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Generalized venocentric lesions in the virus-associated hemophagocytic syndrome
GENERALIZED VENOCENTRIC LESIONS IN THE VIRUS-ASSOCIATED HEMOPHAGOCYTIC SYNDROME MELISSA HELI.ER HOAGLANI),MD, WH.t.l,',.xt H. ZINKtlAM, MD, ANI) GROVKRM. HUTCtlINS, MD We present a case of virus-associated hemophagocytic syndrome, most likely caused by adenovirns infection, in wltich focal destrnction of small veins with expansile nodules of extravasated red cells and bland necrosis were seen. This phenomenon was not described previously in the hemophagocytic syndrome.
CEnical and aulopsy findings in a 4Jt2-year-oM boy who had been healthy until the omet of virus-associated hemophagocytic syndrome are presented. In addition to findings previously reported in association wi!h the syndrome, wMely disseminated perivemdar expansile nodules of bland necrosis were seen. These nodldes were suggesth,e of vessel injuo', wRh extravasation of vascular contents and focal destruction of normal elements. The morphologic similarities of these nodules to earl)' lesions of pulmona D' veno-occlusive disease are discussed. HuM PaT1101. 17:195--198, 1986.
-5 REPORT OF A CASE
Virus-associated hemoplmgocytic syndrome as a specific entity was first described by Risdall et al. in 1979.1 They reported a series of 19 patients with an illness, selflimited in most of the patients, tlmt was characterized by high fever, constitutional symptoms, liver function and coagulation abnormalities, and peripheral blood pancytopenia. Hepatosplenomegaly and bilateral pulmotmry infiltrates were often present. The syndrome developed in five of these patients in the absence of underlying disease. The remainder were immunosuppressed. Two of the previously heahhy and four of the immunosuppressed patients died as a result of the syndrome; tile remainder survived. Since that report three additional case reports of fatal hemophagocytic syndrome, all associated with Epstein-Barr virus (EBV), have been published. -'2-4 Bone nmrrow aspirations and biopsies in these patients tlemonstrated pancytopenia, with marked proliferation of hemophagocytic histiocytes. Lymph node biopsy nmterial dlowed generalized benign histiocytic hyperplasia with hemophagocytosis. In some cases the general lymph node architecture was intact, with lymphocyte depletion and vaszular proliferation in the cortex and burned-out germinal :enters; in others a prominent sinusoidal pattern was seen, ~'ith histiocytes confined to tile sinusoids. In a recent case :eport, Reisman and Greco ~ described nodules of nonsup)urative necrosis in the lymph nodes and spleen of a 17mar-old girl with fatal EBV-associated hemophagocytic .yndrome. 4 Autopsy findings in other organs have inchlded ncreased numbers of benign histiocytes in the sinusoids ln'd portal tracts of the livers with associated hepatocelhllar lecrosis, phagocytic histiocytes in the red pulp of the one pleen examined, and slnall numbers of plmgocytes in the eptomeninges.l Viruses implicated in the development of such benign temophagoc)'tic syndromes inchlde EBV, cytomegalovirus, terpes simplex, varicella-zoster, and adenovirus. 1-4 Similar eversible hemophagocytic responses have been docunented in bone marrow aspirates in association with ru;ella, 5 bacterial, fungai, and mycobacterial infections. 6 ,lany of these reports have not commented on I)'mph node 9 r other systemic abnormalities, and the relation between aese cases and the clinicopathologic entity known as virusssociated hemophagocytic syndrolne is not dear. Fttrther :udies may document the occurrence of this syndrome in ssociation with additional agents. Received June 17, 1985, from the Deparnnents of l'atholog}" ld Pediatrics, The Johns Hopkins Medical Institutiolls, Baltiore, Maryland. Revision accepted for publication July 22, 1985. lpported in part b)" NIH grant LM-03651 from The National bra D' of Medicine. Address correspondence and reprint requests to Dr. utchins: Departtnent of Pathology, The Johns ltopkins ttospital, altimore, MD 21205.
