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

Editorial

Clinicopathological Conferences: a testimonial Luiz Otávio Savassi Rochaa Rocha LOS. Clinicopathological Conferences: a testimonial [editorial]. Autopsy Case Rep [Internet]. 2013; 3(3): 1-4. http://dx.doi.org/10.4322/acr.2013.022

E. E. Franco, Cesare Sacerdotti and Luigi Bogliolo: “I tre sofi”. (Pisa, March 1938) Picture – Personal archive of the author.

The origins of my visceral connection with Clinicopathological Conferences date back to April 18, 1908, the date of birth in Sassari, on the island of Sardinia, of the Italian pathologist Luigi Bogliolo, who graduated from the local Faculty of Medicine in 1930. At medical school, from 1927 to 1930, Bogliolo was teaching assistant of Pathology, under the guidance of the very demanding Professor Enrico Emilio Franco, who was a source of inspiration for him throughout his life. Franco, an Italian of Jewish

a

origin, graduated in 1906 from the University of Padua and, therefore, was a disciple of the School of Giovanni Battista Morgagni, the “Father of Pathological Anatomy”. In the two-year period 1931-1932, Bogliolo was a volunteer assistant at the Institute of Pathological Anatomy and Histology of the University of Sassari, directed by Franco. In late 1932, he moved along with his master to the University of Bari, becoming a staff assistant of the Pathological Anatomy Department. In December 1936, following the footsteps of Franco once more, he moved to the University of Pisa, as Deputy

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 médium provided article is properly cited.

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Director of the Institute of Pathological Anatomy and Histology, where he remained until March 1939. In 1938, in Pisa, the young pathologist earned the title of full professor and, that same year, married Geula Bennoun, a medical student, also of Jewish origin, born in Jaffa, the twin city of Tel Aviv. During the time they worked in Pisa, Bogliolo and Franco were linked, by friendship and profession, to the Chairman of General Pathology, Professor Cesare Sacerdotti, to whom they referred respectfully as “Il professore”. Sacerdotti was a disciple of Camillo Golgi, Nobel Prize winner in Physiology or Medicine in 1906, and Giulio Bizzozero who, in turn, was a disciple of Rudolf Virchow, the “Father of Cellular Pathology”. Bizzozero gained notoriety for his discovery of platelets and their role in hemostasis and, more recently, for his discovery of spiral bacteria in the stomach of dogs, the first step for the identification of the species Helicobacter pylori in the human stomach. As evidence of the prestige they enjoyed in the University of Pisa, the three friends – Bogliolo, Franco, and Sacerdotti – were named “I tre sofi,” or “The three wise men”. Among Bogliolo’s publications during his academic life in Italy, special mention should be made of his induction of sarcomas by injection of the radiological contrast medium Thorotrast (radioactive thorium dioxide) as reported in Mus musculus, var. alba (1937) and in Mus norvegicus (1938).1,2 Despite this experimental evidence, Thorotrast continued to be used until the mid-1950s in prestigious institutions  –  including Massachusetts General Hospital, the Lahey Clinic, and the University of Michigan Hospital – leading to the death of hundreds of patients from malignant neoplasms, especially hepatic hemangioendotheliosarcoma and cholangiocarcinoma. Dismissed from the University of Pisa in January 1939, amid a wave of anti-Semitism that plagued his homeland, Franco was forced to exile in Jerusalem, where he died in 1950 at 68 years of age. In March 1939, Bogliolo was fired from the University of Pisa due to his antifascist position, worsened by his close relationship with Professor Franco and Geula Bennoun, and he was forced to leave his home country as well. After spending a few months in Belgium, Bogliolo, along with his wife, headed to Brazil, arriving in Rio de Janeiro on January 5, 1940. In January 1941, after facing serious difficulties, he became the chief pathologist, at the National Faculty of Medicine (now Faculty of Medicine, Universidade Federal do Rio de Janeiro [UFRJ]), of the Internal Medicine Service

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directed by the renowned clinician, Professor Heitor Annes Dias, nicknamed the “Brazilian Jiménez Díaz”. Perfectly harmonized with Annes Dias, Bogliolo boosted the Clinicopathological Conferences at that institution. Inspired by the memorable lessons of Master Franco, he conducted the autopsies of the cases that were presented in those sessions. Therefore, after the clinical features had been discussed, the diagnostic hypotheses had been formulated, and the possible reasons for death had been considered, he was in charge of the autopsy report. Furthermore, at the end of the session, he used to perform the great synthesis – the epicrisis – correlating the post mortem findings with those observed intra vitam. With the untimely death of Annes Dias in November 1943, Alfredo Balena, Bogliolo’s compatriot and Director of the Faculty of Medicine, University of Minas Gerais (now Faculty of Medicine, Universidade Federal de Minas Gerais [UFMG]), invited him to become the Head of the Department of Pathological Anatomy of the institution Balena helped to found in 1911. In his new home, Bogliolo continued to favor Clinicopathological Conferences from 1944 until his mandatory retirement in 1978. In the autopsy room – considered by him a “sacred temple” – Bogliolo demanded that the cadaver be treated with absolute respect, incorporating the message contained in the famous Latin maxim “Taceant colloquia. Effugiat risus. Hic locus est ubi mors gaudet succurrěre vitae.”, according to which, in an environment where death delights to help the living, there should be no talking or laughing. During my time at the medical school of the UFMG, I was invited by Professor Bogliolo to serve as a teaching assistant at the Department of Pathological Anatomy and Forensic Medicine, headed by the unforgettable master. For four years after graduating, I remained linked to this department. During this period, I had the opportunity to perform many autopsies, cementing my belief in the inestimable pedagogical value of clinicopathological correlation exercises. From May 1995, as Professor of Internal Medicine, I assumed the responsibility for coordinating the Clinicopathological Conferences of the Hospital das Clínicas – UFMG, attended by graduate students, medical residents, professors, and other interested parties. Between May 1995 and June 2013, I personally managed 223 Clinicopathological Conferences. At the 116th Clinicopathological Conference, a case of mucopolysaccharidosis type II (Hunter syndrome)


Clinicopathological Conferences: a testimonial

was discussed. In this case, the patient presented respiratory failure and cardiac involvement, with the finding of apical aneurysm of the left ventricle very similar to the characteristic “vorticilar lesion” of chronic Chagas’ cardiomyopathy, considered by many to be pathognomonic of this condition. At the invitation of Dr. Alfredo José Mansur, Editor of the section Clinicopathological Session of the journal Arquivos Brasileiros de Cardiologia, this case was published in the July 2006 issue.3 At the 215th Clinicopathological Conference, a case of shock due to a clinically unsuspected left adrenal bulky pheochromocytoma with areas of hemorrhage and massive central necrosis was presented. This case was published in the journal Autopsy and Case Reports in 2012.4 In 1992 and 2010, I had two books published, respectively Vida e Obra de Luigi Bogliolo (Life and Work of Luigi Bogliolo), 5 dedicated to the memory of our missing master, and Sessões Anatomoclínicas: valor pedagógico lato sensu (Anatomoclinical Sessions: pedagogical value lato sensu). 6 In the latter, prefaced by Dr. Alfredo José Mansur, I sought to stimulate the dialogue with other disciplines, such as Biology, Medical Education, Public Health, Forensic Medicine, Psychology, History of Medicine, and even Literature – hence the reason for inclusion of the expression “lato sensu” in the title of the book. From April 2007, along with Professor Geraldo Brasileiro Filho, the current editor of the textbook Bogliolo: Patologia,7 I have been participating in the interactive sessions of Telepathology (38 sessions until April 2013), which feature videoconferences in real time of autopsies performed at the Coroner’s Service of the Faculty of Medicine of University of São Paulo (USP). In addition, since September 2012, at the invitation of Dr. Fernando Peixoto Ferraz de Campos and Professor Maria Cláudia Nogueira Zerbini, I have been participating along with teachers of UFMG (including Professor Geraldo Brasileiro Filho) and USP in the interactive meetings, which are also transmitted by videoconference, designed to discuss cases of autopsies performed at the Hospital Universitário – USP (seven meetings through to June 2013). Despite their extraordinary heuristic value, Clinicopathological Conferences have become, in most academic institutions, increasingly rare because of the large reduction in the number of autopsies. This is due, in part, to the overconfidence of modern physicians; having access to highly sophisticated diagnostic

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

technologies, they consider themselves immune to error. Nevertheless, contrary to expectations, the incidence of diagnostic errors detected by autopsy remains significant. A JAMA editorial by Dr. George D. Lundberg explains in a clear, compelling way, why these discrepancies are still prevalent today:8 In fact, there is still a giant gap between what hightech diagnostic medicine can do in theory in ideal circumstances (very much, very well) and what hightech diagnostic medicine does do in practice in real-life circumstances (not nearly so well), when human beings have to decide what, where, when, how, and why to use it. The gap becomes especially obvious when one looks at patients sick unto death.

However, my continuing high regard for the Clinicopathological Conferences lies not only in the confrontation between clinical and pathological diagnoses, a setting in which not only the clinician but also the pathologist may equivocate. The latter, quite often, does not deal with pure, concrete, and objective “facts” in nature, but with complex situations, involving often debatable interpretation. Therefore, without losing sight of the importance of the “product” represented by the report of the autopsy findings, one should focus on the “process”, which is marked by the exercise of clinical judgment, the refinement of the critical spirit, and the cultivation of systematic doubt. Accordingly, by way of conclusion, it is worth evoking the words of João Guimarães Rosa in The devil to pay in the backlands (Grande Sertão: Veredas):9 I mean, the truth is not in the setting out nor in the arriving: it comes to us in the middle of the journey.

REFERENCES 1.

Bogliolo L. Produzione col thorotrast di un sarcoma fusocellulare fascicolato nel Mus musculus var. alba. Pathologica. 1937;29:372-6. Italian.

2.

Bogliolo L. Sopra i blastomi sperimentale da ossido di torio. IIa Nota. Pathologica. 1938;30:422-30. Italian.

3.

Rocha LOS, Quirino BEG, Melo FHC, et al. Progressive respiratory failure in a 33 year-old man with heart disease and remarkable somatic dysmorphism. Clinicopathological session. Case 3/2006. Arq Bras Cardiol. 2006;87:61-9. Portuguese. PMid:16906272.

4.

A r a ú j o S A , C a r m o PA S , P a u l i n o E J r,   e t   a l . Pheochromocytoma-induced shock: a case report. Autopsy Case Rep [Internet]. 2012;2(3):21-30. http://dx.doi. org/10.4322/acr.2012.022

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Autopsy and Case Reports 2013; 3(3): 1-4 5.

Rocha LOS. Vida e obra de Luigi Bogliolo. Belo Horizonte: Fundação Cultural de Belo Horizonte; 1992. Portuguese.

6.

Rocha LOS. Sessões Anatomoclínicas: valor pedagógico lato sensu. Belo Horizonte: Coopmed; 2010. Portuguese.

7.

Brasileiro Filho G, editor. Bogliolo Patologia. 8. ed. Rio de Janeiro: Guanabara Koogan; 2011. Portuguese.

Rocha LOS 8.

Lundberg GD. Low-tech autopsies in the era of high-tech medicine: continued value for quality assurance and patient safety [editorial]. JAMA. 1998;280:1273-4. http://dx.doi. org/10.1001/jama.280.14.1273

9.

Rosa JG. The devil to pay in the backlands. James L. Taylor, Harriet de Onís, translators. New York: Alfred A. Knopf; 1963. p. 52.

Correspondence: Luiz Otávio Savassi Rocha Faculdade de Medicina – Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil E-mail: savassi@estaminas.com.br

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Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Accessory soleus muscle: a case report and clinical applicability William Paganini Mayera,b, Josemberg da Silva Baptistaa, Rogério Albuquerque Azeredoa,b, Fernando Mussob Mayer WP, Baptista JS, Azeredo RA, Musso F. Accessory soleus muscle: a case report and clinical applicability. Autopsy Case Rep [Internet]. 2013; 3(3): 5-9. http://dx.doi.org/10.4322/acr.2013.025

ABSTRACT Variations in leg muscle are uncommon. Literature on this subject is scarce, but when those variations are reported they may cause alterations in joint mechanics or cause some discomfort in the leg and foot. The accessory soleus muscle (ASM) is considered an unusual anatomical variation, with an incidence of 0.5-6.0% in the population through studies in cadavers. During routine preparation of study material in the dissection room of the anatomy laboratory of the Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória/ES – Brazil, an ASM was found in the right inferior limb of a male cadaver fixed in 10% formalin. This supernumerary muscle was 3 cm wide, 9 cm long and 1 cm thick in its most voluminous part, in typical penniform fibers arrangement. It was located in the posteromedial region of the ankle, anterior to the Achilles tendon and posterior to the deep muscles of the leg compartment. Its anterior face covered the tibial nerve and the posterior tibial vessels, while its lower half was covered by the flexor retinaculum into the tarsal tunnel. Reports in the literature show possible compression of a neurovascular bundle because of its intimal position within the tarsal tunnel, which could result in ischemic compartment syndrome. Keywords: Anatomic variation; Muscle, Skeletal; Ankle. INTRODUCTION Supernumerary muscles in the leg and foot can cause discomfort and impairment of joint function; thereby assuming clinical and surgical relevance. Although Cruveilhier first described the accessory soleus muscle (ASM) in 1843,1,2 since then the number of published cases has remained scarce. The incidence of this anatomical variation a b

is estimated to occur in 0.5-6% of the general population.3 This congenital anatomical variation may be unilateral or bilateral, and when symptomatic, the complaints are confined to the malleolar region.4 The paucity of data in the literature is due to asymptomatic cases, which are consequently not reported. The recent reports on the presence of ASM are associated with tarsal tunnel syndrome, a painful

Departamento de Morfologia – Universidade Federal do Espírito Santo, Vitória/ES – Brazil. Setor de Anatomia – Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória, Vitória/ES – 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 médium provided article is properly cited.

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Mayer WP, Baptista JS, Azeredo RA, Musso F.

foot entity secondary to tibial nerve compression.5 Thus, the medical implications of ASM justified the current research, since the recognition of this variation is important to the surgical practice of the ankle and foot,6 especially after the extensive inclusion of minimally invasive surgical techniques.7 In contrast, there is a gap of knowledge regarding the presenting forms of this anatomical variation in the literature. The differential diagnosis with lipoma, hemangioma, synovioma, and myosarcoma of the posterior region of the malleolus medialis2,8 has to be considered. Thus, the aim of this article is to describe in detail the presence of ASM in a cadaver, using the anatomical dissection technique.

CASE REPORT An accessory soleus muscle was found during a routine dissection to study the right lower limb and tarsal tunnel. This finding was detected in the right lower limb of a formalin-fixed male cadaver belonging to the anatomical collection of the Laboratory of Anatomy of the Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória/ES  –  Brazil, and the following description was approved by the Institutional Ethics Committee.

Figure 1 – Medial view of the right ankle showing at point A - the origin of ASM; B - ASM; C - flexor digitorum longus muscle; D - calcaneus; E - medial malleolus; and F - calcaneal tendon.

The ASM has its proximal insertion in the middle third of the tibia, anterior to the soleus muscle by a thickening of its fascia, which formed a laminar tendon (Figure 1). From its proximal origin, the muscle showed an oblique orientation toward the malleolus medialis. The ASM did not receive any fiber from the soleus muscle assuming the shape of a typical penniform muscle (Figure 2). The morphometry revealed the ASM was 3 cm wide, 9 cm long and 1 cm thick in its widest section (Figure 3), becoming thinner towards the tendon ends. The supernumerary muscle was located in the posteromedial region of the ankle anteriorly to the calcaneal tendon and posteriorly to the medial malleolus, flexor digitorum longus, tibialis posterior, and flexor hallucis longus muscles. Its anterior face covered the posterior face of the tibial nerve, as well

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Figure 2 – Posterior view of the right leg showing at point A - ASM; B - medial malleolus; C - calcaneal tendon; and D - gastrocnemius muscles.


Accessory soleus muscle: a case report and clinical applicability

Figure 3 – Anterior view of the ASM showing at point B  -  muscular fibers in a penniform arrangement, obliquely inserting in the soleus muscle tendon; and A - medial malleolus; the circle indicates the location of the muscle’s arterial supply. as the posterior tibial artery and veins, keeping these structures between the ASM (posteriorly) and the posterior face of the medial malleolus (anteriorly). The ASM posterior face was fully related with the calcaneal tendon, and its lower portion was covered by the flexor retinaculum of the ankle into the tarsal tunnel (Figure 4).

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Figure 4 – Relationship of the ASM with the tarsal tunnel structures showing at point A - medial malleolus; B - ASM; and C - flexor digitorum longus muscle; (white arrow) calcaneal tendon; (black arrow) insertion tendon of the ASM; (blue) posterior tibial veins; (orange) posterior tibial artery; and (yellow) tibial nerve.

The distal insertion of this muscle was fixed on the medial surface of the calcaneus about 1 cm anterior and inferiorly the calcaneal tendon (Figure 4), by a rounded and short tendon, more robust than the muscle origin. Moreover, as a posterior compartment muscle of the leg, its innervation was made by a muscular branch of the tibial nerve, and its arterial supply was derived from a branch of the posterior tibial artery, which dipped into the muscle in the upper third of its anterior face (Figure 3). Due to its characteristics and the topography of the fasteners in the leg and foot, it is believed that the contraction of the ASM is able to help the inversion and plantar flexion (Figure 5).

DISCUSSION Unilateral ASM in the retromalleolar region was found, and its topographic relationships were thoroughly revealed using anatomy dissection techniques.

Figure 5 – Schematic illustration of the ASM action. S = superior; I = inferior; A = anterior; P = posterior.

The ASM observed in this report confirm other authors’ findings,4,9-11 both in the origin and insertion of the supernumerary muscle. Five types of insertions have been described for this supernumerary muscle; namely: (1) insertion along the calcaneal tendon; (2) tendinous insertion on the superior calcaneal surface; (3) direct muscular

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insertion on the superior calcaneal surface; (4) direct muscular insertion on the medial calcaneal surface; and (5) tendinous insertion on the medial calcaneal surface. ASM can share the blood supply and innervation with the soleus muscle, or the neurovascular provision may be independent. ASM may be unilateral or bilateral according to Yu and Resnick12 descriptions. Our case of ASM presented the type 5 insertion; that is, a tendinous insertion on the calcaneus medial face. With a careful dissection technique we could see its proximal fixation through the thickening of the soleus muscle fascia. Other authors13,14 could not accurately report this data, or document the origin through images. Surgery of the posterior leg face and deep leg should be carefully studied in order to avoid unnecessary extraction of the ASM, which could increase the muscular volume inside the tarsal tunnel, causing or even worsening the patient’s complaints. Given the topography of the ASM, it is possible to suggest that it plays an important role in the description of clinical syndromes related to the tarsal tunnel, as stated by other authors.2,7,13 The presence of this supernumerary muscle in the retromalleolar position may cause tarsal tunnel syndrome, since it can compress the neurovascular bundle within this osteofibrous tunnel. The individual with this anatomical variation may present pain and paresthesia in the foot as well as a limping gait.15 Furthermore, the clinical examination may disclose in the ankle region a swelling or a non-pitting edema, even in asymptomatic cases. This description supports the suggestion that the diagnostic assessment of this anatomical variation should be performed by magnetic resonance imaging (MRI), since this is a non-invasive method.12 Clinically, it is suggested that the pain is a result of a poor muscular vascularization or is due to ischemic compartment syndrome. Muscular activity increases 20% of the muscle volume consequently contributing to the elevation of intra-compartment pressure and compression on the posterior tibial artery and tibial nerve. Thus, muscles blood flow is reduced, causing pain.16 Unilateral pain in the knee, ankle, and heel, and involuntary movements associated with the second to fifth toe may also be associated with ASM, due to compression of the posterior tibial nerve.17 In addition, the detachment and surgical excision of the ASM for the treatment

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of equinovarus deformity have already been used and show positive outcomes.8 In the past, some anatomists have described this variation as a special plantaris muscle,18 which could have migrated from their femoral origin to the fascia of the soleus muscle or posterior tibial face. Nevertheless, in this report, the plantaris muscle was found intact, which confirms that this ASM is a supernumerary muscular anatomical variation. Literature reviews revealed a higher prevalence of this finding among men (58% of cases).10 Although debatable, it may be suggested that the greater number of symptomatic cases are reported in men due to greater muscle trophism and denser muscle fascia among males. This characteristic contributes to narrowing of the tarsal tunnel, increasing the susceptibility of any imbalance between these structures. On the other hand, the number of women who can present ASM, but are asymptomatic, may be related to the use of high-heeled footwear, which shortens every muscle of the leg’s posterior compartment, thereby decreasing the compression of the tarsal tunnel and consequent symptoms. Currently, there is a spread of “problembased learning,” which correlates clinical situations with human anatomy.19 Examples of such clinical entities involving the compression of neurovascular bundles are carpal tunnel syndrome,20 the superior orbital fissure,21,22 or adductor canal.19 In fact, these clinical entities encourage the study of regional anatomy with professional applications. Thus, the ASM becomes another example of this academic practice in a course of study on compressive syndromes.

REFERENCES 1.

Cruveilhier J. Traité d’anatomie descriptive. 2nd ed. Paris: Béchet jeune; 1843. French.

2.

Dunn AW. Anomalousmusclessimulatingsoft-tissue tumorsin thelower extremities.Reportofthreecases. J Bone Joint Surg Am. 1965;47(7):1397-400. PMid:5837639.

3.

Peterson DA, Stinson W, Carter J. Bilateral accessory soleus: a report on four patients with partial fasciectomy. Foot Ankle. 1993;14(5):284-8. PMid:8349215. http://dx.doi. org/10.1177/107110079301400509

4.

Brodie JT, Dormans JP, Gregg JR, Davidson RS. Accessory soleus muscle. A report of 4 cases and review of literature.


Accessory soleus muscle: a case report and clinical applicability

5.

Clin Orthop Relat Res. 1997;(337):180-6. PMid:9137189. http://dx.doi.org/10.1097/00003086-199704000-00020

insight. Int J Anat Var. 2009 [cited 2013 July 15];2:20-2. Available from: http://www.ijav.org/2009/ijav_09_020-022.pdf

Arriaza Loureda R, Cantos Melián B, Couceiro González G, Sampedro Curbera C, Aizpurua Prada J. Músculo sóleo accesorio. Rev Ortop Traumatol. 2002;1:63-6 [cited 2013 July 14]. Available from: http://apps.elsevier.es/watermark/ ctl_servlet?_f=10&pident_articulo=13028225&pident_ usuario=0&pcontactid=&pident_revista=129&ty=77&acci on=L&origen=zonadelectura&web=http://zl.elsevier.es&la n=es&fichero=129v46n01a13028225pdf001.pdf. Spanish.

14. Reis FP, Aragão JA, Fernandes AC, Feitosa VL, Fakhouri R, Nunes MA. The accessory soleus muscle: case report and a review of the literature. Int J Morphol. 2007;25(4):881-4. http://dx.doi.org/10.4067/S0717-95022007000400032

6.

John MM, Borrelli AH. Asymptomatic accessory soleus muscle. J Foot Ankle Surg. 1999;38(2):150-3. http://dx.doi. org/10.1016/S1067-2516(99)80029-5

7.

Bezerra MJC, Leite JAD, Estrela JE Nº, Romero S. Liberação do túnel do tarso pela técnica endoscópica: uma proposta de acesso cirúrgico. Acta Ortop Bras. 2005;13(1):46. Portuguese. http://dx.doi.org/10.1590/S1413-78522005000100012

8.

Bonnell J, Cruess RL. Anomalous insertion of the soleus muscle as a causes of fixed equinus deformity. A case report. J Bone Joint Surg Am. 1969;51(5):999-1000. PMid:5793857.

9.

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Vanek J, Fourré D. Accessory soleus muscle. Acta Orthop Belg. 1993;59(4):401-3. PMid:8116375.

