagittal section obtained on CT (Figure 3); Note the huge abscess of the aortic valve and aortic root extending to the ventricular septum forming a cleft-shaped organizing fistula (white arrow). The septal abscess extends into the left ventricular wall (black arrow) and protrudes below the pulmonary valve. The left ventricular wall is hypertrophic (2,9 cm). RV- right ventricle, LV- left ventricle, PT- pulmonary trunk.

Figure 9 – A – Photomicrography of the cleft-shaped organizing fistula with granulation tissue (HE, 10X); B – Photomicrography of the abscess extending into the left ventricle (myocardium fibers intermingled with neutrophils) (HE, 20X).

DISCUSSION Endocarditis has been known since the autopsy findings of Lazare Rivière, a professor at Montpellier University (1589-1655). William Senhouse Kirkes in 1852 described a cerebral embolism associated with IE.1 However, the first comprehensive discussion of IE was in 1885 when

Sir William Osler gave the Gulstonian Lecture, calling the entity “malignant endocarditis.”2 Due to its variable clinical presentation, the diagnosis of IE often requires a high index of suspicion. Over time, diagnostic criteria have been validated and updated. In 1994, investigators at Duke University (Durham, NC, USA) modified the previously used von Reyn criteria to include

Infective endocarditis with left to right intracardiac...

echocardiography data and intravenous drug abusers.3 The “Duke criteria,” are now widely used for diagnosis. More recently, it received the amendment of positive serology for Q-fever among the major criterion.4 The incidence of IE is steadily increasing, affecting as many as 12.7 persons per 100,000 per year. The mean age is 60.8 years. The most important risk factors include prosthetic heart valves, intracardiac devices, congenital heart disease, valvular heart disease, and a previous history of IE. While degenerative valve disease, prosthetic valves, and invasive procedures became the most frequent predisposing factors for IE in developed countries, rheumatic valvular disease still remains the predominant factor in developing countries.5,6 Other risk factors include hemodialysis, and coexisting conditions, such as diabetes mellitus, HIV infection, and intravenous drug use.7,8 Diabetes mellitus is not only associated with the increased prevalence of non-rheumatic aortic valve disease, and therefore constitutes a risk factor for IE development, but also is associated with a worse clinical course and outcome.9,10 In one institutional series of native valve endocarditis, bicuspid aortic valve (BAV) was the most important cardiac predisposing factor for IE.11 BAV was detected at autopsy in our patient and represents a frequent congenital heart anomaly, affecting 1–2% of the population.12,13 It may be inherited in an autosomal dominant pattern occurring sporadically and is not only associated with aortic stenosis or regurgitation, but also represents an important risk factor for IE. Streptococci are the second most frequently involved etiological agents in IE, which are only surpassed by Staphylococcus aureus.5 In our case, the isolated pathogen was S. anginosus, which belongs to the Streptococcus milleri (S. milleri) group.14 Despite their close phylogenetic relationships with the other viridans streptococci, the clinical disease spectrum caused by members of the S. milleri group is different from that caused by other viridans streptococci, since they are more prone to abscess formation.15 In 1984, revising the nomenclature, Facklan16 divided the group of S. milleri into three species: S. intermedius, S. constellatus, and S. anginosus. The latter pertains to Lancefield groups F, A, C, and G, and the existence of some ungroupable strains.17 S. milleri is considered a part of the resident flora of the oral cavity and upper respiratory tract. The gastrointestinal tract and urogenital system may also harbor these bacteria but are less commonly colonized. In the

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mouth, S. milleri seems to have predilection for the gingival crevice and the fitting surface of dentures; therefore, it is associated with periodontal diseases such as gingivitis, periodontitis, and odontogenic abscesses. The latter was probably the source of the bacteremia in our case. Transient bacteremia is common and unsuspected in many cases and may follow vigorous tooth brushing. S. milleri bacteremia has been frequently documented after dental extraction or manipulation. Our patient undrewent a root canal treatment, which was most probably the triggering event. IE by S. milleri is infrequent, compared with other streptococci, and accounts for 4-15% of the cases of α-hemolytic streptococcal endocarditis.17 S. milleri has been previously implicated in cases of myocardial abscess associated with endocarditis.18,19 In a series of six cases of S. milleri endocarditis, all were caused by S. anginosus.20 Of the S. milleri group, S. anginosus seems to be the most frequently implicated as being the causative agent of IE.21 Bacteremia also follows invasion of portal circulation by intestinal flora, often, in older inidividuals, by transient, subclinical intestinal ischemia. Normal endothelium of the heart and its valves are resistant to colonization and infection by circulating bacteria. This is supported by the high frequency of bacteremia as opposed to the relatively low frequency of IE. As a reminder, bacteremia can occur not only as a result of invasive procedures, but also after daily events, such as chewing or tooth brushing. Endothelial disruption due to factors such as turbulent blood flow, inflammation, degenerative changes, or catheters and electrodes, can expose the tissue matrix, leading to platelet adherence and fibrin deposition. The resultant micro ulcers and micro thrombi predispose to bacterial adherence and infection.22 In our patient, the bicuspid valve and consequent abnormal leaflet function and motion likely led to turbulent blood flow and fibrin deposition which then served as a nidus for secondary infection. Fever and malaise are the most frequent sign and symptom of native-valve endocarditis. In a series of 50 patients with bicuspid valve endocarditis, the next most frequent sign was the presence of a heart murmur (60% of cases), which was regurgitant in 50% of cases. Other frequent symptoms/signs were night-sweats and weight loss, which occurred in more than one-quarter of patients. Dyspnea occurred in 36% of cases, a change in mentation in 22%, and anorexia in 18%.

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Forster R, Campos FPF, Lovisolo SM, Aiello VD, Martines JAS.

More than 10% of patients had myalgia, dry cough, diarrhea or vomiting, splenomegaly, chest pain, a non-specific vascular phenomena—such as rashes, splinters, or petechiae—arthralgia, and/or chills.11 Our patient presented with weight loss, dyspnea, anorexia, myalgia, dry cough, and chills. The lack of specificity of these symptoms may explain the delayed diagnosis. A high degree of suspicion for IE is warranted in febrile illnesses with non-specific symptoms.

abscess cases.28 In the present case, complete AV block developed as a final event, suggesting that the abscess, until that stage, had not involved the conduction system.

IE is associated with many non-cardiac as well as cardiac complications. Non-cardiac complications include neurologic complications occurring in 20-40% of IE patients, septic emboli, mycotic aneurysms, immune complex related vascular damage, such as in glomerulonephritis and splenic abscess.22 Cardiac complications are represented by hemodynamic disturbance due to valve dysfunction and/or myocardial abscess, which may result in fistula development with or without conduction abnormalities. In a series of 238 patients, more than 50% suffered from one complication, 25% suffered from two complications, and approximately 8% suffered from three or more complications.23 Although patients with a bicuspid aortic valve may be completely asymptomatic, the association of this condition with aortic stenosis, aortic regurgitation, and IE has been known for almost 150 years.12,24 Clinical diagnosis of this condition was unsatisfactory before the widespread use of cross-sectional echocardiography, approximately 25 years ago,12 but it may still pose a diagnostic challenge. In a series of cases over a 30year span, echocardiograms that were performed preoperatively showed a sensitivity as low as 35% for BAV. This rate is improving with modern echoimaging techniques.11 Aortic valve endocarditis can be complicated by periannular extension and abscess formation.25 which as many as 50% of cases.11,26 Increasing patient age and ﬁstulization of the abscess have been previously found to be independent risk factors in both 1-month mortality and overall operative mortality.27 Aortic perivalvular abscesses are associated with first-, second-, and third-degree heart block. High-grade AV block occurred in 10% of cases of IE in a series of aortic perivalvular abscess.27 Additionally, in a large cohort of patients with native aortic valve IE (bicuspid or tricuspid) with perivalvular complications, aorto-cavitary fistula formation was associated with a higher incidence of third-degree heart block (11% vs. 4%, p = 0.07) and moderate to severe heart failure (67% vs. 52%, p = 0.07) compared with unruptured periannular

Myocardial abscess is a potential complication of IE and may develop as a consequence a perivalvular infection or as a result of septic coronary emboli. Similar to fistula formation, it represents a class I, level B indication for urgent surgical intervention.22 An aorto-pulmonary fistula in left-sided IE due to S. aureus in a HIV-positive patient and IV drug user was previously reported.29 Septal myocardial abscess leading to later rupture and formation of a fistula to the pulmonary artery, was described in a 12-month-old child after surgical drainage of a leg abscess. S. aureus was isolated in blood cultures.30 To the best of our knowledge this is the first case report of a fistula involving the left ventricle, aorta, and the pulmonary artery due to S. anginosus IE in an adult patient. In our patient, the perivalvar and interventricular abscess and the fistula connected to the pulmonary trunk was somewhat capped by the pulmonary thrombus. The rapid clinical deterioration, manifested as respiratory insufficiency, was most likely due to the opening of the fistula into the pulmonary artery tree, with consequent overflow and pulmonary edema. Moreover, the giant thrombus attached to the endothelial surface of the pulmonary trunk was the source of subsequent septic embolization to the lungs, which worsened the clinical picture.

CONCLUSION Unfortunately, the diagnosis of IE was missed at the very beginning of this case when specific antibiotics might have prevented this disastrous outcome. The diagnosis of IE often requires a high index of suspicion. A prolonged history of fever and weight loss in a diabetic patient should strongly suggest IE and all efforts should be made to establish the diagnosis. The history of a recent dental procedure certainly should have raised the possibility of IE. Autopsy findings clarified the pathophysiology of this case, and provided further emphasis for the importance of autopsy in the modern era. We should recall the words of William Osler, the father of modern medicine: “Listen to your patient, he is telling you the diagnosis.”

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Osler W. The Gulstonian Lectures, on Malignant Endocarditis. Br Med J. 1885;1:467-70. http://dx.doi.org/10.1136/ bmj.1.1262.467

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Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994;96:2009. http://dx.doi.org/10.1016/0002-9343(94)90143-0

Li J, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000; 30:633-8. PMid:10770721. http://dx.doi. org/10.1086/313753

Bor DH, Woolhandler S, Nardin R, Brusch J, Himmelstein DU. Infective endocarditis in the US. 1998-2009: a nationwide study. PLoS One. 2013;8:e60033. PMid:23527296 PMCid:PMC3603929. http://dx.doi.org/10.1371/journal. pone.0060033

Fedeli U, Schievano E, Buonfrate D, Pellizzer G, Spolaore P. Increasing incidence and mortality of infective endocarditis: a population-based study through a record-linkage system. BMC Infect Dis. 2011;11:48-54. PMid:21345185 PMCid:PMC3051911. http://dx.doi.org/10.1186/1471-233411-48 Correa de Sa DD, Tleyjeh IM, Anavekar NS, et al. Epidemiological trends of infective endocarditis: a populationbased study in Olmsted County, Minnesota. Mayo Clin Proc. 2010;85:422-6. PMid:20435834 PMCid:PMC2861970. http:// dx.doi.org/10.4065/mcp.2009.0585

15. Lefort A, Lortholary O, Casassus P, et al. Comparison between adult endocarditis due to beta-hemolytic streptococci (serogroups A, B, C, and G) and Streptococcus milleri: a multicenter study in France. Arch Intern Med. 2002;162:24506. http://dx.doi.org/10.1016/j.clinmicnews.2005.09.006 16. Facklan RR. The major differences in the American and British Streptococcus taxonomy schemes with special reference to Streptococcus milleri. Eur J Clin Microbiol. 1984;3:91-3. http://dx.doi.org/10.1001/archinte.162.21.2450 17. Whitworth JM. Lancefield group F and related streptococci. J Med Microbiol. 1990;33:135-51. http://dx.doi.org/10.1007/ BF02014323 18. Levandowski RA. Streptococcus milleri endocarditis complicated by myocardial abscess. South Med J. 1985;78:892-3. http://dx.doi.org/10.1099/00222615-33-3-135 19. Wallis DE, Venezio FR, Montoya A, Cook FV, Scanlon PJ. Streptococcus MG-intermedius endocarditis. South Med J. 1986;79:1313-4. http://dx.doi.org/10.1097/00007611198507000-00034 20. Woo PCY, Tse H, Chan K, et al. “Streptococcus milleri” endocarditis caused by Streptococcus anginosus. Diagn Microbiol Infect Dis. 2004;48:81-8. http://dx.doi. org/10.1097/00007611-198610000-00034 21. Kitada K, Inoue M, Kitano M. Experimental endocarditis induction and platelet aggregation by Streptococcus anginosus, Streptococcus constelatus and Streptococcus intermedius. FEMS Immunol Med Microbiol. 1997;19:2532. PMid:14972375. http://dx.doi.org/10.1016/j. diagmicrobio.2003.09.011

Nesseler N, Launey Y, Mallédant Y. Infective endocarditis. N Engl J Med. 2013;369:784-5. PMid:23964952. http://dx.doi. org/10.1056/NEJMc1307282

Movahed MR, Hashenzadeh M, Jamal MM. Significant increase in the prevalence of non-rheumatic aortic valve disease in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2007;115:105-7. PMid:17318769. http://dx.doi.org/10.1055/s-2007-949656

22. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). Eur Heart J. 2009, 30:2369-413. http:// dx.doi.org/10.1111/j.1574-695X.1997.tb01069.x

10. Chirillo F, Bacchion F, Pedrocco A, et al. Infective endocarditis in patients with diabetes mellitus. J Heart Valve Dis. 2010;19:312-20. PMid:20583393.

23. Mansur AJ, Grimberg M, Da Luz PL, Bellotti G. The complications of infective endocarditis. A reappraisal in the 1980s. Arch Intern Med.1992;152:2428-32. PMid:19713420. http://dx.doi.org/10.1093/eurheartj/ehp285

11. Lamas CC, Eykyn SJ. Bicuspid aortic valve: a silent danger: analysis of 50 cases of infective endocarditis. Clin Infect Dis. 2000;30:336-341. PMid:10671338. http://dx.doi. org/10.1086/313646

24. Kahveci G, Bayrak F, Pala S, Mutlu B. Impact of bicuspid aortic valve on complications and death in infective endocarditis of native aortic valves. Tex Heart Inst J. 2009;36:111-6. http://dx.doi.org/10.1001/archinte.1992.00400240050008

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Forster R, Campos FPF, Lovisolo SM, Aiello VD, Martines JAS.

25. Omari B, Shapiro S, Ginzton L, et al. Predictive risk factors for periannular extension of native valve endocarditis. Clinical and echocardiographic analyses. Chest. 1989;96:1273-9. PMid:19436803 PMCid:PMC2676612.

28. Anguera I, Miro JM, Evangelista A, et al. Periannular complications in infective endocarditis involving native aortic valves. Am J Cardiol. 2006;98:1254-60. http://dx.doi. org/10.1053/euhj.1998.1240

26. Tribouilloy C, Rusinaru D, Sorel C. Clinical characteristics and outcome of infective endocarditis in adults with bicuspid aortic valves : a multicentre observational study. Heart. 2010;96:1723-9.

29. Obón Azuara B, Zalba Etayo B, Gutiérrez Cía I, Villanueva Anadón B. [Aorto pulmonary fistula: left-sided infective endocarditis in HIV and intravenous drugs abuser patient. Review of the literature]. An Med Interna. 2007;24:54750. Spanish. PMid:17056342. http://dx.doi.org/10.1016/j. amjcard.2006.06.016

27. Choussat R, Thomas D, Isnard R, et al. Perivalvular abscesses associated with endocarditis: clinical features and prognostic factors of overall survival in a series of 233 cases: Perivalvular Abscesses French Multicentre Study. Eur Heart J. 1999;20:232-41. PMid:20478858. http://dx.doi. org/10.1136/hrt.2009.189050

30. Hershenson JA, Baker PB, Rowland DG. Ruptured Myocardial Abscess Causing Left Ventricle to Pulmonary Artery Communication in an Infant With Community-Associated Methicillin-Resistant Staphylococcus aureus Endocarditis. Arch Path Lab Med. 2011;135:1057-60. PMid:21810000. http://dx.doi.org/10.5858/2010-0144-CRR1

Conflict of interest: None Submitted on: 30th October 2013 Accept on: 7th December 2013 Correspondence: Departamento de Clínica Médica Hospital das Clínicas Faculdade de Medicina da USP Av. Enéas Carvalho de Aguiar, 155 – São Paulo/SP – Brazil CEP: 05403-000 – Phone: +55 (11) 3069-6412 E-mail: robertforster.ufrj@gmail.com

Autopsy and Case Reports 2013; 3(4): 23-8

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Intracardiac metastasis of squamous cell carcinoma of the penis Sheila Aparecida Coelho Siqueiraa, Camila Satie Tomikawaa Siqueira SAC, Tomikawa CS. Intracardiac metastasis of squamous cell carcinoma of the penis. Autopsy Case Rep [Internet]. 2013; 3(4): 23-8. http://dx.doi.org/10.4322/acr.2013.035

ABSTRACT Penile cancer shows variable incidence in different countries with a higher prevalence in developing countries. Squamous cell carcinoma represents the most common histologic type. The seventh decade of life corresponds to the mean age at diagnosis, but it is not an unusual diagnosis among young adults. Most cases present as “in situ” neoplasia or loco regional disease; however, systemic disseminated disease occurs via lymphatic and/or hematogeneous routes. The lymph nodes, liver, and lungs are the most frequently involved sites whereas the heart constitutes an exceptional and atypical site for penile cancer metastases. We report a case of a 79-year-old patient who presented a metastatic squamous cell carcinoma of the penis with intracardiac dissemination. The patient had a past history of cardiomyopathy, which required an artificial cardiac pacemaker implantation. He had been treated 1 year before with a partial penectomy but was admitted for emasculation due to the cancer relapse. During the postoperative period, he experienced sudden respiratory distress and died. The autopsy findings showed metastatic disease into the cardiac right chambers, pulmonary tumoral thrombi, and pulmonary hilar involvement. The authors call attention to the possibility of the presence of pacing leads, cardiomyopathy and the altered low blood flow in the right chambers, as predisposing factors for the tumoral seeding in this case. Keywords: Autopsy; Penile Neoplasms; Neoplasm Metastasis. CASE REPORT A 79-year-old male patient sought medical attention because of the relapse of a lesion in the penile stub. One year earlier, he had been treated with partial penile amputation for squamous cell carcinoma. His past medical history included hypertension and a third-degree atrioventricular block, which required the implantation of an artificial cardiac pacemaker. He was admitted and submitted to emasculation and regional lymphadenectomy. Pathological examination of the surgical specimen a

revealed invasive squamous carcinoma regional lymph-node involvement.

with

Two days after the surgery the patient presented hypotension and marked leukocytosis, but apparently, with no evidence of infection. However, antibiotics and vasoactive drugs were added to the therapeutic regimen in an attempt to achieve hemodynamic stabilization. Doppler

Department of Pathology - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP – Brazil.

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echocardiography revealed diffuse left ventricle hypokinesia; mitral and tricuspid valves insufficiency, and the presence of the pacemaker’s electrode located in the right ventricle. Eight days after surgery the patient experienced sudden respiratory discomfort and died soon after.

AUTOPSY FINDINGS On external examination, the anthropometric measures revealed the body of a man 163 cm in height with a weight of 69 kg. A recent surgical scar measuring 6.5 cm replaced original topography of the external genitalia. At the opening of the thoracic cavity a small amount of pleural effusion was present bilaterally, and a thick pericardium had adhered to the pleura. The heart was enlarged and weighted 530 g (reference mean value [RMV]: 327 g). On sectioning the right chambers, a whitish tumoral structure loosely adhered to the endocardium (Figure 1) was found involving the atrium and the ventricle trespassing the tricuspid valve and covered the pacemaker electrodes. The gross appearance of these structures resembled infectious endocarditis. After microscopic examination, it was clear that the cardiac involvement was represented by neoplastic tissue. On the left ventricle, the papillary muscles were hypertrophied. Histological examination showed myocardial sclerosis and an unspecific inflammatory infiltrate of lymphocytes and eosinophils permeating the myocardiocytes. The tumoral mass was attached to

Siqueira SAC, Tomikawa CS

the endocardium with focal invasion. On microscopy, marked necrosis was present, but preserved areas of squamous cell carcinoma were evident (Figure 2A and 2B). The right and left lungs weighed 660 g and 510 g (RMV: 450 g and 375 g), respectively. The external surface of both lungs was smooth and anthracotic. On sectioning, the parenchyma was reddish and firm. The histologic examination showed several tumoral thrombi (Figure 3), diffuse alveolar damage with hemorrhage, and foci of pneumonia with micro abscesses besides pleural thickening. Mediastinal lymph nodes were enlarged, and the anthracotic pigment was replaced by a whitish firm infiltration, which was represented by neoplastic tissue (Figure 4). The bone marrow was hypercellular at the expense of all cell lineages, but no neoplastic invasion was found. Additional findings comprised non-disrupted, calcified atherosclerotic plaques along the abdominal and thoracic aorta, basilar artery and left coronary artery; an old cerebellar infarction; and nodular prostatic hyperplasia. Gross and microscopic examination of retroperitoneal lymph nodes, and remaining organs were unremarkable. Respiratory insufficiency due to pulmonary tumoral emboli and pneumonia were considered to be the immediate cause of death. Right-sided cardiac metastases were blamed as the source of tumoral emboli.

