Budd-Chiari syndrome

* A case of epithelioid hemangioendothelioma of the liver in a 34-year-old man with clinical and radiologic findings suggestive of Budd-Chiari syndrome is reported. Despite clinical and radiologic findings, percutaneous liver biopsy was suspicious for epithelioid hemangioendothelioma. The patient underwent liver transplantation 2 months later, and histologic examination confirmed this diagnosis. Unusual histopathologic features included extensive areas of capillary-thin vascular structures with open lumina, lack of significant cytologic atypia in the majority of neoplastic cells, and areas with Budd-Chiari-like features in the hepatic parenchyma surrounding the tumor. The neoplastic cells were focally immunopositive for endothelial markers, such as factor VIII-related antigen and CD34 antigen. The unusual clinical presentation may have been due to tumor invasion and fibrous obliteration of terminal hepatic venules and sublobular veins. Epithelioid hemangioendothelioma should be considered when evaluating patients with clinical features of Budd-Chiari syndrome or veno-occlusive disease.

(Arch Pathol Lab Med. 1998;122:846-848)

Epithelioid hemangioendothelioma (EH) of the liver is an unusual tumor that was first described by Ishak et al in 1984.1 To date, over 80 examples of this neoplasm have been reported.l-ll Epithelioid hemangioendothelioma usually presents with nonspecific findings and can clinically mimick neoplastic and nonneoplastic entities. Biopsy specimens may be inconclusive, and the proper diagnosis is sometimes only established on examination of the entire liver, either at transplantation or at autopsy. We report a case of EH with unusual histologic features that clinically presented as a Budd-Chiari syndrome and summarize the difficulties encountered with this tumor.

REPORT OF A CASE

A 34-year-old male Ukranian immigrant presented to our hospital with weight loss of more than 13.5 kg in 1 year, massive ascites, and generalized weakness. The patient gave a history of a single episode of esophageal variceal bleeding at age 26 years, which required transfusion of multiple blood units and was followed by treatment with corticosteroids for 2 years. He had also undergone repair of an atrial septal defect at the age of 8 years. The patient denied a family history of or occupational and social risk factors for liver disease. Interestingly, he was approximately 96 km from Chernobyl during the nuclear accident in 1986.

Physical examination revealed a cachectic man with icteric sclerae, hepatomegaly, ascites, and lower extremity edema. Pertinent laboratory results included total /direct bilirubin 390 /342 Fmol /L (normal 5-21 Fmol/L) serum alkaline phosphatase 1166 IU/L (normal

Magnetic resonance imaging showed a markedly enlarged, nodular liver with heterogeneous signal intensity and caudate lobe hypertrophy. The inferior vena cava and right hepatic vein appeared narrowed but not occluded. No left hepatic vein was identified. These vascular abnormalities were confirmed on hepatic venogram, which showed a markedly attenuated right hepatic vein and the presence of multiple collaterals. On the basis of the clinical, laboratory, and radiologic findings, the patient was thought to have Budd-Chiari syndrome.

PATHOLOGIC FINDINGS

Percutaneous liver biopsy revealed extensive replacement of the parenchyma by fibrous tissue containing scattered vascular structures of varied size. These vessels had capillary-thin walls, open lumina, and a bland, usually single-layered endothelial lining. Some of the cells lining vessels were immunopositive for CD34 antigen (BioGenex, San Ramon, Calif). There was no evidence of chronic hepatitis C virus or cirrhosis. The histopathologic features were thought to be more suggestive of EH than BuddChiari syndrome. The patient was treated with orthotopic liver transplantation 2 months later.

The patient's resected liver weighed 3065 g, measured 25 x 21 x 14 cm, and had a firm, vaguely nodular external surface. The left lobe was shrunken, while the right and caudate lobes were enlarged. On cut surface, the entire left lobe and more than half of the right lobe were occupied by a white-yellow, firm, ill-defined tumor (Figure 1). Occasional smaller foci of similar tumor tissue were present in the remaining right lobe.