10. Hatzantonis C, Agur A, Naraghi A, Gautier S, McKee N. Dissecting the accessory soleus muscle: A literature review, cadaveric study, and imaging study. Clin Anat. 2011;24(7):90310. PMid:21538570. http://dx.doi.org/10.1002/ca.21188 11. Testut L. Les anomalies musculaires chez l’homme: expliquées par l’anatomie comparée leur importance en anthropologie [Internet]. Paris: G. Masson; 1884 [2013 July 15]. Available form: http://ia600307.us.archive.org/30/items/ lesanomaliesmusc00testuoft/lesanomaliesmusc00testuoft. pdf French. 12. Yu JS, Resnick D. MR imaging of the accessory soleus muscle appearance in six patients and a review of the literature. Skeletal Radiol. 1994;23(7):525-8. PMid:7824980. http://dx.doi.org/10.1007/BF00223083 13. Singh S, Suri RK, Mehta V, Loh H, Arora J, Rath G. Bilateral additional bellies of the soleus muscle: anatomical and clinical

15. Doda N, Peh WCG, Chawla A. Symptomatic accessory soleus muscle: diagnosis and follow-up on magnetic resonance imaging. Br J Radiol. 2006;79(946):e129-32. PMid:16980668. http://dx.doi.org/10.1259/bjr/83389292 16. Leswick DA, Chow V, Stoneham GW. Resident’s corner. Answer to case of the month# 94. Can Assoc Radiol J. 2003;54(5):313-5. PMid:14689808. 17. Pla ME, Dillingham TR, Spellman NT, Colon E, Jabbari B. Painful legs and moving toes associates with tarsal tunnel syndrome and accessory soleus muscle. Mov Disord. 1996;11(1):82-6. PMid:8771072. http://dx.doi.org/10.1002/ mds.870110115 18. Frohse F, Frankel M. Die muskeln des menschlichen beines. Jena: Fischer; 1913. German. 19. Oliveira F, Vasconcellos Fontes RB, Silva Baptista J, Mayer WP, Campos Boldrini S, Liberti EA. The connective tissue of the adductor canal--a morphological study in fetal and adult specimens. J Anat. 2009;214(3):388-95. PMid:19245505 PMCid:PMC2673789. http://dx.doi.org/10.1111/j.14697580.2009.01047.x 20. Scalco RS, Pietroski F, Celli LFS, Gomes I, Becker J. Seasonal variation in prevalence of carpal tunnel syndrome. Muscle Nerve. 2013;47(6):925-7. http://dx.doi.org/10.1002/ mus.23754 21. Zachariades N, Vairaktaris E, Papavassiliou D, Papademetriou I, Mezitis M, Triantafyllou D. The superior orbital fissure syndrome. Journal Maxillofac Surg. 1985;13:125-8. http:// dx.doi.org/10.1016/S0301-0503(85)80031-X 22. Gabikian P, Chowdhary AM, Kott B, Lazar DA, Britz GW. Isolated superior orbital fissure syndrome resulting from gunshot wound to the head. Curr Probl Diagn Radiol. 2012 Jul;41(4):112-3. http://dx.doi.org/10.1067/j. cpradiol.2011.07.012

Conflict of interest: None Submitted on: 16th July 2013 Accept on: 15th September 2013 Correspondence: Setor de Anatomia Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória Av. N. Sra. Da Penha, 2190 – Santa Luiza – Vitória/ES – Brazil CEP: 29045-402 – Phone: +55 (27) 33343546 E-mail: william.mayer@emescam.br

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Autopsy and Case Reports 2013; 3(3): 11-19

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis – a review Fernando Peixoto Ferraz de Camposa, Aloísio Felipe-Silvab, Maria Claudia Nogueira Zerbinic Campos FPF, Felipe-Silva A, Zerbini MCN. Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis – a review. Autopsy Case Rep [Internet]. 2013; 3(3): 11-19. http://dx.doi.org/10.4322/acr.2013.023

ABSTRACT Anaplastic large cell lymphoma (ALCL), described less than 30 years ago by Karl Lennert and Herald Stein in Kiel, West Germany, is a T-cell or null nonHodgkin lymphoma, with distinctive morphology (hallmark cells, prominent sinus and/or perivascular growth pattern), characteristic immunophenotype (CD30+, cytotoxic granules protein+, CD3–/+) and specific genetic features as translocations involving the receptor tyrosine kinase called anaplastic lymphoma kinase (ALK) on 2p23 and variable partners genes, which results in the expression of ALK fusion protein. The absence of ALK expression is also observed and is associated with poorer prognosis that seen with ALK expression. ALK-negative ALCL is more frequent in adults, with both nodal and extra nodal clinical presentation and includes several differential diagnoses with other CD30+ lymphomas. Liver involvement by ALCL is rare and is generally seen as mass formation; the diffuse pattern of infiltration is even more unusual. The authors present a case of a 72-year-old man who presented clinical symptoms of acute hepatic failure. The patient had a long history of alcohol abuse and the diagnosis of alcoholic hepatitis was highly considered, although the serum lactic dehydrogenase (LDH) value was highly elevated. The clinical course was fulminant leading to death on the fourth day of hospitalization. Autopsy demonstrated diffuse neoplastic hepatic infiltration as well as splenic, pulmonary, bone marrow, and minor abdominal lymph nodes involvement by the tumor. Based on morphological, immunophenotypical, and immunohistochemical features, a diagnosis of ALK- negative ALCL was concluded. When there is marked elevation of LDH the possibility of lymphoma, ALCL and other types, should be the principal diagnosis to be considered. Keywords: Lymphoma, Large-Cell, Anaplastic; Liver Failure; Anaplastic Lymphoma Kinase; Autopsy.

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 Pathology – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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 médium provided article is properly cited.

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Campos FPF, Felipe-Silva A, Zerbini MCN.

CASE REPORT

C and B, as well as Epstein-Barr virus (EBV), were negative. Plasma protein electrophoresis did not show the presence of an anomalous peak. Serum alpha-fetoprotein value was less than 1.3 ng/mL (reference value [RV] less than 8 ng/mL). Blood and urine cultures were negative.

A 72-year-old man was admitted after a 60day history of poor appetite, progressive weakness, and marked weight loss. His family described mental confusion. Past medical history included hypertension and hypothyroidism under clinical treatment. He had been a heavy drinker since the age of 15 and had a smoking history as well.

Considering the history of intense and long-term alcohol abuse, and the complaints of appetite loss, weakness with associated mental confusion, icterus and laboratory data showing marked leukocyte shift to the left, elevation of the total bilirubin, and hepatocellular enzyme values (aspartate aminotransferase [AST] greater than twice the alanine aminotransferase [ALT]), the diagnosis of alcoholic hepatitis with hepatic failure was strongly considered. The presence of infection was uncertain. The determination of canalicular enzymes within the normal limits as well as the absence of other stigmata of chronic hepatic disease remained odd, as well as the elevated determination of lactic dehydrogenase (LDH) not typical for alcoholic hepatic disease. The patient was admitted and treated with antibiotics, saline intravenous infusion, and thiamine supplementation. On the following days, as the clinical picture deteriorated and the Maddrey scored reached 88, corticosteroid was added to the therapeutic regimen. Hepatic and renal function continued worsening, the platelet count dropped to 8000/mm3, he became comatose, and died on the fourth day of his hospital stay.

On physical examination, he was emaciated, dehydrated, icteric, febrile (temperature 37.8 °C), with tachycardia and tachypnea. Blood pressure was normal. The patient was alert and conscious with spontaneous eye opening, and responded to simple commands. Extrinsic and intrinsic ocular motor function was normal. No extraocular motor deficits were seen, and there was no neck stiffness. Hepatic flapping was not present. No lymph adenomegaly was detected, and the heart and lungs examination was unremarkable. The abdomen was diffusely tender, predominantly in the right hypochondrium where the liver was slightly enlarged. The spleen was not palpable, and there was no sign of peritoneal irritation. The initial laboratory workup is shown in Table 1. Urinalysis showed mild proteinuria, elevated cell count and granular cylindruria, which were interpreted as compatible with chronic hepatopathic glomerulitis. Serologic tests for HIV, human T-cell lymphoma/leukemia virus (HTLV)-I, HTLV-II, hepatitis Table 1 – Initial laboratory workup Exam

Results

RV

Exam

Results

RV

Hemoglobin

11.7

12.3-15.3 g/dL

Urea

181

5-25 mg/dL

Hematocrit

37.1

36.0-45.0%

Creatinine

2.0

0.4-1.3 mg/dL

Leukocytes

5.8

4.4-11.3 × 10 /mm

Potassium

3.8

3.5-5.0 mEq/L

Prom/myel/metam

1/1/1

0

Sodium

140

136-146 mEq/L

Bands

17

1-5%

ALT

67

9-36 U/L

Segmented

71

45-70%

AST

237

10-31 U/L

Eosinophils

0

1-4%

AF

84

10-100 U/L

Basophils

0

0-2.5%

γGT

24

2-30 U/L

Lymphocytes

0

18-40%

Total bilirubin

6.3

0.3-1.2 mg/dL

Monocytes

0

2-9%

Total protein

4.79

6-8 g/dL

Platelets

30

150-400 × 10 /mm

Albumin

2.3

3-5 g/dL

CRP

486

<5 mg/L

LDH

760

120-246

INR

1.46

1.0

Lactate

75.9

4.5-19.8 mg/L

3

3

3

3

AF = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP = Creactive protein; γGT = gamma glutamyl transferase; INR = international normalized ratio; LDH = lactic dehydrogenase; metam = metamyelocyte; myel = myelocyte; prom = promyelocyte; RV = reference value.

d

Maddrey WC, Boitnott JK, Bedline MS, et al. Corticosteroid therapy for alcoholic hepatitis. Gastroenterology. 1978;75:193-9.

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Anaplastic large cell lymphoma ALK-negative...

AUTOPSY FINDINGS The external examination showed a normally developed icteric man, with moderate edema of the lower limbs and genitalia. Few but large ecchymosis were over the abdomen and flanks. Viscera were bile stained. Multiple hemorrhagic foci were in the abdominal viscera and left cerebellar lobe. The thoracic cavity contained 150 cc of serous pleural effusion. Right lung weighed 905 g (reference mean value [RMV]: 450 g) and the left lung 845 g (RMV: 375 g). Lungs were wine-colored and were markedly edematous; multiple scattered friable purulent foci were present, mainly at the right base. Few small, round, firm lymph nodes were in the pulmonary hila. Cardiovascular examination

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showed marked aortic, coronary and renal artery atherosclerosis The abdominal cavity contained 350 cc of clear yellow-citrine ascites. Multiple mildly enlarged lymph nodes were found, particularly periaortic and at the splenic hilum, measuring up to 2.5 cm. They were homogeneous white with effaced nodal architecture on the cut surface (Figure 1A). The spleen was enlarged, weighing 445 g (RMV: 112 g). The splenic parenchyma was markedly congested and friable. Two triangular subcapsular areas (1-3 cm) of infarction were present (Figure 1B). The liver was enlarged, yellowish, softened, and weighed 2516 g (RMV: 1600 g). The surface was nodular. The cut surface showed a mottled pattern with congested wine-colored central areas surrounded by pale yellow halos (Figure 1C). Two thin-walled cysts measuring up to 4.5 cm corresponding to simple biliary cysts were present. Exaggerated mottling was noted on serial slicing (Figure 1D).

Figure 1 – Gross appearance of: A - periaortic lymph node (arrow); B - splenic cut surface showing two areas of infarction; C - hepatic irregular capsular surface with mottled pattern; and D - hepatic cut surface showing a cystic lesion and the diffuse mottled pattern of the parenchyma characterized by congested winecolored central areas surrounded by pale halos. Besides biliary cysts, no focal lesions were detected.

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Autopsy and Case Reports 2013; 3(3): 11-19

Campos FPF, Felipe-Silva A, Zerbini MCN.

Microscopically extensive infiltration by a diffuse population of atypical large pleomorphic cells was observed in the liver, spleen, and lymph nodes. These cells typically exhibited horseshoe or kidney-shaped nuclei with prominent nucleoli and a moderate amount of pink cytoplasm (“hallmark cells”) (Figure 2A).

(Figures 3A and 3B) and hemorrhagic necrosis in zone 3. Typical features of alcoholic hepatitis (massive steatosis, balloon cells, Mallory hyaline, early zone 3 pericellular fibrosis) were not present. The lungs had perivascular foci of neoplastic cells and a marked intraalveolar edema (Figures 3C and 3D).

Neoplastic cells were positive for CD30 (diffuse) (Figure  2B), CD45 (Figure  2C) and CD2 (focal) (Figure  2D). Immunostaining for ALK, perforin, TIA1, epithelial membrane antigen (EMA), anaplastic lymphoma kinase (ALK), CD3, CD20, CD15, EBV (LMP1), PAX5, and CD138 were negative.

In addition to infarcts, the spleen showed extensive angiocentric neoplastic infiltration involving white and red pulp (Figures 4A and 4B). The lymph node architecture was effaced by the diffuse infiltration of neoplastic cells with the same pattern of involvement (Figure 4C). Extensive neoplastic cell necrosis was also present (Figure 4D).

Hepatic involvement was characterized by extensive diffuse neoplastic infiltration of the portal space and the lobular parenchyma. Hepatocytes exhibited slight macro vesicular steatosis

Shock-related lesions were present in the kidneys, which showed acute tubular necrosis, and in the small bowel, which showed as ischemic enteritis. Based on the neoplastic morphology

Figure 2 – Photomicrography of a lymph node. A - Extensive infiltration by atypical large pleomorphic cells exhibiting eccentric, irregular, bi or multinucleated, wreath-shaped nucleus (arrow), with distinct nucleoli (HE 100X); B - Immunostaining for CD 30 (40X); C - Immunostaining for CD 45 (40X); D - Immunostaining for CD 2 (20X).

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Anaplastic large cell lymphoma ALK-negative...

Autopsy and Case Reports 2013; 3(3): 11-19

Figure 3 – A and B - Photomicrography of the liver showing neoplastic infiltration of the lobular parenchyma and portal space (detailed in B); note the focal macrovesicular steatosis; C and D - Photomicrography of the lung showing perivascular tumoral infiltration pattern (C) and marked pulmonary edema (D). and immunophenotypic features, the diagnosis of anaplastic large cell lymphoma (ALCL), ALKnegative was established.

DISCUSSION Anaplastic large cell lymphoma (ALCL) was often misdiagnosed in the past as metastatic carcinoma, melanoma, or malignant histiocytosis. The concept of ALCL evolved during the last two decades to a distinct molecular pathologic entity.1 In 1985, Harald Stein and Karl Lennert with colleagues2 first described the anaplastic large cell lymphoma, delineating a type of tumor with an unusual sinus growth pattern, which strongly expressed CD30 (formerly called Ki-1 antigen) on the cell membrane and other lymphoid markers, but lacked the expression of molecules associated with histiocytic or other cell lineages.3 At first, many questioned this diagnosis as a distinct entity, since the expression of

CD30 could also be seen in reactive processes and other tumors. Some years later, the chromosome translocation t(2;5)(p23,q35) was demonstrated in ALCL cases.4 Subsequent cloning of the chromosomal breakpoints showed that the affected genes were ALK, located at chromosome 2p23, and NPM (encoding nucleophosmin) located at 5q35.5,6 The t(2;5) is the most common karyotypic aberration involving ALK, present in approximately 75% of the ALCLs with ALK rearrangements, and is the only well-known gene partner that imparts a nuclear pattern of ALK+ immunostain.7 In approximately 25% of the remaining cases, a number of variant rearrangements involving 2p23 are seen, including t(1;2)(q21;p23), inversion 2(p23;q35), t(2;3) (p23;q21), t(2;17)(p23;q23), and t(X;2)(q1112;p23).5,7 These chromosomal abnormalities result in the overexpression of the fusion protein ALK. After widespread immunohistochemical analysis with anti-ALK monoclonal antibodies, ALK+ ALCL was defined as a specific entity, and ALK immunostaining is considered a surrogate marker for the genetic

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Campos FPF, Felipe-Silva A, Zerbini MCN.

Figure 4 – A and B - Photomicrography of the spleen, showing in (A) perivascular tumoral infiltration pattern; and (B) white and red pulp tumoral infiltration; C and D - Photomicrography of the lymph node, showing in (C) diffuse infiltration of neoplastic cells; and (D) neoplastic cell necrosis. aberration involving the ALK gene. Tumors with the same characteristics, but without expression the ALK protein, are called ALCL ALK-negative, and are associated with a worse prognosis than ALK+ tumors. The immunophenotype of these neoplastic cells was shown to be T-cell or null cell depending on the number of T-cell antigens tested. In the case reported here, the lineage markers were based on CD3 and CD2 because other cell markers such as CD5 and CD43 did not present reliable staining. This technical failure may be related to inherent autopsy limitation, even in the era of powerful detection/ amplification systems. It is believed that most, if not all, of the null cell cases belong to the T-cell type, as demonstrated by the presence of the T-cell receptor (TCR) gene rearrangement.3 The Revised European-American Lymphoma (REAL) and the new WHO classification include B-cell ALCL with all other diffuse large B-cell non-Hodgkin lymphomas (NHLs), whereas ALCL of T-cell or null phenotype

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is considered a distinct disease entity.8,9 In 2008, the WHO classification separated the ALCL ALK+ from those ALK-negative which are morphologically similar to the ALK+ but do not express the ALK protein.10,11 However, In this classification the WHO considered the ALK-negative ALCL as a provisional entity. Most cases express T-cell-associated and cytotoxic markers and must be distinguished from primary cutaneous ALCL, other subtypes of CD30+ T- or B-cell lymphoma with anaplastic features, and classical Hodgkin lymphoma.12 ALCL can be distinguished from Hodgkin lymphoma by the presence of ALK fusion protein in ALCL-ALK+, and by PAX5 staining which shows expression in Hodgkin lymphoma but is negative in ALK-negative ALCL.12 More recently, Feldman et al.13 demonstrated the translocation t(6;7)(p25.3;q32.3) in ALKnegative ALCL,12 but an immunohistochemical marker that can be used as a surrogate indicator of this translocation is still lacking.


Anaplastic large cell lymphoma ALK-negative...

Except for the small cell variant, this tumor is characterized by a proliferation of cohesive clusters of pleomorphic large lymphoid cells, with a high mitotic index, strongly positive for CD30 and CD4. Expression of EMA and cytotoxic granule proteins are usually present but may lack in ALK-negative ALCL1 as was observed in our case. The large cells exhibit a marked characteristic morphology, represented by an eccentric, irregular, horseshoe, kidney or wreath-shaped nuclei, with distinct nucleoli and abundant cytoplasm, infiltrating the lymph node in a prominent sinus pattern simulating metastatic solid tumors.1,5,14 Multinucleated cells with ReedSternberg-like appearance may also occur.3 Extra nodal infiltration may wipe out the organ architecture by solid, cohesive sheets of neoplastic cells.12 Another morphologic characteristic is the disposition of the large cells surrounding small vessels (“angiocentric”), which is evident with immunostaining for CD30, which highlights the anaplastic cells.3 Because of the wide histologic spectrum of the tumor cell population and the admixture of reactive cells, ALCL is classified in subtypes, namely: common or classic (pleomorphic type are 30-50% ALK+, monomorphic type >80% ALK+); giant-cell rich (30-40% ALK+), small-cell (75% are ALK+), lymphohistiocytic (60% are ALK+), Hodgkin-like (<20% ALK+) and other rare variants.3,5 Among the ALK-negative neoplasias within this classification, only the classical morphology is accepted as ALCL, whereas the small-cell and lymphohistiocytic subtypes should rather be classified as peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). The diagnosis of ALK- negative ALCL is reserved for cases, which present all the features of ALCL ALK+, except for the expression of ALK. In the case reported here, the form of presentation as a diffuse disease did not allow the evaluation of a sinusoidal pattern, but “hallmark cells” and CD30 diffusely positive were present. ALCL can exist as either a widespread systemic syndrome, or as a localized disease. ALCL systemic type comprises 2-3% of non-Hodgkin lymphomas (NHLs) in adults, and 15% of the NHL in pediatrics.1,12,15 Among all systemic ALCL, 1550% are ALK-negative. These tumors affect adults with the median age of 55-60 years with no gender predominance; two-thirds of them present stage III or IV at diagnosis, with B symptoms and high international prognostic index (IPI) score. Lymph node involvement is present in 49% of the patients at the diagnosis. Extranodal involvement occurs in

Autopsy and Case Reports 2013; 3(3): 11-19

the skin, bone, and soft tissues.1 Gastrointestinal tract, hard palate, nasal cartilage, ovary, bronchus, psoas muscle, ocular adnexa, pleura, testis, and breast are only rarely involved.1 Bone marrow involvement is found in 10-30% of cases, but is present in as many as 61% of cases when molecular studies are added to the investigation.1,16,17 Central nervous system involvement and leukaemic phase are rare. Peripheral blood involvement may be seen in pediatric ALK+ ALCL cases or in adults ALCL ALK-negative and may be represented by elevated white blood cell count owing to neutrophilia induced by granulocyte-colony stimulating factor produced by the tumor. Rare patients with ALCL have a hemophagocytic syndrome.1 Compared with the ALCL ALK+, the prognosis of ALCLs ALK-negative is much worse. ALK expression is not unique to ALCL. Since the discovery of ALK in the mid-nineties, the number of neoplasms expressing this protein has expanded. One of the benefits of recognizing ALK in these tumors relates to targeted therapy, a new approach in the treatment of these neoplasias with promising outcomes. Selective kinase inhibitors are one of the most important classes of these medications. As ALK has limited expression in human tissues, it turns to an appealing oncogene to target.18 Liver involvement by NHL can be predominantly secondary, commonly found in advanced diseases; or primary, when the staging investigations failed to show extrahepatic disease (stage IE) or if the disease is predominant in the liver at presentation. In the latter situation, infiltration can be identified at other sites, including the spleen, regional lymph nodes and bone marrow. Some investigators prefer to describe the latter situation as “predominant liver involvement.”19,20 Grossly, hepatic involvement can be as a solitary tumor, multiple nodular masses, or a diffusely infiltrative process,19,21,22 which, although being the less frequent, was the pattern in our patient. Many histologic types of lymphoma affect hepatic parenchyma. Among them, ALCL has been reported to be involved in 7-17% of all the hepatic lymphomas.3,19,23 Clinically, hepatic involvement can vary since asymptomatic disease, recognized during evaluation for incidental hepatic testing abnormality, to fulminant liver failure. Saikia et al.,22 reported two cases of ALCL that presented as acute hepatic failure and retrieved six other cases with the same histology. In general, the first symptoms are nonspecific, such

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Autopsy and Case Reports 2013; 3(3): 11-19

as abdominal discomfort, right upper quadrant pain, fever, weight loss, and anorexia, very similar to the clinical presentation of this case report. Hepatomegaly is detected in up to 82% of cases and jaundice is usually a late manifestation of disease progression, generally associated with periportal adenopathy or underlying cirrhosis.19,24 There is no identifiable specific laboratory pattern for hepatic lymphoma, reflecting the wide histologic and anatomic heterogeneity of the disease. However, it is quite common to have at least one altered liver function test and particularly an elevation of LDH determination. LDH is recognized as a non-specific biochemical marker of lymphomas. In our case, the elevation of LDH was not typical for alcoholic hepatitis, and should have led to the consideration of lymphoma. Thrombocytopenia documented in many reports of hepatic involvement by lymphoma. Rare associations with immune thrombocytopenia have been described.25 26 Lettieri and Berg, described one case with thrombocytopenia in a series of five, and report the occurrence of thrombocytopenia in 86% of NHL liver infiltration in the same article. Besides the immune mechanisms, disseminated intravascular coagulopathy and hypersplenism should also be considered. In our patient, splenomegaly and bone marrow involvement could contributed to cytopenia, but isolated thrombocytopenia would be unusual. Radiographic imaging has not been successful in distinguishing hepatic lymphoma from other liver diseases. Diffusely infiltrative disease, as was the presentation of this case report, can present as hepatomegaly with little alteration in parenchymal density or architectural distortion.19 CT images in our patient, except for the findings of areas compatible with splenic infarction and detection of few small periaortic lymph nodes, did not suggest other diagnoses apart from chronic liver disease. Although rare, advanced liver failure can be caused by lymphomatous infiltration of the liver.26 This condition is observed when the hepatic parenchyma is replaced by diffuse intrasinusoidal propagation of tumor cells, as is often seen in gamma-delta hepatosplenic lymphoma.27 Because of the epidemiological data concerning alcoholic abuse, clinical symptoms resembling alcoholic hepatitis, the absence of palpable adenomegaly, a lack of specific diagnostic imaging, and the rarity of the liver involvement by ALCL, the diagnosis of ALCL was not recognized during life and was only

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Campos FPF, Felipe-Silva A, Zerbini MCN.

established by the autopsy, emphasizing, once again, the important diagnostic and teaching value of this medical tool. Therefore, we call attention to this unusual cause of hepatic failure, in which generally occurs in patients without a previous diagnosis of hepatic disease. If laboratory study results are not typical for liver disease and, particularly, when LDH determination is unexpectedly and significantly elevated, the possibility of lymphoma should be suspected. Percutaneous liver biopsy would certainly establish the correct diagnosis. In our patient the clinical status deteriorated quickly, making biopsy itself of high risk.

REFERENCES 1.

Kinney MC, Higgins RA, Medina EA. Anaplastic large cell lymphoma. Twenty-five years of discovery. Arch Pathol Lab Med. 2011;135:19-43. http://dx.doi.org/10.1043/20100507-RAR.1

2.

Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66:848.

3.

Stein H, Foss HD, Durkop H, et al. CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000;96:3681-95.

4.

Rimokh R, Magaud JP, Berger F, et al. A translocation involving a specific breakpoint (q35) on chromosome 5i is characteristic of anaplastic large cell lymphoma (“Ki-1 lymphoma”). Br J Haematol.1989;73:806.

5.

Kutok JL, Aster JC. Molecular Biology of Anaplastic Lymphoma Kinase- Positive Anaplastic Large-Cell Lymphoma. J Clin Oncol. 2002;20:3691-702.

6.

Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281-4. http:// dx.doi.org/10.1126/science.8122112

7.

Duyster J, Bai RY, Morris SW. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene. 2001;20:562337.

8.

Gascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood. 1999;93:3913-21.

9.

Stansfeld AG, Diebold J, Noel H, et al. Updated Kiel classification for lymphomas [published erratum appears


Anaplastic large cell lymphoma ALK-negative...

Autopsy and Case Reports 2013; 3(3): 11-19

in Lancet 1:372, 1988]. Lancet.1988;1:292. http://dx.doi. org/10.1093/annonc/mdh392

T-Cell Lymphoma Project. Blood. 2008;111:5496-504. http:// dx.doi.org/10.1182/blood-2008-01-134270

10. Mason DY, Harris NL, Delsol G, et al. Anaplastic large cell lymphoma, ALK-negative. In: Swerdlow SCE, Campo E, Harris NL et al., editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 317-9.