Figure 1 – Gross view of the right cardiac chambers. A – Right atrium and tricuspid valve; B – Inside view of the right atrium, note that the metastatic vegetation is growing attached to a sheet of fibrous tissue that covered the pacemaker lead. In both, note the cauliflower-shaped vegetation attached to the endocardium.

Intracardiac metastasis of squamous cell carcinoma of the penis

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Figure 2 – A and B - Photomicrography of the endocardium, myocardium and tumoral mass. In B, note the proximity of the neoplasia and the endocardium (H&E, 100X).

Figure 3 – Photomicrography of the lung showing tumoral thrombi (arrows) (H&E, 100X).

DISCUSSION Penile cancer is a rare entity in Europe and the USA where it accounts for 0.3-0.7% of all malignant tumors in men. The age standardized incidence is 0.3-1 per 100,000 men in European countries and the USA; whereas it is much higher in developing countries: 3 per 100,000 men in parts of India; 8.3 per 100,000 men in Brazil, and even higher in Uganda. The causes of this geographical variation is not well established, but decreased incidence of the disease is associated with better hygiene habits and routine perinatal circumcision.1,2 In 2012 in the USA, it was estimated that the occurrence of 1,570 cases and 310 deaths was due to penile cancer.3 In Brazil, from May 2006 to June 2007, 283 new cases of penile cancer were recorded mainly in the north-

Figure 4 – Photomicrography of mediastinal lymph node showing effacement of the lymph node architecture by neoplastic invasion (H&E, 200X). northeast and southeast regions, which are regions with lower human development indexes.4 Among all the penile malignancies, squamous cell carcinoma is the most prevalent histological type,5 with a relative frequency of approximately 95%, followed by malignant melanoma, basal cell carcinoma, and others.1 The mean age at diagnosis is about 60 years; however, a prospective study in the UK suggested that 25% of men were younger than 50 years of age at diagnosis.6 In a Brazilian series containing 283 new cases of penile cancer, 7.41% of the patients were younger than 35 yearsold.3 Systematic review of publications from 1966 to 2000 found an association between the presence of foreskin and tumor development with

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the lack of local hygiene being highly favoured as a cause.7,8 Circumcision decreases the risk of penile cancer especially if it is performed during the neonatal period.9 Human papillomavirus (HPV), manly subtypes 16 and 18, also play a role in the development of this tumor, since the association was demonstrated in up to 50% of penile cancers with this viral infection.10 Other reported risk factors include genital warts, multiple sexual partners, an early age of first intercourse, HIV infection, smoking (dose-depending effect).1 Penile squamous cell carcinoma usually spreads as follows: sentinel inguinal node(s), superficial inguinal lymph nodes, deep inguinal lymph nodes, pelvic lymph nodes, periaortic lymph nodes, mediastinal lymph nodes, regional dissemination to skin of groin, scrotum, perineum, direct invasion of prostate, and systemic dissemination to multiple sites like liver, lungs, and heart.5,11 In a series involving 14 autopsies of patients with penile squamous cell carcinoma, the distant metastatic sites were concentrated in lymph nodes, liver, lungs, and the heart. The latter was characterized by myocardial involvement and clinically by arrhythmias.11 In contrast, Neuzillet et al.7 reported the metastatic sites of squamous carcinoma of the penis in a decreasing frequency as follows: lymph nodes, lungs, liver, bones, and exceptionally the brain, skin, kidneys, adrenals, and heart. In general, the metastatic involvement of the heart did not provoke much interest, most likely because of its low incidence, as well as the paucity of clinical manifestations. The low incidence is probably due to a combination of factors, such as continuous myocardial contraction, metabolic particularity of the striated cardiac muscle, the rapid blood and lymph flow away from the heart, and restricted lymphatic connections.12,13 The studies conducted by Gassman et al.,14 retrieved 4,124 autopsies of cancer cases during a 20-year period (from 1931 to 1951), in which the heart involvement totaled 217 cases, accounting for approximately 5% of all autopsies. Other autopsy studies show the incidence of metastatic cardiac disease, excluding leukemias, ranging from 0.5 to 19.1%.14-16 This metastatic cardiac involvement is 20-40 times more common than primary cardiac tumors.12,17 The cases in which the myocardium, endocardium, and epicardium were involved, represented 109 cases. The endocardium was predominantly involved in 16 cases (7.3%), and only 5 cases (0.048% of all autopsies) of those 16 were characterized by tumor thrombus in the heart chambers.14 This observation

Siqueira SAC, Tomikawa CS

is in accordance with the Mukai et al. studies,18 which found endocardium involvement in 6% of the cardiac metastatic disease cases. In the studies by Gassman et al.,14 the primary tumor site outside the thorax represented 43% of the cases and only three cases were related to penile carcinoma. Cardiac metastatic disease may developed by: contiguity (as bronchogenic and esophageal carcinomas), true embolic metastasis via coronary arteries and lymphatic spread due to the proximity of lymphatic trunks to the coronary vessels. However, many observers believe that hematogenous spread is the more likely route.14 Interestingly, 80% of this type of metastasis occurs in the right chambers of the heart, probably attributed to the filtering role of the pulmonary circulation and the slower right chambers’ flow.19 Approximately 75% of primary tumors are represented by carcinomas, followed by hematological malignancies, melanomas, and sarcomas.16,18 In our patient’s case, regional lymph nodes were surgically excised, and metastases were found in the heart, lungs, and thoracic lymph nodes. No metastases were found along the iliac and periaortic chains, which led us to accept an initial lymphatic spread, followed by a hematogenous neoplastic spread. As the cardiac tumoral mass was located in the right atrium, the massive presence of tumoral emboli in the lungs was expected and subsequently the pulmonary hilar nodes. We assumed that the pacemaker implantation was motivated by ischemic cardiopathy rather than myocardial neoplastic infiltration, since the latter was not detected in the thorough histologic examination of the heart. As considered by Byun et al.20, metastatic pulmonary emboli might decrease the right cardiac flow, rendering the right chambers more prone to inracavitary seeding. Moreover, in this case, we speculate if the pacemaker may have contributed, to some extent, to facilitate the tumor seeding, like in the case reported by Liao et al.21, where a primary cardiac sarcoma spread along the pacing leads, as the sole metastatic site. To the best of our knowledge, no other report of intracardiac metastasis of penile squamous cell carcinoma associated with the presence of a pacemaker’s electrodes has been found. It remains doubtful whether the presence of these electrodes played any role in this metastatic seeding process. A PubMed search for the keywords metastasis, penis, carcinoma, and heart, revealed only three references concerning cases of metastasis

Intracardiac metastasis of squamous cell carcinoma of the penis

of penile squamous cell carcinoma to the heart. One of the reports was Russian22 and the other was Polish.23 In both cases, the diagnoses were made during autopsy. The third case showed a massive metastatic neoplastic infiltration of the heart, at the level of the interatrial and interventricular septa, the free wall of both ventricles, the perivalvular mitral area, the pericardium, and the ventricular apex. In this case, the diagnosis was made before the patient’s death and was also confirmed during autopsy.24 The same search on Science Direct resulted in a single article reviewing the atypical sites of metastatic penile cancer. In this article, a case of an AIDS patient with multi visceral metastases of squamous cell carcinoma of the penis was reported.25

CONCLUSION The present case report calls attention to the tumoral involvement of locoregional lymph nodes and heart. The lung involvement was secondary to neoplastic embolization. Previous cardiomyopathy and the presence of the pacemaker electrodes were possible risk factors for intracardiac tumoral seeding. Even though this report showed the concomitance of the cited factors, further research is required to investigate whether they represent a coincidence or a statistically significant phenomenon. To the best of our knowledge, this is the first Brazilian report on penile squamous cell carcinoma of the penis with intracardiac metastases.

Autopsy and Case Reports 2013; 3(4): 23-8 5.

Ebele JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004.

Hegarthy PK, Kayes O, Freeman A, Christopher N, Ralph DJ, Minhas S. A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int. 2006;98:526-31. PMid:16925747. http:// dx.doi.org/10.1111/j.1464-410X.2006.06296.x

Neuzillet Y, Méjean A, Lebret T. [Rare locations of metastases from penile cancer]. Prog Urol. 2008;18(Suppl 7):396-8. French. http://dx.doi.org/10.1016/S1166-7087(08)74573-1

Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;205:189-93. http://dx.doi. org/10.1080/00365590050509913

Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst. 1993;85:19-24. http://dx.doi.org/10.1093/jnci/85.1.19

10. Miralles-Guri C, Bruni L, Cubilla AL, Castellsagué X, Bosch FX, de Sanjosé S. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol. 2009;62:870-8. PMid:19706632. http://dx.doi.org/10.1136/jcp.2008.063149 11. Chaux A, Reuter V, Lezcano C, Velazquez E, Codas R, Cubilla AL. Autopsy findings in 14 patients with penile squamous cell carcinoma. Int J Surg Pathol. 2011 Apr;19:164-9. http:// dx.doi.org/10.1177/1066896909333781 12. Borsaru AD, Lau KK, Solin P. Cardiac metastasis: a cause of recurrent pulmonary emboli. Br J Radiol. 2007;80:e50-3. PMid:17495056. http://dx.doi.org/10.1259/bjr/94870835 13. Prichard RW. Tumors of the heart: review of the subject and report on 150 cases. Arch Pathol. 1951;51:98-128.

REFERENCES 1.

Arya M, Kalsi J, Kelly J, Muneer A. Malignant and premalignant lesions of the penis. BMJ. 2013;346:f1149. http://dx.doi. org/10.1136/bmj.f1149 European Association of Urology. Online guidelines [Internet]. [place unknown]: European Association of Urology; 2012. Available from: www.uroweb.org/guidelines/online-guidelines/ American Cancer Society. What are key statistics about penile cancer? [place unknown]; c2013 [cited 2013 May 29]. Available from: http://www.cancer.org/cancer/penilecancer/ detailedguide/penile-cancer-key-statistics Favorito LA, Nardi AC, Ronalsa M, Zequi SC, Sampaio FJ, Glina S. Epidemiologic study on penile cancer in Brazil. Int Braz J Urol. 2008; 34:587-91. PMid:18986562. http://dx.doi. org/10.1590/S1677-55382008000500007

14. Gassman HS, Meadows R Jr, Baker LA. Metastatic tumors of the heart. Am J Med. 1955;19:357-65. http://dx.doi. org/10.1016/0002-9343(55)90124-8 15. Lam KY, Dickens P, Chan ACL. Tumors of the heart: a 20 year experience with a review of 12485 consecutive autopsies. Arch Pathol Lab Med.1993;117:1027-31. PMid:8215825. 16. Shapiro LM. Cardiac tumours: diagnosis and management. Heart. 2001;85:218-22. http://dx.doi.org/10.1136/ heart.85.2.218 17. Butany J, Leong SW, Carmichael K, Komeda M. A 30-year analysis of cardiac neoplasms at autopsy. Can J Cardiol. 2005;21:675-80. PMid:16003450. 18. Mukai K, Shinkai T, Tominaga K, Shimasato Y. The incidence of secondary tumors of the heart and pericardium: a 10-year study. Jpn J Clin Oncol. 1988;18:195-201. PMid:3411785.

Autopsy and Case Reports 2013; 3(4): 23-8 19. Sutsch G, Jenni R, Von Segesser L, Schneider J. Heart tumours: incidence, distribution, diagnosis. Exemplified by 20,305 echocardiographies. Schweiz Med Wochenschr. 1991;121:621-9. PMid:2047823. 20. Byun SW, Park ST, Ki EY, et al. Intracardiac metastasis from known cervical cancer: a case report and literature review. World J Surg Oncol. 2013;11:107. PMid:23702302 PMCid:PMC3667008. http://dx.doi.org/10.1186/1477-781911-107 21. Liao JN, Chen IM, Yang AH, Yu WC. A primary cardiac sarcoma spreading along the pacing leads of a permanent pacemaker. J Am Coll Cardiol. 2012;59:1487. PMid:22497829. http://dx.doi.org/10.1016/j.jacc.2011.07.062

Conflict of interest: None. Submitted on: 3rd June 2013 Accept on: 3rd November 2013 Correspondence: Departamento de Patologia Hospital das Clínicas da Faculdade de Medicina da USP Av. Enéas Carvalho de Aguiar, 155 – São Paulo/SP – Brazil CEP: 05403-000 – Phone: +55 (11) 2661-6281 E-mail: satie.tomikawa@gmail.com

Siqueira SAC, Tomikawa CS 22. Magomedov MK. [Metastasis of squamous cell carcinoma of the penis into the heart]. Arkh Patol. 1998;60:59-61. Russian. PMid:9612515. 23. Swierz J, Poznański J, Stawarz B. [Metastasis of penile cancer to the heart in a 20-year-old patient]. Wiad Lek. 1992;45:314-6. Polish. PMid:1462597. 24. Portero JN, Pardo FL, Pérez RC. Massive intracardiac metastases secondary to squamous cell carcinoma located at the level of the penis. Int J Cardiol. 2008;127:e96-7. PMid:17707529. http://dx.doi.org/10.1016/j.ijcard.2007.04.092 25. Théodore C, Androulakis N, Spatz A, Goujard C, Blanchet P, Wibault P. An explosive course of squamous cell penile cancer in an AIDS patient. Ann Oncol. 2002:475-9. PMid:11996481. http://dx.doi.org/10.1093/annonc/mdf024

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Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Primary diffuse large B-cell lymphoma or lymphomatoid granulomatosis grade 3: a still-puzzling diagnosis in autopsy Fernando Peixoto Ferraz de Camposa, Aloísio Felipe-Silvab, Maria Claudia Nogueira Zerbinic, João Augusto dos Santos Martinesd Campos FPF, Felipe-Silva A, Zerbini MCN, Martines JAS. Primary diffuse large B-cell lymphoma or lymphomatoid granulomatosis grade 3: a still-puzzling diagnosis in autopsy. Autopsy Case Rep [Internet]. 2013; 3(4): 29-36. http:// dx.doi.org/10.4322/acr.2013.036

ABSTRACT Primary lung lymphoma is a rare entity accounting for approximately 0.3% of all primary neoplasia of the lung and includes diffuse large B-cell lymphoma (DLBL) and lymphomatoid granulomatosis (LYG). Considering that clinical features may be similar, whereas epidemiology, morphology, and radiological features are different, the authors report a case of a middle-aged man who presented multiple pulmonary nodules in the lower lobes and groundglass opacities scattered bilaterally on computed tomography. Clinically, he presented a consumptive syndrome with respiratory failure and pleurisy, which progressed until death. The autopsy findings were consistent with lymphomatoid granulomatosis (LYG) grade 3/ diffuse large B-cell lymphoma (DLBL). The authors call attention to the difficulty of establishing an accurate diagnosis, mainly when the demonstration of EBV-infected atypical B-cells fails. Keywords: Lung; Lymphoproliferative Disorders; Respiratory Insufficiency; Autopsy. CASE REPORT A 63-year-old male patient was reportedly well until the unintentional 13 kg of weight loss occurred over the past 3 months, concomitantly presenting dyspnea, dry cough, ventilatory-dependent thoracic pain, hiporexia, but no fever. He was admitted to a medical facility where a thoracocentesis and a pleural biopsy were performed. Pleural fluid was an exudate with lymphomononuclear cellularity predominance and the histologic examination of the pleural biopsy showed inflammatory infiltrate.

Physical examination at admission revealed an ill-looking patient, cachectic, pale, tachypneic with room air oximetry of 82%. He was afebrile and hemodynamic parameters were within normal limits. Clubbed fingers were present. Neurological and cardiac examinations were normal, and no pathologic peripheral adenomegaly was observed. Thoracic examination revealed the presence of pleural effusion along with diffuse wheezing and rales. Cardiac and abdominal examination was unremarkable. Blood gas analysis showed

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hypoxemia with hypocapnia. Serologies for HIV were negative; and Epstein–Barr virus (EBV) and cytomegalovirus (CMV) were positive for IgG but negative for IgM. The thoracic computed tomography (CT) showed the presence of an infiltrative mass with soft-tissue attenuation involving the posterior mediastinum, the chest wall and the pleura, which was associated with pleural effusion and atelectasis of the left lower lobe. The descending aorta and its branches were involved by the mass, but neither vascular invasion nor bone erosion were observed (Figure 1A). In the right lower and middle lobes, diffuse ground-glass opacity and irregular nodules were observed (Figure 1B), as well as smaller nodules present in the left lung. The upper lobes exhibited bullae and pan-lobular emphysema. The patient was initially prescribed ceftriaxone and clarithromycin, non-invasive ventilatory support, and physiotherapy. Since the clinical picture did not improve, the antibiotics were empirically changed to meropenem. Unfortunately, marked impaired clinical status prevented further diagnostic work-up. Respiratory insufficiency worsened and the patient died after 8 days of hospitalization.

Campos FPF, Felipe-Silva A, Zerbini MCN, Martines JAS.

AUTOPSY FINDINGS The ectoscopy revealed a very emaciated cadaver with clubbed fingers. At the opening of the left thoracic cavity, a huge amount of whitish pleural effusion was drained while some fluid was kept enclosed within pleural adhesions. A whitish pleural thickening extended into the interlobular septa, in the lung (Figure 2A). This tissue infiltration involved almost the entire thoracic aorta (Figure 2B), the parietal pericardium, the mediastinum, and the diaphragm to some extent. The lungs were congested and heavy, due to marked edema and congestion. The left lung weighed 871 g and the right lung 975 g (reference value, (RV): 375 g and 450 g, respectively). The superior lobes showed anthracosis and cystic emphysema, which was also present and scattered bilaterally through the remaining lobes. Pulmonary thromboemboli were detected in the segmental and subsegmental branches of the left inferior lobe. The right hemithorax showed serosanguineous pleural effusion. The heart was enlarged, which was mainly due to left ventricular wall hypertrophy (heart weight was 400 g; RV: 276 g). The left ventricular apex exhibited a mural thrombus, and atherosclerosis was mild in the coronaries, while the aorta was markedly involved with calcifications. Pulmonary whitish and firm non-necrotic nodules measuring up to 3 cm were noted in the right inferior lobe and diaphragmatic lung surface; some of them merged with the pleural thickening (Figure 3A). Subcarinal anthracotic and reactive enlarged lymph nodes were present.

Figure 1 – Axial CT of the thorax — A - mediastinum window showing retraction of the base of the left hemithorax. Infiltrative homogeneous mass with soft-tissue attenuation involving the chest wall, pleura, and posterior mediastinum, can be seen, which is associated with pleural effusion and atelectasis of the left lower lobe. Note the involvement of the descending aorta and branches without vascular invasion or bone erosion; B - pulmonary window showing multiple solid pulmonary nodules at the right lung base, some of which exhibit air bronchogram.

Primary diffuse large B-cell lymphoma...

Autopsy and Case Reports 2013; 3(4): 29-36

Figure 2 – A – Gross aspect of the left pleural surface and whitish pleural fluid (bottom). B - “Fish flesh” gross aspect of the tumor involving the thoracic aorta.

Figure 3 – A – Gross aspect of the right lung showing sharply circumscribed nodules; B – Photomicrography of a nodular lesion (HE, 100X); C – Diffuse aspect of lymphoid proliferation in sheets with inflammatory background (HE, 200X); D – Perivascular destructive infiltration (angiocentrism) (HE, 400X). The histologic findings of the pulmonary nodules (Figure 3B), infiltrative pleural lesion, posterior mediastinum, and periaortic involvement were characterized by a proliferation of atypical B-lymphocytes (Figure 3C), sometimes in a sheet-like and angiocentric perivascular pattern (Figure 3D). These cells were immersed in a diffuse background of numerous small T-lymphocytes, histiocytes, and occasional plasma cells, with moderate angiocentric behavior but no central

necrosis. Immunohistochemistry profile of atypical large cells was CD20+ (Figure 4A); PAX5+; CD30−. The proliferation index, accessed by Ki67, was approximately 90%. Small background lymphocytes were mostly CD8+ (Figure 4B). EBV was negative by both in-situ hybridization, and immunohistochemistry gave a negative result. These findings were consistent with a pleuropulmonary diffuse large B cell lymphoma (DLBL) with some features reminiscent of grade 3 lymphomatoid granulomatosis (LYG). The

Autopsy and Case Reports 2013; 3(4): 29-36

Campos FPF, Felipe-Silva A, Zerbini MCN, Martines JAS.