195
A white boy, 4 }'ears and 8 months of age, had been in good heahll until Jnly 12, 1984, when irritability, restlessness, and fever to 40.5~ developed. He was examined by his local physiciatl, and pharyngitis was diagnosed. A regimen of antibiotics was begun. Subsequent cuhures were negative, but diurnal fevers persisted and administration of the antibiotics was continued. On a return visit to his physician, tire patient was found to be anemic and leukopenic. Diarrhea and vomiting developed, and the patient was admitted to another hospital for filrther evaluation of persistent fever. He had continued fever, progressive hepatitis with hepatomegaly and abnornml liver function tests, progressive bilateral lmeumonitis, and progressive pancytopenia. All bacterial and flmgal cultures, as well as a hepatitis serologic panel, were negative. On July 26, 1984, the patient was transferred to The Johns Hopkins Hospital for further evaluation. Additional studies inchlded repeat bacterial and filngal cultures (including stool cultures for Yersinia and Campylobacter), wlficlt were all negative, examination of stool for ova and parasites (negative), and monoscreen (negative). Stool ELISA for adenovirus was positive. Serologic testing for Histoplasma, Chlamydia psittaci, Brucella, Salmonella species, Francisella tldarensis, Leptospira, and EBV, and the Well-Felix reaction for rickettsiae were done; the EBV titer (not fnrther specified) was moderately positive (1:I00), and all other tests were negative. Bone nmrrow aspiration and biopsy on July 27, 1984, revealed macrophages (a few phagocytic) and mast cells, with no evidence of tumor. The patient's letlmrgy and respirator}' distress increased over the next few days, with persistent fever and continued progression of hepatic dysfitnction and leukopenia. On August 2, 1984, he underwent open lung biopsy, which revealed necrotizing vasculitis with liquefaction necrosis and interstitial pneumonitis of uncertain etiology. Cuhures and sections stained for mycobacteria, viruses, fimgi, bacteria, F. tltlarensis, and Legionella were all negative. The patient experienced increasing respirator}" distress and died on August 4, 1984. Autopsy revealed multiple nodules, ranging insize from microscopic to 1.5 cm in diameter, consisting of bland necrosis with little or no inflamnmtory response but active phagocytosis by morphologically normal and atypical nmcrophages (figs. I and 2). The nodules had an expansile appearance, with scattered fibrin rimming destroyed x'essels within the necrosis or rimming the nodtdes themselves, suggesting an exudative phenomenon. The nodtdes were scattered throughout the parenchyma of the hmgs, liver, spleen, abdominal and thoracic lymph nodes, snmll and large bowel, bladder, adrenals, and kidneys. The necrosis appeared to be centered around veins and to affect interstitial connective tissues, with relative sparing of epithelial cells in lungs, liver, pancreas, and kidneys. In addition to tile nodtfles of necrosis, other areas in lymph nodes were
HUMAN PATHOLOGY
.
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Volume 17, No. 2 [February ~986]
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FIGURE 1. Top left, presumed early lesion of necrosis in the spleen. Lymphoid follicles are preserved centrally [arrows], while the necrosis is centered on the perifollicular sinusoid. The penicilliary arteries appeared normal. Similar necrotic areas were seen in lymph nodes. Top right, liver with two lightly stained areas of bland necrosis. Bottom right, expansile pulmonary lesion with interstitial thickening and intra-alveolar accumulation of necrotic debris centered on a pulmonary vein [arrow]. Normal parenchyma is visible at the top of the field and the pleura to the left. [Hematoxylin-eosin stain. Top left, x 50; Top right, x 10; Bottom right, x 40.
196
CASE STUDIES
FIGURE 2. Left, intraparenchymal pulmonary vein with necrosis and inflammation of the wall from the center of a necrotic focus. Arteries were not involved in the process. Right, small artery (A] and vein IV] adjacent to the adrenal capsule showing necrosis and inflammation of the vein and sparing of the artery. Bland necrosis of the adjacent adrenal tissue is evident. (Hematox'ylin-eosin stain. Left, x 400; Right, x 200.]