18. Minoo P, Wang HY. ALK-immunoreactive neoplasms. Int J Clin Exp Pathol. 2012;5:397-410.

11. Delsol G, Falini B, Müller-Hermelink HK, et al. Anaplastic large cell lymphoma (ALCL), ALK-positive. In: Swerdlow SCE, Campos E, Harris NL, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 312-6. 12. Ferreri AJM, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-negative. Crit Rev Oncol Hematol. 2013;85:206-15. http://dx.doi.org/10.1016/j. critrevonc.2012.06.004 13. Feldman AL, Dogan A, Smith DI, et al. Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 2011;117:915-9. http://dx.doi. org/10.1182/blood-2010-08-303305 14. Benharroch D, Meguerian-Bedoyan Z, Lamant L. ALKpositive lymphoma: a single disease with a broad spectrum of morphology. Blood. 1998;91:2076-84. 15. Coiffier B. Treatment of aggressive non-Hodgkin’s lymphoma. Semin Oncol. 1999;26:12-20. 16. Fraga M, Brousset P, Schaifer D, et al. Bone marrow involvement in anaplastic large cell lymphoma. Am J Pathol. 1995;103:82. 17. Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic largecell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report fom the International Peripheral

19. Salmon JS, Thompson MA, Arildsen RC, et al. Non-Hodgkin’s lymphoma involving the liver: clinical and therapeutic consideration. Clin Lymphoma Myeloma 2005;6:273-80. http://dx.doi.org/10.3816/CLM.2006.n.001 20. Aozasa K, Mishima K, Ohsawa M. Primary malignant lymphoma of the liver. Leuk Lymphoma. 1993;76:1336-43. 21. Lei KI, Chow JH, Johnson PJ. Aggressive primary hepatic lymphoma in Chinese patients. Cancer. 1995;76:1336-43. 22. Saikia UN, Sharma N, Duseja A, Bhalla A, Joshi K. Anaplastic large cell lymphoma presenting as acute liver failure: A report of two cases with review of literature. Ann Hepatol. 2010;9:457-61. 23. Tilly H, Gaulard P, Lepage E, et al. Primary anaplastic large cell lymphoma in adults: clinical presentation, immunophenotypes, and outcome. Blood. 1997;90:3727-34. 24. Lei KI. Primary non-Hodgkin’s lymphoma of the liver. Leuk Lymphoma. 1998;29:293-9. 25. Aghai E, Quitt M, Lurie M, et al. Primary hepatic lymphoma presenting as symptomatic immune thrombocytopenia purpura. Cancer. 1987;60:2308-11. 26. Lettieri CJ, Berg BW. Clinical features of non-Hodgkin lymphoma presenting with acute liver failure: a report of five cases and review of published experience. Am J Gastroenterol. 2003;98:1641-6. 27. Myszor M, Record CO. Primary and secondary malignant disease of the liver and fulminat hepatic failure. J Clin Gastroenterol. 1990;12:441-6.

Conflict of interest: None Submitted on: 17th July 2013 Accepted on: 22th August 2013 Correspondence: Departamento de Patologia Faculdade de Medicina da Universidade de São Paulo Av. Dr. Arnaldo, 455 – Cerqueira César – São Paulo/SP – Brazil CEP: 01246-903 – Phone: +55 (11) 3061-7234 E-mail: czerbini@usp.br

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Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Fibrosarcoma: a challenging diagnosis Cristiane Rúbia Ferreiraa, Leonardo Gomes da Fonsecab, Gustavo Henrique Munhoz Piottob, Felipe Correa Geyerc, Paulo Sérgio Martins de Alcântarad Ferreira CR, Fonseca LG, Piotto GHM, Geyer FC, Alcântara PSM. Fibrosarcoma: a challenging diagnosis. Autopsy Case Rep [Internet]. 2013; 3(3): 21-29. http://dx.doi.org/10.4322/acr.2013.024

ABSTRACT Fibrosarcoma represent a rare group of soft tissue malignancies derived from fibrous connective tissue and immature proliferating fibroblasts or undifferentiated anaplastic spindle cells. It affects patients in the fourth and fifth decade of life. Fibrosarcomas can be classified in subtypes such as low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF), and others. Histological features that overlap between types of fibrosarcomas is well known and reported in the literature. We report the case of a 53-yearold patient who presented a tumor in the axillary fossa, which was initially diagnosed as a solitary fibrous tumor. Due to recurrence of the lesion, as well as the presence of distant metastases, the histological revision considered the diagnosis of breast metaplastic carcinoma, since the tumor expressed the p63 antigen and estrogen and progesterone receptors. Unexpected resistance to chemotherapy motivated the diagnosis re-evaluation, which was due to MUC4 expression and morphological characteristics concluded by a hybrid LGFMSSEF tumor. The authors call attention to the difficult diagnosis in cases of soft tissue tumors. A broad panel of immunohistochemical research is required as the clinical course is essential to the final diagnosis. Keywords: Fibrosarcoma; MUC4 protein, human; Drug Therapy; Surgical Procedures, Operative. CASE REPORT A 53-year-old female patient sought medical attention because of the relapse of a painful and progressive-growing mass in the right axillary fossa. Her past medical history also included the surgical removal of a right axillary nodule 3 years ago measuring 7.5 cm, which was compatible with the diagnosis of a solitary fibrous tumor (Figure 1). One year later, another nodule measuring 2.0 cm was excised, and the diagnosis was similar to the former (Figure 2). The entire immunohistochemical

panel used in the diagnostic work up of these two specimens is shown in Table 1. At this time, physical examination showed the presence of a painful tumor, measuring 12 cm, which adhered to deep structures in the right axillary fossa. Breast examination, as well as laboratory analysis, was normal. The computed tomography (CT) of the axillary region showed three conglomerated solid nodules, (the biggest measuring 7.1 cm) with well-

Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. Clinical Oncology Service – Instituto do Câncer do Estado de São Paulo, São Paulo/SP – Brazil. c Pathologic Anatomy Service – Instituto do Câncer do Estado de São Paulo, São Paulo/SP – Brazil. d Department of Surgery – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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 médium provided article is properly cited.

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Autopsy and Case Reports 2013; 3(3): 21-29

Ferreira CR, Fonseca LG, Piotto GHM, Geyer FC, Alcântara PSM.

Figure 1 –  Photomicrography of the first resected tumor. A - Hypocellular area showing a vessel with hemangiopericytoma-like pattern (H&E  –  100X); B - Hypocellular myxohyalin area with a transition to a fibrous hypercellular area (H&E  –  100X); C - Hypercellular area showing bland tumor cells with round to oval nuclei within an abundant hyalinized collagen stroma (HE – 200X). D - Hypercellular area with nests of epithelioid cells (HE – 200X). defined limits and heterogeneous enhancement after the intravenous contrast medium injection.

Revising the first two specimens, positivity for p63 and estrogen receptors was also present.

The patient was submitted to the third surgical procedure, which showed an extensive tumoral mass infiltrating the axillary plexus, the great dorsal muscle, and the serratus muscle. An incisional biopsy was performed due to the non-resectability of the whole tumoral mass. The histological examination showed a spindle cell neoplasia presenting areas of epithelioid aspect, with mild nuclear atypia (Figures 3 and 4).

Further disease staging showed the right hemithorax pleural effusion, pleural nodules measuring up to 1.5 cm and the scattered bilateral pulmonary nodules measuring up to 0.9 cm. Mammography revealed BI-RADS zero, and breast ultrasonography ruled out malignancy in the mammary parenchyma. The postoperative period was uneventful and the patient was referred to an oncological center.

The immunophenotype was positive for p63, CD99, vimentin, and estrogen and progesterone receptors, interpreted as a metaplastic carcinoma (Figures  5A, B and C). Tumoral invasion was present in the adjacent fibro connective tissue and adipose tissues, as well as in the striated muscle.

Once in the oncological center, the patient underwent a pulmonary biopsy, which confirmed the presence of metastatic disease.

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Chemotherapy based on carboplatin AUC 2 and paclitaxel 80mg/m2 weekly (for 3 or 4 weeks


Fibrosarcoma: a challenging diagnosis

Autopsy and Case Reports 2013; 3(3): 21-29

Figure 2 – Photomicrography of the second resected tumor. A - Hypercellular area of the tumor showing a fascicular pattern (H&E  –  100X); B  -  Sharp transition between a fibrous hypercellular and a myxoid hypocellular area (H&E – 100X); C - Hypercellular area showing tumoral cells with round to oval nuclei within an abundant hyalinized collagen stroma (H&E – 400X); D - Detail of the sharp transition of the hypercellular area with nests of epithelioid cells and the myxoid area with bland spindle-shape cells (H&E – 200X). Table 1 – Immunohistochemical panel used in the first two specimens Antigen

Result

Antigen

Result

CD34

Negative

SMA

Negative

Bcl-2

Positive

CD117

Negative

Vimentin

Positive

S100

Negative

CD99

Positive

AE1/AE3

Negative

ER*

Positive

EMA

Negative

PR

Negative

Ki-67

1%

HHF-35

Negative

SMA = smooth muscle actin; EMA = epithelial membrane antigen; ER = estrogen receptor; PR = progesterone receptor. * 6F11 clone, manufacturer Novocastra.

each cycle) was started. After four cycles, CT showed progression of the disease by increment of pleural effusion, pleural nodes, a new bone lesion in

the right shoulder, and an enlargement of the right internal thoracic lymph nodes. Chemotherapy was discontinued and pleurodesis was performed. Motivated by the unexpected chemotherapy failure, the histological and immunohistochemical examination was revised. This time the immuno­ phenotype was positive for MUC4 (Figure 5D) and negative for CK5, CK34BE12, Desmin, S100, and HER-2. The entire immunohistochemical panel used in this revision is shown in Table 2. Thus, the diagnosis of the neoplasia was defined as a hybrid tumor: low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. As the patient’s clinical status remained steady and well, a surgical debulking is being planned.

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Autopsy and Case Reports 2013; 3(3): 21-29

Ferreira CR, Fonseca LG, Piotto GHM, Geyer FC, Alcântara PSM.

Figure 3 – Photomicrography of the third resected tumor. A - Hypercellular area showing cell cords within an abundant hyalinized collagen stroma (H&E  –  100X); B - Hypocellular area showing bland, small cells within a collagenized stroma (H&E  –  100X); C  -  Sharp transition between a fibrous hypercellular and myxoid hypocellular areas with spindle-shape cells (H&E – 200X); D - Area showing large collagen rosette surrounded by spindle-shape cells, a typical pattern of the hyalinizing spindle cells tumor with giant rosettes (H&E – 100X).

DISCUSSION Fibrosarcomas, tumors composed of malignant fibroblastic cells, represent a large group of soft tissue malignancies, classified in the subgroups such as low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF), which seem to share morphologic and molecular characteristics, suggesting a close relationship between these two types of tumor.1 In 1987, Evans2 described the first case of LGFMS, and since then it has remained a rare tumor that typically affects young adults, arising in the deep soft tissues of the proximal extremities or of the trunk. Studies on case series show an incidence of 0.18 per million, accounting for 0.6% of soft tissue sarcomas.3 LGFMS has a quite

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variable morphological spectrum.4 In its classic form, LGFMS is composed by alternating fibrous and myxoid areas with bland spindle or stellate cells in a whorled growth pattern.4,5 A hyalinizing spindle cell tumor with giant rosettes is a variant of LGFMS, with prominent stromal hyalinization and collagen pseudorosettes.6 Sometimes, prominent hemangiopericytoma-like vasculature is also seen.5 Although low-grade soft tissue sarcoma rarely metastasizes, LGFMS metastases have been reported to vary from 5% to 41%. Due to the low grade of malignancy, and therefore the low mitotic rate of these tumors, it is not expected be chemo or radio sensitive.3 The immunohistochemical profile of LGFMS is nonspecific, but it does have a role in the


Fibrosarcoma: a challenging diagnosis

Autopsy and Case Reports 2013; 3(3): 21-29

Figure 4 – Photomicrography of the third resected tumor. A - Hypercellular area showing cords of epithelioid cells with a clear cytoplasm and round to oval nuclei within an abundant hyalinized collagen stroma (H&E – 200X); B - hHypercellular area showing nests of epithelioid cells within an abundant collagenized stroma (H&E – 200X); C - Transition between hypocellular areas with spindle-shape cells (H&E – 200X); D - Large collagen rosette surrounded by spindle-shape cells (H&E – 100X). diagnostic process. Epithelial membrane antigen (EMA) expression has been the most relevant marker in LGFMS (positivity in 43-91%). Focal positivity for smooth muscle actin (SMA), desmin, and CD34 is also reported.7,8 EMA positivity is often focal and is also observed in tumors that may mimic LGFMS, such as soft tissue perineurioma and a subset of solitary fibrous tumors, among others.5 LGFMS has a differential upregulation of the Mucin 4 (MUC4) gene with a corresponding overexpression of the transmembrane glycoprotein MUC4, which is expressed in many epithelial surfaces. Even though little is known about the role of MUC4 in normal mesenchymal cells or mesenchymal tumors, aberrant expression or overexpression of MUC4 has been reported in various carcinomas.5 Doyle et al.5 showed positivity in 100% in a series of 49 LGFMS patients. The detection of the oncogenic chimeric fusion gene FUS-CREB3L2, or rarely

FUS-CREB3L1, resulting from the translocation t(7;16)(q34;p11) or t(11;16)(p11;p11), respectively, represent an important tool in defining the diagnosis of LGFMS.7 LGFMS may display unusual histological features, such as areas of hypercellularity with capillaries, areas of pleomorphism or marked epithelioid cytomorphology mimicking SEF. Therefore, the presence of such findings does not rule out the diagnosis of LGFMS.1 Folpe et al.6 reported that in a series of 77 cases of LGFMS and hyalinizing spindle cell tumor with giant rosettes (HSCT), 45% of cases showed epithelioid areas. The similarity of clinical and histological features between LGFMS and SEF was also reported by Reid et al.9

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Autopsy and Case Reports 2013; 3(3): 21-29

Ferreira CR, Fonseca LG, Piotto GHM, Geyer FC, Alcântara PSM.

Figure 5 –  Photomicrography of the third resected tumor. Immunohistochemistry. A - AE1-AE3 negative (200X); B - Diffuse and strong nuclear positivity for p63 (200X); C - Diffuse and moderate nuclear positivity for estrogen receptor (200X); D - Diffuse cytoplasmatic positivity for MUC4 (200X). In 1995, Meis-Kindblom et al.10 described SEF as a rare variant of fibrosarcoma that occurs in the deep soft tissues of lower extremities, limb girdles, and trunk. Approximately 50% of patients develop local recurrence or distant metastases after resection. Clinically, SEF demonstrates aggressive behavior with a mortality rate of up to 57%. Although Pan et al.11 reported a case with brilliant response to Irinotecan, SEF is known as a chemo-resistant tumor. SEF usually is composed of epithelioid cells with clear or eosinophilic cytoplasm, which is arranged in nests or cords, within a densely sclerotic stroma. Hypocellular fibrous areas with a fascicular growth pattern and myxoid areas may be present in SEFs. In some cases, areas indistinguishable from LGFMS is also observed.10,12,13 Besides histologic overlap with LGFMS, SEF also shows FUS gene rearrangements.1 Similarly to LGFMS, the immunohistochemical profile of SEF is nonspecific. The immunophenotype of SEF shows focal positivity for EMA and weak positivity for S-100.10 Recently, Doyle et al.12 showed that MUC4

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Table 2 – Immunohistochemical panel used in the revision Antigen

Result

Antigen

Result

BCL 2

Positive

CK7

Negative

CD99

Positive

p63

Positive

ER

Positive

S100

Negative

PR

Negative

HER-2

Negative

AE1AE3

Negative

CD34

Negative

35BH11

Negative

CK5

Negative

MUC4

Positive

34BE12

Negative

MUC4 = mucin 4.

expression was present in 78% of SEFs, including 100% of hybrid LGFMS-SEF and 69% in “pureSEFs.” Although MUC4 is a sensitive and relatively specific marker for LGFMS and SEF, its expression is also observed focally among cases of synovial carcinoma, ossifying fibromyxoid tumors, epithelioid gastrointestinal stromal tumors and myoepithelial carcinoma.5,12


Fibrosarcoma: a challenging diagnosis

The treatment of these tumors is challenging. The standard treatment for low-grade sarcomas is surgical removal without adjuvant therapy since the recurrence, if any, is usually local. MarettyNielsen et al.3 published a case series with 14 patients treated in Denmark between 1979 and 2010. The treatment strategies were variable according to clinical presentation. Twelve patients were diagnosed with localized tumors and were treated with surgery. Four cases presented local relapse, without evidence of distant metastasis, and were treated with surgery without adjuvant therapysimilar treatment to the primary tumor. The patients that developed distant metastasis were treated with different strategies, including ifosfamide, doxorubicin hydrochloride, imatinib mesylate, trabectedin, gemcitabine, docetaxel, and palliative radiotherapy. The better response to chemotherapy was observed with trabectedin and resulted in shortterm control of disease progression.3 Herein, we report the case of a 53-year old woman with a relapsing tumor in the axillary fossa. After three years of the initial diagnosis, she presented metastases to the lung and pleura. At this time, the histologic diagnosis was fibromatosislike metaplastic carcinoma, which encouraged us to initiate chemotherapy with carboplatin and paclitaxel. At the end of the fourth cycle the disease unexpectedly progressed, setting the tumor as chemo-resistant. A new histological revision added to the unfavorable clinical course led to the final diagnosis of a hybrid low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. Therapeutic planning involves a surgical debulking attempt, with the intention of an improved of quality of life. The positivity of the immunophenotype for p63 and hormonal receptors was reasonable for the diagnosis of fibromatosis-like metaplastic carcinoma (FMC). Metaplastic carcinoma encompasses a group of neoplasms characterized by differentiation of the neoplastic epithelium into squamous cells and/or mesenchymal-looking elements.14 FMC was formerly called monophasic spindle cell carcinoma, and is a rare entity characterized solely by the sarcomatoid element.15 The latter has a better prognosis compared with the classical form of metaplastic carcinoma, presenting local recurrence and low metastatic potential.16 Histologically, FMC is characterized by bland spindle cells, with mild or absent nuclear atypia, arranged in wavy, interlacing fascicles. Sometimes, cords and clusters of plump spindle and more epithelioid cells are found.14 Immunohistochemical analysis, with a broad panel of cytokeratins, is required for the diagnosis, since

Autopsy and Case Reports 2013; 3(3): 21-29

no specific cytokeratin is expressed in all tumors. Among the cytokeratins, the most useful are CK5/6, CK14, 34βE12, and AE1-AE3.16,17 In addition to cytokeratins, p63 is almost invariably positive in the spindle cells, but not in the ductal carcinomatous component.14,15,17 The majority of these tumors are negative for hormone receptors and HER 2.15,17 The immunohistochemical reaction for p63 has several diagnostic uses, particularly in the evaluation of epithelial neoplasms, like squamous differentiation in poorly differentiated or spindle cell lesions.18 Although there is a virtual absence of expression of p63 in soft tissue tumors, Jo and Fletcher19 reported the expression of this antigen in 9.1% in a series of 650 cases of soft tissue tumors. Among these, 10% of the LGFMS showed multifocal staining. Focal or weak p63 positivity, in the absence of cytokeratin expression, does not allow the diagnosis of spindle cell squamous cell carcinoma. Although an estrogen/progesterone receptor is found in only a subset of breast carcinomas and carcinomas of the ovary and endometrium, it may also be observed in other carcinomas, for example, of the lung, stomach, and thyroid.20 This aberrant positivity is reported to be related to the antibody clone. The estrogen receptor antibody clone 6F11 (Ventana, Tucson, AZ) gives more false-positive results compared with other clones.21 Some authors have advised that weak/moderate expression should be judged more carefully, taking into account the clinical presentation and results of other immunohistochemical reactions.20 The expression of estrogen and progesterone receptors in soft tissue tumors is poorly defined and their significance is uncertain. Valkov et. al.22 observed the occurrence, distribution and prognostic value of these hormonal receptors in non-gastrointestinal stromal tumor soft tissue sarcomas. Estrogen receptor was a positive prognosticator in women, while progesterone receptor was a negative prognosticator in men. The estrogen receptor negative/ progesterone receptor positive profile was a negative prognosticator for the whole patient cohort The results of a disappointing clinical response to the chemotherapy, and the morphological aspects associated with MUC4 expression, the diagnosis of hybrid LGFMS-SEF tumor is strongly supported. The authors call attention to the positive immunophenotype for p63 and estrogen receptor as a pitfall. Fibrosarcoma has always been considered a diagnosis of exclusion. Recent advances in molecular

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Autopsy and Case Reports 2013; 3(3): 21-29

biology with the detection of FUS gene rearrangement and the expression of MUC4, have contributed greatly to the accurate diagnosis of this entity.

REFERENCES 1.

Guillou L, Benhattar J, Gengler C, et al. Translocationpositive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am J Surg Pathol. 2007;31:1387-402. PMid:17721195. http://dx.doi.org/10.1097/PAS.0b013e3180321959

2.

Evans HL. Low-grade fibromyxoid sarcoma: a report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol. 1987;88:615-9. PMid:3673943

3.

Maretty-Nielsen K, Baerentzen S, Keller J, Dyrop HB, Safwat A. Low-grade fibromyxoid sarcoma: incidence, treatment strategy of metastases, and clinical significance of the FUS gene. Sarcoma. 2013;2013:256280. http://dx.doi. org/10.1155/2013/256280

4.

Evans HL. Low-grade fibromyxoid sarcoma: a report of 12 cases. Am J Surg Pathol. 1993;17:595-600. PMid:8333558. http://dx.doi.org/10.1097/00000478-199306000-00007

5.

Doyle LA, Möller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol. 2011;35:733-41. PMid:21415703. http://dx.doi. org/10.1097/PAS.0b013e318210c268

6.

Folpe AL, Lane KL, Paull G, Weiss SW. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol. 2000;24:1353-60. PMid:11023096. http://dx.doi. org/10.1097/00000478-200010000-00004

7.

Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest. 2005;85:408-15. PMid:15640831. http://dx.doi.org/10.1038/labinvest.3700230

Ferreira CR, Fonseca LG, Piotto GHM, Geyer FC, Alcântara PSM. carcinoma. Am J Surg Pathol. 1995;19:979-93. PMid:7661286. http://dx.doi.org/10.1097/00000478-199509000-00001 11. Pan CH, Han XQ, Li JS. CPT-11 Chemotherapy Rescued A Patient with Atypical Sclerosing Epithelioid Fibrosarcoma from Emergent Condition. Chin J Cancer Res. 2012;24:2536. PMid:23359776 PMCid:PMC3555278. http://dx.doi. org/10.1007/s11670-012-0253-1 12. Doyle LA, Wang WL, Dal Cin P, et al. MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am J Surg Pathol. 2012;36:1444-51. PMid:22982887. http:// dx.doi.org/10.1097/PAS.0b013e3182562bf8 13. Antonescu Cr, Rosenblum MK, Pereira P, Nascimento AG, Woodruff JM. Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor. Am J Surg Pathol. 2001;25:699-709. http:// dx.doi.org/10.1097/00000478-200106000-00001 14. Reis-Filho JS, Lakhani SR, Gobbi H, Sneige N. Metaplastic carcinoma. In: Lakhani Sr, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, editors. WHO classification of tumors of the breast. Lyon: IARC; 2012. 15. Tse GMK, Tan PH, Lui PCW, Putti TC. Spindle cell lesions of the breast - the pathologic differential diagnosis. Breast Cancer Res Treat. 2008;109:199-207. PMid:17636400. http://dx.doi.org/10.1007/s10549-007-9652-2 16. Nonnis R, Paliogiannis P, Giangrand D, Marras V, Trignano M. Low-grade fibromatosis-like spindle cell metaplastic carcinoma of the breast: A case report and literature review. Clin Breast Cancer. 2012;12:147-50. PMid:22444721. http:// dx.doi.org/10.1016/j.clbc.2012.01.011 17. Lee AHS. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology. 2008;52:45-57. PMid:18171416. http://dx.doi.org/10.1111/j.1365-2559.2007.02893.x 18. Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in human normal and tumors tissues. Clin Cancer Res. 2002;8:494-501. PMid:11839669 19. Jo VY, Fletcher CDM. p63 Immunohistochemical staining is limited in soft tissue tumors. Am J Clin Pathol. 2011;136:762-6. PMid:22031315. http://dx.doi. org/10.1309/AJCPXNUC7JZSKWEU

8.

Goodlad JR, Mentzel T, Fletcher CD. Low grade fibromyxoid sarcoma: clinicopathological analysis of eleven new cases in support of a distinct entity. Histopathology. 1995;26:229-37. PMid:7797200. http://dx.doi.org/10.1111/j.1365-2559.1995. tb01436.x

20. Bhargava R, Dabbs DJ. Immunohistology of metastatic carcinomas of unknow primary. In: Dabbs DJ, editor. Diagnostic immunohistochemistry: theranostic and genomics applications. 3rd ed. Philadelphia: Saunders Elsevier; 2010. p. 229-30.

9.

Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation. Am J Surg Pathol. 2003;27:1229-36. PMid:12960807. http:// dx.doi.org/10.1097/00000478-200309000-00006

21. Dabbs DJ, Landreneau RJ, Liu Y, et al. Detection of estrogen receptor by immunohistochemistry in pulmonary adenocarcinoma. Ann Thorac Surg. 2002;73:403-5. http:// dx.doi.org/10.1016/S0003-4975(01)03358-6

10. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating

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22. Valkov A, Sorbye S, Kilvaer TK, et al. Estrogen receptor and progesterone receptor are prognostic factors in soft tissue sarcomas. In J Oncol 2011;38:1031-40.