Figure 4 – Immunohistochemistry (400X) showing diffuse CD20 staining (A), in a background of reactive CD8+ T-lymphocytes (B), and histiocytes. mediastinal and abdominal lymph nodes, spleen, liver, and bone marrow were free of neoplasia. Other pulmonary findings were diffuse alveolar damage (acute and organizing), organizing pneumonia, interstitial fibrosis, anthracosis, and respiratory bronchiolitis. Ferruginous bodies and other evidence of asbestos exposure were not detected. Other autopsy findings included acute tubular necrosis and signs of systemic hypertension.

DISCUSSION The lymphoid tissue of the lung is represented by sparse submucosal aggregates of small lymphocytes, which become more pronounced along the bronchioles and central airways and the intraparenchymal, septal, and hilar lymph nodes.1 Various antigenic stimuli trigger an immune response, which leads to lymphoid hyperplasia— often referred to mucosa-associated lymphoid tissue (MALT) or malignant lymphoproliferative disorders.2 Extranodal non-Hodgkin lymphomas have been reported to occur in any organ of the body, but the lung is one of the most common sites, following the gastrointestinal tract, skin, and nervous system.3,4 The so-called primary lung lymphomas (PLLs) are rare, hence the lungs are involved by lymphomas mostly secondarily through hematogenous dissemination of Hodgkin or nonHodgkin lymphomas, or by contiguous invasion from a hilar or mediastinal site.3 PLLs represent only 0.3% of all primary malignancies of the lung, less

than 1% of all cases of non-Hodgkin lymphoma, and 3-4% of all the extra nodal manifestations of non-Hodgkin lymphomas.3,5,6 The most common PLLs are of B-cell lineage and include the marginal zone lymphoma (MZL), which is the most common and accounts for approximately 70% of cases,7 followed by the primary pulmonary DLBL, which accounts for 1220% of cases.8-11 Primary DLBL of the lung occurs mostly during the sixth or seventh decades of life and presents usually symptomatic with dyspnea, cough, and severe impairment of the general clinical status. Although this lymphoma is more frequently associated with HIV infection, it has also been identified in non-immunosuppressed patients, which does not show any clinical difference with the former. A subset of lymphomas arises by transformation of pre-existing or concurrent MZL, small lymphocytic lymphoma, and follicular lymphoma.12 Boone et al.13 reported the case of a DLBL following the treatment of a grade 3 LYG. A newly recognized subset of this lymphoma is the aggressive EBV-DLBL of the elderly, which arises in patients older than 50 years, (mean age of 72 years, with 25% of cases occurring in patients older than 90 years), although rare cases have been described in younger patients. In this subset of DLBCL, pleural effusions have been noted in 9% of cases where atypical cells CD20+ (EBV RNA (EBER+)) over CD3+ background cells are evident in cell-block preparations.14 Radiological findings of this lung lymphoma show that, in general, it constitutes a solitary pulmonary mass accompanied by loco regional invasion, although ground-glass shadows are also reported. Eventually, pleural effusion may also be present.15-17

Primary diffuse large B-cell lymphoma...

LYG is a rare pulmonary disease (less than 3% of all PLLs) with a high mortality rate, which was first described by Liebow et al.18 in 1972. They questioned whether it was part of an inflammatory process or a lymphoproliferative disorder. As time passed, LYG was accepted as a lymphoproliferative disease, although some other uncertainties still remain. LYG is more common among middle-aged adults with a mean age of 48–50 years (range 40–70 years) with male predominance (male to female 2:1). Fever, cough, dyspnea, chest pain, malaise, and weight loss are the most common presenting complaints.19 Eventually, hemoptysis may be present. Clinical features may also reflect a multiorgan systemic disease, because, in addition to pulmonary involvement, the skin, brain, kidneys, and liver may be affected independently or concurrently in the late course of illness.2,19 The characteristic histology of LYG is represented by nodular replacement of the lung parenchyma by a mixed mononuclear cell infiltrate composed of small lymphocytes CD3+ (and characteristics of cytotoxic T-lymphocytes expressing CD8, TIA, and granzyme B),20 large lymphocytes CD20+ with atypia, histiocytes, and occasional plasma cells. In general, the small lymphocytes predominate, but in some cases the large atypical cells comprise the main cellular component. These large cells may resemble immunoblasts with one or two atypical nuclei, often congregating in small nests or larger aggregates, and frequently around vessel walls. These nodules may contain areas of necrosis, which vary from extensive central areas to small fibrinoid foci. The intima and media are affected, and appear thickened, and are associated with luminal narrowing. No vessel necrosis is observed. This pattern is described as an “angiocentric process,” although the blood vessels are secondarily engulfed by the spreading infiltrate, which randomly affects lung parenchyma.2,19 The possible role of EBV in the pathogenesis of LYG was raised in 1990 by Katzenstein and Peiper,21 and subsequently confirmed in several studies. Since then, the presence of EBV-positive cells by in-situ hybridization (ISH) with EBER is now definitional for LYG. However, EBV positivity ranges from 57% to 100% of cases,19,22-25 and by immunohistochemical staining for latent protein 1 and EBV nuclear antigen 2 in some cases where ISH was positive for EBER.19,24 Because of this, in the absence of EBVpositive cells, the diagnosis should be made with caution.26 Beyond the EBV-positive cells, another

Autopsy and Case Reports 2013; 3(4): 29-36

requirement for LYG diagnosis is the presence of a polymorphous background, without which the WHO classifies it as a DLBL.26,27 Evidence of EBV infection may vary in different biopsy sites of the same case, and if the results are negative, they may become positive in subsequent biopsies. In the experience of Katzenstein et al.,19 staining may be focally positive, and some blocks from the same biopsy specimen may be EBV-negative; whereas others are positive, requiring the testing of multiple blocks to avoid falsenegative results. Diverse opinions remain as if LYG constitutes a specific entity due to its histological heterogeneity. In this setting, maybe considering LYG as an entity with different morphological faces could be more accurate.26 Since the Katzenstein et al.28 early study in 1979, it was observed that the percentage of atypical large B-cells was directly related to mortality. Therefore, a grading system from 1 to 3 was proposed. Nevertheless, grading is not that easy; it requires the analysis of multiple slides, once the infiltrate appearance varies from area to area on the same slide and among different slides. In 2008, the WHO27 adopted a grading system based on the quantity of large B-cells and the number staining for EBV by ISH. However, Katzenstein et al.19 experience in 2010 suggested that counting the number of EBV+ cells may not correlate with the grade, but the proportion of large B-cells in the infiltrate seemed to be more accurate. Typical imaging findings include: multiple, bilateral, peribronchovascular nodules or masses with well- or poorly-defined margins, ranging from 0.5 cm to 10 cm distributed predominantly in the lung bases.2,15,29,30 Internal air-bronchogram can be seen,30,31 and the nodule may excavate, disappear, or migrate, which is similar to the behavior found in polyangiitis with granulomatosis. Solitary nodules, alveolar, and reticulonodular opacities may occur, but less frequently. Mediastinal lymphadenomegaly is found in 25% of cases,15,30,32 and pleural effusions have been reported in 33% of cases.28 Groundglass opacities accompanied by signs of pulmonary fibrosis15 as well as pericardial effusion with epicardial mass has already been described.33 Unfortunately, not all cases of LYG present all histologic features recommended for diagnosis, so they require complementation with clinical and radiological data. For this reason Katzenstein et al.19 proposed an algorithm and the following criteria (Table 1).

Autopsy and Case Reports 2013; 3(4): 29-36

Campos FPF, Felipe-Silva A, Zerbini MCN, Martines JAS.

Table 1 – Criteria for diagnosis19 Findings necessary for diagnosis—always present 1. A mixed mononuclear cell infiltrate containing large and small lymphoid cells often along with plasma cells and histiocytes, which replaces lung parenchyma in a nodular manner, and infiltrates blood vessel walls. 2. Variable numbers of CD20+ large B-lymphocytes, often with cytologic atypia, present within a background of CD3+ small T-lymphocytes. Findings supporting the diagnosis—usually, but not always, present 3. Necrosis within the cellular infiltrate 4. Positive ISH for EBER 5. Multiple lung nodules show up radiographically, or skin or nervous system involvement

Treatment is widely variable and depends on the LYG grade. Although reports on spontaneous regression have been reported34, the modalities combination of corticosteroids, antiviral therapy, and α-interferon have been used with minor grades.35,36 Prognosis is extremely poor in grade 3, particularly after a relapse with curative expectation. Meanwhile, in view of the CD20 expression of tumor cells, rituximab has been used either as monotherapy37 or in association with chemotherapy.38 A European Group for Blood and Marrow Transplantation survey identified 6 patients in 10 as disease-free after bone marrow transplantation in a median follow-up of 5.1 years.39 Therefore, the differentiation between LYG and DLBL in our case would not be fundamental for treatment purposes. According to more stringent diagnostic criteria by the WHO in 2008,27 the present case should be classified as DLBCL, especially due to the lack of a demonstrable EBV role. However, if one uses broader clinicopathological criteria (Table 1) this case can be seen as a grade 3 LYG. In our view, this case has more features (clinical, radiological, and morphological) in favor of the diagnosis of LYG, despite the negative result of ISH for EBV. For practical purposes, and respecting the recommended caution, the diagnosis of DLBL was made, along with a comment that this could represent an advanced spectrum of LYG. In fact, a diagnosis of lymphoma is recommended in grades 2 and 3 LYG.19 This case illustrates the hardship in diagnosing a histologically advanced grade LYG and DLBL, which suggests an overlap of these two entities, as well as the difficulty in reaching this diagnosis in a critically ill patient. It is important to emphasize that clinically the distinction in the advanced stage of the disease makes no difference, as these patients need to be treated as lymphoma.

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10. Cordier JF, Chailleux E, Lauque D, et al. Primary pulmonary lymphomas: a clinical study of 70 cases in nonimmunocompromised patients. Chest. 1993;103:201-8. http://dx.doi.org/10.1378/chest.103.1.201

Primary diffuse large B-cell lymphoma... 11. Li G, Hansmann ML, Zwingers T, Lennert K. Primary lymphomas of the lung: morphological, immunohistochemical and clinical features. Histopathology. 1990;16:519-31. http:// dx.doi.org/10.1111/j.1365-2559.1990.tb01157.x 12. Neri N, Jesus Nambo M, Aviles A. Diffuse large B-cell lymphoma primary of lung. Hematology. 2011;16:1102. PMid:21418743. http://dx.doi.org/10.1179/10245331 1X12940641877722 13. Boone JM, Zhang D, Fan F. Lymphomatoid Granulomatosis: a case report with unique clinical and histopathologic features. Ann Clin Lab Sci. 2013;43:181-5. PMid:23694794. 14. Rooper L, Gocke CD, Belchis DA. Pleural fluid cytology of the polymorphous variant of EBV-positive diffuse large B-cell lymphoma: first report and distinction from a reactive process. Case Rep Pathol. 2013. Epub 2013 Sep 3. http:// dx.doi.org/10.1155/2013/450279 15. Ridene I, Radhouani I, Ayadi A, et al. Imagerie des lymphomes pulmonaires primitifs. Rev Mal Respir. 2010;27:1069-76. PMid:21111278. http://dx.doi.org/10.1016/j.rmr.2010.09.011 16. Ooi GC, Chim CS, Lie AK, Tsang KW. Computed tomography features of primary pulmonary non-Hodgkin’s lymphoma. Clin Radiol. 1999;54:438-43. http://dx.doi.org/10.1016/ S0009-9260(99)90828-0 17. Ogata-Suetsugu S, Maeyama T, Takeshita M, et al. A case of diffuse large B-cell lymphoma of the lung demonstrating diffuse ground-glass shadows. Ann Thorac cardivasc Surg. 2011;17:591-4. http://dx.doi.org/10.5761/atcs.cr.10.01651 18. Liebow AA, Carrington CRB, Friedman PJ. Lymphomatoid granulomatosis. Human Pathol.1972;3:457:558. 19. Katzenstein ALA, Doxtader E, Narendra S. Lymphomatoid granulomatosis. Insight gained over 4 decades. Am J Surg Pathol. 2010;34:e35-e48. PMid:21107080. http://dx.doi. org/10.1097/PAS.0b013e3181fd8781 20. Morice WG, Kurtin PJ, Myers JL. Expression of cytolitic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Am J Clin Pathol. 2002;118:391-8. PMid:12219781. http://dx.doi.org/10.1309/PMR7-7XLYF10U-4V1Q

Autopsy and Case Reports 2013; 3(4): 29-36 1996;29:317-24. http://dx.doi.org/10.1111/j.1365-2559.1996. tb01415.x 24. Taniere PH, Thivolet-Bejui F, Vitrey D, et al. Lymphomatoid granulomatosis Fa report on four cases: evidence for B phenotype of the tumoral cells. Eur Respir J. 1998;12:102-6. http://dx.doi.org/10.1183/09031936.98.12010102 25. Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol. 1994;18:753-64. PMid:8037289. http://dx.doi. org/10.1097/00000478-199408000-00001 26. Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol. 2012;25:S39-42. PMid:22214969. http://dx.doi.org/10.1038/modpathol.2011.149 27. Pitaluga S, Wilson WH, Jaffe ES. Lymphomatoid granulomatosis. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumors of Haematopoietic and Lymphoid Tisssues. Lyon: ARC; 2008. p. 247-9. 28. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer.1979;43:360-73. http://dx.doi.org/10.1002/10970142(197901)43:1<360::AID-CNCR2820430151>3.0.CO;2-8 29. Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung:histopathology, clinical manifestations, and imaging features. AJR.1994;163:273-81. PMid:8037014. http://dx.doi. org/10.2214/ajr.163.2.8037014 30. Lee JS, Tuder R, Lynch DA. Lymphomatoid Granulomatosis: Radiologic features and pathologic correlations. AJR. 2000;175:1335-9. PMid:11044036. http://dx.doi.org/10.2214/ ajr.175.5.1751335 31. Chung JH, Wu CC, Gilman MD, et al. Lymphomatoid granulomatosis: CT and FDG-PET findings. Korean J Radiol. 2011;12:671-8. PMid:22043148 PMCid:PMC3194770. http:// dx.doi.org/10.3348/kjr.2011.12.6.671 32. Vahid B, Salerno DA, Marik PE. Lymphomatoid granulomatosis: a rare cause of multiple pulmonary nodules. Respir Care. 2008;53:1227-9. PMid:18718043.

21. Katzenstein AL, Peiper SC. Detection of Epstein-Barr virus genomes in lymphomatoid granulomatosis: analysis of 29 cases by the polymerase chain reaction technique. Mod Pathol. 1990;3:435-41. PMid:2170969.

33. Karabag T, Aydin M, Barut F, et al. Epicardial mass causing cardiac compression. An unusual involvement in lymphomatoid granulomatosis. Tex Heart Inst J. 2012;39:1168. PMid:22412244 PMCid:PMC3298904.

22. Myers JL, Kurtin PJ, Katzenstein A-LA, et al. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol. 1995;19:1300-12. PMid:7573693. http://dx.doi. org/10.1097/00000478-199511000-00011

34. Zhang YX, Ding MP, Zhang T, et al. Lymphomatoid granulomatosis with CNS involvement can lead to spontaneous remission: case study. CNS Neurosci Ther. 2013;19:536-8. http://dx.doi.org/10.1111/cns.12109

23. Nicholson AG, Wotherspoon AC, Diss TC, et al. Lymphomatoid granulomatosis: evidence that some cases represent EpsteinBarrvirus-associated B-cell lymphoma. Histopathology.

35. Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferonalpha 2b. Blood. 1996;87:4531-7. PMid:8639820.

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36. Makol A, Kosuri K, Tamkus D, De M Calaca W, Chang HT. Lymphomatoid granulomatosis masquerading as interstitial pneumonia in a 66-year-old man: a case report and review ofliterature. J Hematol Oncol. 2009,2:39-44. PMid:19732432 PMCid:PMC2741488. http://dx.doi.org/10.1186/1756-87222-39

38. Aoki T, Harada Y, Matsubara E. Long-term remission after multiple relapses in an elderly patient with lymphomatoid granulomatosis after rituximab and high-dose cytarabine chemotherapy without stem-cell transplantation. J Clin Oncol. 2013; 31:e390-3. http://dx.doi.org/10.1200/JCO.2012.47.4999

37. Jordan K, Grothey A, Grothe W, Kegel T, Wolf HH, Schmoll HJ. Successful treatment of mediastinal lymphomatoid granulomatosis with rituximab monotherapy. Eur J Haematol. 2005;74:263-6. PMid:15693798. http://dx.doi.org/10.1111/ j.1600-0609.2004.00367.x

39. Siegloch K, Schmitz N, Wu HS, et al. Hematopoietic stem cell transplantation in patients with lymphomatoid granulomatosis: a European group for blood and marrow transplantation report. Biol Blood Marrow Transplant. 2013;19:1522-5. PMid:23948061. http://dx.doi.org/10.1016/j.bbmt.2013.07.023

Conflict of interest: None Submitted on: 4th November 2013 Accept on: 5th December 2013 Correspondence: Divisão de Clínica Médica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: fpfcampos@gmail.com

Autopsy and Case Reports 2013; 3(4): 37-41

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Primary sclerosing cholangitis associated with severe ulcerative colitis in a young man José Cândido Caldeira Xavier Júniora, Kunie Iabuki Rabello Coelhoa, Ligia Yukie Sassakib, Fabio da Silva Yamashirob, Kelly Cristhian Lima Oliveirab, Maria Aparecida Marchesan Rodriguesa Xavier JCC Jr, Coelho KIR, Sassaki LY, Yamashiro FS, Oliveira KCL, Rodrigues MAM. Primary sclerosing cholangitis associated with severe ulcerative colitis in a young man. Autopsy Case Rep [Internet]. 2013; 3(4): 37-41. http://dx.doi. org/10.4322/acr.2013.037

ABSTRACT Primary sclerosing cholangitis, a chronic progressive cholestatic liver disease, is the most serious hepatobiliary complication of ulcerative colitis (UC). The authors present the case of a severe and intractable form of UC associated with primary sclerosing cholangitis, in which the diagnosis of this hepatobiliary complication was made during the postmortem examination. A 19-year-old man, with an 8-month diagnosis of UC, was non-responsive to any therapeutic approach. He presented at the emergency care unit severely ill and with cachexia, and subsequently died of septic shock. The postmortem examination confirmed the clinical diagnosis of severe UC and disclosed the presence of primary sclerosing cholangitis. Although laboratory tests have shown a typical cholestatic profile with elevated alkaline phosphatase and gamma-glutamyl transferase levels, hepatic dysfunction was related to sepsis. This report highlights how challenging the diagnosis of primary sclerosing cholangitis can be and shows the value of the postmortem examination to add important information to a medical diagnosis. Keywords: Cholangitis, Sclerosing; Colitis, Ulcerative; Autopsy. CASE REPORT A 19-year-old man presented at the emergency care unit complaining of lower abdominal pain, cramps, and bloody mucus diarrhea for several weeks. He had a previous history of chronic diarrhea and a confirmed diagnosis of ulcerative colitis (UC) (Figure 1A) 8 months earlier. At that time, he had pancolitis, which initially improved with oral mesalazine. However, the diarrhea relapsed and treatment with prednisone was carried out. As the outcome remained unfavorable, corticotherapy was replaced by azathioprine. The physical examination on admission disclosed a

a b

severely ill patient who was pale and dehydrated. He had a tender, distended abdomen with a positive rebound test, and cutaneous lesions of pyoderma gangrenosum, which was later confirmed by a skin biopsy. Abdominal plain radiography and computed tomography revealed ascites and colonic wall edema, not fulfilling the criteria for toxic megacolon. The results of the laboratory tests on admission are summarized in Table 1. Liver function tests showed increased levels of alkaline phosphatase and gamma-

Department of Pathology – Faculdade de Medicina – Universidade Estadual Paulista, Botucatu/SP, Brazil. Department of Internal Medicine – Faculdade de Medicina – Universidade Estadual Paulista, Botucatu/SP, Brazil.

Autopsy and Case Reports 2013; 3(4): 37-41 Xavier JCC Jr, Coelho KIR, Sassaki LY, Yamashiro FS, Oliveira KCL, Rodrigues MAM.