characterized b)" extreme sinnsoidal distention b)' relatively normal erythrophagocytic histiocytes. The necrotic areas in the spleen, peripancreatic and retroperitoneal tissues, bladder, anti some areas of the hmg contained collections of markedly atypical cells with bizarre angular hyperchromatic nuclei, a more elongated appearance, and no evi",lence of hemophagncytic activity. These cells were believed :o be degenerating rather titan malignant histiocytes. The :ells wi~re widel)' scattered, and none could be localized for .~lectron microscopy or immunoperoxidase cell typing. ~,Iarked depletion of iymphocytes was seen in all lymplm"eticular organs. The marrow was hypocelhdar, with de:reases in all cell lines; macrophages, some of which conained phagocytosed erythrocytes, were present. T h e hymus was markedly involuted. Postnlortem cuhures of pleen and hmg, which were positive for Candida, probably epresented contaminants, as no histologic evidence of ungal infection was found. Bacterial, viral and fungal postnortem ctdtures of liver, hmg, and spleen were otherwise legative. No viral inclusions were fotmd. ~ISCUSSION The 41&-year-old child of the present report had a fultinant illness characterized clinically by fever, irritability, ad pharyngitis. Pancytopenia, progressive hepatitis, and neumonitis developed. Bacterial and fimgal cuhures, se)logic testing for hepatitis, monoscreen, and serologic
197
testing for Histoplasma, C. psittaci, Brucella, Salmonella species, F. tularensis, Leptospira, and rickettsiae were all negative. The EBV titer was moderately positive, anti stool ELISA was positive for adenovirus. Autopsy findings were consistent with a virus-associated hemoplmgocytic syndrome. Marked henaophagocytosis involved the entire lympboreticular system, including the liver, spleen, lymph nodes, and bone marrow. In addition, marked depletion of lymphocytes was observed in these organs. In addition, nod)des of bland necrosis, with little or no inflatnmatory response and ranging in diameter up to 1.5 cm, were widely disseminated througlmut the viscera, involving lungs, liver, spleen, abdominal and thoracic lymph nodes, small and large bowel, adrenals, and kidneys. Many of these nodules appeared to be centered around veins and had an exudatire expansile appearance. Widely disseminated expansile nodules, as seen in this case, had not been documented previously in virus-associated hemophagocytic syndromes. T h e recent report by Reisman and Greco 4 of a case of fatal EBV-associated hemophagocytic syndrome in a 17-year-old girl described nodules of bland necrosis, but these nodules were found only in lymph nodes and spleen and did not have the extensive distribution seen in the present case. Also noteworthy was the apparent venocentricity of many of the nodules in this case. In many areas, particulari)" within the lungs, small venules were seen in various stages of destruction, surrounded by expansile nodules of fibrin,
HUMAN PATHOLOGY
Volume "IL No. 2 (February 1986] REFERENCES
fresh a n d d e g e n e r a t i n g erythrocytes, and necrotic material suggestive o f vessel injury, with r e s n h a n t extravasation o f vasctflar contents a n d focal d e s t r u c t i o n o f n o r m a l elements. Such a p h e n o m e n o n had not b e e n described previously in association with a viral illness, a h h o u g h it is o f interest that s o m e a u t h o r s have suggested a possible viral etiology for p u h n o n a r y veno-occlusive disease, v-ll in which tire lesions, in the earl)" stages, show s o m e m o r p h o l o g i c similarities to tho'se o f the p r e s e n t case. M c D o n n e l l et at3 ~ recently described fever, interstitial fibrosis, a n d iymplmdenitis with e r y t h r o p h a g o c y t o s i s , features s u p p o r t i n g a viral origin for the illness, in a case o f p u h n o n a r y veno-occlusive disease. A systenfic c o m p o n e n t has not b e e n associated with the pulm o n a r y lesions in that disease process. In s u m m a r y , we d e s c r i b e a case o f virus-associated h e m o p h a g o c y t i c s y n d r o m e that, in a d d i t i o n to f i n d i n g s previously described in association with the s y n d r o m e , invoh'ed widely disseminated nodnles of bland necrosis, ntany periventflar, suggestive o f systemic small vessel injnry with r e s n h a n t extravasation o f vascnlar contents a n d focal necrosis. T h e m o r p h o l o g i c sinfilarities o f these lesions to the earl)' lesions o f p u h n o n a r y veno-occlusive disease a r e mentioned. Hemophagocytic responses within bone m a r r o w aspirates lmve b e e n d o c u m e n t e d in association with o t h e r infectious agents, a n d f l t r t h e r studies lnay b r o a d e n the list o f o r g a n i s m s k n o w n to cause this distinctive clinicopathologic phenomenon.
1. Risdall RJ, McKenna RW, Nesbit ME, et ah Virus-associated hemophagocytic syndrome. A benign histioc)tic proliferation distinct from malignant histiocytosis. Cancer 44:993,1979 2. Wilson ER, Malluh A, Stagno S, et al: Fatal Epstein-Barr virus-associated hemophagocytic syndrome. J l'ediatr 98:260, 1981. 3. Look AT, Naegele RF, Callihan T, et al: Fatal Epstein-Barr virns infection in a child with acute lymphoblastic leukemia in remission. Cancer Res 41:4280, 1981 4. Reis,nan RI', Greco MA: Virus-associated hemophagocytic syndrome due to Epstein-Barr virus. Hum l'athnl 15:290, 1984 5. Zinkham Wit, Medearis DN Jr, Osborn JE: Blood and bone-marrow findings in congenital rubella. J Pediatr 71:512, 1967 6. Chandra P, Chandhery SA, Rosner F, et at: Transient histiocytosiswid~ siriking phagocytosis of platelets, leukocytes, and er)throcytes. Arch Intern Med 135:989, 1975 7. TingelstadJB, Aterman K, Lambert EC: Puhnonary venons obstruction. Report of a case mimicking primary puhnonary artery hypertension, with a review of the literature. Am J Dis Child 117:219, 1969 8. Carrington CB, l.iebow AA: Puhnonary veno-occlusive disease, ttnm Pathol 1:322, 1970 9. Braun A, Greenberg SD, Malik S, et al: Puhnonary veno-occlusivedisease associated with puhnonary phlebitis. Arch l'athol 95:67, 1973 10. McDonnell PJ. Summer WR, Hutchins GM: Pulmonary veno-occlusive disease: morphnlogic changes suggesting a viral cause. JAMA 246:667, 1981 11. Wagenvoort CA: Puhnonary veno-occlusive disease: entity or syndrome? Chest 69:82, 1976