Fibrosarcoma: a challenging diagnosis

Autopsy and Case Reports 2013; 3(3): 21-29

Conflict of interest: None Submitted on: 22th August 2013 Accept on: 19th September 2013 Correspondence: Serviço de Anatomia Patológica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9384 E-mail: crisrf@hu.usp.br

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Autopsy and Case Reports 2013; 3(3): 31-40

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Renal small B-cell lymphoma with plasmacytic differentiation presenting with monoclonal gammopathy and disseminated intravascular coagulation syndrome Paula de Oliveira Pádua Prestesa, Carolina Toniolo Zenattib, Luiz Felipe Adsuara de Sousaa, Artur Chinen Nagaminec, Aloísio Felipe-Silvad Prestes POP, Zenatti CT, Sousa LFA, Nagamine AC, Felipe-Silva A. Renal small B-cell lymphoma with plasmacytic differentiation presenting with monoclonal gammopathy and disseminated intravascular coagulation syndrome. Autopsy Case Rep [Internet]. 2013; 3(3): 31-40. http://dx.doi.org/10.4322/acr.2013.026

ABSTRACT Primary renal lymphomas are very rare. However, the kidney may be a site of metastasis, usually from a disseminated aggressive lymphoma. A 58-yearold woman was brought to the medical facility due to acute mental confusion, severe hypotension, septic shock, and signs of disseminated intravascular coagulation. Laboratory tests showed severe leukopenia, renal failure, altered liver function, and elevated serum lactate dehydrogenase levels. Protein electrophoresis revealed hypergammaglobulinemia with a monoclonal peak of IgG lambda. The clinical outcome was fulminant and the patient died less than 24 hours after admission. Autopsy revealed an indolent B-cell lymphoma with extensive plasmacytic differentiation infiltrating the right renal sinus and involving the submandibular and sublingual glands, cervical and peri-aortic lymph nodes, multiple microscopic foci in pituitary and adrenal glands, lung, breast, liver, thyroid, and bone marrow. Numerous IgG4-positive plasma cells were detected by immunohistochemistry although other histological features of IgG4-related disease were missing. There was also extensive hemorrhagic necrosis of the adrenal glands and purulent cystitis, which was probably responsible for the septic shock. The authors concluded that the kidney was most likely the primary site of the indolent lymphoma, as that was the site with the largest tumor mass. Infiltration of other organs was considered as dissemination of the disease. The differential diagnosis with mucosaassociated lymphoid tissue and lymphoplasmacytic lymphoma is discussed. Keywords: Lymphoma; Kidney; Lymphoma, B-Cell, Marginal Zone; Immunoglobulin G; Pyelonephritis; Shock, Septic; Waterhouse-Friderichsen Syndrome; Autopsy.

Department of Internal Medicine – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Instituto de Infectologia Emílio Ribas, São Paulo/SP – Brazil. c Physical Medicine and Rehabilitation Department – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. d Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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 médium provided article is properly cited.

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Autopsy and Case Reports 2013; 3(3): 31-40

Prestes POP, Zenatti CT, Sousa LFA, Nagamine AC, Felipe-Silva A.

CASE REPORT

peripheral perfusion, tachycardia, and blood glucose determination of 15 mg/dL. Petechiae emerged on the trunk and spontaneous bleeding was observed from oral and nose mucosa, as well as from venipuncture sites.

A 58-year-old woman previously diagnosed with hypertension, who was regularly taking losartan, hydrochlorothiazide, and propranolol, was brought to the emergency room by her family who reported a 1-day history of watery diarrhea, abdominal pain, and vomiting, followed by mental confusion and fever. She had a past history of acute pyelonephritis caused by multi-sensitive E. coli.

Despite the mechanical ventilatory support and the attempt of hemodynamic stabilization with intra­ venous norepinephrine, the patient died 7 hours after admission. Serum protein electrophoresis undertaken postmortem revealed a hypergammaglobulinemia of 2.85 g/dL (RV: 0.5‑1.6 g/dL) with a monoclonal peak of IgG lambda. Blood culture was negative while the culture of urinary bladder contents collected at autopsy was positive for multiresistant Klebsiella pneumoniae and Enterobacter cloacae complex, which were interpreted as probable contaminants.

On physical examination, the patient was pale and dehydrated with a normal respiratory pattern. Blood pressure was 90/58 mmHg, pulse rate 130 beats per minute, respiratory rate 20 breaths per minute, axillary temperature 36  °C, room air oximetry 93%, and blood glucose of 68  mg/dL. On neurological examination the patient showed mental confusion, but neither motor deficit signs nor meningeal irritation were disclosed. Pupils were isochoric and reactive to light. Examination of the lungs and heart were normal. The abdomen was distended and diffusely painful, but the rebound sign was negative; liver was palpable until 3 cm below the right costal margin. The initial laboratory workup is shown in Table 1.

Autopsy Findings Gross examination of the cephalic segment showed a congested brain, pituitary gland hyper­ plasia exhibiting a reddish surface (Figure 1), cervical lymphadenomegaly with lymph nodes measuring up to 1.8 cm at the longest axis, and enlarged submandibular and sublingual glands.

The patient was submitted to volemic resuscitation simultaneously with a prescription of ceftriaxone and metronidazole focusing the clinical hypothesis of abdominal sepsis due to acute gastroenteritis. The clinical outcome worsened during the following hours with severe hypotension, poor

Small bilateral yellowish pleural effusion was disclosed at the chest cavity opening. The right lung weighed 636g (RV: 450 g) and left lung 598 g (RV: 375 g) and showed up wine-colored, with marked

Table 1 – Initial laboratory workup Exam

Result

RV

Exam

Result

RV

Hemoglobin

11.9

12.3-15.3 g/dL

Creatinine

3.7

0.4-1.3 mg/dL

Hematocrit

36.6

36.0-45.0%

Sodium

140

136-146 mEq/L

Leukocytes

1180

4.4-11.3 × 10³/mm

Potassium

3.0

3.5-5.0 mEq/L

Myelocytes

4

0

AST

116

10-31 U/L

Metamyelocytes

8

0

ALT

25

9-36 U/L

Bands

21

1-5%

Total bil

2.1

0.3-1.2 mg/dL

Segmented

34

46-75%

Direct bil

1.5

until 0.2 mg/dL

Eosinophils

2

1-4%

Albumin

2.7

3.0-5.0 g/dL

Basophils

1

0-2.5%

(PT) INR

4.59

1

Lymphocytes

26

18-40%

R (ATPT)

4.43

until 1.25

Monocytes

4

2-9%

Cai

1.07

1.15-1.35 mmol/L

Platelets

28100

150-400 × 10³/mm

Lactate

97.7

3.0-13.2 mg/dL

Urea

83

10-50 mg/dL

CRP

262

< 5.0 mg/L

3

3

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATPT = activated thromboplastin time; bil = bilirubin; Cai = ionized calcium; CRP = C-reactive protein; INR = international normalized ratio; PT = prothrombin time; R = ratio; RV = reference value.

32


Renal small B-cell lymphoma with plasmacytic differentiation...

Autopsy and Case Reports 2013; 3(3): 31-40

Figure 1 – A - Gross view of the base of the encephalon, showing the enlarged and congested pituitary gland; B - Photomicrography of the pituitary tissue (left) infiltrated by plasmocitoid cells (right) (H&E; 400x). edema more pronounced in the lower lobes. The pericardial sac opening showed the presence of small yellow-citrine effusion. The heart weighed 336 g (RV: 262 g) with moderate concentric left ventricular hypertrophy. At the opening of the abdominal cavity, the spleen was mildly enlarged and periaortic lymphadenopathy was detected (lymph nodes measured up to 3 cm at the longest axis). The left kidney weighted 178 g and the right kidney 284  g (RV for both kidneys: 288 g), both presenting simple cysts measuring less than 2 cm each. The kidneys cut-section showed foci of hemorrhage in the corticomedullary transition, bilaterally. Diffuse thickening of the sinus, and intense infiltration of the right renal pelvis by a white tissue of imprecise limits extending to the renal cortex and measuring 8.0 cm at its longest axis, characterized the gross examination of the right kidney (Figure 2). The ureters were preserved. The urinary bladder showed mucosal hyperemia containing purulent content (Figure 3A). The adrenal glands showed a bilateral hemorrhagic aspect (Figure 3B). The cause of death was attributed to septic shock of urinary origin, accompanied by disseminated intravascular coagulation and hemorrhagic necrosis of the adrenals, clinically known as Waterhouse-Friderichsen syndrome. Microscopic examination of the right kidney showed an infiltrating lymphoid proliferation of small and monotonous lymphocytes with extensive

plasmacytic differentiation. Immunohistochemistry showed that the lymphocytes were positive for CD20, CD138+, and cytoplasmic monotypic lambda light chain, and negative for CD3, CD5, CD23, and cyclin D1. The proliferation index, as assessed by Ki67, was approximately 5%. The tumor was classified as small B-cell lymphoma with extensive plasmacytoid differentiation, most likely an extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT), although lymphoplasmacytic lymphoma (LPL) could be an important differential diagnosis. The same cellular pattern was found infiltrating submandibular and sublingual glands (Figure 4) with some periductular fibrosis but neither obliterative phlebitis nor typical lymphoepithelial lesions were detected. Monotonous lymphoplasmacytic infiltration was also seen in abdominal and cervical lymph nodes (Figure  5), and the pituitary gland. Curiously, immunohistochemistry showed numerous IgG4positive plasma cells (more than 50 per high-power field) in the kidney and lymph nodes, with a ratio of IgG4 to IgG higher than 50% (Figure 6). However, storiform fibrosis, obliterative phlebitis, eosinophils, and other histopathological signs of IgG4-related disease were not detected. Microscopic foci of lymphoplasmacytic infiltrates were detected in the adrenal glands, lungs, liver, breast, and thyroid. Bone marrow had a mild multifocal interstitial infiltration pattern but with fewer plasma cells. The spleen was not infiltrated and showed reactive changes related to sepsis. The stomach, pancreas and gastrointestinal (GI) tract showed signs of shock and hypoxia related to sepsis, but lymphoplasmacytic infiltration was not detected.

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Autopsy and Case Reports 2013; 3(3): 31-40

Prestes POP, Zenatti CT, Sousa LFA, Nagamine AC, Felipe-Silva A.

Figure 2 – A - Gross view of the right kidney showing hilar infiltration by a white, soft, poorly circumscribed tumoral mass. Photomicrography of the renal tissue: B  -  Diffuse infiltration of the renal tissue by a small cell lymphoma (H&E, 100x); C  -  Lymphoma infiltration around kidney arteries and nerves (H&E, 200x); D - Immunohistochemistry for AE1+AE3 (pan-keratin) showing residual atrophic tubular structures (AE1+AE3, 200x).

Figure 3 – A - Gross view of the opened urinary bladder with yellowish purulent content; B - Gross view of the hemorrhagic bilateral adrenal glands.

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Renal small B-cell lymphoma with plasmacytic differentiation...

Autopsy and Case Reports 2013; 3(3): 31-40

Figure 4 – Photomicrography of the submandibular gland. A - Infiltrated submandibular gland with some atrophic ductular structures and mild periductular fibrosis (H&E, 200x); B - Areas of plasmacytic differentiation (H&E, 400x).

Figure 5 – Photomicrography of lymph node. A - Abdominal lymph node with architectural effacement (H&E, 25x); B - Small B cell lymphoma with monotonous small lymphoid cells and some plasma cells (H&E, 400x); C - Immunohistochemistry for CD20 demonstrating B cells (brown) (400x); D - Immunohistochemistry for kappa and E - lambda light chain demonstrating cytoplasmatic staining in plasma cells (400x).

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Autopsy and Case Reports 2013; 3(3): 31-40

Prestes POP, Zenatti CT, Sousa LFA, Nagamine AC, Felipe-Silva A.

Figure 6 – Immunohistochemistry for immunoglobulins. A - Plasma cells expressing IgG in the lymph node (400x); B - Plasma cells expressing IgG4 in the kidney (400x).

DISCUSSION This case most likely represents a primary renal MALT lymphoma with extensive plasmacytic differentiation. LPL is an important and sometimes difficult differential diagnosis, which warranted, in this case, the descriptive diagnosis of small B-cell lymphoma with plasmacytic differentiation. All types of marginal zone lymphomas (MZL)—MALT type, splenic, and nodal-may show prominent plasmacytic differentiation. Differentiating marginal zone lymphomas from other small B-cell lymphomas with plasmacytic differentiation, especially LPL or from plasma cell neoplasms, may be a difficult task.1,2 MALT lymphomas, first described by Isaacson and Wright3 represent 7-8% of non-Hodgkin lymphomas and have specific clinicopathological features.4 The GI tract is the most commonly affected site, which is involved in two-thirds of cases, with the stomach being the most common location (85%). However, any extranodal anatomic site can be involved with MALT lymphoma, including lung (14%), ocular adnexa (12%), skin (11%), thyroid (4%), breast (4%), salivary glands, bladder, and more rarely, the kidneys.5-7 MZL occurs mainly in the sixth decade of life and presents a slight female predominance (male:female ratio = 1:1.2).1,7 Despite the overlap of morphological features, the distinction between nodal and extranodal marginal B-cell lymphoma is

36

clinically important, since their clinical behavior is distinct.8 Due to an interaction between the lymphoma cells and mucosal adhesion molecules,9,10 the MALT lymphomas remain localized in their primary site for a long time.11,12 Dissemination to multiple organs is not uncommon, occurring in over 25% of cases of gastric MALT lymphoma and 45% of extragastric cases.4,6 Unlike its nodal counterpart, the extranodal MALT lymphoma shows a less aggressive course, presenting as a slow-growing mass or diffuse submucosal thickening that can be mistaken for a benign inflammatory process or “pseudo lymphoma”. The 5-year survival is generally greater than 85%, even with multifocal involvement.8 The extranodal MZL arises in organs (e.g. stomach, lung, salivary glands, and lacrimal glands) that normally are free of lymphoid tissue but can accumulate lymphoid B-cells in response to autoimmune disorders or chronic infections.2,13 The latter may occur secondary to chronic infection by Helicobacter pylori, Borrelia burgdorferi and Chlamydia psittaci in the stomach, skin, and eye, respectively. Chronic autoimmune entities related to extranodal MZL comprises Hashimoto’s thyroiditis, sialadenitis associated (or not) to Sjoegren’s syndrome, systemic lupus erythematosus, and sarcoidosis.5,8,14-21 In the present case, it is suspected that chronic pyelonephritis triggered the development of the


Renal small B-cell lymphoma with plasmacytic differentiation...

Autopsy and Case Reports 2013; 3(3): 31-40

lymphoma in the renal pelvis, similar to other authors’ descriptions.22-24

The lymphoma cells express surface monotypic immunoglobulins, or, more rarely, cytoplasmic immunoglobulin, usually IgM. Additionally, monoclonal gammopathy is a common phenomenon in MALT lymphoma, most likely due to paraprotein production by clonal lymphoplasmacytic cells.8,26,27 Approximately one-third of extragastric MALT lymphomas have extensive plasma cell differentiation, which permits the differential diagnosis with plasmacytomas or lymphoplasmacytic lymphomas. In the case reported here, the monoclonal IgG lambda was shown by immunohistochemistry and confirmed by serum protein electrophoresis and immunofixation.

Notwithstanding the rarity, we inferred the kidney as the primary site of the present case since it represented the location of the largest tumor mass. Another point in favor of dissemination from the kidney to other sites was the absence of chronic inflammatory conditions in all organs except the kidney. However, we cannot rule out the possibility of the occurrence of multicentric lesions, which can occur in MALT lymphomas.4 Approximately 25% of patients with gastric MALT lymphoma and 45% of patients with extragastric MALT lymphoma have multiple sites of disease at the time of the diagnosis.25,26 It is frequently assumed as dissemination of the disease when multiple sites of MALT lymphoma are present at the time of the diagnosis. However, many studies explored the clonal relationship of multiple MALT lymphomas by the polymerase chain reaction of the immunoglobulin heavy chain (IgH) gene rearrangement, but the results are controversial. Konoplev et al.4 analyzed the IgH gene rearrangement in four patients with multifocal disease. In three of those patients, the neoplastic clones were distinct and unrelated. These observations suggest that multifocal sites in MALT lymphoma may not be equivalent to disease dissemination. Different chromosomal/genotype alterations found in neoplasias that arise in different sites corroborate the hypothesis of multicentricity. The translocation t(11;18)(q21;q21) is the most common, found most often in MALT lymphomas of the lung and stomach. In contrast, chromosomal abnormalities t(14;18)(q32;q21), t(1;14)(p22;q32), and t(3;14) (p14.1;q32) are more common in all other sites of this disease. The t(14;18) is most characteristic in MALT lymphomas of the orbit, skin, and salivary glands. The t(1;14) is rare, but is most commonly found in the intestinal MALT. The t(3;14) is more often present in the lymphomas of the thyroid, skin, and orbit.4 This analysis was not performed in this case, so it was not possible to differentiate between a disseminated and a multicentric disease with certainty. There are some cases in which the MALT lymphoma may present recurrent manifestations at the primary site, with potential for dissemination and progression of high-grade B-cell lymphoma. Involvement of lymph nodes and bone marrow seem to be related to this worse prognosis.6,25

The present case represents an advanced stage in the current MALT lymphoma staging scheme once several sites were already involved at the time of diagnosis.28,29 Reports on kidney involvement by MALT lymphomas are scarce. In 2010, Peces et al.8 reported a case of a kidney MALT lymphoma and after a thorough search in the English literature retrieved 30 other unequivocal cases of B-cell MALT lymphomas involving the kidney. In this series, 12 cases concomitantly exhibited the neoplasia in the kidney and other sites; therefore, the authors considered the difficulty of being able to tell in which organ the lymphoma originated.8 Poor prognosis is related to the association with nodal and/or bone marrow dissemination in comparison with patients with multiple organ involvement. The management of advanced stage disease, as in the case reported here, is considerably arduous. In advanced cases, there seems to be no difference between letting the disease follow its natural course and undertaking therapeutic interventions, such as surgery, chemotherapy, and/ or radiotherapy.30,31 In a series of 180 treated patients with histologic confirmation of nongastric MALT and a median follow-up of 3.4 years, a relapse, histologic transformation, or the appearance of a second tumor was observed in 40% of the cases.6 The patient of this report presented clinical septic shock and disseminated intravascular coagulation, identified at autopsy, which was the immediate cause of death. The WaterhouseFriderichsen syndrome was most likely secondary to urinary infection and sepsis. Given the history of previous urinary infections and considering the immunocompromised patient, it is possible that the bacterial agents from the urinary system were responsible for the purpura fulminans. The bilateral

37


Autopsy and Case Reports 2013; 3(3): 31-40

adrenal hemorrhage, as observed in this case, is found in 1% of autopsies.32 LPL is an important differential diagnosis not only because of the morphological features, but also because of the presence of a paraprotein (IgG) and bone marrow involvement. However, in the present case, bone marrow involvement was mild. Furthermore, other features more often related to LPL were lacking, such as the involvement of the spleen and IgM paraprotein.33 IgG4-related disease is a recently described systemic autoimmune fibro-inflammatory condition characterized by tumefactive lesions, storiform fibrosis, and frequently elevated serum IgG4 levels. The closest histopathological mimickers of IgG4related disease are lymphomas; however, in contrast to B-cell lymphomas, the lymphoid inflammatory infiltrate in IgG4-related disease is composed primarily of T cells.34 Kidney manifestations of IgG4related disease include tubulointerstitial nephritis, glomerular disease, inflammatory pseudotumors and chronic sclerosing pyelitis.35 Recent reports have demonstrated a possible link between MZL and IgG4-related disease including IgG4-producing MALT lymphoma and lymphomas arising in previous IgG4 disease.36-39 The present case may represent an IgG4-producing lymphoma.

Prestes POP, Zenatti CT, Sousa LFA, Nagamine AC, Felipe-Silva A.

REFERENCES 1.

Isaacson PG, Chott A, Nakamura S, Müller-Hermelink HK, Harris NL, Werdlow SH. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Swerdlow S, Campo E, Harris NL, editors. International Agency for Research on Cancer. WHO classification of tumors of haematopoietic and lymphoid tissue. Genève: World Health Organization; 2008. p. 214-7.

2.

Zinzani PL. The many faces of marginal zone lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:42632.

3.

Isaacson PG, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer.  1984;53:2512-24. http://dx.doi. org/10.1002/1097-0142(19840601)53:11<2515::AIDCNCR2820531125>3.0.CO;2-C

4.

Konoplev S, Lin P, Medeiros J. et al. Clonal relationship of extranodal marginal zone lymphomas of mucosaassociated lymphoid tissue involving different sites. Am J Clin Pathol. 2010;134:112-8. PMid:20551275. http://dx.doi. org/10.1309/AJCP0HT6ZGSZKNFT

5.

Thieblemont C, Berger F, Coiffier B. Mucosa-associated lymphoid tissue lymphomas. Curr Opin Oncol.1995;7:415-20. http://dx.doi.org/10.1097/00001622-199509000-00005

6.

Emanuele Z, Annarita C, Pedrinis E, et al. Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood. 2003;101:2489-95. PMid:12456507. http:// dx.doi.org/10.1182/blood-2002-04-1279

7.

Porcaro AB, D‘Amico A, Novella G, et al. Primary lymphoma of the kidney. Report of a case and update of the literature. Arch Ital Urol Androl. 2002;74:44-7. PMid:12053451

8.

Peces R, Vega-Cabrera C, Peces C, Pobes A, Fresno MF. B-cell lymphoma of MALT involving the kidney and monoclonal gammopathy: a case report with revision of the literature. Nefrologia. 2010;30:681-686. PMid:21113219. http://dx.doi. org/10.3265/Nefrologia.pre2010.Jun.10428.

9.

Dogan A, Du M, Koulis A, Briskin MJ, Isaacson PG. Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa associated lymphoid tissue. Am J Pathol. 1997;151:1361-9. PMid:9358762 PMCid:PMC1858078.

CONCLUSION In summary, we report a rare case of a probable primary kidney MALT lymphoma with systemic dissemination diagnosed at autopsy. The early diagnosis was missed because of the lack of diagnostic suspicion. The increased volume of the salivary glands and recurrent urinary infections could have helped to raise the suspicion of an immunologic disturbance. Catastrophic Waterhouse-Friderichsen syndrome, probably related to urinary sepsis, was the immediate cause of death in this advanced stage, indolent, and underdiagnosed lymphoma.

ACKNOWLEDGEMENTS The authors thank Dr. L. Jeffrey Medeiros for important comments and suggestions on the manuscript.

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10. Brandtzaeg P, Farstad I, Haraldsen G. Regional specialization of the mucosal immune system: primed cells do not always home along the same track. Immunol Today. 1999:20:267-77. http://dx.doi.org/10.1016/S0167-5699(99)01468-1 11. Isaacson PG. Gastric MALT-lymphoma: from concept to cure. Ann Oncol.1999;10:637-45. http://dx.doi. org/10.1023/A:1008396618983 12. Raderer M, Isaacson PG. Extranodal lymphoma of MALTtype: Perspective at the beginning of the 21st century. Expert


Renal small B-cell lymphoma with plasmacytic differentiation...