Figure 1 – Photomicrography of the intestinal mucosa showing pathologic features of ulcerative colitis (UC). A – Severe chronic active colitis (HE, 200X); B – Rectal mucosa showing atrophy, crypt distortion, and an infiltrate of lymphocytes and plasma cells (HE, 400X). Table 1 – Initial laboratory workup Exam

Results

Exam

Results

Hemoglobin

6.1

14-18 g/dL

Urea

50.0

19-42 mg/dL

Hematocrit

18.8

40-57%

Creatinine

2.7

0.8-1.5 mg/dL

Leucocytes

35.5

4–11 x 10 /mm

Potassium

7.8

3.5-5.0 mEq/L

Bands

5.0

1-5%

Sodium

151

137-145 mEq/L

Segmented

63.0

45-70%

ALT

125

9-36 U/L

Eosinophilis

1.0

1-4%

AST

10-31 U/L

Basophilis

1.0

0-2.5%

ALP

188.0

10-100 U/L

Lymphocytes

24.0

18-40%

γGT

538.0

2-30 U/L

Monocytes

3.0

2-9%

Total bilirubin

5.6

0.3-1.2 mg/dL

Platelets

150-400 x 103/mm3

Total protein

4.2

6-8 g/dL

CRP

Albumin

1.6

3-5 g/dL

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP = C-reactive protein; γGT = gamma-glutamyl transferase; RV = reference value.

glutamyl transferase plus a slight elevation of the transaminases. A rectosigmoidoscopy was performed, and rectal biopsies ruled out a cytomegalovirus infection. An immunoassay for the Clostridium difficile infection was negative. The risk of intestinal perforation was considered and the patient was referred to the surgery department for possible colectomy. However, due to the severe clinical status impairment, colectomy could not be undertaken and the patient died of septic shock.

AUTOPSY FINDINGS The postmortem examination showed a malnourished patient weighing about 40 kg,

measuring 157 cm, with two necrotizing cutaneous lesions: one in the right scapular region measuring 2 cm, and the other close to the right areolar region measuring 0.5cm. At the opening of the abdominal and thoracic cavities, there was 3.000 mL of serosanguineous ascites and serous pleural effusion with 300 mL in each hemithorax. Gross examination of the gastrointestinal tract revealed involvement of the entire colon by extensive shallow ulcers and pseudopolyps (Figure 2), along with intestinal perforations in the right colon and acute suppurative peritonitis. Histologically, there was severe inflammation in all segments of the colon with effacement of the mucosal architecture. Mucosal inflammation and crypt atrophy were also found in

Primary sclerosing cholangitis...

Autopsy and Case Reports 2013; 3(4): 37-41

Figure 2 – Gross features of UC: erythematous mucosa with a cobblestone appearance due to shallow ulcers interspersed with pseudopolyps.

Figure 3 – Photomicrography of the liver. A – Widened portal area with bridging fibrosis and inflammation (HE, 100X); B – Concentric periductal fibrosis (arrow) and chronic inflammation in a portal area (HE, 200X).

the rectum (Figure 1B). The distal ileum presented backwash inflammation. The liver weighed 1550 g (reference value, RV: 1400-1600 g), was macroscopically green colored, with a poorly defined nodular appearance at the cut surface. The histopathological examination revealed chronic inflammation surrounding the bile ducts together with concentric periductal fibrosis and bridging portal fibrosis characterizing primary sclerosing cholangitis (PSC) (Figure 3). Bile ducts were lacking in some portal tracts, but the extrahepatic main biliary tree was preserved. The spleen was enlarged and soft, weighing 220 g (RV: 150 g). The kidneys were also enlarged and weighed 205 g and 190 g, the right and left, respectively (RV: 115-155 g). Histologically there

was acute nonspecific splenitis and acute tubular necrosis in the kidneys, respectively.

DISCUSSION In the present case, the autopsy findings confirmed the clinical diagnosis of severe UC and disclosed the presence of PSC, the most serious hepatobiliary complication of UC. Extraintestinal complications are common in patients with UC. Minor hepatobiliary abnormalities can occur in up to 50% of patients, but clinically significant liver disease has been detected in less than 10% of patients.1 The clinical association between UC and PSC was described by Smith and Loe (1965).2 The prevalence of PSC in patients with UC varies between 2.4% and 7.4%,3,4 but UC has been found

Autopsy and Case Reports 2013; 3(4): 37-41 Xavier JCC Jr, Coelho KIR, Sassaki LY, Yamashiro FS, Oliveira KCL, Rodrigues MAM.

in up to 80% of patients with PSC.5,6 The activity of UC does not correlate with the severity of PSC and vice versa.7 The diagnosis of primary sclerosing cholangitis used to be a challenging task in pauci or asymptomatic patients.8 However, when fatigue, pruritus, and jaundice are present, suspicions should be raised. Laboratory tests usually show elevated determinations of alkaline phosphatase, gammaglutamyltransferase as well as total bilirubins.8,9 The diagnosis of primary sclerosing cholangitis is usually confirmed after the development of a complication, like infectious cholangitis. In the present case, the diagnosis of primary sclerosing cholangitis was made only during the postmortem examination by the histological findings of onion skin fibrosis around the bile ducts, along with chronic inflammation surrounding bile ducts. Although laboratory tests showed a typical cholestatic profile, the diagnosis of PSC was not initially considered due to the critical clinical status of the patient. Although the mechanism of the association of PSC and UC is still not explained, shared inflammatory pathways or a common agent may be involved in the pathogenesis of both diseases.10 The hypothesis of autoimmune-mediated mechanisms for PSC has been supported by the presence of various autoantibodies, including perinuclear antineutrophil cytoplasmic antibodies or anti-nuclear antibodies in the serum of PSC patients.11 However, the presence of these markers does not help to define PSC due to their lack of specificity. Some studies have suggested that UC present in PSC patients represents a distinct clinical and pathologic entity.12-14 However, a recent investigation of the pathologic characteristics and distribution of colonic disease in patients with primary sclerosing cholangitis reported that UC patients with PSC had similar pathologic findings in the colon compared with UC patients without PSC.15 An increased frequency of rectal sparing has been reported in UC patients with PSC;12,16 however, this finding was not observed in our patient. Joo et al. (2009),15 in a matched case control study, showed that the diagnostic procedure of identifying UC in patients with PSC was performed at a significantly earlier age compared with UC patients without PSC, as observed in the present case.

The finding of pancolitis, in our patient, is in agreement with previous studies that showed UC of the entire colon in patients with PSC, based on clinical and endoscopic data.12,16 In contrast to recent reports that have observed less severe disease activity in UC patients with PSC,12-14,16 our patient presented a severe and fulminant form of UC with backwash ileitis. Severe and uncontrollable symptoms may occur in up to 30% patients with UC (especially in those who are quite young when diagnosed) thus requiring a colectomy, which effectively cures the intestinal disease.17,18 In our patient, a colectomy could not be performed due to the severe clinical status impairment. Mortality in UC remains debated. Older studies reported a reduced survival in patients with UC,19 whereas recent studies show that the risk of dying in patients with UC does not differ from that of the general population.20,21 A meta-analysis of mortality in UC, derived from population-based cohorts, revealed that the overall mortality is not increased among patients with UC. However, a subgroup of patients with newly diagnosed and extensive disease, like our patient, is at a greater risk of dying from the disease and from surgical complications.21

CONCLUSION The case described herein emphasizes how challenging the clinical diagnosis of primary sclerosing cholangitis can be, especially when associated with a severe form of UC. It highlights the value of postmortem examinations to add important information to medical diagnoses.

REFERENCES 1.

Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a populationbased study. Am J Gastroenterol. 2001;96:1116-22. PMid:11316157. http://dx.doi.org/10.1111/ j.1572-0241.2001.03756.x

Smith M, Loe S. Sclerosing cholangitis: review of recent case reports and associated diseases and four new cases. Am J Surg. 1965;110:239-46. http://dx.doi.org/10.1016/00029610(65)90018-8

Aadland E, Schrumpf E, Fausa O, et al. Primary sclerosing cholangitis: a long-term follow-up study. Scand J Gastroenterol.1987;22:655-64. PMid:3659828. http:// dx.doi.org/10.3109/00365528709011139

Primary sclerosing cholangitis... 4.

4.Shepherd HA, Shelby WS, Chapman RWG, et al. Ulcerative colitis with persistent liver dysfunction. Quart J Med. 1983;52:503-13. PMid:6657913.

Broomé U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis. 2006;26:31-40. PMid:16496231. http://dx.doi. org/10.1055/s-2006-933561

Takikawa H, Manabe T. Primary sclerosing cholangitis in Japan - analysis of 192 cases. J Gastroenterol. 1997;32:1347. http://dx.doi.org/10.1007/BF01213311

Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis. 1991;11:31-9. PMid:2047887. http://dx.doi. org/10.1055/s-2008-1040420

Angulo P, Lindor KD. Primary sclerosing cholangitis. Hepatology.1999;30:325-32. PMid:10385674. http://dx.doi. org/10.1002/hep.510300101 Schrumpf E, Boberg KM. Primary sclerosing cholangitis: challenges of a new millenium. Dig Liver Dis. 2000;32:753-5. http://dx.doi.org/10.1016/S1590-8658(00)80350-3

10. Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2011;25:727-39. PMid:22117638 PMCid:PMC3236286. http://dx.doi.org/10.1016/j. bpg.2011.10.009 11. Angulo P, Peter JB, Gershwin ME, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol. 2000;32:182-7. http://dx.doi.org/10.1016/S01688278(00)80061-6 12. Loftus EV, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:916. PMid:15591511 PMCid:PMC1774346. http://dx.doi. org/10.1136/gut.2004.046615 13. Lundqvist K, Broomé U. Differences in colonic disease activity in patients with ulcerative colitis with and without primary sclerosing cholangitis: a case control study. Dis

Autopsy and Case Reports 2013; 3(4): 37-41 Colon Rectum. 1997;40:451-6. PMid:9106695. http://dx.doi. org/10.1007/BF02258391 14. Moayyeri A, Daryani N, Bahrami H. Clinical course of ulcerative colitis in patients with and without primary sclerosing cholangitis. J Gastroenterol Hepatol. 2005;20:36670. PMid:15740478. http://dx.doi.org/10.1111/j.14401746.2005.03727.x 15. Joo M, Abreu-e-Lima P, Farraye F, et al. Pathologic features of ulcerative colitis in patients with primary sclerosing cholangitis: a case-control study. Am J Surg Pathol. 2009;33:854-62. PMid:19295408. http://dx.doi.org/10.1097/ PAS.0b013e318196d018 16. Faubion WA Jr, Loftus EV, Sandborn WJ, Freese DK, Perrault J. Pediatric ‘‘PSC-IBD’’: a descriptive report of associated inflammatory bowel disease among pediatric patients with PSC. J Pediatr Gastroenterol Nutr. 2001;33:296-300. http:// dx.doi.org/10.1097/00005176-200109000-00013 17. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. A long-term follow-up of 1116 patients. Dig Dis Sci.1993;38:1137-46. PMid:8508710. http://dx.doi.org/10.1007/BF01295733 18. Sands BE. Inflammatory bowel disease: past, present and future. J Gastroenterol. 2007;42:16-25. PMid:17322989 PMCid:PMC2780674. http://dx.doi.org/10.1007/s00535006-1995-7 19. Gyde S, Prior P, Dew MJ, Saunders V, Waterhouse JA, Allan RN. Mortality in ulcerative colitis. Gastroenterology. 1982;83:36-43. PMid:7075944. 20. Jess T, Loftus Jr EV, Harmsen WS, et al. Survival and cause specific mortality in patients with inflammatory bowel disease: A long-term outcome study in Olmsted County, Minnesota, 1940-2004. Gut. 2006;55:12485. PMid:16423890 PMCid:PMC1860022. http://dx.doi. org/10.1136/gut.2005.079350 21. Jess T, Gamborg M, Munkholm P, Sørensen TI. Overall and cause-specific mortality in ulcerative colitis: metaanalysis of population-based inception cohort studies. Am J Gastroenterol. 2007;102:609-17. PMid:17156150. http:// dx.doi.org/10.1111/j.1572-0241.2006.01000.x

Conflict of interest: None Submitted on: 13th September 2013 Accept on: 3rd December 2013 Correspondence: Departamento de Patologia Faculdade de Medicina da Universidade Estadual Paulista Av. Rua Bento Lopes, s/n - Distrito de Rubião Jr. – Botucatu/SP – Brazil CEP: 18618970 – Phone: +55 (11) 3811-6238 E-mail: mariar@fmb.unesp.br

Autopsy and Case Reports 2013; 3(4): 43-7

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Wharton’s jelly absence: a possible cause of stillbirth Eduarda Bittencourt Damascenoa, Patrícia Picciarelli de Limab Damasceno EB, Lima PP. Wharton’s jelly absence: a possible cause of stillbirth. Autopsy Case Rep [Internet]. 2013; 3(4): 43-7. http://dx.doi.org/10.4322/acr.2013.038

ABSTRACT The umbilical cord is a structure that provides vascular flow between the fetus and the placenta. It contains two arteries and one vein, which are surrounded and supported by gelatinous tissue known as Wharton’s jelly. There are many umbilical cord abnormalities that are related to the prognosis of fetus survival and birth weight. The authors report a case of umbilical cord constriction due to the localized absence of Wharton’s jelly, which was undiagnosed antenatally and had a fatal outcome. A review of the association between the absence of Wharton’s jelly and an unfavorable pregnancy outcome was undertaken. Keywords: Umbilical Cord; Wharton Jelly; Stillbirth.

CASE REPORT A male stillborn fetus was delivered at 33 weeks and 4 days of gestational age through a vaginal birth, which was the second pregnancy of a 32-year-old woman. The mother had a history of a previous ectopic pregnancy and left salpingectomy, plus type II diabetes mellitus

and arterial hypertension—the latter two without medical control. The woman stopped feeling the fetal movements 6 hours before hospital admission. An ultrasound examination diagnosed intrauterine fetal demise, and the labor was induced with misoprostol.

AUTOPSY FINDINGS The external examination showed a male stillbirth, weighing 2.260 g (z score: 0.59, 72 percentile, small for gestational age),¹ with marked maceration. A marked reduction of diameter over a 1-cm length segment of the umbilical cord at 3 cm distant from the fetal insertion site. No external or internal malformations were found (Figure 1A and 1B).

a b

On gross examination, the placenta measured 15.0 × 14.0cm in diameters, corresponding to an area of 164 square centimeters (–1,4 z score and 1 percentile, small for gestational age),² 2.5cm of mean thickness (3.0 z score and 99 percentile, large for gestational age)² and weighed 425.0 g (1.1 z score and 87 percentile, adequate for gestational age).² The insertion of the umbilical

Department of Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

Autopsy and Case Reports 2013; 3(4): 43-7

Damasceno EB, Lima PP.

cord was marginal (Figure 1C). At microscopy, there were a mild subchorionic hematoma with thrombosis and few foci of dystrophic calcification of the trophoblastic villi. Thrombosis, hemorrhagic endovasculopathy or villi fibrosclerosis, which could be also associated with obstruction of fetoplacental circulation, were not present.

At microscopy, absence of Wharton’s jelly was evidenced in the constricted segment. (Figures 2B and 2C).

The umbilical cord measured 73.0 cm of length (4.5 z score and 99 percentile, large for gestational age),² and 2.2 cm in diameter (measured 3 cm from the fetal skin) (3.3 z score and 99 percentile, large for gestational age),² and was composed of three vessels. In the segment close to the placenta, the umbilical cord was morphologically normal, without areas of constriction. The umbilical coil index was 0,12, just above the lower limit of normality. In contrast, close to its insertion into the fetal abdomen, it presented an abrupt reduction in the diameter (corresponding to a 50% in the diameter reduction) (Figures 1A, 1B, 1D and 2A).

The umbilical cord—the fetal lifeline—is a structure that connects the fetus to the placenta, and is crucial for fetal development. It is composed of two arteries and one vein and is cushioned by a special type of mucous connective tissue known as Wharton’s jelly. At birth, the average diameter and circumference of the umbilical cord in a normalterm infant is 1.5 cm and 3.6 cm, respectively.3,4 Wharton’s jelly seems to have the function of the adventitia layer, which is lacking in the umbilical cord, and binds and encases the umbilical vessels. Wharton’s jelly is an amorphous substance, which is rich in glycosaminoglycans, proteoglycans, and

DISCUSSION

Figure 1 – Gross examination of the stillbirth. A and B – Constriction of the umbilical cord close to its insertion into the fetal surface; C – External examination of the placenta and the umbilical cord. Note the marginal insertion of the umbilical cord at the placenta; D – Sequential cuts of the umbilical cord.

Wharton’s jelly absence: a possible cause of stillbirth

Autopsy and Case Reports 2013; 3(4): 43-7

Figure 2 – Gross and microscopy examination of the umbilical cord, showing the morphology of the constricted segment. A – Gross aspect of the constricted segment of the umbilical cord showing the absence of Wharton’s jelly; B – The absence of Wharton’s jelly at the umbilical cord; C – A segment of the umbilical cord with scant Wharton’s jelly. predominantly hyaluronic acid. It is surrounded by myofibroblasts, which are mesenchymal cells with the characteristics of both fibroblasts and smooth-muscle cells. Myofibroblasts have both fibrogenesis and contractile functions and produce increasing amounts of type I, II, and V collagen fibrils during the pregnancy, giving Wharton’s jelly elastic and contractile properties as well as microfibrils.5 Hyaluronic acid is the most common glycosaminoglycan—a hydrophilic component of Wharton’s jelly that absorbs water and electrolytes. Umbilical cord elasticity confers resistance to external pressure, and acts as a physical buffer in the regulation of fetoplacental blood circulation and umbilical vessels.5,6 It has been speculated that the cells of Wharton’s jelly may participate in the regulation of umbilical blood flow. In some cases, the reduction in fetal growth could be directly associated with Wharton’s jelly decrement, leading to hypoplasia of the umbilical vessels. If Wharton’s jelly is poorly developed, or if the vessels remain unprotected, they become more prone to compression.7,8 The sonographic umbilical cord diameter and area increase as a function of gestational age until the 32nd week of pregnancy. After that, a reduction in the diameter of the umbilical cord can be observed due to the water content of Wharton’s jelly at the end of the pregnancy.8 Over a 1 year period, Proctor et al.9 studied 497 umbilical cords of gestational ages ranging from 18 weeks to 41 weeks. They found that the umbilical cord diameter increases as the gestational age progresses until 28 weeks when it reaches a plateau at approximately 1.0 cm. These findings are in agreement with the antenatal ultrasound assessment of the umbilical cord that describes an increase in diameter

with gestational age until the third trimester.9 Using Proctor’s nomogram, they identified and classified the umbilical cord diameter as thin (< 10th percentile), average (10th–90th percentile) and thick (> 90th percentile), and concluded that the umbilical cord components were responsible for the diameter variation. According to this standard, the cord of the present case was a thick one. Their findings show that a significant increase in the vessel area (specifically an increase in the umbilical artery wall area) is responsible for a thick umbilical cord diameter, while a significant decrease in Wharton’s jelly area is responsible for a thin umbilical cord diameter.9 Pathologic studies and case reports demonstrated that a thin umbilical cord is associated with oligohydramnios, fetal distress, and adverse pregnancy outcome.9 Silver et al.10 reported that in post-term pregnancies, the umbilical cord diameter is smaller in patients with oligohydramnios compared with normal amniotic fluid. In addition, these authors found a higher incidence of antepartum variable decelerations in patients with a small umbilical cord diameter compared with those with a normal umbilical cord. Raio et al.11 found an association between the presence of a thin umbilical cord and the delivery of an infant who is small for its gestational age. Proctor et al.9 showed that there was a relationship between the umbilical cord diameter and gross placental pathologic features. A thin umbilical cord was associated with low placental weight percentile, a single umbilical artery, and a marginal umbilical cord insertion. Marked reductions in the diameter of the umbilical cord may be referred to as constrictions, stricture, torsion, and coarctation. When present,

Autopsy and Case Reports 2013; 3(4): 43-7

they are frequently found close to the fetal insertion site, as was observed in our case. They are more prevalent in long cords and marked coiled cords. In these cases, the obstruction of blood flow occurs by the same mechanism as with excessive coiling. None morphological evidence of fetoplacental vascular obstruction was observed in the present case. Some authors suggested that it is either a primary deficiency of Wharton’s jelly, or is due to a secondary phenomenon caused by a gradual decrease in Wharton’s jelly at the fetal end of the cord.7 It has been suggested that the umbilical cord constriction could be due to a degeneration of Wharton’s jelly around the vessels, since normal development of the vessel would not be possible in the absence of embryonal mesenchyme, although no mucoid or degenerative changes were demonstrated.7 Other possible physiopathologic mechanisms for this anomaly could be an incomplete fusion of the amniotic covering and the mesenchyme of the umbilical cord during early development, or a hypoplasia of this amniotic covering with a secondary loss of Wharton’s jelly.7 In 1961, Bergman, Lundin and Malmstrom12 described the first case in which a segment of the umbilical arteries were devoid of their Wharton’s jelly covering. The most common complication of this anomaly results in fetal demise, but cord constrictions have also been implicated in fetal growth restriction and fetal intolerance to labor;5 in the present case, fetal weight was adequate for gestation age. A different umbilical cord anomaly related to the lack of Wharton’s jelly is known as insertio funiculi furcate. In those cases, the insertion site is normal, but as the cord vessels loose the Wharton’s jelly their vessels become separated before reaching the placental surface. In a velamentous insertion, the umbilical cord is inserted into the membranes and the umbilical vessels remain unprotected for some distance before reaching the placenta. An increased incidence of fetal distress and perinatal mortality has been described in association with both velamentous insertion and insertio funiculi furcata.7. Baergen13 describes four cases of stillbirth and umbilical cord constriction. In all the four cases, the absence of Wharton’s jelly around the umbilical cord arteries described so far were associated with acute fetal distress and perinatal death, and this may have been due to compression of the unprotected vessels. According to Baergen,13 this is consistent with animal studies in which fetal lambs that were subjected to intermittent partial chord

Damasceno EB, Lima PP.

occlusion develop cerebral necrosis and serious fetal neurologic damage. Chronic partial obstruction can also lead to fetal growth restriction. Abnormally coiled cords, abnormally short or long cords, velamentous cord insertions, constrictions, true knots, cord entanglement, and cord prolapse have all been associated with an increased risk of fetal demise, neurologic injury, or abnormal development outcome.13 In the present case, we observe a thick and under to normal coiled cord. Filiz et al.5 investigated the relationship between the amount of Wharton’s jelly and its protective role in umbilical cord vessels, and hence, on fetal growth. Their study enrolled 299 women and concluded that the “quality” and characteristics of Wharton’s jelly were both important in its protective role. Abnormal situations, such as a decrease in the hyaluronic acid content of Wharton’s jelly and Wharton’s jelly fibrosis, may affect the mechanical characteristics of the cord, which leads to impaired fetal circulation, anoxia, and fetal death.5

CONCLUSION The changes in the quantity or quality of Wharton’s jelly affects the diameter of the umbilical cord and the hemodynamics of its vessels, leading to impaired fetal blood flow and consequently low weight gain and fetal demise. The constriction in the umbilical cord due to the absence of Wharton’s jelly, which was seen in our case, much probably was the cause of fetal death since the autopsy did not show any malformations or other disorders. We highlight the need to study the umbilical cords in all cases of stillbirth.