MORPHOLOGIC CHANGES IN PRIMARY NEUROENDOCRINE CARCINOMA OF THE SKIN FOLLOWING RADIATION THERAPY STUARTJ. SCIINI'I-F, MD, HELEN WANG, hiD, ANt} ANN M. DVORAK, MD
A case ofprimaly neuroendocrine carcinoma of the skin (NECS) treated by radiation therapy is reported. Biopsy prior to irradiation showed a tumor with the characteristic light microscopic, immunohistochemical, and ultrastructural features of NECS. Following external beam irradiation, 6,000 rad, the size of the lesion decreased markedly. Examination of the excised residual mass revealed dense fibrous connective tissue with entrapped nests of large tumor cells that differed markedly from those in the previous biopsy specimen. The neoplast& cells in the excised mass had abundant, vacuolated, eosinophilic cytoplasm and pleomolphic nuclei. In spite of these marhed morphologic alterations, the original immunohistochemical phenotype was retained. These obselT,ations suggest that radiation may induce profduml histologic changes in NECS. HUM PATIIOt. 17:198--201, 1986.
o r location, radiation tlterapy is s o m e t i m e s used to acltieve local t u m o r controlY ,4 While these n e o p l a s m s a p p e a r to be radiosensitive, 4 no descriptions o f the m o r p l m l o g i c effects o f radiation oll such t u m o r s have b e e n published. We recently studied a case o f a large c u t a n e o u s n e u r o e n d o c r i n e carcinoma, treated by incisional biopsy, r a d i o t h e r a p y , a n d s u b s e q n e n t excision, a n d thus had the o p p o r t u n i t y to study the effects o f t u m o r i c i d a l doses o f ionizing radiation on this neoplasm. REPORT OF A CASE A previously healthy 60-year-old white m a n p r e s e n t e d in A u g u s t 1984 with a o n e - y e a r lfistory o f a right inguinal mass; the mass lind initially b e e n c o n s i d e r e d by iris physician to be a reactive l y m p h n o d e , a n d no f n r t h e r e v a h m t i o n o r t h e r a p y was instituted. Several weeks p r i o r to the 1984 admission, r a p i d e n l a r g e m e n t o f the mass was observed. Physical exanfination on admission r e v e a l e d a lmrd, fixed, n o n t e n d e r , n o n e r y t h e n t a t o u s , n o d n l a r , a p p a r e n t l y subcntaneons lesion, i n f e r i o r a n d lateral to the f e m o r a l canal. Surgical exploration revealed a mnltilobulated, fixed t u m o r , a n t e r i o r to the f e m o r a l fascia and artery, that m e a s u r e d 7 cnt in greatest d i m e n s i o n . Incisional biopsy was p e r f o r m e d . S u b s e q u e n t e x a m i n a t i o n s r e v e a l e d no e v i d e n c e o f metastatic disease. T h e patient r e c e i v e d e x t e r n a l b e a m irradiation (6,000 rad) to the right inguinal region, wlfich resulted in m a r k e d d e c r e a s e in the size o f the t u m o r , to a p p r o x i l n a t e l y 3 cm. I n J a n u a r y 1985, he was r e a d m i t t e d to the hospital for excision o f the residual mas.s. Surgical e x p l o r a t i o n at that t i m e r e v e a l e d a 4 x 3-cm mass, densely a d h e r e n t to the s a p h e n o n s vein. T h e mass and a s e g m e n t o f vein were excised. T h e patient was alive witltout e v i d e n c e o f disease f o u r m o n t h s a f t e r the second snrgical p r o c e d u r e .
Primary nenroendocrine carcinoma of the skin (Merkel cell t u m o r ) is now a well-recognized entity. T h e clinical, light nficroscopic, ultrastructnral, a n d i m m u n o h i s tochenfical features w e r e detailed in recent reportsY -4 T h e o p t i m a l t r e a t m e n t o f these t u m o r s has not b e e n established; h o w e v e r , at the least, wide local excision is indicated to p r e v e n t local r e c u r r e n c e s , which have been d o c t m t e n t e d in a p p r o x i m a t e l y o n e tlfird o f the r e p o r t e d cases. 2 W h e n tum o r s a r e not a m e n a b l e to wide resection d u e to their size
Received May 28, 1985, from the Del~artments of Pathology, Beth Israel ttospital attd tlarvard Medical School and the Charles A. Dana Research Institute, Beth Israel ttospital, Boston, Massachusetts. Revision accepted for publication July 29, 1985. Supported by USPItS grant CA-28834. Address correspondence and repri,tt requests to Dr. Schnitt: Department of Pathology, Beth Israel ltospital, 330 Brookline Avenue, Boston, MA 02215.