Autopsy and Case Reports 2013; 3(3): 31-40

Rev Anticancer Ther. 2001;1:53-64. PMid:12113133. http:// dx.doi.org/10.1586/14737140.1.1.53

and prostate. Scand J Urol Nephrol. 1998;32:234-6. http:// dx.doi.org/10.1080/003655998750015665

13. Isaacson PG. Gastrointestinal Lymphoma. Hum Pathol.1994;25:1020-29. http://dx.doi.org/10.1016/00468177(94)90060-4

25. Raderer M, Wohrer S, Streubel B, et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24:3136-41. PMid:16769982. http://dx.doi. org/10.1200/JCO.2006.06.0723

14. Hyjek E, Isaacson PG. Primary B cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis Hum Pathol. 1988;19:1315-26. http://dx.doi.org/10.1016/S00468177(88)80287-9 15. Hyjek E, Smith WJ, Isaacson PG. Primary B-cell lymphoma of salivary glands and its relationship to myoepithelial sialadenitis. Hum Pathol. 1988;19:766-76. http://dx.doi. org/10.1016/S0046-8177(88)80259-4 16. Zucca E, Bertoni F, Roggero E, et al. Molecular analysis of the progression from Helicobacter pylori-associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach. N Engl J Med. 1998;338:804-10. PMid:9504941. http://dx.doi.org/10.1056/NEJM199803193381205 17. Jonsson V, Wiik A, Hou-Jensen K, et al. Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders. J Intern Med. 1999;245:277-86. http://dx.doi. org/10.1046/j.1365-2796.1999.0443f.x 18. Miklos JA, Swerdlow SH, Bahler DW. Salivary gland mucosaassociated lymphoid tissue lymphoma immunoglobulin V (H) genes show frequent use of V1-69 with distinctive CDR3 features. Blood. 2000;95:3878-84. PMid:10845923 19. Campo E, Chott A, Kinney MC,  et  al. Update on extranodal lymphomas. Conclusions of the Workshop held by the EAHP and the SH in Thessaloniki, Greece. Histopathology. 2006;48:481-504. PMid:16623775 PMCid:PMC1448691. http://dx.doi.org/10.1111/j.13652559.2006.02369.x 20. Qiu L, Unger PD, Dillon RW, et al. Low-grade mucosa associated lymphoid tissue lymphoma involving the kidney: report of 3 cases and review of the literature. Arch Pathol Lab Med. 2006;130:86-9. PMid:16390244 21. Mortlock AM, Lim CSE, Morgan H, et al. Renal MALToma: an unusual lymphoma in a patient with lupus. Lupus. 2006;15:6135. http://dx.doi.org/10.1177/0961203306071920 22. Garcia M, Konoplev S, Morosan C,  et  al. Malt Ly m p h o m a i n v o l v i n g t h e k i d n e y. A m J C l i n Pathol. 2007;128:464-73. PMid:17709321. http://dx.doi. org/10.1309/0T2UKUKV91W3QR6W 23. Li B, Zhang W, Tian W, Qiu L. Primary renal mucosaassociated lymphoid tissue lymphoma, the result of chronic pyelonephritis? Chinese-German J Clin Oncol. 2008;7:55-8. http://dx.doi.org/10.1007/s10330-007-0148-7 24. Araki K, KubotaY, Lijima Y, et al. Indolent behavior of low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue involved in salivary glands, renal sinus

26. Asatiani E, Cohen P, Ozdemirli M, Kessler CM, Nabromatis B, Cheson BD. Monoclonal gammopathy in extranodal marginal zone lymphoma (ENMZL) correlates with advanced disease and bone marrow involvement. Am J Hematol. 2004;77:1446. PMid:15389912. http://dx.doi.org/10.1002/ajh.20157 27. Charitaki E, Liapis K, Moutzouris DA, et al. Primary renal MALT lymphoma presenting with cryoglobulinaemia. Nephrol Dial Transplant. 2011;26:3819-21. PMid:21878472. http:// dx.doi.org/10.1093/ndt/gfr478 28. Rohatiner A. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol. 1994;5:397-400. PMid:8075046 29. Thieblemont C, Bergern F, Dumontet C, et al. Mucosaassociated lymphoid tissue lymphoma is a disseminated disease in one third of  158 patients analyzed. Blood. 2000;95:802-6. PMid:10648389 30. Altman DG, De Stavola BL, Love SB, Stepniewska KA. Review of survival analyses published in cancer journals. Br J Cancer. 1995;72:511-8. http://dx.doi.org/10.1038/ bjc.1995.364 31. Ferreri AJ, Freschi M, Dell’Oro S, Viale E, Villa E, Ponzoni M. Prognostic significance of the histopathologic recognition of low-and high-grade components in stage I-II B-cell gastric lymphomas. Am J Surg Pathol. 2001;25:95-102. http://dx.doi. org/10.1097/00000478-200101000-00011 32. Kovacs KA, Lam YM, Pater JL Bilateral massive adrenal hemorrhage. Assessment of putative risk factors by the case-control method. Medicine. 2001;80:45-53. http://dx.doi. org/10.1097/00005792-200101000-00005 33. Lin P, Molina TJ, Cook JR, Swerdlow SH. Lymphoplasmacytic lymphoma and other non-marginal zone lymphomas with plasmacytic differentiation. Am J Clin Pathol. 2011;136:195210. PMid:21757593. http://dx.doi.org/10.1309/ AJCP8FOIVTB6LBER 34. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539-51. PMid:22316447. http://dx.doi. org/10.1056/NEJMra1104650 35. Cornell L. IgG4-related kidney disease. Curr Opin Nephrol Hypertens. 2012;21:279-88. PMid:22487688. http://dx.doi. org/10.1097/MNH.0b013e32835265ac 36. Sato Y, Ohshima K, Takata K, et al. Ocular adnexal IgG4-producing mucosa-associated lymphoid tissue

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Autopsy and Case Reports 2013; 3(3): 31-40 lymphoma mimicking IgG4-related disease. J Clin Exp Hematop. 2012;52:51-5. http://dx.doi.org/10.3960/jslrt.52.51 37. Go H, Kim JE, Kim YA, et al. Ocular adnexal IgG4-related disease: comparative analysis with mucosa-associated lymphoid tissue lymphoma and other chronic inflammatory conditions. Histopathology. 2012;60:296-312. PMid:22211288. http://dx.doi.org/10.1111/j.1365-2559.2011.04089.x

Prestes POP, Zenatti CT, Sousa LFA, Nagamine AC, Felipe-Silva A. 38. Venkataraman G, Rizzo KA, Chavez JJ, et al. Marginal zone lymphomas involving meningeal dura: possible link to IgG4-related diseases. Mod Pathol. 2011;24:355-66. PMid:21102421. http://dx.doi.org/10.1038/modpathol.2010.206 39. Sato Y, Takata K, Ichimura K, et al. IgG4-producing marginal zone B-cell lymphoma. Int J Hematol. 2008;88:428-33. PMid:18839275. http://dx.doi.org/10.1007/s12185-008-0170-8

Conflict of interest: None Submitted on: 16th May 2013 Accept on: 20th September 2013 Correspondence: Serviço de Anatomia Patológica Hospital Universitário da Universidade de São Paulo Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9384 E-mail: aloisiosilva@hu.usp.br

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41

Autopsy and Case Reports 2013; 3(3): 41-48

Article / Clinical Case Report Artigo / Relato de Caso Clínico Black esophagus: exploring the dark Robert Forstera, Délcio Aparecido Dursoa, Edoardo Filippo de Queiroz Vattimob, Luis Massuo Marutac, Ana Luiza Werneck-Silvac, Vilma Takayasud, Marcia Yoshie Kanegaed, Fabiana Roberto Limae Forster R, Durso DA, Vattimo EFQ  et  al. Black esophagus: exploring the dark. Autopsy Case Rep [Internet]. 2013; 3(3): 41-48. http://dx.doi.org/10.4322/acr.2013.027

ABSTRACT Black esophagus is a rare but underdiagnosed disease. It occurs most frequently in severely ill patients and carries a high mortality rate. Cause of death is usually attributed to the comorbid conditions. Treatment is directed at the underlying cause, acid suppression and keeping the patient nil-peros. Surgery is needed in complicated cases and stenosis is the most feared longterm sequel. In the present article, two cases are described and literature is reviewed. Keywords: Esophageal Diseases; Esophagitis; Critical Illness; Diabetic Ketoacidosis. CASE 1 A 47-year-old male patient was admitted complaining of macroscopic hematuria and weight loss of 20 kg over the last two months. On physical examination bilateral massive abdominal masses were palpable extending from the flanks to the iliac fossae bilaterally. Laboratory tests showed marked metabolic acidosis, hyperkalemia and electrocardiographic alterations, which required prompt intravenous infusion of calcium gluconate and hemodialysis. Urinalysis showed pyuria. Abdominal ultrasound imaging and computed tomography scan revealed hepatic and renal polycystic disease. The kidneys were markedly enlarged extending from their original site until the iliac fossae and their architecture was effaced by

multiple cysts. On the following days the patient suffered an ischemic stroke and a pulmonary thromboembolism. Outcome was characterized by daily fever despite of the use of broad-spectrum antibiotics and negative blood and urine cultures. A PET SCAN was performed which was compatible with infection of multiple and bilateral renal cysts. Therefore bilateral nephrectomy was performed, and because of technical difficulties adrenals were also excised. Surgery was technically challenging, the patient remained hypotensive and required packed red blood-cell transfusion. After ICU discharge the patient started experiencing epigastric pain and heartburn. Esophagogastroduodenoscopy (EGD) (Figure  1) revealed necrotizing esophagitis

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

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 médium provided article is properly cited.

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Autopsy and Case Reports 2013; 3(3): 41-48

Forster R, Durso DA, Vattimo EFQ et al.

Figure 1 – Esophagoscopy from proximal (A) to distal (D) esophagus, showing acute necrotizing esophagitis. Black esophagus. compatible with the endoscopic diagnosis of “black esophagus”. The duodenal bulb was deformed by scarred ulcers and a small ulcer was visible in the anterior wall. Enteral nutrition, a proton pump inhibitor, a prokinetic drug and sucralfate were prescribed. A week later, control EGD showed an effacement of the blackened areas, which had been replaced by a diffuse fibrinous esophagitis. Recovery was uneventful since then. The patient went on hemodialysis and resumed oral feeding.

CASE 2 A 45-year-old male patient was admitted after a two-day history of dyspnea, odynophagia, nausea, vomiting, generalized weakness and drowsiness. On physical examination he was dehydrated, tachycardic, tachypneic, normotensive, afebrile, conscious but drowsy. He had been diagnosed with type 2 diabetes mellitus 5 years earlier but did not follow a regular treatment, giving up the use of the

42

prescribed hypoglycemic agents during the last year. The initial laboratory workup was compatible with the diagnosis of diabetic ketoacidosis with a blood glucose of 469 mg/dL (reference value (RV) < 100 mg/dl), venous blood pH 7.14 (RV; 7,35-7,45), bicarbonate 9 mEq/L (RV; 24 mEq/l), and urinalysis showing marked ketonuria. Glycated hemoglobin was 15,1% (RV < 5,7%) After metabolic control, the patient started complaining of heartburn and odynophagia. Esophagogastroduodenoscopy revealed friable esophageal mucosa, shallow ulcerations and extensive areas of mucosal necrosis along the medial and distal third of the esophagus consistent with the diagnosis of “black esophagus” (Figure 2). Histopathological examination of the esophageal biopsy specimen showed a marked acute inflammatory infiltrate, foci of liquefactive necrosis, presence of rare bulky endothelial and stromal cells, foci of intravascular fibrin, lack of representation of stratified squamous epithelium, with dark brown granular material (Figure 3). The


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Autopsy and Case Reports 2013; 3(3): 41-48

Figure 2 – Endoscopic view of the esophagus (A to D) showing acute esophageal necrosis. Black esophagus.

Grocott stain was negative for the presence of fungi. Cytomegalovirus (CMV) and herpes virus were absent on immunohistochemical research. Serologies for HIV and CMV were negative. The patient was kept nil-per-os and prescribed parenteral hydration, proton pump inhibitor, sucralfate and fluconazole. Esophagogastroduodenoscopy, undertaken on the third day, still showed darkened esophageal mucosa, now covered by patches of fibrinous material (Figure 4). The gastric mucosa was intact but a bulbar ulcer surrounded by scarred areas was present. On the sixth day another EGD was performed showing remission of the esophagitis as well as of the duodenal ulcer.

DISCUSSION Acute esophageal necrosis (AEN), also referred to as “black esophagus” or necrotizing

esophagitis, is a rare clinical entity, named by its characteristic presentation as a circumferential black-appearing necrotic esophageal mucosa on esophagogastroduodenoscopy (EGD). A 2010 review of the literature disclosed only 112 cases,1 though black esophagus is likely an underdiagnosed syndrome. Large series of autopsies and reviews of esophagogastroduodenoscopies have estimated a prevalence ranging from 0,01% to 0,28%.2-4 There is a remarkable predominance among men, which are four times more commonly affected than women. Peak incidence occurs in the seventh decade, with the average age of 68.4 years.1 Generally, at least two comorbidities are present.4 Renal insufficiency, mostly acute (2933%), diabetes mellitus (21-27%), cancer (18-29%) and hypertension (17-21%) are most frequently associated. Duodenal ulcers (25-33%) are a frequent concomitant finding.4,5 On diagnosis, other frequently associated clinical conditions are cardiac, pulmonary and renal disease, coagulopathy, ketoacidosis, cirrhosis, malnutrition, acute alcohol

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Forster R, Durso DA, Vattimo EFQ et al.

Figure 3 – Photomicrograph of the esophagus. A - granulation tissue of the ulcer bed; B - fibrinoid necrosis with countless polymorphonuclear leukocytes; C - acute inflammatory infiltration and thrombosed capillary within the granulation tissue; D - higher magnification of the ulcer bed showing neovascularization, reactive stromal and endothelial cells with enlarged nuclei.

intoxication, alcohol abuse, acute alcoholic hepatitis, peptic disease, acute fatty liver of pregnancy, acute pancreatitis and sepsis.2,6 The etiology of acute esophageal necrosis is multifactorial. Hemodynamic instability or lowflow states, impaired mucosal barrier and massive influx of acid gastric contents into the esophagus seem to be the main contributing factors.5 In some cases infection is superposed or may represent an additional contributing factor.3 Simultaneous presence of these insults seems to be necessary to trigger the development of acute necrotizing esophagitis. The important role of ischemia in the pathogenesis of black esophagus is demonstrated by the high frequency of concomitant malperfusion states, the association with duodenal ulcers and almost universal involvement of the distal esophagus (97% of cases,5 which is the less vascularized third. It is supplied by branches of the left gastric and

44

inferior phrenic arteries.7 The proximal two thirds of the esophagus are well vascularized, receiving its blood supply from branches off the inferior thyroid, bronchial arteries and vessels deriving from the thoracic aorta. Significant vasculopathy as seen in diabetes mellitus, atherosclerosis, cardiovascular and renal diseases are frequent risk factors that may predispose to ischemic injury. Impaired tissue perfusion states, as observed during cardiac arrhythmias, congestive heart failure, systemic inflammatory response syndrome, such as in severe acute pancreatitis, lactic- and ketoacidosis, acute blood loss, trauma, hypothermia and shock are some of the conditions related to the ischemic compromise of the esophagus. Thromboembolic phenomena and hypercoagulability states, such as in solid or hematological malignancies, antiphospholipid antibody syndrome and atherosclerosis have also


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Autopsy and Case Reports 2013; 3(3): 41-48

Figure 4 – Endoscopic view of the esophagus (A to D) showing partial recovery of the necrotic esophagitis, covered by patches of fibrinous material.

been implicated in the genesis of AEN.2,8-12 Cases of isolated esophageal ischemia are rare due to its rich arterial supply. Hence, ischemia seems to be the trigger event of AEN in the presence of impaired mucosal repair and augmented acid reflux. The latter is better explained by diminished mucosal buffering, disrupted local protective barriers and impaired defense mechanisms due to a variety of causes such as sepsis, malnutrition, acidosis, renal insufficiency, cancer, chronic pulmonary disease, acute or chronic decompensated diabetes mellitus, immunosuppressive states such as acquired immunodeficiency syndrome (AIDS) and other critical illnesses. Chemical damage due to acid reflux may be caused by gastric outlet obstruction as a consequence of edema and inflammation associated with duodenal ulcers or by transient gastroparesis due to alcohol intoxication, ketoacidosis, hyperglycemia and systemic inflammatory states. Postoperative recumbency, gastric volvulus, hiatal hernia, decreased intraesophageal luminal pressure and decreased lower esophageal sphincter resting

pressure (as observed in cases of chronic alcohol abuse6) represent other causes of increased acid reflux leading to injury of the vulnerable mucosa. Both, impaired mucosal defense mechanisms and augmented acid content in the esophagus may lay the ground to ischemic injury and precipitate necrosis of the distal esophagus. Massive acid reflux impairs local blood flow autoregulation and thus limits the mucosal buffering and luminal clearance capacity, hence predisposing to ischemic and/or acid injury. Since the first description by Goldenberg  et  al., in 1990, oxyradical formation from ischemia and reperfusion injury is known to play an important role in the pathogenesis of black esophagus.13 Opportunistic infections in immunocom­ promised patients are not a rare finding. Herpes simplex virus I, Lactobacillus acidophilus, Candida albicans, Penicillium chrysogenum and cytomegalovirus were some of the isolated agents.

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Autopsy and Case Reports 2013; 3(3): 41-48

On histology the esophageal necrosis may be restricted to the mucosa but may extend into the submucosa and muscularis mucosae. Fullthickness necrosis of the esophageal wall has been described in surgical and autopsy specimens. Abundant necrotic debris and spot-like or confluent hemorrhagic areas replace the viable epithelium. Acute inflammatory infiltrate, predominantly of neutrophilic granulocytes, has been described, but may be absent. Vascular thrombi and deranged muscle fibers are occasionally associated findings.5,14 The most common clinical presentation is upper gastrointestinal bleeding represented by at least one of the following: hematemesis, melena or coffee ground emesis, accounting for up to 90% of the presentations in the largest reviews of literature on AEN.1,5 At the other end of the spectrum, asymptomatic presentation has been described.5,15 Less frequent symptoms include epigastric pain and dysphagia, nausea, lightheadedness and other nonspecific symptoms. On esophagogastroduodenoscopy, AEN classically presents as a black-appearing circum­ ferential necrosis of the mucosa in the distal third of the esophagus, usually extending up to the distal two thirds and eventually the entire esophagus. Characteristically, the esophageal necrosis is sharply limited by the Z-line and gastric mucosa is usually spared. Yellow exudates and a friable mucosa may be present. Duodenal ulcers are a frequently associated finding. Black esophagus can be staged as follows: Stage 0 refers to a viable, pre-necrotic and normal appearing mucosa; Stage 1 represents the typical circumferential black friable necrotic mucosa sharply ending at the Z-line. In Stage 2, black spots and thick white, removable exudates cover the pink friable mucosa in a “chess-board” pattern. In Stage 3, the esophageal mucosa regains its normal appearance while on histologic analysis granulation tissue may still be present. Strictures and stenosis may occur as sequelae in stages 2 and 3. Stage 3 may occur as early as 1 or 2 weeks from initial presentation.1,5 Cultures for virus and bacteria, as well as fungi should be ordered on endoscopically biopsied material, particularly in immunocompromised individuals, to exclude an infectious etiology or superimposed infection.5

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Forster R, Durso DA, Vattimo EFQ et al.

Differential diagnosis includes pseudo­ melanosis, melanocytosis, coal dust deposition, malignant melanoma and acanthosis nigricans. Distinction of those entities from AEN is easily made by the absence of true necrosis and ulceration in the latter. For diagnosis of acute esophageal necrosis, ingestion of caustic agents should be excluded by history and absence of oropharyngeal findings.16 Up to 10% of patients have been reported to experience esophageal strictures or true esophageal stenosis, which configure  the most common complication.5 Perforation and mediastinitis are other common complications. In the largest literature review, mortality rates ranged from 3a, 8% to 38%.1 Nevertheless, only approximately 6% of cases were directly related to the black esophagus syndrome, but rather to the usually severe comorbid conditions.1,3-5 Autopsy disclosed black esophagus as the immediate cause of sudden death in a patient with mental retardation and a history of alcohol abuse.14 In other sudden death autopsy cases, AEN has been related to fatal upper GI hemorrhage, but in these cases it was not clear whether comorbidities were present.17,18 The mainstay of treatment of black esophagus is correction of the the underlying cause, hydration, re-establishment of the patient’s volemic status and correcting anemia. Parenteral nutrition may be needed in malnourished patients, while passage of a nasogastric tube should be avoided due to the risk of perforation. Treatment further includes keeping the patient nil-per-os, full-dose proton pump inhibitor or H2 antagonist therapy associated with sucralfate.2,4,5 The use of antibiotics in AEN is controversial. While antibiotics have been associated with necrotizing esophagitis in a few reports,19 empiric antimicrobial treatment should be promptly started in rapid clinical deterioration, suspected esophageal perforation, mediastinitis and unexplained fever. Immunosuppressed patients, such as AIDS patients, cirrhotics, transplant recipients or patients in dialysis should be highly considered to receive antibiotics.2 Surgical treatment is mandatory in cases of esophageal perforation, mediastinitis and abscess formation. After the healing phase, surgical treatment may be necessary in stenosis refractory to endoscopic dilation attempts.


Black esophagus: exploring the dark

Case 1 refers to a 47 year-old patient which had bilateral nephrectomy because of infected polycystic renal disease. This patient received broad-spectrum antibiotics and hemodialytic treatment. During the postoperative period, he started complaining of epigastralgia, pyrosis and refused oral feeding. Probably due to the severity of the underlying disease, acute esophageal necrosis was not diagnosed since the beginning, once EGD showed a typical stage 2 injury. The middle and distal esophagus were affected by necrotic mucosa and alternating white exudates (Figure 1). This endoscopic pattern is called “chess-board” due to its appearance. In the same figure  the sharp limit between the necrosed esophageal mucosa and the normal gastric mucosa denotes the richer arterial supply and acid-resistance of the gastric mucosa. Renal failure, the most frequent comorbidity present in patients with black esophagus was present in this patient. It has been postulated that acidosis impairs local blood flow regulation. Severe infection and hypotension may also have been involved in homeostasis derangement. Prolonged decubitus and postoperative gastroparesis may have contributed to acid reflux into the esophagus. Hemodynamic instability and the inflammatory state may have been the precipitating factors for injury to a dysfunctional mucosa. The presence of duodenal ulcers on initial EGD, another frequent simultaneous finding in AEN, reenforces the hypothesis of hemodynamic instability, systemic inflammation and fasting as precipitating events. Whether the ischemic stroke and pulmonary thromboembolism and related alteration of blood coagulation contributed to the pathogenesis of black esophagus is speculative. After treatment of the associated conditions a new EGD revealed fibrinous patches, effacement of the black areas and friable pink mucosa. This reminds us of the amazingly fast and efficient regeneration capacity of the esophageal mucosa after the offending factors have been reversed. Case 2 refers to a 45 year-old male patient with type 2 diabetes, who presented to the emergency room with repeated vomiting, severe dehydration and hyperglycemia. The diagnosis of diabetic ketoacidosis was made. Acute diabetic gastroparesis and dysfunction of the lower esophageal sphincter due to glucose toxicity contributed to stasis and acid reflux. Associated relative ischemia due to dehydration and immune dysfunction demonstrated by the patient’s elevated glycated hemoglobin (Hb1Ac)

Autopsy and Case Reports 2013; 3(3): 41-48

levels, seemed to have contributed to necrotic injury of the esophagus in this acutely ill patient. Diabetes mellitus and diabetic ketoacidosis are two frequently cited comorbid conditions in patients presenting with AEN. The proposed impairing effect of acidosis on arterial blood flow regulation in the esophageal wall may have been an additional factor predisposing to necrotizing esophagitis. Repeated vomiting could have been a possible precipitating factor in this case. Due to the multitude of symptoms present in diabetic ketoacidosis, which overlap with those of black esophagus, attention was drawn to the esophageal disorder only after stabilization and reversal of ketoacidosis. This may be one of the causes of underdiagnosis of AEN. In this case difficult distinction between necrotic debris and candidiasis led to addition of oral fluconazole to the standard therapeutic regimen. Histologic analysis of the biopsy specimens showed typical findings in early black esophagus. Microvascular thrombosis, observed in this case and described in previous reports, may have been a consequence of endothelial dysfunction of diabetes mellitus. Neovascularization, reactive stromal and endothelial cells with enlarged nuclei also found in this case are early regenerative changes (Figure 2). The therapeutic regimen adopted in this case led to symptomatic control and near-normalization of the endoscopic findings in 48 hours. In view of the distinct possible appearances during the healing process, maybe subdivision of the proposed staging system2,5 in an early 2a and a late 2b stage without necrosis, as follow-up EGD revealed in this case, could be useful. The outcome in this case corresponds to the majority of the cases when the offending conditions are reverted and appropriate treatment is adopted. In conclusion, AEN is a rare and underdiagnosed disease. Critical illness and multiple comorbidities are usually associated. It may be interpreted as a sign of poor prognosis, as mortality rate is up to 38%. Cause of death is usually attributed to the comorbid illness, but deaths due to black esophagus have been reported. Treatment is directed at reversal of the underlying cause, acid suppression and keeping the patient nil-peros. Further research is needed to clarify the exact involved pathophysiological mechanisms.

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REFERENCES 1.

Day A, Sayegh M. Acute oesophageal necrosis: A case report and review of the literature. Int J Sur. 2010;8:6-14. http://dx.doi.org/10.11604/pamj.2013.14.109.2000

2.

Gurvits GE. Black esophagus: acute esophageal necrosis syndrome. World J Gastroenterol. 2010;16:3219.

3.

Augusto F, Fernandes V, Cremers MI, et al. Acute necrotizing esophagitis: a large retrospective case series. Endoscopy. 2004;36:411. http://dx.doi.org/10.1055/s-2004-814318

4.

Grudell ABM, Mueller PS, Viggiano TR. Black esophagus: report of six cases and review of the literature, 1963-2003. Dis Esophagus. 2006;19:105-10.

5.

Gurvits GE, Shapsis A, Lau N, et al. Acute esophageal necrosis: a rare syndrome. J Gastroenterol. 2007;42:29. http://dx.doi.org/10.1007/s00535-006-1974-z

6.

Hong JW, Kim SU, Park HN, Seo JH, Lee YC, Kim H. Black esophagus associated with alcohol abuse. Gut Liver. 2008;2:133-5. http://dx.doi.org/10.5009/gnl.2008.2.2.133

7.

Patti MG, Gantert W, Way LW. Surgery of the esophagus. Anatomy and physiology. Surg Clin North Am. 1997;77:959-70.

8.

Cappell MS. Esophageal necrosis and perforation associated with the anticardiolipin antibody syndrome. Am J Gastroenterol. 1994;89:1241-5.

9.

Odelowo OO, Hassan M, Nidiry JJ, Marshalleck JJ. Acute necrotizing esophagitis: a case report. J Natl Med Assoc. 2002; 94:735-7.

Forster R, Durso DA, Vattimo EFQ et al. 10. Hawari R, Pasricha PJ. Esophageal infarction. Curr Treat Options Gastroenterol. 2007;10:57-60. 11. Yasuda H, Yamada M, Endo Y, Inoue K, Yoshiba M. Acute necrotizing esophagitis: role of nonsteroidal antiinflammatory drugs. J Gastroenterol. 2006;41:193-7. http:// dx.doi.org/10.1007/s00535-005-1741-6 12. Burtally A, Gregoire P. Acute esophageal necrosis and lowflow state. Can J Gastroenterol. 2007;21:245-7. 13. Goldenberg SP, Wain SL, Marignani P. Acute necrotizing esophagitis. Gastroenterology. 1990;98:493-6. 14. Tsokos M, Herbst H. Black oesophagus: a rare disorder with potentially fatal outcome. A forensic pathological approach based on five autopsy cases. Int J Legal Med. 2005;119:14652. http://dx.doi.org/10.1007/s00414-004-0509-5 15. Rejchrt S, Douda T, Kopácová M, et al. Acute esophageal necrosis (black esophagus): endoscopic and histopathologic appearance. Endoscopy. 2004;36:1133. http://dx.doi. org/10.1055/s-2004-825971 16. Gumaste VV, Dave PB. Ingestion of corrosive substances by adults. Am J Gastroenterol. 1992;87:1-5. 17. Tsokos M. Black esophagus. Forensic Sci Med Pathol. 2011;7:374-6. 18. Jacobsen NO, Christiansen J, Kruse A. Incidence of oesophageal necrosis in an autopsy material. APMIS. 2003;111:591-4. http://dx.doi.org/10.1034/j.16000463.2003.1110509.x 19. Mangan TF, Colley AT, Wytock DH. Antibiotic associated acute necrotizing esophagitis. Gastroenterology. 1990;99:900.