REFERENCES 1.

Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth charts. Lancet. 1992;339:2837. http://dx.doi.org/10.1016/0140-6736(92)91342-6

Benirschke K, Kaufman P, Baergen RN. Pathology of the human placenta. 5th ed. New York: Springer; 2006.

Moinian M, Meyer WW, Lind J. Diameters of umbilical cord vessels and the weight of the cord in relation to clamping time. Am J Obstet Gynecol. 1969;105:604. PMid:5824881.

Patel D, Dawson M, Kalyanam P, et al. Umbilical cord circumference at birth. Am J Dis Child. 1989;143:638-9. PMid:2729201.

Wharton’s jelly absence: a possible cause of stillbirth 5.

Filiz A, Rahine B, Keskin HL, Esra AK. Positive correlation between the quantity of Wharton’s jelly in the umbilical cord and birth weight. Taiwan J Obstet Gynecol. 2011;50:33-6. PMid:21482372. http://dx.doi.org/10.1016/j.tjog.2009.11.002 Takechi K, Kuwabane Y, Mizuna M. Ultrastructure and immunohistochemical studies of Wharton’s jelly umbilical cord cells. Placenta. 1993;14:235-45. http://dx.doi.org/10.1016/ S0143-4004(05)80264-4 Labarrere C, Sebastiani M, Siminovich M, Torassa E, Althabe O. Absence of Wharton’s jelly around the umbilical arteries: an unusual cause of perinatal mortality. Placenta. 1985;6:555-9. http://dx.doi.org/10.1016/S0143-4004(85)80010-2

Di Naro E, Ghezzi F, Raio L, Franchi M, D’Addario V. Umbilical cord morphology and pregnancy outcome. Eur J Obstet Gynecol Reprod Biol. 2001;96:150-7. http://dx.doi. org/10.1016/S0301-2115(00)00470-X

Proctor LK, Fitzgerald B, Whittle WL, et al. Umbilical cord diameter percentile curves and their correlation to birth weight and placental pathology. Placenta.

Autopsy and Case Reports 2013; 3(4): 43-7 2013;34:62-6. PMid:23174148. http://dx.doi.org/10.1016/j. placenta.2012.10.015 10. Silver RK, Dooley SL, Tamura RK, Depp R. Umbilical cord size and amniotic fluid volume in prolonged pregnancy. Am J Obstet Gynecol. 1987;157:716-20. http://dx.doi.org/10.1016/ S0002-9378(87)80036-4 11. Raio L, Ghezzi F, Di Naro E, et al. Sonographic measurements of the umbilical cord and feftal anthropometric parameters. Eur J Obstet Gynecol Reprod Biol. 1999;83:135-45. http:// dx.doi.org/10.1016/S0301-2115(98)00314-5 12. Bergman P, Lundin P, Malmstrom T. Mucoid degeneration of the Wharton’s jelly: an umbilical cord threatening foetal life. Acta Obstet Gynecol Scand. 1961;40:372-8. PMid:13867744. http://dx.doi.org/10.3109/00016346109159935 13. Baergen R. Cord abnormalities, structural lesions and cord “accidents”. Semin Diagn Pathol. 2007;24:2332. PMid:17455859. http://dx.doi.org/10.1053/j. semdp.2007.02.004

Conflict of interest: None Submitted on: 6th November 2013 Accept on: 10th December 2013 Correspondence: Departamento de Patologia Hospital das Clínicas Faculdade de Medicina Universidade de São Paulo Av. Dr. Enéas Carvalho de Aguiar, 155 – 10 andar – São Paulo/SP – Brazil CEP: 05503-000 – Phone: +55 (11) 2661.6092 E-mail: dudabd93@yahoo.com.br

Autopsy and Case Reports 2013; 3(4): 49-51

Article / Clinical Case Reports Artigo / Relato de Caso Clínico Pyloric Brunner’s gland hamartoma with atypical hyperplasia Luciano Lenza,b, Aloísio Felipe-Silvaa,c, Frank Nakaoa,b, Nelson Miyajimaa,d, Ermelindo Della Liberaa,b, Dalton Marques Chavesa,d, Beatriz Monica Sugaia, Maria Rachel da Silveira Rohra,b Lenz L, Felipe-Silva A, Nakao F, et al. Pyloric Brunner’s gland hamartoma with atypical hyperplasia. Autopsy Case Rep [Internet]. 2013; 3(4): 49-51. http://dx.doi.org/10.4322/acr.2013.039

ABSTRACT Brunner’s gland hamartoma (BGH) is an extremely rare benign digestive tumor, generally located in the duodenal bulb. We report the case of a 51-year-old asymptomatic man with a large pedunculated BGH arising from the pylorus. It was successfully removed en bloc by endoscopic resection. Keywords: Brunner Glands; Hamartoma; Pylorus. INTRODUCTION Brunner’s glands were first described by Brunner in 1688. They are branched acino-tubular glands located in the submucosa and lined with cuboidal-to-columnar clear cells in the glands and cuboidal cells in the duct.1 These glands are most commonly located in the duodenum, although they may be found infrequently in the pylorus.2 Brunner’s gland hamartoma (BGH) is a rare tumor that was first described by Salvioli in 1876.2 BGH represents 5-10% of small bowel tumors and occurs most commonly in the fifth and sixth decade of life, with no gender or race predominance. Most of the lesions are small, asymptomatic and detected incidentally. Clinical symptoms are caused

by obstruction, leading to postprandial pain and bleeding.3 Other, less common presentations of BGH include recurrent acute pancreatitis and duodenal intussusception.3 The distribution of BGH is duodenal bulb (57%), the second (27%) and third (5%) portions of the duodenum, the pyloric channel (5%), jejunum (2%), and proximal ileum (2%).4 They are mostly pedunculated, and generally sized from 1 to 9 cm in diameter, although Brunner’s gland polyps greater than 2 cm are exceedingly rare.1,3 Brunner’s gland hamartoma can be treated either by endoscopic or surgical excision.1,2 We report a case of successful endoscopic removal of a BGH arising from the pylorus.

CASE REPORT A 51-year-old man underwent upper endoscopy and colonoscopy as a part of a routine health survey. He was asymptomatic, and his medical history and physical examination were

unremarkable. Routine blood tests including a complete blood cell count and chemistry studies had normal results. Some diverticula and a small adenoma (2 mm) were found in his colonoscopy.

Fleury Medicina e Saúde, São Paulo/SP – Brazil Department of Endoscopy – Universidade Federal de São Paulo, São Paulo/SP – Brazil. c Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. d Gastrointestinal Endoscopy Service – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. a b

Autopsy and Case Reports 2013; 3(4): 49-51

Gastroduodenoscopy demonstrated a 15 × 14 × 8 mm pendunculated polyp covered with normal mucosa and originating from the pylorus (Figure 1A and B). The tumor was resected by diathermic polypectomy without complications. The urease test was negative. Histological sections showed diffuse hyperplasia of Brunner’s glands in lobular aggregates, interspersed with fibrous bundles and foci of adipose tissue. The lesion was lined with flattened duodenal mucosa with foci of pyloric metaplasia, findings consistent with a diagnosis of hamartoma. A central area (Figure 2A) showed the substitution of Brunner’s glands by a lobulated nodular growth of tubular glands with reduced cytoplasmatic mucin, mild nuclear and architectural atypia, rare mitotic figures and a slightly reactive desmoplastic stroma (Figure 2B). These findings were interpreted as an atypical hyperplasia, as defined by Sakurai et al.,5 since Ki67 staining was only mildly elevated (less than 5%) and unequivocal features of malignancy were not seen. Resection margins were clear.

Lenz LT, Felipe-Silva A, Nakao FS et al.

DISCUSSION The exact prevalence of BGH is difficult to determine because of the variation in nomenclature throughout the medical literature. The most common localization is the duodenum.6 Only 5% of these lesions arise from the pyloric channel.4 Although commonly an incidental finding, BGH has been associated with pain, obstruction, hemorrhage and intussusception.6 Accurate diagnosis of BGH can be demanding, a combination of upper endoscopy or barium contrast studies of the small bowel can be helpful.7 However, since these are submucosal lesions, endoscopic biopsies may be nondiagnostic and, on the other hand, endoscopic ultrasound can be very useful.2,7 Finally, the precise diagnosis is only made on histopathologic evaluation of the resection specimen.8 The distinction between Brunner’s gland hyperplasia and Brunner’s gland hamartomas is arbitrary. Brunner’s gland hyperplasia is considered

Figure 1 – A - Endoscopic view of the pyloric polyp with white light; B - Pyloric Brunner’s gland hamartoma; virtual chromoendoscopy (i-scan).

Figure 2 – Photomicrography of the Brunner’s gland hamartoma: A - central nodular area of atypical lobular growth (H&E, 12.5x); B - atypical hyperplasia. Packed tubular glands with mild nuclear atypia, mitotic figures (in the center) and slight stromal desmoplasia (H&E, 400x).

Pyloric Brunner’s gland hamartoma with atypical hyperplasia

if the lesion is <5 mm in size, either solitary or multiple, and BGH is named if it is >5 mm and unique.1 Brunner’s gland hyperplasia is commonly encountered in association with peptic duodenitis. Endoscopically, it presents as a nodular duodenitis. This nodularity should be distinguished from genuine single polyps, referred to as Brunner’s gland hamartoma or adenoma.9,10 In view of the nomenclature generally used for the gastrointestinal tract, the term “adenoma” is considered a misnomer because the lesion is not neoplastic,9 the histologic architecture of these lesions consists of a combination of ductal and acinar structures with fibromuscular and adipose elements.4 Therefore, the best term for these uncommon lesions is really hamartoma, even though the etiology is basically unknown.9 Nevertheless, many factors were proposed for its pathogenesis, such as local irritation, parasympathetic activity, chronic pancreatitis, Helicobacter pylori infection and Billtoth II reconstruction. Other differential diagnosis includes leiomyomas, adenomas, lipomas, PeutzJeghers syndrome, adenocarcinomas, carcinoids, lymphomas, leiomyosarcomas, pancreatic or ampullary neoplasm.1 Asymptomatic small BGH usually requires no therapy. Although, treatment is suggested for larger tumors, even if asymptomatic, to prevent development of complications such as bleeding or obstruction.1 Surgery has been the traditional method of treatment of these lesions.2 However, endoscopic excision can be a less invasive alternative.3 Recurrence after endoscopic or surgical excision has not been reported.1 The present case showed a BGH with atypical histology in an unusual localization that was treated with endoscopic polypectomy.

REFERENCES 1.

Jung Y, Chung IK, Lee TH, et al. Successful endoscopic resection of large pedunculated Brunner’s gland hamartoma

Autopsy and Case Reports 2013; 3(4): 49-51 causing gastrointestinal bleeding arising from the pylorus. Case Rep Gastroenterol. 2013;7:304-7. PMid:23904842 PMCid:PMC3728612. http://dx.doi.org/10.1159/000354138 2.

Block KP, Frick TJ, Warner TF. Gastrointestinal bleeding from a Brunner’s gland hamartoma: characterization by endoscopy, computed tomography, and endoscopic ultrasound. Am J Gastroenterol. 2000;95:1581-3. PMid:10894601. http:// dx.doi.org/10.1111/j.1572-0241.2000.02124.x

Shemesh E, Ben Horin S, Barshack I, Bar-Meir S. Brunner’s gland hamartoma presenting as a large duodenal polyp. Gastrointest Endosc. 2000;52:435-6. PMid:10968871. http:// dx.doi.org/10.1067/mge.2000.108291

Bayan K, Tuzun Y, Yilmaz S, Yilmaz G, Bilici A. Pyloric giant Brunner’s gland hamartoma as a cause of both duodenojejunal intussusception and obscure gastrointestinal bleeding. Turk J Gastroenterol. 2009;20:52-6. PMid:19330736.

Sakurai T, Sakashita H, Honjo G, Kasyu I, Manabe T. Gastric foveolar metaplasia with dysplastic changes in Brunner gland hyperplasia: possible precursor lesions for Brunner gland adenocarcinoma. Am J Surg Pathol. 2005;29:1442-8. PMid:16224210. http://dx.doi.org/10.1097/01. pas.0000180449.15827.88

Patel ND, Levy AD, Mehrotra AK, Sobin LH. Brunner’s gland hyperplasia and hamartoma: imaging features with clinicopathologic correlation. AJR Am J Roentgenol. 2006;187:715-22. PMid:16928936. http://dx.doi.org/10.2214/ AJR.05.0564

Mumtaz R, Shah IA, Ramirez FC. Brunner’s gland hamartoma simulating a pancreatic mass with duodenal obstruction. Gastrointest Endosc. 2002;56:932-4. http://dx.doi.org/10.1016/ S0016-5107(02)70380-5

Melzer E. Giant Brunner’s gland hamartoma. Gastrointest Endosc. 2003;58:314-5. PMid:12872119. http://dx.doi. org/10.1067/mge.2003.353

Shepherd N, Warren B, Wiliiams G. Morson and Dawson’s gastrointestinal pathology. 5th ed. West Sussex: WileyBlackwell; 2013.

10. Kyungeun K, Jang S, Song H. Clinicopathologic characteristics and mucin expression in brunner’s gland proliferating lesions. Dig Dis Sci. 2013;58:194-201. PMid:22836185. http://dx.doi. org/10.1007/s10620-012-2320-3

Conflict of interest: None Submitted on: 8th October 2013 Accept on: 3rd December 2013 Correspondence: Av. Aratãs, 200, Apto. 121 B – São Paulo/SP – Brazil CEP: 04081-000 – Phone: +55 (11) 3969-1260 E-mail: luciano.lenz@terra.com.br

Autopsy and Case Reports 2013; 3(4): 53-62

Article / Clinical Case Report Artigo / Relato de Caso Clínico Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis Fernando Peixoto Ferraz de Camposa, Cristiane Rúbia Ferreirab, Angélica Braz Simõesb, Paulo Sergio Martins de Alcântarac, Brenda Margatho Martinesd, Adriano Ferreira da Silvad, Deborah Azzi-Nogueirae, Luiz Roberto Giorgetti de Brittof, Luiz Gustavo Dufner-Almeidae, Luciana Amaral Haddade Campos FPF, Ferreira CR, Simões AB, et al. Unilateral giant renal angiomyolipoma and pulmonary lymphangio leiomyomatosis. Autopsy Case Rep [Internet]. 2013; 3(4): 53-62. http://dx.doi.org/10.4322/acr.2013.040

ABSTRACT Angiomyolipomas (AMLs) are mesenchymal neoplasms, named so because of the complex tissue composition represented by variable proportions of mature adipose tissue, smooth muscle cells, and dysmorphic blood vessels. Although AMLs may rise in different sites of the body, they are mostly observed in the kidney and liver. In the case of renal AMLs, they are described in two types: isolated AMLs and AMLs associated with tuberous sclerosis (TS). While most cases of AMLs are found incidentally during imaging examinations and are asymptomatic, others may reach huge proportions causing symptoms. Pulmonary lymphangioleiomyomatosis (LAM) is a rare benign disease characterized by cystic changes in the pulmonary parenchyma and smooth muscle proliferation, leading to a mixed picture of interstitial and obstructive disease. AML and LAM constitute major features of tuberous sclerosis complex (TSC), a multisystem autosomal dominant tumor-suppressor gene complex diagnosis. The authors report the case of a young female patient who presented a huge abdominal tumor, which at computed tomography (CT) show a fat predominance. The tumor displaced the right kidney and remaining abdominal viscera to the left. Chest CT also disclosed pulmonary lesions compatible with lymphangioleiomyomatosis. Because of sudden abdominal pain accompanied by a fall in the hemoglobin level, the patient underwent an urgent laparotomy. The excised tumor was shown to be a giant renal AML with signs of bleeding in its interior. The authors call attention to the diagnosis of AML and the huge proportions that the tumor can reach, as well as for ruling out the TSC diagnosis, once it may impose genetic counseling implications.. Keywords: Angiomyolipoma; Kidney Diseases; Lymphangioleiomyomatosis; Hemorrhage; Nephrectomy; Tuberous Sclerosis.

Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. c Department of Surgery – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. d Diagnostic Imaging Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. e Department of Genetics and Evolutionary Biology – Instituto de Biociências – Universidade de São Paulo, São Paulo/SP – Brazil. f Department of Physiology and Biophysics – Instituto de Ciências Biomédicas – Universidade de São Paulo, São Paulo/ SP – Brazil. a b

Autopsy and Case Reports 2013; 3(4): 53-62

Campos FPF, Ferreira CR, Simões AB et al.

CASE REPORT A 26-year-old Caucasian female patient sought medical care, complaining of a 2-month right flank pain. Initially, this symptom had a 30-minute duration and was usually triggered by physical exertion or by trunk flexion. The pain improved with rest. Gradually, the pain became more frequent and more intense, accompanied by stiffness of the abdominal wall and increased abdominal volume reaching proportions that resembled the abdomen of an advanced pregnancy. She reported weight loss of 3 kg in this period, postprandial bloating, and progressive exertional dyspnea. Fever was absent. Her past medical history included two pregnancies, one cesarean section 6 years before, and one vaginal delivery, 4 years ago. She was a smoker and her alcoholic beverage consumption was mild. On physical examination the patient was in good general condition, weight was 57 kg, height was 1.59 m (BMI = 22.5), blood pressure was 120/80 mmHg; pulse rate was 72 beats per minute, and she was afebrile. Examination of the skin, nails, and gums was normal. Upon inspection, the abdomen was asymmetric, right bulged where a hardened mass was palpable and painful, displacing the liver forward and to the left. The remainder of the physical examination was normal. Initial laboratory tests are shown in Table 1. Urinalysis was normal. Serum determination of carcinoembrionic antigen (CEA) was < 0.5 ng/ mL (reference value [RV] until 2.5 ng/mL), cancer antigen–125 (CA-125) 17 U/mL (RV: until 35 U/mL);

carcinoma antigen 15-3 (CA 15-3) 5.5 U/mL (RV: until 38.5 U/mL); carbohydrate antigen 19-9 (CA 199) 3.6 (RV: until 37 U/mL). The abdominal plain x-ray showed a homogeneous opacification occupying almost the entire right hemi abdomen displacing the bowel loops to the left (Figure 1). The abdominal sonographic examination showed a poorly defined mass blurring the intra-

Figure 1 – Abdominal plain radiography showing the displacement of the bowel loops to the left and a homogeneous opacity filling the right hemiabdomen.

Table 1 – Initial laboratory workup Exam

Result

Exam

Result

Hemoglobin

14.0

12.3-15.3 g/dL

Glucose

70-99 mg/dL

Hematocrit

42.1

36.0-45.0%

Creatinine

0.72

0.4-1.3 mg/dL

Leukocytes

6.19

4.4-11.3 × 10³/mm3

Urea

10-50 mg/dL

Segmented

46-75%

Sodium

138

136-146 mEq/L

Eosinophil

1-4%

Potassium

4.7

3.5-5.0 mEq/L

Basophil

0-2.5%

CRP

< 5 mg/L

< 5.0 mg/L

Lymphocyte

18-40%

INR

1.10

1.0

Monocyte

2-9%

6.7

6.0-8.0 g/dL

Platelet

339

150-400 × 10³/mm3

Albumin

4.2

3.0-5.0 g/dL

CRP = C-reactive protein; INR = international normalized ratio; RV = reference value; TP = total protein.

Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis

and retroperitoneal adipose tissue, preventing the identification of the pancreas and adjacent structures. This mass predominantly occupied the epigastric and mesogastric areas, shifting the intestinal bowels to the left and the right kidney anteriorly and to the left. The abdominal computed tomography (CT) disclosed a huge retroperitoneal mass measuring 18.0 × 17.0 × 8.7 cm, occupying almost the entire right side of the abdomen, exhibiting an intimate

Autopsy and Case Reports 2013; 3(4): 53-62

relationship with the inferior pole of the right kidney. The right adrenal gland, pancreas, and intestinal bowels were shifted to the left. The heterogeneous mass was richly vascularized, presenting calibrous vessels adjacent to its inferior portion and exhibited a density predominantly of adipose tissue (Figures 2 and 3). Evident lymph adenomegaly was not identified. The remaining organs in the abdomen were normal. Thoracic CT showed the presence of multiple cystic images throughout the lungs including the involvement of apices and costophrenic recesses (Figure 4) compatible with the diagnosis of lymphangioleiomyomatosis, without causing any change in the pulmonary function test. Brain CT and Doppler echocardiography were normal. With these clinical, laboratory and imaging features, the hypothesis of angiomyolipoma (AML) was raised and surgery was indicated, due to the tumor size. While waiting for surgery, the patient presented an acute worsening of pain, hypotension, and pallor. At this time, a fall of 5.3 g/dL in hemoglobin determination and 16.9% in hematocrit was observed.

Figure 2 – Abdominal computed tomography (CT) – portal phase – coronal reformatted image showing a huge mass occupying half of the abdominal volume, crossing the midline, predominantly composed of adipose tissue interspersed with multiple vascular structures. The right kidney is displaced medially. Note the relationship of the mass with the renal parenchyma at its lower pole.

Urgent laparotomy was undertaken and the surgical findings corresponded to a large tumoral mass originating from the anterior surface of the right kidney weighing 2,700 g enclosed into the retroperitoneum (Figure 5). The right renal and adrenal arteries and veins held the tumor blood supply. The right kidney and right adrenal were excised in conjunction with the tumoral mass. Postoperative recovery was uneventful, and the patient was discharged after 9 days. Microscopic examination showed a tumor composed of three tissue components: mature

Figure 3 – Abdominal axial CT. A – (Image without intravenous contrast injection.) A huge mass occupying the right half of the abdomen, crossing the midline, and consisting predominantly of adipose tissue is observed; B – Arterial phase; C – Portal phase. Note that the tumoral mass is interspersed with multiple vascular structures and the relationship of mass to the renal parenchyma at its lower pole.

Autopsy and Case Reports 2013; 3(4): 53-62

adipose tissue, convoluted thick-walled blood vessels with frequent hyalinization of the media, and interlacing bundles of smooth muscle often with perivascular arrangement (Figure 6). The immunohistochemical panel was positive for muscle actin and markers associated with melanoma antigen HMB-45 and Melan-A in the muscular component of the neoplasm (Figure 7).

Campos FPF, Ferreira CR, Simões AB et al.

GENETICS ANALYSIS The patient reported here had no definite clinical diagnosis of TSC, suggesting isolated AML and LAM. Somatic mutations in either TSC1 or TSC2 genes have been reported in isolated AMLs and LAM.1,2 Most mutations in isolated renal AMLs have been reported in the TSC2 gene, mapped

Figure 4 – Thoracic CT, lung window. A – Coronal; B – Right sagittal; C – Left sagittal. A, B, and C show several thin-walled pulmonary cysts that are relatively homogeneous in form and dimensions, diffusely distributed throughout the lung fields, including the apices and costophrenic sulci, compatible with lymphangioleiomyomatosis.

Figure 5 – Gross examination of the tumoral mass represented by a large yellowish and hemorrhagic mass measuring 24 cm in its longest axis; A – Right kidney depicted in the centrum of the tumor mass, losing definition of its contour at the inferior pole; B – Tumor covered by peritoneum; C- Note the abundance of the adipose tissue of the tumoral mass.

Figure 6 – Photomicrography of the tumoral mass. A and B - Renal angiomyolipoma (AML) composed of adipose tissue, smooth muscle, and vessels (HE 10 × 20).

Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis

Autopsy and Case Reports 2013; 3(4): 53-62

Figure 7 – Photomicrography of the tumoral mass. Renal AML showing positive immunoreactivity. A – Smooth muscle actin (AML); B – HMB-45; C – Melan A.

Figure 8 – A - Part of the short arm of human chromosome 16 is depicted, showing the localization of TSC2 gene, which partially overlaps with PKD1 gene. Molecular, polymorphic markers informative in this study are presented, as well as the estimated distance (kilobases, Kb) between consecutive ones; B - Silverstained polyacrylamide gels, in which PCR amplification products (8 µL) have been electrophoresed, show the migration of DNA bands. Approximate molecular sizes are 91, 130, 189, 121, 124, 118 and 133 basepairs (bp), respectively for D16S283, STR7, D16S291, KG8, D16S3395, STR3 and D16S521. Two bands observed within the expected size are indicated by arrowheads for every locus, each corresponding to the amplification of a distinct allele. Slower-moving bands may correspond to heteroduplexes formed by hybridization between strands from different allele amplifications or unspecific products. Arrows indicate a very faint band in the tumor sample as compared to the leukocyte DNA amplification in both D16S291 and KG8 loci. Two results are presented for the KG8 locus, each one from a different sample preparation of DNA from the AML-containing paraffin block.

Autopsy and Case Reports 2013; 3(4): 53-62

to 16p13.3.3 Therefore, we searched for loss of heterozygosity at 16p13.3, comparing patient DNA from leukocytes and AML tissue. We analyzed 11 microsatellites, with primers available at http:// www.ncbi.nih.gov/unists. After paraffin removal from tissue sample, DNA was purified (QIAGEN, Germantown, MD), and polymerase chain reaction (PCR) was performed, disclosing seven informative microsatellites (heterozygous in patient blood sample). Loss of heterozygosity was detected at KG8 microsatellite marker, for which the leukocyte DNA revealed heterozygosity, and the tumor sample had convincing amplification of a single allele, whereas for the other one very low intensity PCR amplification was observed (Figure 8, arrow). PCR testing of a DNA sample prepared from novel AML paraffin sections disclosed KG8 heterozygosity even for the tumor sample. One possible explanation is the presence of more endothelial and fibroblast cells in the latter sample, which are part of the tumor but should not have the mutation. Nevertheless, we also observed loss of heterozygosity at the D16S291

Campos FPF, Ferreira CR, Simões AB et al.

marker, for which the lower allele band was missing when compared to the leukocyte amplification product (Figure 8, arrow). Further immunohistochemistry analyses have been carried out to address the expression of the TSC proteins, hamartin (TSC1) and tuberin (TSC2), with the following antibodies: rabbit polyclonal anti-hamartin (HF6, a kind gift of Vijaya Ramesh, Massachusetts General Hospital, Boston, MA)4 and rabbit polyclonal anti-tuberin (TSC2, IA22, Sigma, St Louis, MI). We detected reasonable levels of hamartin (TSC1) and relatively low levels of tuberin (TSC2) in the AML, when compared to the negative control where the primary antibody has been omitted (Figure 9). On the other hand, staining under the same conditions was observed similarly for both hamartin and tuberin in the normal kidney tissue (Figure 10), supporting the observation of relatively low expression of the TSC2 gene in the AML.

Figure 9 – Photomicrography of the tumoral mass. Renal AML shows positive immunoreactivity for hamartin (TSC1) in (A) and light staining for tuberin (TSC2) in (B) when compared to the negative control (C, antirabbit antibody). 200 X magnification.

Figure 10 – Photomicrography of the kidney. Kidney sections have been submitted to immunohistochemistry under the same conditions as in Figure 9. Renal tissue shows relatively similarly strong immunoreactivity for hamartin (TSC1, A) and tuberin (TSC2, B), when compared to the negative control (C, anti-rabbit antibody). 200 X magnification.

Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis

DISCUSSION Renal AMLs are benign mesenchymal neoplasm, named so by Morgan et al.5 because of the complex tissue composition represented by a variable proportion of mature adipose tissue, smooth muscle cells, and dysmorphic blood vessels. However, Grawitz, in 1900, had already used this denomination to describe a large renal tumor comprised of fat, muscle, and blood vessels.6-8 AMLs are derived from a unique cell that has been designated as perivascular epithelioid cell. The classical perivascular epithelioid cell is typically clustered around blood vessels and may be scattered haphazardly within an AML.9,10 These cells show positive immunoreactivity for HMB-45 and other melanocytic markers. Other studies showed that tumor cells of pulmonary lymphangiomyomatosis also express HMB-45, as well as sugar tumor of the lung, creating the concept of a family of tumors called PEComas.11 The World Health Organization recognized the PEComa family as a group of mesenchymal tumors composed of these distinctive perivascular epithelioid cells.12 By definition, AML is considered to be benign even in the event of vascular or regional lymph node involvement, which is regarded as indicative of multifocal growth rather than an aggressive behavior.13,14 They may involve surrounding tissues like perinephric fat, renal sinus, renal vein, lymph nodes, and adrenal glands; invade the inferior vena cava and the right atrium, posing a frequent challenge to be differentiated from renal cell carcinoma.6,15 Classical AMLs present abundant fat tissue and therefore are somewhat easily diagnosed by CT or magnetic resonance imaging (MRI). However, many of them are not suspected because of the lack of fat tissue evidence, being called poor-fat AMLs, which do not differ in prognosis from the classical ones. AMLs may also be classified as monophasic when they are composed predominantly or exclusively of one component, or triphasic when the three components (smooth muscle, fat and dysmorphic blood vessels) are present. The AMLs were recently classified as regular or clinically benign AMLs (when no epithelioid component is present) and epithelioid angiomyolipoma (EAML) (formerly called atypical AML), which are composed partially or entirely of atypical large epithelioid cells with abundant cytoplasm, vesicular nuclei, and prominent nucleoli.16 This denomination requires the presence of a minimum of 5% of the epithelioid component.15 Approximately one-third of the EAML have been reported to present metastasis or local recurrences.16,17 Epithelioid cellular morphology also can be seen in regular benign AMLs. Consequently,

Autopsy and Case Reports 2013; 3(4): 53-62

the term ‘‘epithelioid’’ as it applies to AMLs should be restricted to a morphologic description of cells with an epithelioid pattern as opposed to a spindle cell pattern, regardless of whether or not there is cytological atypia. Therefore, Brimo et al.16 denote AMLs with epithelioid morphology as ‘‘epithelioid AMLs’’ that are then divided into epithelioid AMLs with and without atypia—the former category associated, in the literature, with malignant potential.16 Although angiomyolipoma may rise in different sites of the body; namely, hard palate, adrenal gland, mediastinum, pancreas, and pelvis, they are mostly observed in the kidney and liver.17-22 Renal AML has an incidence varying between 0.02% and 0.3% (in patients without tuberous sclerosis complex [TSC]). They are described in two types: isolated angiomyolipoma and angiomyolipoma associated with TSC.6,7,15,23 The former represents almost 80% of cases, which typically develop in middle-aged women, and the latter represents the remaining 20% associated to TSC, known as Bourneville disease.6,24 Despite the fact that there is no significant difference in the frequency of AML detected in asymptomatic males or females, in patients treated surgically for AML, females outnumber males by a ratio of 4.8:1 in those with TSC, and 4.5:1 in those without TSC.25,26 The consistent increased frequency in females may be due, in part, to hormonal differences as AMLs express progesterone and estrogen receptors, and perhaps explains the rapid growth and higher propensity to hemorrhage during pregnancy.6,27 While most cases of AML are found incidentally during imaging examinations and are asymptomatic, others may reach huge proportions presenting life-threatening symptoms or encroaching insidiously on the normal renal parenchyma leading to renal failure.28,29 When symptomatic (40% of the cases), AML can present as a palpable mass, flank pain, or hematuria. Usually tumors do not uniformly become symptomatic until they reach the size of 4 cm; after that, symptoms will be present in 6880% of patients.30 Ruptures and renal hemorrhage have been reported to occur with lesions > 4 cm.7,15 Dysmorphic blood vessels within AML may appear thick, but they lack normal elastin; they are tortuous and do not show normal tapering.6 Aneurysms frequently develop as the AML enlarges, which can rupture causing retroperitoneal hemorrhage accompanied by sudden flank or back pain and signs of shock—the dreadful morbidity associated with AML, called Wunderlich syndrome.31 This complication occurs in 50–60% of the cases,6 and in up to 20% imposes nephrectomy.23

Autopsy and Case Reports 2013; 3(4): 53-62

Pulmonary lymphangioleiomyomatosis (LAM) is a rare benign disease characterized by cystic changes in the pulmonary parenchyma and smooth muscle proliferation, leading to a mixed picture of interstitial and obstructive disease. Complications of this entity may comprise pneumothorax, chylothorax, and hemoptysis. Similarly to AML, LAM exhibits estrogen receptors reacting to hormonal influence. Anti-estrogen drugs (like tamoxifen) have proved to be beneficial in slowing the disease process.7 AML and LAM constitute major features of TSC diagnosis. The association between AML and TSC accounts for 20%. In these cases, AMLs are typically large lesions and bilateral; on the other hand, 80% of patients with TSC present AML. LAM is also a major feature for clinical diagnosis of TSC and can be detected in 26-39% of these patients. The concomitance of LAM and AML in patients with TSC diagnosis is 60%.15,32,33 Regarding the revised criteria for the clinical diagnosis of TSC,34 the presence of two major features are sufficient for definite clinical diagnosis, but when AML and LAM are simultaneously present, another feature of TSC is required for a definite diagnosis.35 In the case reported here, the patient did not present skin or nail abnormalities; the brain CT and Doppler echocardiogram were normal. Fundoscopic examination was normal. Based on as much clinical and laboratory data as we were able to get, the diagnosis of TSC could not be achieved. Imaging diagnosis of AML include ultrasound, color flow Doppler, CT, MRI. The classical ultrasound appearance of an AML is the hyper-reflective lesion with acoustic shadowing. AML has been described as the most hyper-reflective renal lesion, due to a combination of its fat content, the blood vessels within the tumor, and its heterogeneous nature.36,37 The subset of an AML with a minimal fat component, which represents a minority, will present as isoreflective to renal parenchyma. The demonstration of fat on CT is highly suggestive of AML, although not pathognomonic, but remains the major discriminative sign between AML and renal cell carcinoma (RCC). In an acute setting, CT is the most useful imaging examination, assessing hemorrhage and establishing an underlying diagnosis.38 Diagnosis of AML by MRI also depends on the detection of fat within the lesion, which is assessed by the difference between fat-suppressed and non-fat-suppressed sequences.30 In case of equivocal imaging results, a biopsy may be used to discriminate from other renal lesions. The immunohistochemistry of the spindled

Campos FPF, Ferreira CR, Simões AB et al.

and epithelioid smooth muscle cells of AML are positive for vimentin, muscle-specific actin, smooth muscle actin, desmin, and CD 117 (c-KIT).10,39 The development of human melanoma black-45 (HMB45) and other melanocytic markers such as Melan A, has increased the reliability of the biopsies, as virtually all AMLs stain positive for these antibodies. Epithelial markers such as cytokeratin, frequently seen in RCC, are absent in AML, and HBM-45 is negative in RCC.40 Treatment of AML depends on the tumor size, the presence of symptoms, and, more recently, on the size of aneurysms detected by angiography. Symptomatic patients with lesions ≥ 4 cm or aneurysm > 5 mm should be treated with selective transcatheter renal artery embolization, enucleation, or partial nephrectomy. Patients asymptomatic should be monitored every 6 months.41,42 The 2012 International Tuberous Sclerosis Complex Consensus Conference recently reviewed the guidelines for management of TSC patients, and recommend that asymptomatic, growing AMLs larger than 3 cm should have mTOR inhibitors as first–line therapy.43 The optimal treatment of AML is logically focused on sparing renal tissue23, but in case of huge tumors and hemorrhage accompanied by hemodynamic instability or shock, nephrectomy is unavoidable. We observed loss of heterozygosity in two loci linked to TSC2 gene, KG8 and D16S291. Although a second sample was not able to confirm KG8 results, we should take into consideration that the tumor has not been microdissected and it is composed of different cell types involved in blood vessel and interstitium formation that should lack the mutation. KG8 and D16S291 are adjacent markers in our study. PKD1 gene lies between them, in a 200-Kb DNA segment. No intragenic microsatellite is available for the TSC2 gene. KG8 lies in its very 3’-end (see Figure 8). Therefore, the two losses of heterozygosity observed in this study are indicative of a single mutational event in the tissue that originated the tumor, probably a deletion of one copy of TSC2. The extension of this TSC2 somatic gene deletion could not be ascertained, though it should include its 3’-end and extends downstream for at least 200 Kb. Moreover, our results suggest that the other somatic mutational hit, which is necessary to the oncogenic cascade, is unlikely to be a large deletion within the region where the microsatellites are located. It could be either, an intragenic deletion, a point mutation or an inactivating posttranslational modification of the TSC2 protein.44 Due to the paucity of polymorphic microsatellite markers within the TSC2 gene and the low quality of DNA obtained from the paraffin-embedded sample, we

Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis

could not search for the second mutation. On the other hand, we performed immunohistochemistry analyses that indicated relatively low levels of TSC2 expression when compared to the negative control, corroborating that the patient has inactivating mutations in the TSC2 gene. In agreement, staining for the TSC1 protein (hamartin) disclosed relatively higher expression levels in the AML, and expression similar to tuberin (TSC2) in the kidney tissue.

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Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA. 2000;97:6085-90. http://dx.doi.org/10.1073/ pnas.97.11.6085

Crooks DM, Pacheco-Rodriguez G, DeCastro RM, et al. Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci USA. 2004;101:17462-7. PMid:15583138 PMCid:PMC536045. http://dx.doi.org/10.1073/pnas.0407971101

Qin W, Bajaj V, Malinowska I, Lu X, et al. Angiomyolipoma have common mutations in TSC2 but no other common genetic events. PLoS One. 2011;6:e24919. PMid:21949787 PMCid:PMC3174984. http://dx.doi.org/10.1371/journal. pone.0024919

Murthy V, Haddad LA, Smith N, Pinney D, Tyszkowski R, Brown D, Ramesh V. Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney. Am J Physiol Renal Physiol. 2000;278:F737-46. PMid:10807585.

Morgan GS, Straumfjord JV, Hall EL. Angiomyolipoma of the kidney. J Urol. 1951;65:525-7. PMid:14825528.

Wahab S, Rizwan AK, Thapa M, Wahab A, Ahmad I. Giant Angiomyolipoma associated with a dilated vessel prone to hemorrhage. Iran J Kidney Dis. 2009;3:168-71. PMid:19617667.

Nasir Kiran, Ahmad A. Giant renal angiomyolipoma and pulmonary lymphangiomyomatosis. Saudi J Kidney Dis Transpl. 2010;21:314-9.

Grawitz P. Demonstration eines grossen Angio-Myo-Lipoms der Niere. Deutsch Med Wochenschr. 1900;26:290.