198
CEnical and aulopsy findings in a 4Jt2-year-oM boy who had been healthy until the omet of virus-associated hemophagocytic syndrome are presented. In addition to findings previously reported in association wi!h the syndrome, wMely disseminated perivemdar expansile nodules of bland necrosis were seen. These nodldes were suggesth,e of vessel injuo', wRh extravasation of vascular contents and focal destruction of normal elements. The morphologic similarities of these nodules to earl)' lesions of pulmona D' veno-occlusive disease are discussed. HuM PaT1101. 17:195--198, 1986.
-5 REPORT OF A CASE
Virus-associated hemoplmgocytic syndrome as a specific entity was first described by Risdall et al. in 1979.1 They reported a series of 19 patients with an illness, selflimited in most of the patients, tlmt was characterized by high fever, constitutional symptoms, liver function and coagulation abnormalities, and peripheral blood pancytopenia. Hepatosplenomegaly and bilateral pulmotmry infiltrates were often present. The syndrome developed in five of these patients in the absence of underlying disease. The remainder were immunosuppressed. Two of the previously heahhy and four of the immunosuppressed patients died as a result of the syndrome; tile remainder survived. Since that report three additional case reports of fatal hemophagocytic syndrome, all associated with Epstein-Barr virus (EBV), have been published. -'2-4 Bone nmrrow aspirations and biopsies in these patients tlemonstrated pancytopenia, with marked proliferation of hemophagocytic histiocytes. Lymph node biopsy nmterial dlowed generalized benign histiocytic hyperplasia with hemophagocytosis. In some cases the general lymph node architecture was intact, with lymphocyte depletion and vaszular proliferation in the cortex and burned-out germinal :enters; in others a prominent sinusoidal pattern was seen, ~'ith histiocytes confined to tile sinusoids. In a recent case :eport, Reisman and Greco ~ described nodules of nonsup)urative necrosis in the lymph nodes and spleen of a 17mar-old girl with fatal EBV-associated hemophagocytic .yndrome. 4 Autopsy findings in other organs have inchlded ncreased numbers of benign histiocytes in the sinusoids ln'd portal tracts of the livers with associated hepatocelhllar lecrosis, phagocytic histiocytes in the red pulp of the one pleen examined, and slnall numbers of plmgocytes in the eptomeninges.l Viruses implicated in the development of such benign temophagoc)'tic syndromes inchlde EBV, cytomegalovirus, terpes simplex, varicella-zoster, and adenovirus. 1-4 Similar eversible hemophagocytic responses have been docunented in bone marrow aspirates in association with ru;ella, 5 bacterial, fungai, and mycobacterial infections. 6 ,lany of these reports have not commented on I)'mph node 9 r other systemic abnormalities, and the relation between aese cases and the clinicopathologic entity known as virusssociated hemophagocytic syndrolne is not dear. Fttrther :udies may document the occurrence of this syndrome in ssociation with additional agents. Received June 17, 1985, from the Deparnnents of l'atholog}" ld Pediatrics, The Johns Hopkins Medical Institutiolls, Baltiore, Maryland. Revision accepted for publication July 22, 1985. lpported in part b)" NIH grant LM-03651 from The National bra D' of Medicine. Address correspondence and reprint requests to Dr. utchins: Departtnent of Pathology, The Johns ltopkins ttospital, altimore, MD 21205.