Conflict of interest: None Submitted on: 03rd August 2013 Accepted on: 10th September 2013 Correspondence: Departamento de Clínica Médica Hospital das Clínicas da Faculdade de Medicina da USP Av. Dr. Enéas Carvalho de Aguiar, 255 – São Paulo/SP – Brazil CEP: 05403-000 – Phone: +55 (11) 2661-6300 E-mail: robertforster.ufrj@gmail.com

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Autopsy and Case Reports 2013; 3(3): 49-58

Article/Clinical Case Report Artigo/Relato de Caso Clínico Co-infection of disseminated histoplasmosis and tuberculosis in an AIDS patient Bruno Tomazinia, Raquel Bandeirab, Thiago Aragãoa, Julio Cesar Andreotti Borgesa, Rafael Sasdellia, Valéria Pereira Salgadoc, Fernando Peixoto Ferraz de Camposd, Patricia Picciarelli de Limae Tomazini B, Bandeira R, Aragão T,  et  al. Co-infection of disseminated histoplasmosis and tuberculosis in an AIDS patient. Autopsy Case Rep [Internet]. 2013; 3(3): 49-58 http://dx.doi.org/10.4322/acr.2013.029

ABSTRACT Histoplasmosis is a fungal disease caused by the dimorphic fungus Histoplasma capsulatum, recognized as an AIDS-defining illness since the Center for Disease Control’s revision criteria in 1985. This infection is reported to be present in 5-20% of AIDS patients, and in 95% of the cases it is manifested in its disseminated form. Serum antibodies and/or antigen research can make diagnosis, but the demonstration of the agent by culture or histopathological examination remains the gold standard methods. Co-infections in patients with AIDS are well known; however, reports on disseminated tuberculosis and histoplasmosis are scarce. The authors report the case of a female patient who presented a short-course history of weight loss, fever, and mild respiratory symptoms, with hepatosplenomegaly and lymphadenopathy. Laboratory workup called attention to anemia, altered liver, canalicular enzymes, liver function tests, high titer of lactate dehydrogenase (LDH), and pulmonary nodules on thoracic computed tomography. Incidental finding of yeast forms within the leukocytes during a routine blood cell count highlighted the diagnosis of histoplasmosis. The patient started receiving amphotericin B but succumbed soon after. The authors emphasize the possibility of this co-infection, the diagnosis of severe infection through the finding of yeast forms within peripheral leukocytes, and for the high titer of LDH in aiding the differential diagnosis. Keywords: Histoplasmosis; Tuberculosis; Acquired Immunodeficiency Syndrome; Autopsy. CASE REPORT A 38-year-old Caucasian woman sought medical attention complaining of intermittent fever over the past month. She referred weight loss of 10 kg during this period, a cough, and daily

fever during the last week. She was prescribed clarithromycin for 7 days without relief of the respiratory symptoms or fever defervescence. In the course of her history, right flank and epigastric

Department of Internal Medicine, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo/SP – Brazil. Infectious Diseases Institute, Hospital Emílio Ribas, São Paulo/SP – Brazil. c Clinical Laboratory Service, Hospital Universitário, Universidade de São Paulo, São Paulo/SP – Brazil. d Department of Internal Medicine, Hospital Universitário, Universidade de São Paulo, São Paulo/SP – Brazil. e Anatomic Pathology Service, Hospital Universitário, Universidade de São Paulo, São Paulo/SP – Brazil. a b

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 médium provided article is properly cited.

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Tomazini B, Bandeira R, Aragão T. et al..

pain was added to the clinical complaints. Her past medical history comprised the diagnosis of asthma. The physical examination on admission showed an ill-looking patient, pale, dehydrated, icteric, and febrile (axillary temperature was 38.9°C). Her pulse was regular at 160 beats per minute; blood pressure was 100/60 mmHg; respiratory frequency 22 respiratory movements per minute; room air oximetry was 96%; and body mass index was 26.4. Vesicular and crusted lesions were present in the left buccal rhyme, and a serpiginous, paleedged ulcerated lesion was identified in the center of the tongue besides moniliasis of the oral cavity. Lymphadenopathy was palpable in the left cervical chain. Examination of the lungs and heart were unremarkable. The abdomen was slightly distended and diffusely tender; the liver was palpable 4 cm below the costal margin; and a dull tone was obtained on the percussion of the Traube’s space. Bowel sounds were present and normal and no signs of peritoneal irritation were found. Mild lower limbs edema was present bilaterally. The initial laboratory workup is shown in Table 1.

contrast injection, measuring 2.5 × 2.0 mm in the anterior margin of the left lobe, and another of 8 mm in the right margin of the right lobe. The spleen was enlarged with multiple hypodense nodular lesions. Adenomegaly with signs of central necrosis/ liquefaction were found along the retroperitoneal, para-aortic, pericaval and iliac chains, as well as in the para-rectal fossa, presacral, and perisplenic regions. A well-delineated mass, measuring 47 mm × 28 mm, was found in the left ischiorectal fossa. The pulmonary CT showed small nodular noncalcified images scattered in both lungs.

Anti-HIV serology showed positivity for Elisa and Western Blot. Serology for hepatitis B and C resulted as follows: anti-HCV negative, anti-HBsAg negative, anti-HBs positive, anti-HBc positive (IgM negative), anti-HBe positive.

The patient was prescribed 600 mL of packed red blood cells, ceftriaxone, clarithromycin, and sulfamethoxazole/trimethoprim, acyclovir, ivermectin, as well as methylprednisolone. She progressed rapidly to respiratory insufficiency requiring orotracheal intubation and mechanical ventilation. On the second day of the hospital stay norepinephrine was initiated for hemodynamic stabilization. On the third day the laboratory detected yeast forms inside the neutrophils when counting the blood cells during routine examination, bringing the attention for the diagnosis of disseminated histoplasmosis (Figure 1). Amphotericin was started but the patient died later the same day.

Abdominal computed tomography (CT) showed an enlarged liver with poorly-defined nodular images, hypodense even after iodine

Samples of blood culture were positive for Histoplasma capsulatum and Mycobacterium tuberculosis.

Table 1 – Initial laboratory workup Exam

Result

RV

Exam

Result

RV

Hemoglobin

6.8

12.3-15.3 g/dL

Creatinine

0.83

0.4-1.3 mg/dL

Hematocrit

20.9

36.0-45.0%

Potassium

3.8

3.5-5.0 mEq/L

Leukocytes

9.3

4.4-11.3 × 103/mm3

Sodium

130

136-146 mEq/L

Bands

16

1-5%

ALT

584

9-36 U/L

Segmented

73

45-70%

AST

104

10-31 U/L

Eosinophils

1

1-4%

Alkaline P

813

10-100 U/L

Basophils

0

0-2.5%

γGT

487

2-30 U/L

Lymphocytes

5

18-40%

Total bilirubin

3.32

0.3-1.2 mg/dL

Monocytes

2

2-9%

Total protein

5.3

6-8 g/dL

Platelets

156

150-400 × 10 /mm

Albumin

1.7

3-5 g/dL

INR

2.06

1.0

LDH

5598

120-246 U/L

Urea

51

5-25 mg/dL

CRP

392

<5 mg/L

3

3

ALT = alanine aminotransferase; Alkaline P = alkaline phosphatase; AST = aspartate aminotransferase; CRP = C-reactive protein; γGT= gammaglutamyltransferase; INR = international normalized ratio; LDH = lactic dehydrogenase; RV = reference value.

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Autopsy and Case Reports 2013; 3(3): 49-58

Figure 1 – Photomicrography of the peripheral blood smear showing leukocytes phagocytizing yeast forms of Histoplasma capsulatum (Leishman 100x).

AUTOSPY FINDINGS The ectoscopy was unremarkable except for the presence of a hematic-crusted lesion measuring 3 cm on the left buccal rhyme, which was not represented for microscopy in order to respect and preserve the exposed area. At the thoracic cavity overture, bilateral serosanguineous pleural effusion was evidenced. The lungs were partially aerated and the bases were congested. The right lung weighed 670 g (mean reference value [MRV]: 450 g) and the left weighed 540 g (MRV: 375 g). On the section surface, multiple whitish nodules measuring up to 0.2 cm were bilateral and diffusely scattered throughout both lungs (Figure 2A). The surrounding parenchyma was friable and wine-colored. On microscopic examination, the pulmonary parenchyma showed diffuse ill-defined granulomas; a few of them had rare giant-cells and caseous necrosis. The Ziehl-Neelsen and Gocott staining evidenced the abundant presence of both acidfast bacilli (AFB) and round-form organisms compatible with Histoplasma capsulatum, inside the macrophages (Figure 3). Some areas also showed alveolar spaces filled in by suppurative infiltrate surrounded by areas of organizing pneumonia as well as pulmonary edema. Gross examination of the pericardium, heart, and valve apparatus was normal.

At the opening of the abdominal cavity, 400 mL of a yellow citrine ascites were present. The spleen was enlarged, weighing 631 g (RV: 112 g), showing a softened consistency. Multiple yellowish nodules measuring up to 1.0 cm were diffusely distributed throughout the parenchyma (Figure 2B). On microscopy, white pulp depletion was evident. Multiple micro infarctions and abscesses were present, as well as ill-defined granulomas, which were crammed by yeast forms and some AFB (Figure 4). The liver was congested and weighed 2670 g (RV range: 1320-1740 g). On microscopy, centrilobular hepatic necrosis and marked macrovesicular steatosis were observed. Additionally, multiple necrotic hepatocyte foci were present in conjunction with countless ill-defined granulomas distributed in the portal spaces and within the hepatic lobules. Ziehl-Neelsen and Grocott staining showed round organisms compatible with Histoplasma capsulatum as well as AFB inside the macrophages (Figure 5). Gastric mucosa showed signs of stress bleeding, and in the duodenum wine-colored nodules of 0.2 cm were present, represented by small foci of submucosal hemorrhage on microscopy. In some of these areas, yeast forms were depicted, by Grocott stain, without eliciting an intense inflammatory response. The kidneys were normal in size (both weighed 478 g, RV range: 240-

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Figure 2 – Gross examination of: A - Lung parenchyma with nodules (arrows); B - Splenic cross-sections showing yellowish nodules; C - Both kidneys showing small yellowish nodules protruding trough the capsule; D - Gross view of the cross section of the aortoiliac lymph node conglomerate, showing abundant purulent secretion.

Figure 3 – Photomicrography of the lung. A - Note an ill-defined granuloma with central caseous necrosis, and a giant cell (HE 20x); B - Round-form organisms compatible with Histoplasma capsulatum, (Grocott 40x); C – Shows the presence of acid-fast bacilli (AFB) (arrows) (Ziehl-Neelsen 100x). 350 g) and presented, bilaterally, yellowish nodules measuring up to 0.5 cm. Some of them were seen at the cortical surface, draining pus-like material when digitally compressed (Figure 3C). On microscopy, these nodules represented abscesses with round-

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form organisms compatible with Histoplasma capsulatum as well as AFB inside the macrophages, stained by Grocott and Ziehl-Neelsen, respectively. Marked acute tubular necrosis was also present (Figure 6).


Co-infection of disseminated histoplasmosis...

Autopsy and Case Reports 2013; 3(3): 49-58

Figure 4 – Photomicrography of the spleen. A - Splenic abscess margin, (HE 10x); B - Round-form organisms compatible with Histoplasma capsulatum, (Grocott 40x); C – The presence of AFB (arrow), (Ziehl-Neelsen 100x).

Figure 5 – Photomicrography of the liver. A - Note an ill-defined granuloma and macrovesicular steatosis (HE 20x); B - Round-form organisms compatible with Histoplasma capsulatum, (Grocott 40X); C - The presence of AFB (Ziehl-Neelsen 100x).

Figure 6 – Photomicrography of the kidney. A - Intra renal abscess (HE 20x); B - Round-form organisms compatible with Histoplasma capsulatum, (Grocott 100x); C - The presence of AFB (Ziehl-Neelsen 100x). Extensive lymphadenopathy was observed along the para-aortic, peri-iliac, submandibular and cervical chains. The lymph nodes measured up to 2 cm and at the section surface did not show necrosis, but on microscopy necrosis and granulomas sketches were present. A lymph node conglomerate, measuring 10 × 10 × 7 cm was present in the right aortoiliac region, adhering to the iliopsoas muscle,

which at the cut section exhibited a huge amount of purulent secretion drainage (Figure 3D). On microscopy, the affected lymph nodes showed the replacement of normal nodal architecture by a suppurative process and ill-defined granulomas that were overcrowded by AFB and round-form organisms compatible with Histoplasma

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capsulatum depicted by the Ziehl-Neelsen and Grocott staining, respectively (Figure 7). The bone marrow was hypercellular at the expense of the granulocytic lineage, showing scattered necrotic foci with sketches of granuloma. Ziehl-Neelsen and Grocott staining evidenced AFB and round-form organisms compatible with Histoplasma capsulatum, respectively (Figure 8). The microscopic examination of the adrenal gland showed necrotic foci inside which round-form organisms compatible with Histoplasma capsulatum were found (Figure 9). The microscopic examination of the tongue evidenced intense inflammatory cell infiltration and rupture of the continuity solution, and the presence of abundant round-form organisms compatible with Histoplasma capsulatum in the corium (Figure 10). The remaining abnormalities.

organs

did

not

show

DISCUSSION Histoplasmosis is a fungal disease, first described by Samuel Darling in 1905 in Panama,1 who identified this pathogen in a patient presumed to have died of tuberculosis. Although distributed in the temperate climate areas worldwide, it is endemically found in river valleys from North and Central America, parts of Europe, Africa, East Asia, Australia, and Brazil.2,3 The infection usually begins in the lungs4 by inhaling airborne, microscopic fungal spores of the dimorphic fungus Histoplasma capsulatum, which remains in a mycelial form at ambient temperatures and grows as yeast at body temperature in mammals. Once in the alveoli, inhaled micronidia are englobed by alveolar macrophages where they replicate and spread to regional lymph nodes, and thereafter throughout the reticuloendotelial system. Oral Histoplasma capsulatum infection has been reported in association with HIV infection. Hence oropharyngeal mucosa should also be considered

Figure 7 – Photomicrography of the lymph node. A - Ill-defined granuloma with central necrosis, (HE 20x); B - Round-form organisms compatible with Histoplasma capsulatum, (Grocott 40x); C - The presence of AFB (Ziehl-Neelsen 100x).

Figure 8 –  Photomicrography of the bone marrow. A - Hypercellularity of the bone marrow and an illdefined granuloma with central necrosis. (HE 40x); B - Round-form organisms compatible with Histoplasma capsulatum (Grocott 40x); C - The presence of AFB (Ziehl-Neelsen 100x).

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Figure 9 – Photomicrography of the adrenal gland. A - Edema and acute inflammatory cell infiltration of the zona reticularis. (HE 20X); B - Round-form organisms (arrow) compatible with Histoplasma capsulatum, within the zona fasciculata (Grocott 100x).

Figure 10 –  Photomicrography of the tongue. A  -  Inflammatory cell infiltration of the corium and a small continuity solution of the papilla, (HE 20x); B - Note round-form organisms compatible with Histoplasma capsulatum, (Grocott 100x). another “port of entry” of this fungal infection. Infected macrophages and sensitized T cells enlist monocytes through cytokines induction, to fight the organism, forming a granuloma. When this T-cell mediated immune response fails, a progressive spread of infection to other organs ensues.2,5 Although mucocutaneous lesions usually indicate disseminated disease, occasionally patients may present seemingly isolated mucocutaneous lesions with no apparent active disease elsewhere.6,7 The patient of this report presented a lesion in the median sulcus of the tongue, which on microscopy, showed to be fully infiltrated by inflammatory cells

and yeast forms. In this case, it is difficult to state the initial inoculum. The clinical manifestations vary with the intensity of conidia exposure and host immunity. In healthy or immunocompetent individuals, the infection courses asymptomatic, or mildly symptomatic and self-limited, but can be potentially lethal in immunosuppressed patients, when even small inoculum can cause severe pulmonary infection or disseminated histoplasmosis (DH).2 The latter has been described amongst patients with diabetes mellitus; hematologic malignancies;

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transplant recipients, carriers of the HIV virus infection, and those under tuberculosis treatment or under corticotherapy.5,8,9 Histoplasmosis is present in 5-20% of AIDS patients, and occurs in its disseminated form in about 95% of cases when the CD4 determination is below 150 cells/mm3,9-12 The development of histoplasmosis during the deep state of immunosuppression of AIDS, in an endemic area, may be due to primary infection, reinfection, or reactivation.12 Clinically disseminated histoplasmosis manifests as fever, malaise, diarrhea, anorexia, and weight loss. Physical examination usually displays hepatosplenomegaly and lymph adenopathy. Mucosa and skin lesions also may be present in some patients.13-15 Diarrhea, in these cases, may be due to Salmonella, Shigella or Giardia co-infection.9,16 Progressive disseminated histoplasmosis is a relentlessly life-threatening infection characterized by multiorgan involvement, the outcome of which will result in coagulopathy, shock, respiratory failure, hepatic failure, and renal insufficiency.13 Laboratory findings are non-specific and show anemia, thrombocytopenia, and increased levels of alkaline phosphatase, ferritin, C-reactive protein, and erythrocyte sedimentation rate. Leukopenia may be found in 50% of patients. Elevated lactic dehydrogenase (LDH) levels are highly prevalent in patients with AIDS and disseminated histoplasmosis, reaching 84.2% in some Brazilian series.15,17 LDH determination greater than 600 U/L shows a high specificity for the diagnosis of histoplasmosis in patients with AIDS when compared with Pneumocystis jiroveci pneumonia18 and other opportunistic infections presenting fever and pulmonary infiltrates.19 Moreover, this biochemical marker is an isolated factor of poor prognosis in the course of the disease.20 Some reports have been showing the diagnosis of histoplasmosis through the analysis of peripheral blood smears. This finding is usually related to severe cases. Round-form organisms of 3-4 µm, with basophilic cytoplasm and a false impression of a peripheral capsule, are depicted inside the leukocytes.21-23. This diagnostic method has a limited use because of its low sensitivity, which has been shown to be 12%.22 Diagnosis can be established by antibody assays through immunodiffusion or complement fixation tests, which show specificity around 80%. It seems that the usefulness of these tests is

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controversial in AIDS patients since Mandel et al.8 reported three cases that had negative results. The research for polysaccharide antigen by an enzyme immunoassay in urine, serum, and other body fluids may be used for the rapid diagnosis of disseminate histoplasmosis. The cytology and culture of bronchial aspirates and cultures of blood, bone marrow, or biopsied tissues, together with the histopathological examination, represent the definitive diagnosis. Blood culture positivity has been reported in 54% of cases, bone marrow culture in 56%, while bone marrow biopsy yielded the diagnosis in 69% of the patients.9 The predictive value of these diagnostic methods will vary with host factors, such as the inflammatory response and the severity of infection.2,24 Since 1985, DH has been considered an AIDS-defining illness,25 and it is not uncommon to find it concurrently with other opportunistic infection, indicating the need for a careful search for co-infections. In a series of 104 cases of DH, Gutierrez et al.14 found 27 patients co-infected (25.9%) and among them, tuberculosis was present. Johnson et al.9 reported a series of 48 cases of DH in AIDS patients, where coinfection was found in 8 cases (16%). Two patients had Pneumocystis jirovecii pneumonia, two had Mycobacterium avium complex, and one from each had cryptococcal pneumonia, tuberculosis, pulmonary nocardiosis, or paracoccidioidomycosis. The association of disseminated histoplasmosis and disseminated tuberculosis is scarcely described in the literature.4,26-28 Furthermore, a few cases of histoplasmosis were reported to be misdiagnosed as tuberculosis in Europe and Malaysia.29,30 Clinical features do not allow the identification of this coinfection in AIDS patients; nevertheless, they have important treatment and prognosis implications. Both infections are implicated in pulmonary, lymph node, and miliary involvement, and share many similar signs and symptoms. The clinical, laboratory, and radiological abnormalities often overlap, making the specific diagnosis a tough task. In a retrospective study of 14 patients with these three co-infections, the clinical manifestations most often found were: weight loss (85.7%), asthenia (78.5%), and fever (64.2%). The diagnosis of histoplasmosis was made primarily by histopathology and tuberculosis by direct microscopic examination.31 Facing the suspicion of co-infection, tuberculosis should be initially considered, given its


Co-infection of disseminated histoplasmosis...

higher prevalence and the importance of preventing it spreading. The diagnosis of histoplasmosis usually arises later, when the specific treatment for tuberculosis did not succeed.31 The patient of this report presented a shortcourse disease with non-specific symptoms. She denied a previous diagnosis of HIV infection, but the weight loss, the presence of oral moniliasis, and tomographic signs indicating tuberculosis early raised the suspicion of HIV infection, which was later confirmed by serologic tests. The presence of anemia and lymphopenia was attributed to the diagnosis of AIDS, and the alterations of the liver and canalicular enzymes, as well as hypoalbuminemia, were considered as taking part of the miliary tuberculosis. The high titers of LDH remained unexplained until the incidental discovery of yeast structures within the leukocytes. This information took the medical staff by surprise, since the respiratory insufficiency was being attributed to a probable Pneumocystis jirovecii co-infection, due to its higher frequency. High titers of LDH and the presence of yeast forms inside the leukocytes, in these cases, are strongly related to poor prognosis.

CONCLUSION We have learned through this case, that whenever facing a severe case of a patient with the diagnosis of AIDS, we should always be on lookout for co-infections. Moreover, a high determination of serum LDH should always raise suspicion for the diagnosis of DH. If the clinical signs support the diagnosis of this fungal infection, then depending on the severity of the illness empiric treatment should be started to give the patient an optimum chance for survival.

ACKNOWLEDGEMENTS The authors are thankful for Erica Chimara PhD and Dulce Helena de Matos PhD from the Instituto Adolfo Lutz of São Paulo / SP  –  Brazil, for the identification of the pathogens and Thiago Rodrigo Noronha pharmaceutic of the Clinical Laboratory of Hospital Universitário – Universidade de São Paulo – São Paulo/SP – Brazil, who kindly provided the pictures from peripheral blood.

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REFERENCES 1.

Darling ST. A protozoan general infection producing pseudotubercles in the lungs and focal necroses in the liver, spleen, and lymph nodes. JAMA. 1906;46:1283-5. http://dx.doi.org/10.1001/jama.1906.62510440037003

2.

Kauffman CA. Histoplasmosis. Clin Chest Med. 2009;30:217-25. PMid:19375629. http://dx.doi.org/10.1016/j. ccm.2009.02.002

3.

Ajello L. Distribution of histoplasma capsulatum in the United States. In: Ajello L, Chick W, Furculow MF, editors. Histoplasmosis. Springfield: Charles C. Thomas; 1971. p. 103-22. PMid:4325151.

4.

Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis In the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine. 1990;69:36174. http://dx.doi.org/10.1097/00005792-199011000-00004

5.

Subramanian S, Abraham OC, Rupali P, et al. Disseminated histoplasmosis. JAPI. 2005;53:185-9. PMid:15926599.

6.

Boden RA, Conn D. Disseminated histoplasmosis with an oral lesion. Report of a case. Oral Surg Oral Med Oral Pathol. 1967;23:549-56. http://dx.doi.org/10.1016/00304220(67)90551-8

7.

Greenspan HCG, MacPhal LA, SehiØdt M. Oral histoplasma capsulatum infection in association with HIV infection: a case report. J Oral Pathol Med. 1992;21:85-9. http://dx.doi. org/10.1111/j.1600-0714.1992.tb00985.x

8.

Mandel W, Goldbert DM, Neu HC. Histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med. 1986;81:974-8. http://dx.doi.org/10.1016/00029343(86)90390-6

9.