Weeks DA, Malott RL, Arnesen M, et al. Hepatic angiomyolipoma with striated granules and positivity with melanoma-specific antibody (HMB-45): a report of two cases. Ultrastruct Pathol. 1991;15:563-71. http://dx.doi. org/10.3109/01913129109016264

10. Ashfaq R, Weinberg AG, Albores-Saavedra J. Renal angiomyolipomas and HMB-45 reactivity. Cancer. 1993;71:3091-7. http://dx.doi.org/10.1002/10970142(19930515)71:10%3C3091::AIDCNCR2820711032%3E3.0.CO;2-5

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11. Bonetti F, Pea M, Martignoni G, et al. Clear cell (‘sugar’) tumor of the lung is a lesion strictly related to angiomyolipoma - the concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC). Pathology. 1994;26:230-6. 12. Folpe AL. Neoplasms with perivascular epithelioid cell differentiation (PEComas). In: Fletcher CDM, Unni KK, Mertens F, editors. Pathology and genetics of tumors of soft tissue and bone. Lyon: IARC Press; 2002. (IARC WHO Classification of Tumours Series). 13. Davis CJ, Woodward PJ, Dehner LP, et al. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. 14. Murphy WM, Grignon DJ, Perlman EJ. Tumors of the kidney, bladder, and related urinary structures. Washington: American Registry of Pathology; 2004. 15. Lane BR, Aydin H, Danforth T, et al. Clinical correlates of renal angiomyolipoma subtypes in 209 patients: Classic, fat poor, tuberous sclerosis associated and epithelioid. J Urol. 2008;180:836-43. PMid:18635231. http://dx.doi. org/10.1016/j.juro.2008.05.041 16. Brimo F, Robinson B, Guo C, Zhou M, Latour M, Epstein JI. Renal epithelioid angiomyolipoma with atypia: A series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg Pathol. 2010;34:71522. PMid:20410812. 17. Yang L, Feng XL, Shen S, et al. Clinicopathological analysis of 156 patients with angiomyolipoma originating from different organs. Oncol Lett. 2012;3:586-90. http://dx.doi.org/10.3892/ ol.2012.554 18. Alvarez AC, Fernández SJ, Fernández CM, et al. Sporadic oral angiomyolipoma. Case report. Med Oral Patol Oral Cir Bucal. 2007;12:E391-3. 19. Elsayes KM, Narra VR, Lewis JS Jr, et al. Magnetic resonance imaging of adrenal angiomyolipoma. J Comput Assist Tomogr. 2005;29:80-2. http://dx.doi.org/10.1097/01. rct.0000152863.97865.47 20. Amir AM, Zeebregts CJ, Mulder HJ. Anterior mediastinal presentation of a giant angiomyolipoma. Ann Thorac Surg. 2004;78:2161-3. http://dx.doi.org/10.1097/01. rct.0000152863.97865.47 21. Heywood G, Smyrk TC, Donohue JH. Primary angiomyolipoma of the pancreas. Pancreas. 2004;28:443-5. http://dx.doi. org/10.1097/00006676-200405000-00014 22. Gronchi A, Diment J, Colecchia M, et al. Atypical pleomorphic epithelioid angiomyolipoma localized to the pelvis: a case report and review of the literature. Histopathology. 2004;44:292-5. http://dx.doi.org/10.1111/j.03090167.2004.01801.x 23. Bisslerr JJ, Kingswood JC. Renal amgiomyolipoma. Kidney Int. 2004;66:924-34. PMid:15327383. http://dx.doi.org/10.1111/ j.1523-1755.2004.00838.x

Autopsy and Case Reports 2013; 3(4): 53-62 24. Hajdu SI, Foote FW Jr. Angiomyolipoma of the kidney: report of 27 cases and review of the literature. J Urol. 1969;102:396-401. PMid:5343474. 25. Fujii Y, Ajima J, Oka K, et al. Benign renal tumors detected among healthy adults by abdominal ultrasonography. Eur Urol. 1995;27:127. 26. Eble JN. Angiomyolipoma of kidney. Semin Diagn Pathol. 1998;15:21-40. PMid:9503504. 27. Henske EP, Ao X, Short MP, et al. Frequent progesterone receptor immunoreactivity in tuberous sclerosis-associated renal angiomyolipomas. Mod Path.1998;11:665-8. 28. Schillinger F, Montagnac R. Chronic renal failure and its treatment in tuberous sclerosis. Nephrol Dial Transplant. 1996;11:481-5. http://dx.doi.org/10.1093/oxfordjournals. ndt.a027315 29. Clarke A, Hancoc E, Kingswood C, et al. End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant. 1999,14:988-91. http://dx.doi.org/10.1093/ ndt/14.4.988 30. Halpenny D, Snow G, McNeil G, Torreggiani WC. The radiological diagnosis and treatment of renal angiomyolipoma - current status. Clin Radiol. 2010;65:99108. http://dx.doi.org/10.1016/j.crad.2009.09.014 31. Chesa Ponce N, Artiles Hernandez JL, Ponce socorro JM, et al. Wunderlich’s syndrome as the ﬁrst manifestation of a renal angiomyolipoma. Arch Esp Urol. 1995;48:305-8. 32. Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micro nodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Resp Care Med. 2001;164:661-8. http://dx.doi.org/10.1164/ ajrccm.164.4.2011025 33. Costello LC, Hartman TE, Ryu JH, et al. High frequency of pulmonary lymphangioleiomiomatosis in women with tuberous sclerosis complex. Mayo Clin Proc. 2000;75:591-4. http://dx.doi.org/10.4065/75.6.591 34. Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus

Campos FPF, Ferreira CR, Simões AB et al. Conference. Pediatr Neurol. 2013;49:243-54. http://dx.doi. org/10.1016/j.pediatrneurol.2013.08.001 35. Northrup H, Koenig MK, Au KS. Tuberous Sclerosis Complex. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Gene Reviews™ [Internet]. Seattle: University of Washington; 1993 - [updated 2011 Nov 23]. 36. Charboneau JW, Hattery RR, Ernst EC 3rd, et al. Spectrum of sonographic ﬁndings in 125 renal masses other than benign simple cyst. AJR Am J Roentgenol. 1983;140:87-94. http://dx.doi.org/10.2214/ajr.140.1.87 37. Hartman DS, Goldman SM, Friedman AC, et al. Angiomyolipoma: ultrasonic-pathologic correlation. Radiology. 1981;139:451-8. 38. Sherman JL, Hartman DS, Friedman AC, et al. Angiomyolipoma: computed tomography-pathologic correlation of 17 cases. AJR Am J Roentgenol. 1981;137:1221-6. http:// dx.doi.org/10.2214/ajr.137.6.1221 39. Makhlouf HR, Remotti HE, Ishak KG. Expression of KIT (CD117) in angiomyolipoma. Am J Surg Pathol. 2002;26:4937. http://dx.doi.org/10.1097/00000478-200204000-00012 40. Lienert AR, Nicol D. Renal angiomyolipoma. BJU International. 2012;11 Suppl 4:25-7. http://dx.doi.org/10.1111/j.1464410X.2012.11618.x 41. Oesterling JE, Fishman EK, Goldman SM, et al. The management of renal angiomyolipoma. J Urol. 1986;135:11214. 42. Yamakado K, Tanaka N, Nakagawa T, et al. Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology. 2002;225:78-82. http:// dx.doi.org/10.1148/radiol.2251011477 43. Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:255-265. http://dx.doi. org/10.1016/j.pediatrneurol.2013.08.002 44. Han S, Santos TM, Puga A, et al. Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res. 2004;64(3):812-6. http://dx.doi.org/10.1158/0008-5472. CAN-03-3277

Conflict of interest: None Submitted on: 21th May 2013 Accept on: 28th November 2013 Correspondence: Divisão de Clínica Médica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: fpfcampos@gmail.com

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Article / Clinical Case Reports Artigo / Relato de Caso Clínico Unusual tomographic findings of complicated necrotizing pancreatitis Rosa Maria Silveira Sigrista, Samira Ineida Morais Gomesa, Daniela Tavares Possagnoloa, Brenda Margatho Ramos Martinesb Sigrist RMS, Gomes SIM, Possagnolo DT, Martines BMR. Unusual tomographic findings of complicated necrotizing pancreatitis. Autopsy Case Rep [Internet]. 2013; 3(4): 63-8. http://dx.doi.org/10.4322/acr.2013.041

ABSTRACT Acute pancreatitis (AP) is a potential life-threatening disease, which originates from inflammatory involvement of the pancreas and surrounding tissues. Serious complications eventuate and treatment is difficult. AP is classified in both interstitial edematous pancreatitis, which occurs in 70-80% of patients, and necrotizing pancreatitis, which occurs in 20-30% of patients. Diagnosis is based on the presence of two of the following criteria: abdominal pain, increased serum determination of amylase and/or lipase more than three times the reference value, and characteristic tomographic findings. Among the latter, there is the pancreatic and surrounding tissue damage as well as that related to distant organ involvement. This case report shows the fatal case of a male patient with a history of heavy alcoholic abuse admitted with the diagnosis of necrotizing pancreatitis. The authors call attention to the unusual tomographic findings; namely, a huge duodenal hematoma and a large hemoperitoneum, ischemic involvement of the spleen and kidneys, as well as pancreatic and peripancreatic necrosis. Keywords: Pancreatitis, Acute Necrotizing; Hemoperitoneum; Duodenal Diseases. INTRODUCTION The incidence of acute pancreatitis (AP) ranges from 50 to 80 cases per year per 100,000 inhabitants in the United States and around 20 cases per 100,000 inhabitants in Brazil.1 Biliary origin accounts for 38% of all cases mostly associated with micro calculi (< 5 mm), and 36% of cases are associated with alcohol consumption. Other less common causes include drugs (corticosteroids, didanosine and pentamidine, valproic acid, chemotherapy agents, and statins), hypertriglyceridemia, hypercalcemia, pancreatic duct obstruction caused by tumor, a b

biliary parasites, trauma, retrograde endoscopic cholangiopancreatography, viral infections, polyarteritis nodosa, developmental abnormalities, as well as pancreas divisum and annular pancreas.2,3 The inflammatory process starts when trypsin, a proteolytic pancreatic enzyme, is inappropriately activated on the pancreas itself, instead of into the duodenum. This enzymatic activation results in glandular autodigestion and triggers an inflammatory cascade. The release of cytokines in the circulation will result in a systemic

Department of Radiology – Instituto do Coração – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Diagnostic Imaging service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

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inflammatory response syndrome (SIRS). Ischemic damage has been recognized as an important mechanism in the pathogenesis of AP, especially in patients with necrotizing pancreatitis.4,5

Sigrist RMS, Gomes SIM, Possagnolo DT, Martines BMR.

on contrasted-enhanced CT into less than 30% and greater than 30%.10 Other forms of presentation include peripancreatic necrosis alone and pancreatic parenchymal necrosis with peripancreatic necrosis, which is the most common type of presentation.9

The diagnosis of AP is based on the presence of two of these three criteria:6 a) Clinical presentation: upper abdominal pain usually, vomiting, nausea; b) Biochemical criteria: increased serum determination of amylase and/or lipase more than three times the reference value; c) Imaging findings, either ultrasound, computed tomography (CT), or magnetic resonance.7 Currently, multidetector computed tomography (MDCT) is the imaging examination of choice to confirm the diagnosis of pancreatitis, to evaluate its extension, and to identify eventual complications. MDCT has sensitivity of 92-95% and specificity of 98-100% for the diagnosis of severe pancreatitis. The acute tomographic findings of pancreatitis comprise an increase in pancreatic volume, the blurring of pancreatic outlines, the heterogeneous enhancement of the pancreatic parenchyma after intravenous contrast injection, and the densification of peripancreatic adipose tissue.8 According to the revisedAtlanta classification,9 AP may be classified as interstitial edematous pancreatitis and necrotizing pancreatitis. The former accounts for 70-80% of the cases and may be associated with localized or diffuse enlargement of the pancreas with normal homogeneous enhancement or slightly heterogeneous enhancement of the pancreatic parenchyma related to edema. The peripancreatic and retroperitoneal tissue may be normal or may show mild inflammatory changes with varying amounts of peripancreatic fluid collection. Necrotizing pancreatitis, in turn, accounts for 2030% of the cases, and shows two distinct phases. The early phase, which occurs in the first week, is characterized by both pancreatic inflammation with varying degrees of edema/ischemia, necrosis, and liquefaction. The late phase is mostly characterized by increased necrosis, infection, and persistence of organ dysfunction. Parenchymal necrosis is divided

CASE REPORT A 42-year-old man sought emergency medical care complaining of upper abdominal pain accompanied by fever, loss of appetite, postprandial bloating, weakness, and constipation over the last 40 days. More recently, vomiting supervened. His past medical history included hospitalization due to alcoholic pancreatitis 2 years ago, alcoholism (daily ingestion of 100 g of alcohol for 30 years), smoking, and abuse of marijuana, cocaine, and crack. He had been abstinent for the past 40 days. On physical examination, he was conscious, pale and dehydrated. His pulse was 108 beats per minute; blood pressure was 176/116 mmHg; axillary temperature was 36.7 °C; and oximetry was 96% with nasal O2 supplementation. The abdomen was tender in the epigastrium and left hypochondrium where a mass was palpable. The bowel sounds were decreased, and no signs of peritoneal irritation were present. Laboratory findings included a mild anemia, leukocytosis, renal failure (creatinine 7.7 mg/dL; urea 165 mg/dL; and potassium 5.6 mEq/L), normal bilirubin and hepatic enzymes determination, prolonged prothrombin time (international normalized ratio 2.04) and high serum determination of amylase (1018 U/L), lipase (739 U/L) and lactic dehydrogenase (760 U/L)* Imaging examination will be shown in the discussion. The clinical course was characterized by shock, multiple organ failure, and visceral and intraperitoneal bleeding. Death occurred in the following days despite the support treatment. No surgical treatment could be attempted because of the patient’s poor clinical status.

* Reference values: urea 5–25 mg/dL; creatinine 0.4-1.3 mg/dL; potassium 3.5-5.0 mEq/L; amylase 20-160 U/L; lipase < 60 U/L; and LDH 120-246 U/L.

Unusual tomographic findings of complicated necrotizing pancreatitis

DISCUSSION Upon arrival at the hospital, the middle-aged patient, who was an alcoholic and already had a diagnosis of pancreatitis, had two of the three criteria for the diagnosis of pancreatitis;9 namely, upper abdominal pain, vomiting, nausea, and an amylase determination of 1.018 U/L (more than three times higher than the reference value in adults). The high serum amylase level is not only a diagnostic requirement, but also a marker of severity.9 Unfortunately, on admission the patient already had multiple organ failure, which also characterized the severity of the disease.

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peripancreatic tissue involvement and the presence of hematic material (Figure 1). This combined type of pancreatic and peripancreatic necrosis occurs in 75% to 80% of necrotizing pancreatitis.9 Along with the necrotic destruction of the pancreatic parenchyma, MDCT also showed acute necrotic collections, steatonecrosis (Figure 2), and a circumscribed, homogeneous peripancreatic fluid collection with a well-defined capsule posteriorly to the gastric greater curvature. This finding may correspond to a pseudocyst or encapsulated necrosis—a diagnosis often challenging by MDCT.

According to the revised Atlanta 9 classification, morphological criteria defined by MDCT should be considered in conjunction with the clinical parameters for better establishing the severity of pancreatitis, for confirming the diagnosis, and for eventually elucidating the etiology.11 The attenuation of normal pancreatic parenchyma is around 40-50 Halsfield Units (HU). After contrast administration, the pancreas must have a homogeneous enhancement, achieving an attenuation between 100 and 150 HU. If the entire pancreas, or a part of it, does not show this enhancement, or if it is less than 30 HU, low perfusion is very likely and necrosis may supervene.12 Although contrasted MDCT must be performed in patients with severe AP, it is not recommended to undertake it less than 72 hours after the onset of symptoms if the diagnosis of complications is the major concern, unless unexplained clinical deterioration ensues.7-9 A repeat examination should be undertaken if the clinical picture drastically changes, such as the sudden onset of fever, the suspicion of bleeding, or there are signs of sepsis.9

Figure 1 – Multidetector axial computed tomography (CT) of the abdomen, showing necrosis in the pancreatic head and tail (white arrows) and peripancreatic necrosis (arrowhead).

Necrosis, a result of thrombosis or damage to pancreatic microcirculation, develops early in the course of severe acute pancreatitis (rarely before 48 hours), and is fully established by 96 hours after the onset of symptoms.3,13 In this case report, MDCT was performed on admission concomitantly with a sudden drop in the hematocrit, and repeated when signs of shock were present. The diagnosis of necrotizing pancreatitis was made because of the presence of pancreatic necrosis in more than 30% of the gland with

Figure 2 – Multidetector CT of the abdomen, axial section. The white arrow shows an area with steatonecrosis.

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Pseudocysts, extensive inflammation, regional necrosis, and infection may cause erosion in the visceral vessels, with or without the development of pseudoaneurysms, leading to severe bleeding in the gastrointestinal tract, the retroperitoneal space, and the peritoneal cavity.3,14 Acute erosion of visceral arteries, although unusual, is a catastrophic complication. Gastrointestinal bleeding or severe intra-abdominal hemorrhage associated with acute pancreatitis is related to a significantly higher risk of death.15,16 Another rare complication observed in MDCT in this patient was an intramural duodenal hematoma (Figure 3). Considered a life-threatening complication, intramural duodenal hematoma is most commonly observed after abdominal trauma, endoscopic sclerotherapy, duodenal biopsies, or coagulopathy; however, it may be observed in the course of acute pancreatitis, and is frequently associated with impaired gastric emptying, duodenal perforation, and sepsis.17 Few cases of duodenal hematoma secondary to pancreatitis have been reported and its origin may be caused by pancreatic enzyme injury against duodenal vessels.18

Sigrist RMS, Gomes SIM, Possagnolo DT, Martines BMR.

the hemoperitoneum. MDCT has a high sensitivity to detect small amounts of hematic liquid in the peritoneal cavity, as well as evaluate vascular complications.19,20 The patient of this case report had a huge hemoperitoneum, and taking into account the magnitude of the drop in hematocrit determination the intraperitoneal bleeding was massive (Figure 4). The mortality rate among patients with hemoperitoneum seems to be related to the etiology of bleeding and location. In patients with acute or chronic pancreatitis, this complication rate is 60.4% and 57.1%, respectively. The arteries more involved with mortality are the splenic (20.5%), the gastroduodenal (27.9%), and the upper pancreatoduodenal arteries (46.1%).14 In the case reported here, ischemic complications were found in the kidneys and spleen where hypoattenuating areas were interpreted as infarctions (Figure 5).

In this case reported, we also observed a moderate amount of blood adjacent to the celiac trunk vessels and the upper mesenteric artery. We inferred that the pancreatic inflammatory process and necrosis may have contributed to erode these vessels and consequently caused

Acute renal failure (ARF) is a common complication of severe AP associated with increased morbidity and mortality. The precise mechanism of ARF in patients with severe AP has not been clarified. It involves several factors, such as hypoxia, the release of pancreatic enzymes affecting the renal microcirculation, decreased renal perfusion pressure due to abdominal compartment syndrome, intra-abdominal hypertension, and hypovolemia. Endotoxins and free radicals also play an important role in the physiopathology of severe AP and ARF.21

Figure 3 – Multidetector CT of the abdomen, coronal reformation, showing tapering of the lumen of the second duodenal portion caused by intramural duodenal hematoma (white arrow).

Figure 4 – Axial Multidetector CT of the abdomen. Arrowheads indicate hyperattenuated areas corresponding to free fluid in the abdominal cavity, indicating hemoperitoneum.

Unusual tomographic findings of complicated necrotizing pancreatitis

Autopsy and Case Reports 2013; 3(4): 63-8

REFERENCES

Figure 5 – Multidetector CT of the abdomen, coronal reformation, showing splenic hypodense areas suggestive of splenic infarction (white arrow), showing hypoattenuating areas in both kidneys compatible with renal infarctions (black arrows).

Splenic involvement in AP is rare; however, in this case, we observed hypoattenuating areas permeating the splenic parenchyma (Figure 4). The contiguity between the pancreatic tail and the splenic hilum may constitute a gateway to the inflammatory process.22 The liver is another organ that can be affected by AP. In this case, we observed thin perivesicular hypoattenuating areas, which may correspond to perfusion hepatic disorders. The pancreatic inflammatory process extended along the hepatoduodenal gastrohepatic ligament and the portal vein, reaching the Glisson’s capsule. Perfusion changes caused by AP usually reach the right liver lobe. Systemic mediators and the local inflammatory process are responsible for this damage.23 This patient presented severe complications, some of them rare. We highlight the fact that MDCT was an excellent auxiliary method for all the above mentioned diagnoses, proving to be not only useful for diagnosis, but also crucial for the follow-up of any patient with AP.

De Campos T, Parreira JG, Utiyama E, Rasslan. Pesquisa nacional sobre condutas na pancreatite aguda. Rev Col Bras Cir. 2008;35(5):304-10. Portuguese. http://dx.doi. org/10.1590/S0100-69912008000500006

Sakorafas GH, Tsiotou AG. Etiology and pathogenesis of acute pancreatitis: current concepts.J Clin Gastroenterol. 2000;30(4):343-56. PMid:10875461.

Trout AT, Elsayes KM, Ellis JH, Francis RI. Imaging of acute pancreatitis: prognostic value of computed findings. J Comput Assist Tomogr. 2010;34(4):485-95. http://dx.doi. org/10.1097/RCT.0b013e3181d344ca

Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400. PMid:17032204.

Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet. 2008;371(9607):143-52. PMid:18191686.

Sarr MG, Banks PA, Bollen TL, et al. Revision of the Atlanta classification of acute pancreatitis. Gut. 2013;62(1):102-11.

Baron T. Managing severe acute pancreatitis. Cleve Clin J Med. 2013;80(6):354-9. PMid:23733900. http://dx.doi. org/10.3949/ccjm.80gr.13001

Turner M. Pancreatitis: role of US and CT. Gastrointest Endosc. 2002;56(6 Suppl):S241-5. PMid:12447275.