195
A white boy, 4 }'ears and 8 months of age, had been in good heahll until Jnly 12, 1984, when irritability, restlessness, and fever to 40.5~ developed. He was examined by his local physiciatl, and pharyngitis was diagnosed. A regimen of antibiotics was begun. Subsequent cuhures were negative, but diurnal fevers persisted and administration of the antibiotics was continued. On a return visit to his physician, tire patient was found to be anemic and leukopenic. Diarrhea and vomiting developed, and the patient was admitted to another hospital for filrther evaluation of persistent fever. He had continued fever, progressive hepatitis with hepatomegaly and abnornml liver function tests, progressive bilateral lmeumonitis, and progressive pancytopenia. All bacterial and flmgal cultures, as well as a hepatitis serologic panel, were negative. On July 26, 1984, the patient was transferred to The Johns Hopkins Hospital for further evaluation. Additional studies inchlded repeat bacterial and filngal cultures (including stool cultures for Yersinia and Campylobacter), wlficlt were all negative, examination of stool for ova and parasites (negative), and monoscreen (negative). Stool ELISA for adenovirus was positive. Serologic testing for Histoplasma, Chlamydia psittaci, Brucella, Salmonella species, Francisella tldarensis, Leptospira, and EBV, and the Well-Felix reaction for rickettsiae were done; the EBV titer (not fnrther specified) was moderately positive (1:I00), and all other tests were negative. Bone nmrrow aspiration and biopsy on July 27, 1984, revealed macrophages (a few phagocytic) and mast cells, with no evidence of tumor. The patient's letlmrgy and respirator}' distress increased over the next few days, with persistent fever and continued progression of hepatic dysfitnction and leukopenia. On August 2, 1984, he underwent open lung biopsy, which revealed necrotizing vasculitis with liquefaction necrosis and interstitial pneumonitis of uncertain etiology. Cuhures and sections stained for mycobacteria, viruses, fimgi, bacteria, F. tltlarensis, and Legionella were all negative. The patient experienced increasing respirator}" distress and died on August 4, 1984. Autopsy revealed multiple nodules, ranging insize from microscopic to 1.5 cm in diameter, consisting of bland necrosis with little or no inflamnmtory response but active phagocytosis by morphologically normal and atypical nmcrophages (figs. I and 2). The nodules had an expansile appearance, with scattered fibrin rimming destroyed x'essels within the necrosis or rimming the nodtdes themselves, suggesting an exudative phenomenon. The nodtdes were scattered throughout the parenchyma of the hmgs, liver, spleen, abdominal and thoracic lymph nodes, snmll and large bowel, bladder, adrenals, and kidneys. The necrosis appeared to be centered around veins and to affect interstitial connective tissues, with relative sparing of epithelial cells in lungs, liver, pancreas, and kidneys. In addition to tile nodtfles of necrosis, other areas in lymph nodes were
HUMAN PATHOLOGY
.
.,.~i~.,
,
,
~-
"
Volume 17, No. 2 [February ~986]
.
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FIGURE 1. Top left, presumed early lesion of necrosis in the spleen. Lymphoid follicles are preserved centrally [arrows], while the necrosis is centered on the perifollicular sinusoid. The penicilliary arteries appeared normal. Similar necrotic areas were seen in lymph nodes. Top right, liver with two lightly stained areas of bland necrosis. Bottom right, expansile pulmonary lesion with interstitial thickening and intra-alveolar accumulation of necrotic debris centered on a pulmonary vein [arrow]. Normal parenchyma is visible at the top of the field and the pleura to the left. [Hematoxylin-eosin stain. Top left, x 50; Top right, x 10; Bottom right, x 40.
196
CASE STUDIES
FIGURE 2. Left, intraparenchymal pulmonary vein with necrosis and inflammation of the wall from the center of a necrotic focus. Arteries were not involved in the process. Right, small artery (A] and vein IV] adjacent to the adrenal capsule showing necrosis and inflammation of the vein and sparing of the artery. Bland necrosis of the adjacent adrenal tissue is evident. (Hematox'ylin-eosin stain. Left, x 400; Right, x 200.]
characterized b)" extreme sinnsoidal distention b)' relatively normal erythrophagocytic histiocytes. The necrotic areas in the spleen, peripancreatic and retroperitoneal tissues, bladder, anti some areas of the hmg contained collections of markedly atypical cells with bizarre angular hyperchromatic nuclei, a more elongated appearance, and no evi",lence of hemophagncytic activity. These cells were believed :o be degenerating rather titan malignant histiocytes. The :ells wi~re widel)' scattered, and none could be localized for .~lectron microscopy or immunoperoxidase cell typing. ~,Iarked depletion of iymphocytes was seen in all lymplm"eticular organs. The marrow was hypocelhdar, with de:reases in all cell lines; macrophages, some of which conained phagocytosed erythrocytes, were present. T h e hymus was markedly involuted. Postnlortem cuhures of pleen and hmg, which were positive for Candida, probably epresented contaminants, as no histologic evidence of ungal infection was found. Bacterial, viral and fungal postnortem ctdtures of liver, hmg, and spleen were otherwise legative. No viral inclusions were fotmd. ~ISCUSSION The 41&-year-old child of the present report had a fultinant illness characterized clinically by fever, irritability, ad pharyngitis. Pancytopenia, progressive hepatitis, and neumonitis developed. Bacterial and fimgal cuhures, se)logic testing for hepatitis, monoscreen, and serologic
197