Johnson PC, Khardori N, Najjar AF, et al. Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am J Med. 1988;85:1552-8. http://dx.doi.org/10.1016/S0002-9343(88)80334-6

10. Suh KN, Anekthansnon T, Marius PR: Gastrointestinal histoplasmosis in patients with AIDS: case report and review. Clin Infect Dis. 2001,32:482-91. PMid:11170958. http:// dx.doi.org/10.1086/318485 11. McKinsey DS, Spiegel RA, Hutwanger L, et al. Prospective study of histoplasmosis in patients infected with human immunodeficency virus: incidence, risk factors, and pathophysiology. Clin Infect Dis. 1997;24:1195-203. http:// dx.doi.org/10.1086/513653 12. Wheat LJ, Kaufman CA. Histoplasmosis. Infect Dis Clin North Am. 2003;17:1-19. http://dx.doi.org/10.1016/S08915520(02)00039-9

57


Autopsy and Case Reports 2013; 3(3): 49-58 13. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115-32 PMid:17223625 PMCid:PMC1797635. http://dx.doi.org/10.1128/CMR.00027-06 14. Gutierrez ME, Canton A, Sosa N, et al. Disseminated histoplasmosis in patients with AIDS in Panama: a review of 104 cases. Clin Infect Dis. 2005;40:1199-202. PMid:15791523. http://dx.doi.org/10.1086/428842 15. Pontes LB, Leitão TMJS, Lima GG, et al. Características clínico-evolutivas de 134 pacientes com histoplasmose disseminada associada a SIDA no estado do Ceará. Rev Soc Bras Med Trop. 2010;43:27-31. Portuguese. PMid:20305964. http://dx.doi.org/10.1590/S0037-86822010000100007 16. Wheat LJ, Rubin RH, Harris NL, et al. Systemic salmonelosis in patients with disseminated histoplasmosis. Arch Intern Med. 1987;147:561-4. http://dx.doi.org/10.1001/ archinte.1987.00370030165032 17. Mora DJ. Disseminated histoplasmosis in acquired Immunodeficiency syndrome patients in Uberaba, MG, Brazil. Mycoses. 2008,51:136-40. PMid:18254750. http:// dx.doi.org/10.1111/j.1439-0507.2007.01459.x 18. Butt AA, Michaels S, Greer D, Clark R, Kissinger P, Martin DH. Serum LDH level as a clue to the diagnosis of histoplasmosis. AIDS Read. 2002;12:317-21. PMid:12161854. 19. Corcoran GR, Abdely H, Flanders CD, Geimer J, Patterson FT. Markedly elevated serum lactate dehydrogenase levels are a clue to the diagnosis of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis. 1997;24:942-4. http:// dx.doi.org/10.1093/clinids/24.5.942 20. Couppié P, Sobesky M, Aznar C, et al. Histoplasmosis and acquired immunodeficiency syndrome: a study of prognostic factors. Clin Infect Dis. 2004;38:134-8. PMid:14679459. http://dx.doi.org/10.1086/379770 21. Singh NK, Nagendra S. Histoplasma capsulatum in peripheral blood smear. BMJ Case Reports. 2009. Available from: http://casereports.bmj.com/content/2009/bcr.05.2009.1877. full?sid=ba402f77-198a-44c5-8d26-c1604bad68d1 doi:10.1136/bcr.05.2009.1877 http://dx.doi.org/10.1136/ bcr.05.2009.1877

Tomazini B, Bandeira R, Aragão T. et al.. 22. Casanova-Cardiel LJ, Ruiz-Ordaz I. Histoplasma capsulatum in the peripheral blood of patients with AIDS. Report of 4 cases with an increase of lactate dehydrogenase. Rev Invest Clin. 1993;45:67-70. PMid:8484068. 23. Kennedy GA, Curnow JL, Gooch J, et al. Histoplasma capsulatum in peripheral blood smears. Br J Haematol. 2002;116:503. http://dx.doi.org/10.1046/j.00071048.2001.03276.x 24. McKinsey DS, McKinsey JP. Pulmonary histoplasmosis. Semin Respir Crit Care Med. 2011;32:735-44. PMid:22167401. http://dx.doi.org/10.1055/s-0031-1295721 25. Center for Disease Control (US). Revision of the case definition of acquired immune deficiency syndrome for national reporting - United States. MMWR. 1985;34:373-5. PMid:2989677. 26. Jeong HW, Sohn JW, Kim MJ, et al. Disseminated histoplasmosis and tuberculosis in a patient with HIV infection. Yonsei Med J. 2007;48:531-4. http://dx.doi.org/10.3349/ ymj.2007.48.3.531 27. Pinotti AFF, Severo LC, Randon M, Rigatto M, Haase HB. Disseminated histoplasmosis associated with tuberculosis in immunosuppressed patients. Rev Ass Med Brasil. 1983;29:6870. 28. Rezende RE, Brunaldi MO, Girão MS. Esophageal histoplasmosis associated with disseminated tuberculosis in acquired immunodeficiency syndrome. J Trop Med Hyg. 2009,80:347-50. 29. Pometta R, Rovato C, Vivani MA, et al. Chronic pulmonary histoplasmosis in a patient with a recent history of tuberculosis and persistent round lung lesions. Eur J Clin Microbiol Infect Dis.1999;18:229-31. http://dx.doi.org/10.1007/s100960050267 30. Chan KS, Looi LM, Chan SP. Disseminated histoplasmosis mimicking military tuberculosis: a case report. Malays J Pathol. 1993;15:155-8. PMid:8065179. 31. Agudelo CA, Restrepo CA, Molina DA, et al. Tuberculosis and histoplasmosis co-infection in AIDS patients. Am J Trop Med Hyg. 2012;87:1094-8. PMid:23128292. http://dx.doi. org/10.4269/ajtmh.2012.12-0292

Conflict of interest: None Submitted on: 30th June 2013 Accepted on: 14th September 2013 Correspondence: Divisão de Clínica Médica Hospital Universitário da USP Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9275 E-mail: fpfcampos@gmail.com

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Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia Hirschsprung’s disease: the importance of early diagnosis Aline Franzolli Neumanna, Patricia Picciarelli de Limab, Ana Maria Andrello Gonçalves Pereira de Meloc Neumann AF, Lima PP, Melo AMAGP. Hirschsprung’s disease: the importance of early diagnosis. Autopsy Case Rep [Internet]. 2013; 3(3): 59-66. http://dx.doi.org/10.4322/acr.2013.030

ABSTRACT Congenital intestinal aganglionosis, also called Hirschsprung disease (HD), is defined as the absence of ganglionic cells in the myenteric (Auerbach) and submucosal (Meissner) plexus, due to a failure in the enteric nervous system development. The extent of intestinal involvement may vary according to the age of embryo development in which this failure occurs. It is not unusual for other malformations to be present, as well as chromosomal trisomies, manly trisomy 21. Enterocolitis is a frequent, life threatening, and feared complication of HD. Moreover, oligohydramnios is a well-known condition frequently associated with malformations, including those related to the gastrointestinal tract. The authors report the case of a newborn that presented a delayed meconium passage. On the third day of life, he presented enterocolitis—the outcome of which was favorable with clinical treatment. While the diagnosis of HD was awaiting confirmation, the enterocolitis relapsed and this time he died due to septic shock. The autopsy findings were compatible with a short segment of congenital intestinal aganglionosis. No other malformation was found. The authors call attention for an early diagnosis of HD whenever the meconium passage does not happen for at least 48 hours and for the risk factors of enterocolitis. This case also demonstrates HD associated with oligohydramnios. Keywords: Hirschsprung Disease; Enterocolitis Necrotizing; Infant, Newborn; Autopsy. CASE REPORT A 17-day-old boy was brought to the hospital after a 1-day history of diarrhea and deterioration in his general status. He was born at 37weeks’ gestation through a cesarean section, weighing 3170 g, with a previous diagnosis of oligohydramnios.

Until the third day of life, meconium was not passed, and therefore his condition worsened with bloating and recurrent vomiting. The passage of meconium occurred only after an enema on the third postnatal day. The diagnosis of megacolon

Department of Pathology – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo, São Paulo/SP – Brazil. Anatomic Pathology Service – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. c Department of Pediatrics – Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil. a b

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 médium provided article is properly cited.

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congenitum associated with neonatal sepsis was considered, and the newborn was prescribed a 10day course of antibiotics. He was discharged on the fifteenth postnatal day for an ambulatory diagnostic investigation. At home, evacuation did not occur, and he began to have diarrhea and foul-smelling vomiting. The following day, at 17 days old, he was taken back to the hospital, where he arrived floppy, dehydrated, with cold and cyanotic extremities. He had an axillary temperature of 37.5 °C, a pulse of 200 beats per minute, respiratory frequency of 70 respiratory movements per minute, capillary filling time of 6 seconds, immeasurable blood pressure, and weighed 2905 g. The abdomen was distended despite the presence of intestinal sounds. With the diagnosis of septic shock he was promptly treated with volume resuscitation and broad-spectrum antibiotics. As the clinical status progressively worsened, mechanical ventilatory support and vasoactive drugs were required. Regardless of the efforts, the patient remained in shock, presenting metabolic acidosis, intravascular disseminated coagulation and multiple organ dysfunctions. The pediatric surgeon, considering the diagnosis of Hirschsprung disease (HD) and necrotizing enterocolitis performed a loop-transversostomy, aiming to attain urgent digestive tract decompression. The postoperative outcome was troublesome and the newborn died on the third day of hospitalization.

Neumann AF, Lima PP, Melo AMAGP.

Autopsy Findings The external examination showed a moderate abdominal distention, as well as a colostomy above the umbilicus, which was apparently free of infection (Figure 1A). At the opening of the skull, enlarged gyri, shallow sulci, and meningeal congestion were evidenced (Figure 1B). The abdominal cavity contained mild yellow-citrine ascites. The small bowel loops and the colon were dilated and covered by a wine-colored serosa (Figures 2A and 2B). The lungs, kidneys, and liver had severe congestion (Figure 2A). The distal duodenum, jejunum, ileum, and colon also showed a wine-colored mucosa with partial loss of wrinkling. Areas of ulceration recovered by fibrin and hemorrhagic content in the lumen (Figure 3) were found. The entire colon presented a 3.5 cm perimeter and a wall thickness of 0.2 cm. In contrast, the distal rectum and the sigmoid presented with a perimeter of 1.0 cm and 0.3 cm in wall thickness, featuring a non-dilated short segment. The colostomy was performed before this segment (Figures 3B and 3C). Microscopic research of the small and large intestines was held through a representative strip from the distal ileum to the rectum. The ileum, ascending, transverse, and descending colon showed the presence of the submucosal and myenteric plexus, with the ganglionic cells exhibiting the usual morphology normally distributed (Figures 4, 5, and 6A). In contrast, these cells were rarely observed in the transition of the descending colon and the sigmoid (Figure  6B). In the distal sigmoid and rectum, the ganglionic cells were absent

Figure 1 – A - Frontal view of the newborn showing a mild abdominal distention and colostomy above the umbilical cord segment, apparently free of infectious signs; B - Cerebral edema, enlarged gyri, shallow sulci, and meningeal congestion.

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Figure 2 – Gross view of the thoracoabdominal monoblock. A - Moderate dilation of the large bowels, winecolored serosa covering the small and large bowels (arrow); B  -  Dissected gastrointestinal tract showing wine-colored serosa extending from the duodenum (arrowhead) up to the distal segments of the colon.

Figure 3 – Gross view of small and large intestines segments. A - An ileal segment exhibiting a poorwrinkled and wine-colored mucosa with ulcerated areas and hemorrhagic content; B - Ileal segment, cecum, ascending, transverse, and descending colon. Note the dilation of the cecum lumen up to the transverse colon close to the colostomy (arrow). The descending colon downstream exhibits a discrete and slight reduced diameter (arrowhead); C - Sigmoid segment and proximal rectum with reduced diameter and thickened wall; D - Detail of the sigmoid colonic mucosa with fibrinous ulcerative areas and wine-colored mucosa.

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in the submucosal as in the myenteric plexus, where the nervous fibers were thickened (Figure  7). The immunohistochemical analysis revealed negativity for calretinin in the segment of the sigmoid and rectum, but rare positive calretinin cells could be identified in the transition of the descending colon and sigmoid (Figure  8A). Immunohistochemistry for S100 protein demonstrated Schwann cell proliferation in the aganglionic sigmoid and rectum segments (Figure  8B). Acute fibrinous serositis was also found, therefore characterizing the diagnosis of enterocolitis. Yeast-like structures,

Neumann AF, Lima PP, Melo AMAGP.

PAS positive, compatible with Candida sp, were found over the colon serosa (Figure  8B, arrow). Additionally, both intestines presented ischemic areas, and neutrophilic inflammatory infiltration along the mucosa and in patchy areas of the muscular layer (Figure  9A). The remaining organs showed shock-related alterations, characterized by cerebral edema, pulmonary congestion, acute tubular necrosis, acute splenitis, marked hepatic congestion with microvesicular steatosis, and tiny ulcerated gastric mucosal lesions.

Figure 4 – Photomicrography of the cecum in A and ascending colon (H&E 400X) in B, showing the presence of ganglionic cells in the submucosa and in the myenteric plexus, respectively (H&E 200X).

Figure 5 – Photomicrography of A - transverse colon and B - descending colon, both showing the presence of myenteric ganglionic cells (H&E 400X).

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Figure 6 – Photomicrography. A - Descending colon showing the presence of myenteric ganglionic cells; B - Descending to sigmoid colon transition showing scanty myenteric ganglionic cells (H&E 400X).

Figure 7 – A and B - Photomicrography of the sigmoid (A) and rectum (B) with absence of ganglionic cells and enlargement of the nervous bundle (H&E 400X).

Figure 8 – Photomicrography. A - Descending colon and sigmoid transition showing immunohistochemical positive reaction for calretinin (H&E 400X). In the sigmoid and rectum, calretinin reaction was negative; B - Immunohistochemical reaction for S100 in the rectum, showing nervous bundle proliferation in the affected region (H&E 400X).

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Neumann AF, Lima PP, Melo AMAGP.

Figure 9 – Photomicrography. A - Small bowel ischemic and hemorrhagic mucosa with enteritis (H&E 200X); B - Serositis of the colon with the presence of hyphae and spores of Candida sp (arrow) (H&E 400X).

DISCUSSION In 1886, the Danish pediatrician, Harald Hirschsprung, first described what was later named Hirschsprung disease.1 The pathogenesis of the disease remained unknown for decades until the mid-1940s when the absence of submucosal and myenteric ganglionic cells were considered to be the cause of the disease.1 Embryological studies show that around the fifth week of gestation neuroblasts derived from the developing neural crest first appear in the esophagus. These cells migrate towards the craniocaudal direction to the rest of the developing gut, until the twelfth week of gestation. Thus, the extent of aganglionosis is defined from the point where migration of neuroblasts, through the intestinal wall, is interrupted. When this stoppage occurs in the seventh week the total colon aganglionosis occurs. Likewise, if the break in neuroblast migrations occurs in the ninth week it results in aganglionosis of the descending colon, sigmoid, and rectum. Migration breaks occurring between the tenth and twelfth week result in the aganglionosis being confined to the sigmoid and rectum.1,2 After the caudal migration of neuroblasts, they will be distributed within the deeper and upper layers of the intestinal wall, following maturation into ganglion cells. The latter process may also fail, leading to the absence of ganglionic cells in the myenteric and submucosal plexus.2 Therefore, congenital intestinal aganglionosis was defined as the absence of ganglionic cells in the myenteric (Auerbach) and submucosal (Meissner) plexus, due to a failure in the enteric nervous system development.3 HD is classified according to the extension of the neuroenteric involvement, as

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follows: a) ultrashort aganglionosis when the disease is confined to the anal canal; b) short segment, which accounts for 80-90% of cases and is the classic form of HD disease involving the sigmoid and rectum; c) long segment, accounting for 10% of all cases, characterized by the absence of ganglionic cells extending proximally beyond the splenic flexure or transverse colon; d) total colonic aganglionosis, represents 5% of the cases, and refers to aganglionosis of the entire colon; and e) total colonic aganglionosis with occasional extension of aganglionosis into small bowel.1 Genetic mutations were described in 10 different genes contributing to HD development. Among them, the most common are: gene RET (accounting for 7-35% of the cases), gene EDNRB (7% of the cases) and gene END3 (<5% of the cases), and others like GDNF and SOX103.4 The HD is associated with several genetic syndromes such as Down syndrome (trisomy 21), abnormalities of the urogenital tract, hypertrophic pyloric stenosis, intestinal malrotation, Meckel’s diverticulum, and anorectal anomalies.4,5 The gold standard diagnostic investigation is carried out by rectal suction biopsy, which is performed 3 cm above the pectinate line, allowing examination of the submucosa, which demonstrates the absence of ganglionic cells and the presence of hypertrophic nervous bundles in the submucosa. (The aganglionic cell zone is observed at the same degree on both plexuses).1,6 Usually, the normal histology reveals 1-5 ganglionic cells in the plexus per each millimeter of normal rectal mucosa. It is noteworthy that in the newborn the ganglionic cells


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are often smaller, and the nucleoli and cytoplasmic granules are not prominent, challenging their identification. As the 2 cm intestine wall above the pectinate line is usually a scanty zone in ganglionic cells and nervous fibers, HD may be misdiagnosed; therefore, the pathologic evaluation should consider this particularity during the biopsy evaluation.6 In these cases, the biopsy may reveal a rectal squamous epithelium of transitional type, indicating the proximity of the pectinate line, and should be noted in the histopathological report.

diagnosis. The thorough research for ganglionic cells and nervous bundles along the entire gut confirmed the diagnosis in its short variant. Calretinin was an ancillary diagnostic tool, confirming the absence of ganglionic cells in the sigmoid and rectum as well as the enlarged nervous bundle in this region. In this case, no other malformation, frequently observed in cases of HD, could be detected. It’s interesting to note in the present case the previous diagnosis of oligohydramnios, which is well known to be associated with malformations.11

In challenging cases, the immunohisto­ chemistry is recommended by the reactions with neuron-specific enolase, RET oncoprotein, BCL2, cathepsin D, and PGP 9.5. However, in routine clinical practice, none of the generic neuronal markers offers a significant advantage over thorough histologic research stained with hematoxylin- eosin.6

In the nineteenth century, Härald Hirsch­ sprung had already recognized the association of enterocolitis in his hallmark description of congenital megacolon,12 when he noted some pathologic findings of Hirschsprung-associated enterocolitis (HAEC) at autopsies, including crypt abscesses, mucosal ulceration and transmural necrosis. However, in 1962, Bill and Chapman13 first described HAEC as a clinical syndrome, which was clinically characterized by explosive, watery, diarrhea with foul-smelling stools, vomiting, fever, rectal bleeding, abdominal distention, and prostration. Despite the fact that the occurrence has been reported in different age groups, it is characteristically observed among full-term neonates. The suspicion should be raised whenever the passage of meconium does not occur 24 hours or at least 48 hours after birth. Failure to recognize HD in the early perinatal period places children at greater risk of HAEC.14 On the other hand, when HD is diagnosed outside the neonatal period, the development of HAEC is less frequent, probably because children in this group may present improved mucosal defenses.15 Contributing factors for the development of HAEC include: family history, trisomy 21, and previous episodes of HAEC. Some investigators also consider long-segment disease as more prone to HAEC development.14

At present, acetylcholinesterase (AChE) expression in the affected tissue is of diagnostic importance in HD. The histochemical reaction measures the activity of acetylcholinesterase, which indirectly means the presence of acetylcholine. AChE is useful in confirming the diagnosis of Hirschsprung disease, by revealing activity of this enzyme in hypertrophied nerve fibers.7 The main advantage of this method is that superficial biopsies are sufficient to reveal the activity of the enzyme, confirming the diagnosis HD. However, this method requires frozen tissue samples, and the results may be difficult to interpret. False negative reaction may occur, which results in delayed diagnosis and treatment, particularly in cases of total colonic aganglionosis and prematurity, where AChE might be missing in the nervous bundle hyperplasia.7 Barshack et al.8 described the use of calretinin as a diagnostic test adjuvant due to its ability to be expressed in nerve endings and ganglion cells of the myenteric and submucosal plexuses of the entire normal colon and small intestine. This finding was further confirmed by other author’s studies.9,10 In the case reported here, the diagnosis of HD was suspect from the beginning when the newborn did not show any meconium passage until the third day after birth. The first enterocolitis was promptly treated with a favorable outcome. However, the relapsed enterocolitis was severe, and did not respond satisfactorily to clinical and surgical treatment attempts. At autopsy, the dilation of the small and large bowels was in conformity with this

The mean incidence of HAEC is 25% of all the HDs, and the mortality rate varies between 17% and 50% of these cases.16 Nonetheless, in recent decades, decreased mortality and morbidity due to better diagnosis and early treatment has been seen. Although debatable, it seems that the HAEC etiology is multifactorial. Basically, the implicating causes include: obstruction, infection, ischemia, and hypersensitivity.

CONCLUSION 65


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HD is not a frequent entity, but should always be considered when facing a delayed meconium passage in neonates, especially if accompanied by oligohydramnios and associated with another syndrome or anomaly. The diagnosis can be performed with a simple biopsy followed by a thorough histological analysis of a hematoxylin and eosin stained slice. If not treated early, HD may lead to developmental delay, a high index of complications almost always associated with severe enterocolitis, and which presents a high mortality rate.

REFERENCES 1.

Santos JCM Jr. Megacólon - Parte I: Doença de Hirschsprung. Rev Bras Coloproct. 2002:196-209. Portuguese.

2.

Parisi MA. Hirschsprung disease overview. In: Pagon RA, Adam MP, Bird TD, et al., editors. Gene Reviews™ [Internet]. Seattle: University of Washington; 1993-2013 [cited 2013 May 10]. Available from: http://www.ncbi.nlm.nih.gov/books/ NBK1439/.

3.

4.

5.

6.

7.

Villar MAM, Jung MP, Cardoso LCA, et al. Doença de Hirschsprung: experiência com uma série de 55 casos. Rev Bras Saúde Mater Infant. 2009;9:285-91. Portuguese. http://dx.doi.org/10.1590/S1519-38292009000300007 Acheux V, Moal FD, Kaariainen H, et al. Loss-of function mutations in SIP1 Smad Interacting Protein 1 Result in a Syndromic Hirschsprung Disease. Hum Mol Genet. 2001;10:1503-10. Badner JA, Sieber WK, Garver KL, et al. A genetic study of Hirschsprung’s disease. Am J Hum Genet. 1990;46:568-80. Fiorino K, Liacouras CA. Congenital aganglionic megacolon (Hirschsprung disease). In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, editors. Nelson textbook of pediatrics. 19th ed. Philadelphia: Saunders Elsevier; 2011. chapter 324.3. Arruda Lourenção TAPL, Takegawa BK, Ortolan EV, Terra SA, Rodrigues MA. A useful panel for the diagnosis

Neumann AF, Lima PP, Melo AMAGP. of Hirschsprung disease in rectal biopsies: calretinin immunostaining and acetylcholinesterase histochesmistry. Ann Diagn Pathol. 2013;7:352-6. http://dx.doi.org/10.1016/j. anndiagpath.2013.04.004 8.

Barshack I, Fridman E, Goldberg I, Chowers Y, Kopolovic J. The loss of calretinin expression indicates aganglionosis in Hirschsprung’s disease. J Clin Pathol. 2004;57:712-6. http://dx.doi.org/10.1136/jcp.2004.016030

9.

Holland SK, Ramalingam P, Podolsky RH, et al. Calretinin immunostaining as an adjunct in the diagnosis of Hirschsprung disease. Ann Diagn Pathol. 2011;15:323-8. http://dx.doi. org/10.1016/j.anndiagpath.2011.02.010

10. Morris IM, Soglio DDB, Ouimet A, Aspirot A, Patey N. A study of calretinin in Hirschsprung pathology, particularly in total colonic aganglionosis. J Pediatr Surg. 2013;48:1037-43. http://dx.doi.org/10.1016/j.jpedsurg.2013.02.026 11. Stoll C, Alembik Y, Roth MP, Dolt B. Study of 224 cases of oligohydramnios and congenital malformations in a series of 225,669 consecutive births. Community Genet. 1998;1:7177. 12. Hirschsprung H. Suhtragheit neugeborener infolge dilatationen und hyperthrophie des colons. Jahruch Kinderheikunde. 1887;27:1. 13. Bill AH Jr, Chapman ND. The enterocolitis of Hirschsprung’s disease: its natural history and treatment. Am J Surg. 1962;103:70-4. http://dx.doi.org/10.1016/0002-9610(62)900168 14. Frykman PK, Short SS. Hirschsprung-associated enterocolitis: prevention and therapy. Semin Pediatr Surg. 2012;21:32835. http://dx.doi.org/10.1053/j.sempedsurg.2012.07.007 15. Hanimann B, Inderbitzin D, Briner J, et al. Clinical relevance of Hirschsprung-associated neuronal intestinal dysplasia. Eur J Pediatr Surg. 1992;2:147-9. 16. Astruc CT, Auber F, Suremain N, et al. Enterocolite compliquant une maladie de Hirschsprung diagnostiquee tardivement. Arch Pediatr 2012;19:819-22. French. http:// dx.doi.org/10.1016/j.arcped.2012.05.012

Conflict of interest: None Submitted on: 16th May 2013 Accepted on: 24th August 2013 Correspondence: Serviço de Anatomia Patológica Hospital Universitário da USP Av. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9384 E-mail: patpicciarelli@yahoo.com.br

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Article / Clinical Case Reports Artigo / Relato de Caso Clínico Unusual presentation of high-grade neuroendocrine carcinoma of the Urinary bladder with small-cell and large-cell features Vitor Fiorin de Vasconcellosa, João Lapa Lima Trancosob, Aloísio Felipe-Silvac, Angélica Braz Simõesc, Pedro José dos Santos Netod, Oscar Eduardo Hidetoshi Fugitae, Carla Rachel Onof, Carlos Alberto Buchpiguelf Vasconcellos VF, Trancoso JLL, Felipe-Silva A, et al. Unusual presentation of high-grade neuroendocrine carcinoma of the Urinary bladder with small-cell and large-cell features. Autopsy Case Rep [Internet]. 2013; 3(3): 67-75. http://dx.doi. org/10.4322/acr.2013.028

ABSTRACT High-grade neuroendocrine carcinoma of the urinary bladder comprehends small-cell and large-cell variants. It is a rare and aggressive neoplasm, mostly diagnosed in advanced stages. It is more frequently encountered among Caucasian men in the sixth decade of life. Urinary symptoms are the most common clinical presentation. Diagnosis is generally not troublesome once the lesions are easily detectable by imaging exams and cystoscopy. This neoplasia is associated with tobacco smoking, and is frequently associated with other carcinomatous components such as urothelial carcinoma, adenocarcinoma, and sarcomatoid carcinoma. The authors report a case of an apparently healthy female patient who presented cervical lymph node enlargement not accompanied by systemic symptoms. The supraclavicular lymph node biopsy revealed metastatic small cell carcinoma. The computed tomography scan showed a bladder wall nodular thickening, enlarged lymph nodes along the iliac, periaortic, mediastinal, cervical and supraclavicular chains, as well as an insufflating lytic bone lesion in the right iliac wing. The positron emission tomography-fluorodeoxyglucose (PETFDG) added to these findings, the presence of a paraesophageal lymph node, lymphadenomegaly in the gluteal region and a vertebral lytic lesion in T10. Resected specimen of the bladder tumor revealed a high-grade neuroendocrine carcinoma with small-cell and large-cell features. Keywords: Carcinoma, Small Cell; Carcinoma, Neuroendocrine; Urinary Bladder Neoplasm; Lymphatic Diseases.