Thoeni R. The Revised Atlanta Classification of Acute Pancreatitis: its importance for the radiologist and Its effect on treatment. Radiology. 2012;262(3):751-64. PMid:22357880. http://dx.doi.org/10.1148/radiol.11110947

10. Bollen TL, Singh VK, Maurer R, et al. Comparative evaluation of the modified CT severity index and CT severity index in assessing severity in acute pancreatitis. AJR Am J Roentgenol. 2011;197(2):386-92. http://dx.doi.org/10.2214/ AJR.09.4025 11. Bharwani N, Patel S, Prabhudesai S, Fotheringham T, Power N. Acute pancreatitis: the role of imaging in diagnosis and management. Clin Radiol. 2011;66(2):164-75. PMid:21216333. http://dx.doi.org/10.1016/j.crad.2010.09.003 12. Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology. 2002;223(3):603-13. PMid:12034923. 13. Isenmann R, Buchler M, Uhl W, Malfertheiner P, Martini M, Beger HG. Pancreatic necrosis: an early finding in severe acute pancreatitis. Pancreas. 1993;8(3):358-61. PMid:8483878. 14. Flati G, Salvatori F, Porowska B, et al. Severe hemorrhagic complications in pancreatitis. Ann Ital Chir. 1995;66(2):233-7.

Autopsy and Case Reports 2013; 3(4): 63-8 15. Bretagne JF, Heresbach D, Darnault P, et al. Pseudoaneurysm and bleeding psedocysts in chronic pancreatitis: radiological findings and contribution to diagnosis in 8 cases. Gastrointest Radiol. 1990;15(1):9-16. http://dx.doi.org/10.1007/ BF01888725 16. Sand JA, Seppanen SK, Nordback IH. Intracystic hemorrhage in pancreatic pseudocysts: initial experiences of a treatment protocol. Pancreas. 1997;14(2):187-91. http://dx.doi. org/10.1097/00006676-199703000-00012

Sigrist RMS, Gomes SIM, Possagnolo DT, Martines BMR. 19. Federle MP, Goldberg HI, Kaiser JA, Moss AA, Jeffrey RB Jr, Mall JC. Evaluation of abdominal trauma by computed tomography. Radiology. 1981;138(3):637-44. PMCid:1306082. 20. Turner, A. The role of US and CT in pancreatitis. Gastrointest Endosc. 2002;56(6 Suppl):S241-5. PMid:12447275. 21. Petejova N, Martinek A. Acute kidney injury following acute pancreatitis: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;157(2):105-13. PMid:23774848. http:// dx.doi.org/10.5507/bp.2013.048

17. Ma JK, Ng KK, Poon RT, Fan ST. Pancreatic-induced intramural duodenal haematoma. Asian J Surg. 2008 Apr;31(2):83-6. PMid:18490220. http://dx.doi.org/10.1016/ S1015-9584(08)60063-9

22. Siu T. Percutaneous drainage of spontaneous subcapsular haematoma ofthe spleen complicating chronic pancreatitis. Surgeon. 2004;2(1):52-5. PMid:15570808.

18. Bodnar Z, Várvölgyi C, Tóth, J, Sápy P, Kakuk, G. Intramural duodenal hematoma complicating acute necrotizing pancreatitis. Gastrointest Endosc. 2000;52(6):791-3. PMid:11115923.

23. Tutcu S, Serter S, Kaya Y, et al. Hepatic perfusion changes in an experimental model of acute pancreatitis: Evaluation by perfusion CT. Eur J Radiol. 2010;75(2):203–6. PMid:19501998. http://dx.doi.org/10.1016/j.ejrad.2009.04.072

Conflict of interest: None Submitted on: 5th August 2013 Accepted on: 6th December 2013 Correspondence: Departamento de Radiologia Incor – Faculdade de Medicina da USP Av. Dr. Enéas Carvalho de Aguiar, 44 – Cerqueira César – São Paulo/SP – Brazil CEP: 05403-900 – Phone: +55 (11) 2661-5604 E-mail: rosasigrist@hotmail.com

Autopsy and Case Reports 2013; 3(4): 69-71

Image in Focus Imagem em Foco Renal papillary necrosis Stephen A. Gellera, Fernando P. F. de Camposb Geller SA, Campos FPF. Renal papillary necrosis. Autopsy Case Rep [Internet]. 2013; 3(4): 69-71. http://dx.doi. org/10.4322/acr.2013.042

Picture provided by Dr. Stephen A. Geller - personal archive.

Figure 1 – Renal papillary necrosis. Irregularly round or oval areas of yellow necrosis are seen in renal papilla and medullary areas of the kidney from a 62-year-old female with type 1 diabetes mellitus. A urinary tract infection was also present as evidenced by the mildly inflamed renal pelvis epithelium (acute pyelitis). In 1877, Dr. Nikolaus Friedreich1 (18251882; student of Virchow who became Professor of Pathology at Heidelberg and who also described Friedreich’s ataxia) first described renal papillary necrosis (RPN) in patients with prostatic hypertrophy and secondary hydronephrosis. Thereafter in 1937, Froboese2 and Günther3 emphasized the association of this entity with diabetes mellitus. These authors also observed renal papillary necrosis in cases of urinary tract obstruction even in the absence of diabetes mellitus. a b

In 1952, Mandel’s4 report corroborated the latter findings, suggesting that urinary tract infection played a role in the pathogenesis of RPN. His report showed the presence of urinary infection in 95% of cases of RPN, in autopsy studies. It was in the late 1950s that analgesics emerged as a major etiological factor of RPN.5 Since then some series reported that analgesic abuse accounted for 80 – 90% of cases of RPN.5-7 In this setting non-steroidal anti-inflammatory drugs (NSAID) are also included with their incidence increasing

Department of Pathology and Laboratory Medicine – Weill Medical College of Cornell University – New York – USA. Department of Internal Medicine – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil.

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as these medications are more often utilized. The risk highest is for phenacetin (no longer used in many countries) and acetaminophen. In general, the risk for analgesic nephropathy is cumulative. More recently, it has been shown that these drugs are harmful to human kidneys in the presence of volume depletion, underlying renal disease as well as long-term abuse.8 Other causes of RPN include: sickle-cell hemoglobinopathies9,10, postrenal transplants11, chronic liver disease12, shock and severe dehydration, the latter mainly observed during infancy.5 The principal causes are summarized in Table 1. Table 1 – Major causes of renal papillary necrosis (RPN) Analgesic nephropathy Sickle cell nephropathy Diabetes mellitus, often with urinary tract infection Prolonged use of NSAIDs

An expanded list of causes is summarized with the English language mnemonic “POSTCARDS” (pyelonephritis, obstructive uropathy, sickle cell disease, tuberculosis, chronic liver disease, analgesic/alcohol, renal transplant rejection, diabetes mellitus, systemic vasculitis).13 The frequency of RPN in different disease conditions is unknown because of underdiagnosed paucior asymptomatic cases. However approximately 30% of all cases of RPN occur in the setting of diabetes mellitus. In these cases, hyperglycemia is usually uncontrolled, and urinary tract infections are frequently seen. The relationship of RPN with diabetic microangiopathy could be demonstrated either in vivo or in an autopsy series.14 Friedreich5 proposed a vascular mechanism to explain the RPN regardless of underlying disease. Unequivocally, this mechanism is observed in sickle cell disease, where vasa recta are obstructed by the sickling erythrocytes. In case of analgesics and NSAID, ischemia can be demonstrated in the medulla and vasa recta due to direct inhibition of cyclooxygenase-mediated production of 8 prostaglandins. A direct toxic effect on cells of the medulla is also involved in the pathogenesis of RPN. Damage to these cells may similarly

Geller SA, Campos FPF.

reflect as effects on vasculature, since medullary interstitial cells synthesize prostaglandins. Studies have also shown that ischemia results from direct endothelial cell damage.15 Regardless the involved mechanism, the end result is reduced prostaglandin production, leading to decreased vascular perfusion, vasoconstriction and eventually ischemic necrosis.8 The lack of specific symptoms, in the early stages, makes diagnosis challenging. Later clinical features include: nocturia, dysuria, pyuria, hematuria (most notably microscopic hematuria), ureteral colic, necrotic papillae voided in the urine6 and back pain. Renal function studies may also reveal decreased glomerular filtration rate (GFR), increased urea blood nitrogen (BUN) and renal tubular acidosis. Eventually RPN leads to death or chronic renal failure.8 Histologically, renal papillary necrosis is characterized by coagulative necrosis of the renal papilla and the background medullary pyramids. Subsequently the necrotic foci can become infected either from ascending cystitis or hematogenous dissemination and be seen as acute liquefactive necrosis with potential abscess formation. The papilla, whether infected or not, can cause renal tubular obstruction. Sloughed papilla can be seen in cytopathology preparations of urine. In time fibrosis and calcification occur. Bilateral involvement, or involvement of a solitary kidney, can lead to renal failure. If renal papillary necrosis is complicated by infection can lead to death, particularly in the diabetic patient who may or may not have other significant medical problems. Even in the non-diabetic patient, renal papillary necrosis is potentially fatal. As a last note, it has been suggested that the first description of RPN is in the record of Beethoven’s autopsy.16 The translation of the original Latin of the report says, “every one of their calices was occupied by a calcareous concretion of a wart-like shape and is large as a split pea.” In a subsequent paper17, the wording of the translation was changed to “every single calyx was filled with a calcareous concretion like a pea which had been cut across the middle.” In addition, the renal capsule is described as a “cellular membrane of an inch thick,” indicative of chronic renal inflammation rather than acutely occurring RPN. This may, instead of RPN, be a description of extensive nephrolithiasis in association with chronic pyelonephritis. When RPN develops it is typically irregular and does not affect “every single” papilla. Further the necrotic papilla slough and break off, to be excreted, and evidence would similarly not be present throughout. “Wart-

Renal papillary necrosis

like,” the descriptive term used, is not likely to be RPN, and, although color descriptors appear in other parts of the report, there is no use of “yellow,” typical of necrosis, in the kidney section. The pathologist, Johann Wagner, was experienced and highly regarded, including by his student Karl von Rokitansky, developer of the great Viennese school of pathology. As was the custom of the time the report concentrates on explaining clinical problems and the prostate gland, likely enlarged in a 57 year old man and possibly the cause of at least partial obstruction and subsequent pyelonephritis, is not mentioned. In addition it is highly unlikely that he would have mistaken the papilla for a calyx, since the anatomy of the kidney had been well described by Marcello Malpighi (1628-1694) two centuries before.

Keywords: Kidney Papillary Necrosis; Diabetes Mellitus; Urinary Tract Infections; Antiinflammatory Agents, Non-Steroidal. REFERENCES 1.

Friedreich N. Über Necrose der Nierenpapillen bei Hydronephrose. Virchows Arch Pathol Anat. 1877;69:30812. http://dx.doi.org/10.1007/BF02326121 Froboese C. Uber sequestrierende Marknekrosen der Nieren bei Diabetes Mellitus. Verh Deutsch Ges Pathol. 1937;30:431-43.

Autopsy and Case Reports 2013; 3(4): 69-71 6.

Harvald B. Renal papillary necrosis. A clinical survey of sixty-six cases. Am J Med. 1963;33:481-6. http://dx.doi. org/10.1016/0002-9343(63)90147-5

Hultengren N. Renal papillary necrosis. A clinical study of 103 cases. Acta Chirurg Scand. 1961;277:1-84.

Brix AE. Renal papillary necrosis. Toxicol Pathol. 2002;30:6724. http://dx.doi.org/10.1080/01926230290166760

Harrow BR, Sloane JA, Liebman NC. Roentgenologic demonstration of renal papillary necrosis in sickle cell trait. N Engl J Med. 1963;268:969. PMid:13953018. http://dx.doi. org/10.1056/NEJM196305022681802

10. Voulgarelis M, Ziakas P. Renal papillary necrosis unmasking sickle cell disease. N Engl J Med. 2005;352:1237. PMid:15788500. http://dx.doi.org/10.1056/NEJMicm030682 11. Edmondson RPS, Fawcet TW, Jones NF, Cade R, Tarrant DG, Juncos LI. Papillary necrosis in a transplanted kidney. Br Med J. 1972;1:547. http://dx.doi.org/10.1136/bmj.1.5799.547 12. Edmondson HA, Reynolds TB, Jacobson HG. Renal papillary necrosis with special reference to chronic alcoholism. Arch Intern Med. 1966:118:255. PMid:5947305. http://dx.doi. org/10.1001/archinte.1966.00290150069013 13. Powell C, Donohoe JM, Mydlo JH. Papillary necrosis [Internet]. Medscape; 2012. [cited 2013 Oct 2]. Available from: http:// emedicine.medscape.com/article/439586-overview#a0102 14. Groop L, Laasonen L, Edgren J. Renal papillary necrosis in patients with IDDM. Diabetes Care. 1989;12:198-202. http://dx.doi.org/10.2337/diacare.12.3.198

Guenther GW. Die Papillennekrosen der Niere bei Diabetes. München Med Wschr. 1937;84:1695.

15. Wolf DC, Turek JJ, Carlton WW. Early sequential ultrastructural renal altrations induced by 2-bromoethylamine hydrobromide in the Swiss ICR mouse. Vet Pathol. 1992;29:528-35. http:// dx.doi.org/10.1177/030098589202900607

Mandel EE. Renal medullary necrosis. Am J Med. 1952;13:322-7. http://dx.doi.org/10.1016/0002-9343(52)902866

16. Schwarz A. Beethoven’s renal disease based on his autopsy: a case of papillary necrosis. Am J Kid Dis. 1993;21:643-52. PMid:8503419.

Renal papillary necrosis. Lancet. 1982;320:588-90. http:// dx.doi.org/10.1016/S0140-6736(82)90665-1

17. Davies PJ. Beethoven’s nephropathy and death: discussion paper. J Roy Soc Med. 1999;86:159-61.

Stephen A. Geller, M.D. Department of Pathology and Laboratory Medicine Weill Medical College of Cornell University New York - USA geller16st@gmail.com Fernando P. F. de Campos, PhD Department of Internal Medicine Hospital Universitário - USP São Paulo/SP - Brazil fpfcampos@gmail.com

Autopsy and Case Reports 2013; 3(4): 73-4

Nominata

Nominata of the Reviewers of the volume 3, 2013 The Editors of Autopsy and Case Reports thank the peer reviewers listed below for the excellent collaborative work, opinions and comments on the papers published in 2013. Their hard work certainly contributed to maintaining the scientific level of this journal. Reviewers

Specialty

Institution

Alfredo José Mansur

Cardiology

INCOR - HC - FMUSP - São Paulo/SP - Brazil

Aloísio Felipe-Silva

Pathology

HU - USP - São Paulo/SP - Brazil

Ana Cristina Aoun Tannuri

Surgery

FMUSP - São Paulo/SP - Brazil

Ana Luiza Werneck da Silva

Endoscopy

HU - USP - São Paulo/SP - Brazil

Anna-Luise Arnold Katzenstein

Pathology

Upstate Medical University - Syracuse/NY - USA

Antonio Carlos de Campos

Odontology

HU - USP - São Paulo/SP - Brazil

Antonio Nascimento

Pathology

Hospital A. C. Camargo - São Paulo/SP - Brazil

Ary Nasi

Surgery

HC - FMUSP - São Paulo/SP - Brazil

Beatriz Mônica Sugai

Endoscopy

Fleury Medicina e Saúde- São Paulo/SP - Brazil

Caio Robledo D’Angioli Costa Quaio

Geneticist

FMUSP e Mendelics Analise Genomica - São Paulo/SP - Brazil

Calógero Presti

Surgery

HC - FMUSP- São Paulo/SP - Brazil

Carlos Eduardo Bacchi

Pathology

Laboratório Bacchi - São Paulo/SP - Brazil

Cláudia Regina G. C.de Oliveira

Pathology

FMUSP - São Paulo/SP - Brazil

Dagoberto Callegaro

Neurology

HC - FMUSP - São Paulo/SP - Brazil

Dani Ejzenberg

Gynecology

HI Saúde da Mulher - São Paulo/SP - Brazil

Elisa Ryoka Baba

Endoscopy

HC - FMUSP- São Paulo/SP - Brazil

Emílio Marcelo Pereira

Pathology

Salomão Zoppi Diagnósticos - São Paulo/SP - Brazil

Eric L. Matteson

Rheumatology

Mayo Clinic – Rochester/MN - USA

Evandro Sobroza de Mello

Pathology

HC - FMUSP e ICESP - São Paulo/SP - Brazil

Fabio Rocha Fernandes Távora

Pathology

UFC – Fortaleza/CE - Brazil

Fernando Peixoto Ferraz de Campos Internal Medicine

HU - USP - São Paulo/SP - Brazil

Fernando Nalesso Aguiar

Pathology

ICESP - São Paulo/SP - Brazil

Francy Reis da Silva Patricio

Pathology

UNIFESP - São Paulo/SP - Brazil

Geraldo Brasileiro Filho

Pathology

UFMG - Belo Horizonte/MG - Brazil

Ivan Benaduce Casella

Surgery

FMUSP - São Paulo/SP - Brazil

Jagdish Butany

Pathology

University of Toronto - Toronto/ON - Canada

Jorge Manoel Buchdid Amarante

Infectology

Hospital Samaritano - São Paulo/SP - Brazil

José Aderval Aragão

Pathology

UFS - São Cristóvão/SE - Brazil

José Cabeçadas

Pathology

Instituto Português de Oncologia - Lisboa - Portugal

José Carlos Oliveira de Morais

Pathology

UFRJ - Rio de Janeiro/RJ - Brazil

José Jukemura

Surgery

HC - FMUSP- São Paulo/SP - Brazil

Juliana Pereira

Hematology

HC - FMUSP e ICESP- São Paulo/SP - Brazil

Katia Ramos Moreira Leite

Pathology

FMUSP - São Paulo/SP - Brazil

Leonardo de Abreu Testagrossa

Pathology

HC - FMUSP e Fleury Medicina e Saúde - São Paulo/SP - Brazil

Luiz Antonio Machado César

Cardiology

INCOR - HC - FMUSP- São Paulo/SP - Brazil

Luiz Cesar Peres

Pathology

Sheffield Children’s Hospital - Sheffield - UK

Nominata

Autopsy and Case Reports 2013; 3(4): 73-4

Reviewers

Specialty

Institution

Luiz Otávio Savassi Rocha

Internal Medicine

UFMG - Belo Horizonte/MG - Brazil

Manoel de Souza Rocha

Radiology

HC - FMUSP - São Paulo/SP - Brazil

Marcello Fabiano de Franco

Pathology

UNIFESP - São Paulo/SP - Brazil

Marcelo Abrantes Giannotti

Pathology

ICESP - São Paulo/SP - Brazil

Marcio Ricardo Taveira Garcia

Radiology

ICESP - São Paulo/SP - Brazil

Marco Aurélio Lana Peixoto

Neurology

UFMG - Belo Horizonte/MG - Brazil

Maria Del Pilar Esteves Diz

Oncology

ICESP - São Paulo/SP - Brazil

Maria Mercês Santos

Surgery

HC - FMUSP - São Paulo/SP - Brazil

Maria Regina Vianna

Pathology

CICAP - São Paulo/SP - Brazil

Paulo Kauffman

Surgery

FMUSP - São Paulo/SP - Brazil

Paulo Roberto Merçon de Vargas

Pathology

UFES - Vitória/ES - Brazil

Peter G. Isaacson

Pathology

Royal Free Hospital - London - UK

Rafael Ferreira Coelho

Surgery

HC - FMUSP e HIAE - São Paulo/SP - Brazil

Regina Schultz

Pathology

HC - FMUSP - São Paulo/SP - Brazil

Rosa Maria Rodrigues Pereira

Rheumathology

FMUSP - São Paulo /SP - Brazil

Stephen A. Geller

Pathology

Weill Medical College - Cornell University - New York/NY - USA

Tatiana Pfiffer

Gynecology

Hospital Oswaldo Cruz - São Paulo/SP - Brazil

Thales de Brito

Pathology

FMUSP, IMT USP - São Paulo/SP - Brazil

Vera Demarchi Aiello

Pathology

INCOR - HC - FMUSP - São Paulo/SP - Brazil

Vera Lucia Aldred

Pathology

FMUSP - São Paulo/SP - Brazil

Vera Luiza Capelozzi

Pathology

FMUSP - São Paulo /SP - Brazil

William Dean Wallace

Pathology

University of California - Los Angeles/CA - USA

Legend CICAP – Centro Imunohistoquímica Citopatologia Anátomo Patológico FMUSP – Faculdade de Medicina da Universidade de São Paulo HC-FMUSP – Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo HIAE – Hospital Israelita Albert Einstein HU-USP – Hospital Universitário da Universidade de São Paulo IMT-USP – Instituto de Medicina Tropical da Universidade de São Paulo ICESP – Instituto do Câncer do Estado de São Paulo INCOR HC FMUSP – Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo UFC – Universidade Federal do Ceará UFES – Universidade Federal do Espirito Santo UFMG – Universidade Federal de Minas Gerais UNIFESP – Universidade Federal de São Paulo UFRJ – Universidade Federal do Rio de Janeiro UFS – Universidade Federal de Sergipe