testing for Histoplasma, C. psittaci, Brucella, Salmonella species, F. tularensis, Leptospira, and rickettsiae were all negative. The EBV titer was moderately positive, anti stool ELISA was positive for adenovirus. Autopsy findings were consistent with a virus-associated hemoplmgocytic syndrome. Marked henaophagocytosis involved the entire lympboreticular system, including the liver, spleen, lymph nodes, and bone marrow. In addition, marked depletion of lymphocytes was observed in these organs. In addition, nod)des of bland necrosis, with little or no inflatnmatory response and ranging in diameter up to 1.5 cm, were widely disseminated througlmut the viscera, involving lungs, liver, spleen, abdominal and thoracic lymph nodes, small and large bowel, adrenals, and kidneys. Many of these nodules appeared to be centered around veins and had an exudatire expansile appearance. Widely disseminated expansile nodules, as seen in this case, had not been documented previously in virus-associated hemophagocytic syndromes. T h e recent report by Reisman and Greco 4 of a case of fatal EBV-associated hemophagocytic syndrome in a 17-year-old girl described nodules of bland necrosis, but these nodules were found only in lymph nodes and spleen and did not have the extensive distribution seen in the present case. Also noteworthy was the apparent venocentricity of many of the nodules in this case. In many areas, particulari)" within the lungs, small venules were seen in various stages of destruction, surrounded by expansile nodules of fibrin,
HUMAN PATHOLOGY
Volume "IL No. 2 (February 1986] REFERENCES
fresh a n d d e g e n e r a t i n g erythrocytes, and necrotic material suggestive o f vessel injury, with r e s n h a n t extravasation o f vasctflar contents a n d focal d e s t r u c t i o n o f n o r m a l elements. Such a p h e n o m e n o n had not b e e n described previously in association with a viral illness, a h h o u g h it is o f interest that s o m e a u t h o r s have suggested a possible viral etiology for p u h n o n a r y veno-occlusive disease, v-ll in which tire lesions, in the earl)" stages, show s o m e m o r p h o l o g i c similarities to tho'se o f the p r e s e n t case. M c D o n n e l l et at3 ~ recently described fever, interstitial fibrosis, a n d iymplmdenitis with e r y t h r o p h a g o c y t o s i s , features s u p p o r t i n g a viral origin for the illness, in a case o f p u h n o n a r y veno-occlusive disease. A systenfic c o m p o n e n t has not b e e n associated with the pulm o n a r y lesions in that disease process. In s u m m a r y , we d e s c r i b e a case o f virus-associated h e m o p h a g o c y t i c s y n d r o m e that, in a d d i t i o n to f i n d i n g s previously described in association with the s y n d r o m e , invoh'ed widely disseminated nodnles of bland necrosis, ntany periventflar, suggestive o f systemic small vessel injnry with r e s n h a n t extravasation o f vascnlar contents a n d focal necrosis. T h e m o r p h o l o g i c sinfilarities o f these lesions to the earl)' lesions o f p u h n o n a r y veno-occlusive disease a r e mentioned. Hemophagocytic responses within bone m a r r o w aspirates lmve b e e n d o c u m e n t e d in association with o t h e r infectious agents, a n d f l t r t h e r studies lnay b r o a d e n the list o f o r g a n i s m s k n o w n to cause this distinctive clinicopathologic phenomenon.
1. Risdall RJ, McKenna RW, Nesbit ME, et ah Virus-associated hemophagocytic syndrome. A benign histioc)tic proliferation distinct from malignant histiocytosis. Cancer 44:993,1979 2. Wilson ER, Malluh A, Stagno S, et al: Fatal Epstein-Barr virus-associated hemophagocytic syndrome. J l'ediatr 98:260, 1981. 3. Look AT, Naegele RF, Callihan T, et al: Fatal Epstein-Barr virns infection in a child with acute lymphoblastic leukemia in remission. Cancer Res 41:4280, 1981 4. Reis,nan RI', Greco MA: Virus-associated hemophagocytic syndrome due to Epstein-Barr virus. Hum l'athnl 15:290, 1984 5. Zinkham Wit, Medearis DN Jr, Osborn JE: Blood and bone-marrow findings in congenital rubella. J Pediatr 71:512, 1967 6. Chandra P, Chandhery SA, Rosner F, et at: Transient histiocytosiswid~ siriking phagocytosis of platelets, leukocytes, and er)throcytes. Arch Intern Med 135:989, 1975 7. TingelstadJB, Aterman K, Lambert EC: Puhnonary venons obstruction. Report of a case mimicking primary puhnonary artery hypertension, with a review of the literature. Am J Dis Child 117:219, 1969 8. Carrington CB, l.iebow AA: Puhnonary veno-occlusive disease, ttnm Pathol 1:322, 1970 9. Braun A, Greenberg SD, Malik S, et al: Puhnonary veno-occlusivedisease associated with puhnonary phlebitis. Arch l'athol 95:67, 1973 10. McDonnell PJ. Summer WR, Hutchins GM: Pulmonary veno-occlusive disease: morphnlogic changes suggesting a viral cause. JAMA 246:667, 1981 11. Wagenvoort CA: Puhnonary veno-occlusive disease: entity or syndrome? Chest 69:82, 1976
MORPHOLOGIC CHANGES IN PRIMARY NEUROENDOCRINE CARCINOMA OF THE SKIN FOLLOWING RADIATION THERAPY STUARTJ. SCIINI'I-F, MD, HELEN WANG, hiD, ANt} ANN M. DVORAK, MD
A case ofprimaly neuroendocrine carcinoma of the skin (NECS) treated by radiation therapy is reported. Biopsy prior to irradiation showed a tumor with the characteristic light microscopic, immunohistochemical, and ultrastructural features of NECS. Following external beam irradiation, 6,000 rad, the size of the lesion decreased markedly. Examination of the excised residual mass revealed dense fibrous connective tissue with entrapped nests of large tumor cells that differed markedly from those in the previous biopsy specimen. The neoplast& cells in the excised mass had abundant, vacuolated, eosinophilic cytoplasm and pleomolphic nuclei. In spite of these marhed morphologic alterations, the original immunohistochemical phenotype was retained. These obselT,ations suggest that radiation may induce profduml histologic changes in NECS. HUM PATIIOt. 17:198--201, 1986.