Department of Internal Medicine, Hospital das Clínicas, Faculdade de Medicina,Universidade de São Paulo, São Paulo/SP – Brazil. Department of Internal Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo/SP – Brazil. c Anatomic Pathology Service, 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 Surgery, Hospital Universitário, Universidade de São Paulo, São Paulo/SP – Brazil. f Institut of Radiology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo/SP – Brazil. a b

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 médium provided article is properly cited.

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CASE REPORTS A 63-year-old female patient sought medical attention because of a left cervical bulging for the last 2 weeks and right flank pain radiating to the dorsum. She denied fever, weight loss, or any gastrointestinal or genitourinary complaints. The past medical history included hypertension and previous tabagism. The physical examination of the patient’s cervical region showed the presence of enlarged lymph nodes along the left anterior and posterior cervical chains and a firm mass bulging on the left supraclavicular fossa corresponding to a cluster of enlarged lymph nodes. The cervical computed tomography (CT) scans showed lymphadenomegaly on the cervical (levels III and IV), supraclavicular and upper mediastinal regions, measuring up to 3.0 × 2.3 cm, determining contralateral deviation of the trachea (Figure 1). The patient was submitted to a cervical lymph node biopsy, which revealed the presence

Vasconcellos VF, Trancoso JLL, Felipe-Silva A, et al.

of metastatic small-cell neuroendocrine carcinoma (Figure 2). CT scans showed mediastinal (Figure 3), and periaortic (Figure 4), pericaval, common iliac, and right internal and external iliac chains (Figure 5) lymph node enlargements. Some lymph nodes showed a heterogeneous aspect, which was probably related to necrotic liquefaction. On the right iliac wing, an insufflating, lytic lesion disrupting the cortical bone was present (Figure 6). No other bone lesions were found. The CT scan showed a 2.0 cm-nodular bladder wall thickening on the right posterolateral wall (Figure  7). The ultrasonographic examination revealed a vegetating lesion at the same area, without evidence of muscular extension.

Figure 1 – Computed tomography (CT) of the cervical region. A - Coronal reformation; B - Sagittal reformation, showing lymphadenomegaly (arrows) on the left side of the neck and superior mediastinum.

Figure 2 –  Photomicrography of the lymph node biopsy with metastatic tumor. A  - Small cells with nuclear molding, scant cytoplasm, and mitotic figures in a necrotic background (H&E, 400X); B - Positive immunohistochemistry staining for synaptophysin (400X).

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Figure 3 – Axial computed tomography of the thorax showing mediastinal lymph nodes enlargement (arrows). A - Involving the pre vascular space; B - The carinal topography.

Figure 4 – CT of the abdomen. A  - Coronal reformation; B  - Axial plane – both showing periaortic lymphadenomegaly (arrows).

Figure 5 – Axial CT of the pelvis. A  - Lymphadenomegaly along the external iliac chain; B  - along the common iliac chain. The patient underwent transurethral resection of the bladder lesion. The histopathological and immunohistochemical examination confirmed the diagnosis of a high-grade neuroendocrine carcinoma. The resected tumor was mostly composed of infiltrative, solid sheets of small and

intermediate cells, often overlapping with scanty cytoplasm, similar to the metastatic sample on cervical lymph node (Figure  8A). Chromatin was granular with small or absent nucleoli and numerous mitotic figures were seen. In other areas (about 20%), tumor cells had larger and more pleomorphic nuclei,

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Vasconcellos VF, Trancoso JLL, Felipe-Silva A, et al.

Figure 6 – CT of the pelvis, bone window. A - Axial plane; B – Coronal reformation, both showing a lytic bone lesion (arrows) with a slight soft tissue involvement in the right iliac wing.

Figure 7 – CT of the pelvis. A - Coronal reformation; B - Sagittal reformation, both showing nodular thickening of the right posterolateral wall of the urinary bladder (arrows).

with prominent nucleoli and some multinucleated cells. These findings were interpreted as a large-cell neuroendocrine carcinoma component (Figure 8B, 8C, 8D). Areas of adenocarcinoma with goblet cells and micropapillary urothelial carcinoma were present in about 10% of the specimen (Figure 9). Invasion of the urinary bladder muscular wall and lymphatics was evident on histology. The immunohistochemical staining of both pathological specimens are summarized in Table 1. The focal positivity for the p63 antibody in the metastasis was suggestive of a squamous or urothelial epithelium as the primary lesion. During the hospitalization, the patient did not present any urinary symptom or any compressive symptom associated with lymphadenopathy. Complementary staging was held by a positron emission tomography-fluorodeoxyglucose (PET-FDG) examination from the base of the skull to the thighs, which revealed increased glycolytic metabolism in area of focal thickening of the urinary bladder wall, compatible with primary neoplastic lesion. There was an increase of glycolytic

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metabolism in multiple cervical lymph nodes, mediastinal, abdominal and pelvic lymph nodes, consistent with secondary involvement. PET-FDG also showed lytic bone lesions with increased glycolytic metabolism in the spine and the right iliac, compatible with secondary metastatic involvement. This exam seemed to be superior to CT alone by the demonstration of the paraesophageal lymph node, which was not enlarged (Figure 10A and B), the lymphadenomegaly between the right muscles gluteus maximus and gluteus medius (Figure 10C and D), as well as the presence of the vertebral lytic lesion in T10. The remaining lesions depicted on PET-FDG were also detected by the CT. Data obtained by PET-FDG were consistent with the poor differentiation and the high mitotic index (Ki-67 between 60%-70%). The primary neoplasm became evident after the administration of furosemide, when FDG diluted with urine, highlighted the bladder lesion (Figure 10 E and F). With this diagnosis and staging, the patient was discharged for further treatment at an oncologic center.


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Figure 8 – Photomicrography of the bladder tumor. A - Areas of small-cell neuroendocrine carcinoma, (H&E, 400X); B - Areas of large-cell neuroendocrine carcinoma with comedonecrosis (H&E, 100X); C - Areas of large-cell neuroendocrine carcinoma with nuclear palisading with more abundant cytoplasm (H&E, 400X); D - Larger and more pleomorphic nuclei, with prominent nucleoli (H&E, 400X) were consistent with a largecell neuroendocrine carcinoma component (compare to small-cell carcinoma in A).

Figure 9 –  Photomicrography of the bladder tumor. A  -  Adenocarcinoma component (H&E, 200X); B - Goblet cells in the adenocarcinoma component (H&E, 400X); C - Micropapillary component (H&E, 400X); D - Chromogranin-positive immunohistochemistry in solid areas with neuroendocrine pattern (400X).

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Figure 10 – PET-FDG image acquisition and CT. A and B disclose a metastatic paraesophageal lymph node (arrow); C and D show a metastatic lymph node between the gluteus maximus and gluteus medius muscles (arrow); E and F show the bladder lesion after furosemide administration (arrow).

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Table 1 – Immunohistochemical panel Antigen

Result Lymph node metastasis

Urinary bladder primary

AE1 + AE3

Negative

Positive focal

Vimentin

Positive focal

NA

Chromogranin A

Positive focal

Positive focal

Synaptophysin

Positive

Positive

CK7

Negative

Positive (differentiated)

CK20

Negative

Positive (focal adenocarcinoma)

TTF-1

Negative

NA

CDX-2

Negative

NA

Ki67

Positive 60–70%

NA

p63

Positive focal

NA

EMA

Positive focal

NA

35Beta H11

Negative

Positive

CD99

Positive

NA

CD56

Positive

NA

S100

Negative

NA

CEA

NA

Positive (focal adenocarcinoma)

NA – non available.

DISCUSSION Small-cell carcinoma (SmCC), also called undifferentiated carcinoma, anaplasic SmCC, neuroendocrine SmCC or “oat-cell” carcinoma, is a well-established histological variant of epithelial tumors of the lung, first described in 1926.1 Since 1930, after the first description of an extrapulmonary small-cell carcinoma by Duguid et al.,2 this neoplasia has been reported in many anatomical locations within the body like the esophagus, other organs of the gastrointestinal tract, head and neck and genitourinary tract.3 In the most recent consensus of the World Health Organization (WHO) and the International Agency for research on Cancer (IARC), neuroendocrine tumors (NETs), formerly called carcinoid tumors, are classified separately from neuroendocrine carcinomas (NECs) of lowand high-grade malignancy. “Atypical carcinoids,” accompanied by local invasion, lymph node metastases, as well as distant metastases, correspond to low-grade NECs, whereas the classic small-cell carcinomas are classified as high-grade NECs.4

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In 1981, Cramer  et  al.5 reported the first case of small-cell carcinoma of the urinary bladder (SmCCB), in a 69-year-old man with urinary bladder irritability and hematuria. Despite the significant number of reports on this neoplasia variant since then, SmCCB remains rare and corresponds to 0.5-0.7% of all urinary bladder neoplasms.6,7 The reported incidence is less than 1-9/1,000,000 inhabitant. From 1980 until 2011, fewer than 1000 cases of SmCCB have been reported.7 Similarly to the urothelial carcinoma of the urinary bladder (UCB), the SmCCB is more frequent among men than women (76% and 24%, respectively). Caucasians are involved in 91% of the cases with the median age at diagnosis of 73 years,8 and 65% of the cases present a history of tobacco smoking.9 The most common clinical features are related to the urinary tract, including hematuria, dysuria, nocturia, frequency, obstructive symptoms, and hypogastric and/or pelvic pain.9 Among the NETs of the urinary bladder, a few cases of carcinoid tumors show immunoreactivity for polypeptides, such as calcitonin and subunit of β-human chorionic gonadotropin, without clinical expression.10,11 Paraneoplastic syndromes, such as ectopic secretion of adrenocorticotropic hormone (ACTH) and hypercalcemia, are scarcely found among SmCCB,12,13 differently from the SmCC of the lung.7 In the case reported here, urinary symptoms and the lack of clinical and laboratory systemic involvement routinely found in advanced stage of neoplasias were noticeably absent. Considering the clinical presentation as isolated cervical and supraclavicular lymph adenomegaly in an apparently healthy patient, the diagnosis of bladder tumor was not raised among the differential diagnosis. Only after the incidental finding of the urinary bladder wall thickening on CT examination was this diagnosis taken into account. The histopathological examination of the lymph node biopsy could only provide the diagnosis of metastatic small-cell carcinoma of unknown origin. The sole epidemiological data favoring urinary bladder neoplasm was tabagism. The biological behavior of SmCCB is characterized by its higher aggressiveness and consequently by a poorer prognosis when compared to the urothelial carcinoma of the bladder.6 Therefore, SmCCB usually presents at diagnosis as an advanced metastatic undifferentiated disease (high-grade). In a series of 88 cases conducted at the MD Anderson Cancer Center over 18 years,14 only 4.5% (n = 4 patients) were diagnosed in early

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stage (Ta/T1), while 40.1% (n = 36) were T2; 28.3% (n = 25) as T3-T4a (stage III), and 26.1% (n = 23) as T4b-M1 (stage IV). The spreading pattern typically involves the lymph nodes, the liver, and bones, which is similar to urothelial carcinoma of the bladder.9 Central nervous system metastases are less frequent when compared with SmCC of the lung.15 In the case reported here, it was surprising that regional disease or contiguity dissemination was not observed facing the presence of extensive lymphatic spread. The lymphatic involvement ascended from the right internal and external iliac chain to the retroperitoneal, mediastinal, and supraclavicular chains. At the moment of the diagnosis, hepatic or pulmonary metastases were not present at CT, PET-FDG and neither by biochemical determinations. The finding of a lytic and insufflating bone lesion at the right iliac wing detected by CT, and a vertebral lesion on PET-FDG represented the sole extranodal metastases. The neuroendocrine carcinoma (NEC) staging usually do not benefit from PET-FDG, due to their mild avidity for glucose, which show a low glycolytic metabolism. In this case it was useful because of the high mitotic index expressed by the tumor. On the other hand, when somatostatin-analog tracers labeled with gallium-68 are used, the PET scan hast a better impact. Small, round cells with hyperchromatic nucleus, nucleolus and chromatin dispersed in a “salt and pepper” discernible pattern, scanty cytoplasm, and organelles, characterize the smallcell carcinoma on light microscopy. Mitotic rate is usually high, as well as tumor necrosis and crush artifact.7 Pathogenesis of SmCCB is still obscure. However, several hypotheses were proposed to explain its origin. The strongest theory suggests that the origin of SmCCB may be a multipotential common stem cell that has the ability to differentiate into various cell types depending on the influence of a specific transformation or progression-related gene. This may explain the coexistence of SmCCB with transitional cell carcinoma and the heterogeneity of the immunohistochemical staining (cytokeratin and endocrine markers).7 Many other histological types may coexist in the same tumor: adenocarcinoma, squamous cell carcinoma, and sarcomatoid urothelial carcinoma.15,16 The detection of this coexistence is important because it is associated with the prognosis. Patients with the mixed component have

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a median survival time, independently if metastatic or non-metastatic disease of two to three times higher than pure SmCCB histology.17 Immunohistochemistry is of paramount importance in the diagnosis of neuroendocrine SmCCB. In this setting, positive reactions to epithelial and neuroendocrine markers range from 30% to 100% of cases. It is remarkable the positivity to chromogranin A (22-89%), synaptophysin (6776%), CD56 and cytokeratin 8-18 (CK8-18), and some of these tumors may express TTF-1 (33%). Less specific are cytokeratin 7 (CK7) (60%) and epithelial membrane antigen (EMA) (80%).6,7,18 In the case reported here, most of the tumor was represented by SmCCB associated with large-cell neuroendocrine carcinoma and a micropapillary urothelial carcinoma, showing a high mitotic activity. Besides the morphology, immunohistochemistry confirmed the diagnosis through the positive expression of chromogranin A, synaptophysin and CD56. The 5-year survival rate for patients with SmCCB ranged from 8% to 40%, no matter the staging. When properly staged, advanced disease presents a 5-year survival of 4-10.5%.13,18 Large-cell neuroendocrine carcinoma of the urinary bladder is an even rarer lesion, with many overlapping clinical and pathological features with SmCCB including presentation at advanced stages and poor prognosis.19,20 In summary, we present an exceedingly rare case of a high-grade neuroendocrine carcinoma of the urinary bladder with small and large cell features, which presented clinically with cervical lymph node enlargement and no urinary symptoms.

REFERENCES 1.

Cicin I, Karagol H, Uzunoglu S, et al. Extrapulmonary smallcell carcinoma compared with small-cell lung carcinoma: a retrospective single-center study. Cancer. 2007;110:106876. PMid:17614337. http://dx.doi.org/10.1002/cncr.22887

2.

Duguid JB, Kennedy AM. Oat cell tumors of mediastinal glands. J Pathol Bacteriol. 1930;33:93-9.

3.

Wong YN, Jack RH, Mak V, Henrik M, Davies EA. The epidemiology and survival of extrapulmonary small cell carcinoma in South East England, 1970-2004. BMC Cancer. 2009;9:209. http://dx.doi.org/10.1186/1471-2407-9-209


Unusual presentation of high-grade neuroendocrine... 4.

Algaba F, Sauter G, Schoenberg MP. Small cell carcinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. World Health Organization Classification of Tumours. p. 135-6.

5.

Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer. 1981;47:724-30. http://dx.doi. org/10.1002/1097-0142(19810215)47:4<724::AIDCNCR2820470417>3.0.CO;2-2

6.

7.

8.

9.

Moretto P, Wood L, Emmenegger U, et al. Management of small cell carcinoma of the bladder: Consensus guidelines from the Canadian Association of Genitourinary Medical Oncologists (CAGMO). Can Urol Assoc J. 2013;7: e4456. PMid:23671508 PMCid:PMC3650822. http://dx.doi. org/10.5489/cuaj.220 Ismaili N. A rare bladder cancer - small cell carcinoma: review and update. Orphanet J Rare Dis. 2011;6:75. PMid:22078012 PMCid:PMC3253713. http://dx.doi.org/10.1186/1750-11726-75 Koay EJ, Teh BS, Paulino AC, Butler EB. A Surveillance, epidemiology, and end results analysis of small cell carcinoma of the bladder: epidemiology, prognostic variables, and treatment trends. Cancer. 2011;117:5325. PMid:21567387. http://dx.doi.org/10.1002/cncr.26197

Autopsy and Case Reports 2013; 3(3): 67-75 12. Reyes CV, Soneru I. Small cell carcinoma of the urinary bladder with hypercalcemia. Cancer.1985;56:2530-3. http:// dx.doi.org/10.1002/1097-0142(19851115)56:10<2530::AIDCNCR2820561035>3.0.CO;2-4 13. Choong NW, Quevedo JF, Kaur JS. Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer. 2005;103(6):1172-8. PMid:15700264. http://dx.doi. org/10.1002/cncr.20903 14. Siefker-Radtke AO, Dinney CP, Abrahams NA, et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M. D. Anderson cancer experience. J Urol. 2004;172:481-4. PMid:15247709. http://dx.doi.org/10.1097/01.ju.0000132413.85866.fc 15. Ismaili N, Arifi S, Flechon A, et al. Small cell cancer of the bladder: pathology, diagnosis, treatment and prognosis. Bull Cancer. 2009;96:e30-44. http://dx.doi.org/10.1684/ bdc.2009.0883 16. Abrahams NA, Moran C, Reyes AO, et al. Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology. 2005;46:57-63. PMid:15656887. http://dx.doi.org/10.1111/j.1365-2559.2004.01980.x 17. Ismaili N, Ghanem S, Mellas N, et al. Small cell carcinoma of the urinary bladder: a case report and review of the literature. J Cancer Res Ther. 2009;5:133-6. PMid:19542673. http:// dx.doi.org/10.4103/0973-1482.52790

Cheng L, Pan CX, Yang XJ. Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer. 2004;101:957-62. PMid:15329903. http://dx.doi. org/10.1002/cncr.20456

18. Serrano FA, MD, Sánchez-Mora N, Arranz JA, et al. Large Cell and Small Cell Neuroendocrine Bladder Carcinoma. Am J Clin Pathol. 2007;128:733-9. PMid:17951193. http:// dx.doi.org/10.1309/HTREM6QYQDYGNWYA

10. Mascolo M, Altieri V, Mignogna C, et al. Calcitonin-producing well-differentiated neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder: case report. BMC Cancer. 2005;5:88. http://dx.doi.org/10.1186/1471-2407-5-88

19. Engles CD, Slobodov G, Buethe DD, et al. Primary mixed neuroendocrine carcinoma of the bladder with large cell component: a case report and review of the literature. Int Urol Nephrol. 2012;44:1021-5. PMid:22392568. http://dx.doi. org/10.1007/s11255-012-0148-6

11. Martignoni G, Eble JN. Carcinoid tumors of the urinary bladder. Immunohistochemical study of 2 cases and review of the literature. Arch Pathol Lab Med. 2003;127:e22-4. PMid:12562289.

20. Martín IJ, Vilar DG, Aguado JM,  et  al. Large cell neuroendocrine carcinoma of the urinary bladder. Bibliographic review. Arch Esp Urol. 2011;64:105-1. PMid:21399243.

Conflict of interest: None Submitted on: 27th July 2013 Accept on: 14th September 2013 Correspondence: Departamento de Clínica Médica 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) 3069-6412 E-mail: vitor.vasconcellos@gmail.com

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Autopsy and Case Reports 2013; 3(3): 77-79

Image in Focus Imagem em Foco Esophageal involvement in progressive systemic sclerosis Stephen A. Gellera, Fernando P. F. de Camposb Geller SA, Campos FPF. Esophageal involvemnt in progressive systemic sclerosis. Autopsy Case Rep [Internet]. 2013; 3(3): 77-79. http://dx.doi.org/10.4322/acr.2013.031

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

Figure 1 – Esophagus (right), stomach, and pylorus with proximal duodenum (left) showing marked esophageal dilation and severe chronic and acute inflamation (esophagitis).

Progressive systemic sclerosis (PSSc) is a chronic disease of unknown etiology characterized by progressive, abnormal accumulation of fibrous tissue in the skin and many organs. Characteristically, there is induration and thickening of the skin (scleroderma), abnormalities involving muscles, joints, and viscera. The first description was likely by William and Robert Watson in 1754.

a b

In the following century, Robert Graves, in Dublin (1843), and the French physician, Maurice Raynaud (1865), described peripheral vasoconstriction of the hands, relating it to scleroderma, which was present in 90-95% of the patients with PSSc. It is generally considered that the initiation of PSSc is due to the combined effects of abnormal immune response and vascular damage, leading

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.

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 médium provided article is properly cited.

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Autopsy and Case Reports 2013; 3(3): 77-79

to local accumulation of growth factors that affect fibroblasts and stimulate collagen production. The vascular involvement in PSSc is not just limited to the microcirculation of the skin, but also is seen in other targeted organs including the heart, lungs, kidneys, and gastrointestinal tract. Clinical and pathological evidence strongly support the concept that the primary insult in targeted organs is directed at blood vessels, and that this injury results in tissue ischemia, fibrosis, and ultimately major organ malfunction. The esophagus was the first visceral organ recognized as being involved in PSSc and it remains the most common site. The alimentary tract is affected in as many as 90% of patients and any part of the gastrointestinal tract may be involved. Of PSSc patients with visceral involvement, 7590% show esophageal changes, but approximately half of these patients are asymptomatic. Typically, the lower two-thirds of the esophagus has excessive collagenization of the esophageal wall with atrophy and replacement of muscle, particularly the inner circular layer of the muscularis propria. Small arteries often show vasculitis and there is nerve damage due to the vasa nervorum involvement. These alterations sometimes lead to severe narrowing with subsequent reflux and dilation. The image is of the upper gastrointestinal tract from the autopsy from a 54-year-old woman with long-standing PSSc. The greatly dilated esophagus is to the right and the relatively unremarkable duodenum is to the left, with the similarly unremarkable stomach in the center. The typical â&#x20AC;&#x153;rubber-hoseâ&#x20AC;? constriction is not prominent, but the esophagus is narrowed and rigid at the esophagogastric junction, and is greatly dilated with erosions and ulceration, marked chronic inflammation, and thinning of the wall. Complications of reflux, including Barrett metaplasia and adenocarcinoma, can sometimes be seen, but were not present in this patient. The diagnosis is generally not problematic since other features of PSSc are usually manifest. However, other collagen vascular diseases can also involve the esophagus, including systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, and mixed connective tissue disorders. The macroscopic changes seen in this case can also occur in achalasia and Chagas megaesopohagus.

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Geller SA, Campos FPF.

Two different physiopathologic mechanisms are recognized in the scleroderma esophageal dysfunction: a) impairment of neuromuscular electrical transmission; and b) progressive loss of muscle strength in the distal esophagus as well as in the lower esophageal sphincter. It is quite likely that the neurological involvement precedes the muscular atrophy and fibrosis. Dysphagia and pyrosis are the most common symptoms. Likewise, early satiety, regurgitation of food, progressive weight loss, malnutrition, or impaction of food may also be observed. These symptoms are the result of the disruption of peristalsis, gastroesophageal reflux, peptic stricture, and occasionally the presence of candidiasis. The severity of these abnormalities increases with disease progression, establishing a certain parallelism between the intensity of motor problems and disease severity. Esophageal manometry detects early dysfunction and is altered in 90% of cases. The most common findings are motor abnormalities, lack or decreased pressure of the distal esophageal high-pressure zone, moderate to severe gastroesophageal reflux, abnormal acid clearance, and decreased frequency of peristaltic contractions. Gastroesophageal reflux rather than impaired motility is the major cause of esophageal symptoms. Endoscopy reveals an atonic esophagus covered by pale mucosa and the presence of ulcers and, often, cicatricial stenosis. Lateral chest films of patients with scleroderma frequently reveal segmental air or air along the entire esophagus rarely with dilation or air-fluid level; the latter being more suggestive of tumor, stricture, or achalasia.

Keywords: Scleroderma, Systemic; Esophagus. BIBLIOGRAPHY Akesson A, Wollheim FA. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol. 1989;28:281. http://dx.doi.org/10.1093/rheumatology/28.4.281 Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum. 1975;4:351-68. http://dx.doi.org/10.1016/0049-0172(75)90017-7


Esophageal involvement in progressive systemic sclerosis

Autopsy and Case Reports 2013; 3(3): 77-79

Dinkler M. Zur lehre von der sklerodermie. Deutsch Arch Klin Med. 1891;48:514-77.

Rocco VK, Hurd ER. Scleroderma and scleroderma-like disorders. Semin Arthritis Rheum.1986;16:22-69.

Ducrotté P. Atteinte oesophagienne au cours des maladies systémiques: les dysphagies. Acta Endosc. 2006;36:617-22. French. http://dx.doi.org/10.1007/BF03003764

Savarino E, Mei F, Parodi A, et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology. 2013;52:1095100. http://dx.doi.org/10.1093/rheumatology/kes429

Garrison FH. An introduction to the history of medicine. 4th ed. Philadelphia: WB Saunders; 1929.

Turner R, Lipshutz W, Miller W, et al. Esophageal dysfunction in collagen disease. Am J Med Sci. 1973;265:191.

Matucci-Cerinic M, Kahaleh B, Wigley FM. Evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65:195362. http://dx.doi.org/10.1002/art.37988

Vischio J, Saeed F, Karimeddini M, et al. Progression of esophageal dysmotility in systemic sclerosis. J Rheumatol. 2012;39:986-91. http://dx.doi.org/10.3899/jrheum.110923

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

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Autopsy & Case Reports  

Autopsy & Case Reports, Volume 3 number 3 2013, ISSN 2236-1960. Serviço de Biblioteca e Documentação Científica do Hospital Universitário da...

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