o r location, radiation tlterapy is s o m e t i m e s used to acltieve local t u m o r controlY ,4 While these n e o p l a s m s a p p e a r to be radiosensitive, 4 no descriptions o f the m o r p l m l o g i c effects o f radiation oll such t u m o r s have b e e n published. We recently studied a case o f a large c u t a n e o u s n e u r o e n d o c r i n e carcinoma, treated by incisional biopsy, r a d i o t h e r a p y , a n d s u b s e q n e n t excision, a n d thus had the o p p o r t u n i t y to study the effects o f t u m o r i c i d a l doses o f ionizing radiation on this neoplasm. REPORT OF A CASE A previously healthy 60-year-old white m a n p r e s e n t e d in A u g u s t 1984 with a o n e - y e a r lfistory o f a right inguinal mass; the mass lind initially b e e n c o n s i d e r e d by iris physician to be a reactive l y m p h n o d e , a n d no f n r t h e r e v a h m t i o n o r t h e r a p y was instituted. Several weeks p r i o r to the 1984 admission, r a p i d e n l a r g e m e n t o f the mass was observed. Physical exanfination on admission r e v e a l e d a lmrd, fixed, n o n t e n d e r , n o n e r y t h e n t a t o u s , n o d n l a r , a p p a r e n t l y subcntaneons lesion, i n f e r i o r a n d lateral to the f e m o r a l canal. Surgical exploration revealed a mnltilobulated, fixed t u m o r , a n t e r i o r to the f e m o r a l fascia and artery, that m e a s u r e d 7 cnt in greatest d i m e n s i o n . Incisional biopsy was p e r f o r m e d . S u b s e q u e n t e x a m i n a t i o n s r e v e a l e d no e v i d e n c e o f metastatic disease. T h e patient r e c e i v e d e x t e r n a l b e a m irradiation (6,000 rad) to the right inguinal region, wlfich resulted in m a r k e d d e c r e a s e in the size o f the t u m o r , to a p p r o x i l n a t e l y 3 cm. I n J a n u a r y 1985, he was r e a d m i t t e d to the hospital for excision o f the residual mas.s. Surgical e x p l o r a t i o n at that t i m e r e v e a l e d a 4 x 3-cm mass, densely a d h e r e n t to the s a p h e n o n s vein. T h e mass and a s e g m e n t o f vein were excised. T h e patient was alive witltout e v i d e n c e o f disease f o u r m o n t h s a f t e r the second snrgical p r o c e d u r e .
Primary nenroendocrine carcinoma of the skin (Merkel cell t u m o r ) is now a well-recognized entity. T h e clinical, light nficroscopic, ultrastructnral, a n d i m m u n o h i s tochenfical features w e r e detailed in recent reportsY -4 T h e o p t i m a l t r e a t m e n t o f these t u m o r s has not b e e n established; h o w e v e r , at the least, wide local excision is indicated to p r e v e n t local r e c u r r e n c e s , which have been d o c t m t e n t e d in a p p r o x i m a t e l y o n e tlfird o f the r e p o r t e d cases. 2 W h e n tum o r s a r e not a m e n a b l e to wide resection d u e to their size
Received May 28, 1985, from the Del~artments of Pathology, Beth Israel ttospital attd tlarvard Medical School and the Charles A. Dana Research Institute, Beth Israel ttospital, Boston, Massachusetts. Revision accepted for publication July 29, 1985. Supported by USPItS grant CA-28834. Address correspondence and repri,tt requests to Dr. Schnitt: Department of Pathology, Beth Israel ltospital, 330 Brookline Avenue, Boston, MA 02215.
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