On microscopic examination, large areas showed extensive replacement of the hepatic parenchyma by fibrous tissue that was rich in vascular structures. Most of these capillary-thin vessels were lined by flat endothelial cells without atypia (Figure 2). In other vessels, the endothelial cells were plump, vacuolated, and somewhat epithelioid (Figure 3). Many portal vein branches and terminal hepatic venules were occluded by fibrous tissue, some with recanalization, and some patent veins were lined by epithelioid endothelial cells. Rarely, polypoid projections (tufts) appeared within vascular lumina (Figure 3). The fibrous tissue contained thick collagen bundles in some areas and had a looser texture in others. Focally, the fibrous tissue was infiltrated by small clusters and cords of plump cells, some with signet ring-like features (Figure 4). The interface between the infiltrating tumor margin and the adjacent hepatic parenchyma was slightly more hypercellular than most tumor areas, with neoplastic cells replacing sinusoidal-lining cells. Sections from the caudate and portions of the right lobe showed a Budd-Chiari-like picture with marked zone 3 congestion, sinusoidal dilatation, hemorrhage, and hepatocyte drop-out. There were no features of chronic hepatitis C or cirrhosis. Cells lining the vascular structures and infiltrating the fibrous tissue were strongly positive for vimentin (BioGenex) and negative for cytokeratin (Dako Corporation, Carpinteria, Calif). A minority of these cells were positive for factor VIII-related antigen (Dako) and CD34 antigen (Figure 4, B). Expression of factor VIII-related antigen was more intense than that of CD34 antigen.

COMMENT

Epithelioid hemangioendothelioma arising in the liver usually comes to clinical attention because of nonspecific symptoms, such as abdominal pain, nausea, fatigue, or fever At operation, the tumor is often found to be multifocal. Presentation with ascites and hepatomegaly, mimicking veno-occlusive disease or Budd-Chiari syndrome, is unusual, but has been reported previously.2?--7,1 In the present case, clinical features and imaging studies showing attenuation or disappearance of hepatic veins and hypertrophy of the caudate lobe were strongly suggestive of Budd-Chiari syndrome. It was the liver biopsy that raised the possibility that this patient actually had EH, and this diagnosis was confirmed when the liver was resected.

A constellation of unusual histologic features made the present case distinct from previously reported EH cases.l Most of the tumor consisted of dilated, capillary-thin vessels, with some areas composed of dense fibrovascular tissue. Obliterated veins and clusters of infiltrating tumor cells were found in these fibrotic areas. The nontumorous liver had features suggestive of Budd-Chiari syndrome. These changes may have been due to obstruction of the hepatic venous outflow by tumor-induced fibrosis.

Several typical EH features were either absent or inconspicuous in this case. Epithelioid cells with a cuboidal to polygonal shape, eosinophilic cytoplasm, and hyperchromatic nuclei were absent. Most vascular structures were lined by endothelial cells with minimal pleomorphism. The interface between the infiltrating tumor and hepatic parenchyma, which in EH is rich in pleomorphic tumor cells, was only slightly more cellular than the remaining tumor areas. Tufts of epithelioid tumor cells growing within vascular lumina were seen only rarely, and wellformed glomeruloid structures were absent.

Since 1984, when Fukayama et al7 first reported an EH case spreading through the hepatic veins, at least 8 cases mimicking Budd-Chiari syndrome or veno-occlusive disease have been reported.zs,b,io "I These reports emphasized occlusion of terminal hepatic venules, centrilobular fibrosis, portal tract preservation, and enlargement of uninvolved hepatic lobes, especially the caudate lobe. There were no significant characteristics in the demographic and risk factors among these patients.25b.lo The cause of death was liver failure due to tumor replacement in 18 out of 23 patients.lzilo,ll Tumor metastases to other organs, mainly lung and bone, were seen in up to 60% of cases. Some patients who underwent liver transplantation, like our case, remained tumor-free for 1 to 11 years following the transplant." A Budd-Chiari-like clinical picture may rarely be observed in hepatic angiosarcoma.lz

The etiology of EH remains unknown. On the basis of immunohistochemical findings, Demetris et al'3 have recently suggested that EH lesions may be derived from primitive "reticuloendothelial" cells, which coexpress endothelial (factor VIII and CD34) and dendritic (factor XIIIa) cell markers and can differentiate along both endothelial and dendritic pathways. In our case, an interesting aspect of the clinical history was the patient's exposure to radiation approximately 10 years prior to presentation. To our knowledge, however, there are no reports to date linking radiation exposure with the development of EH.

The authors thank Micha Zeffren and Norman Katz for photographic assistance.

References

1. Ishak KG, Sesterhenn IA, Goodman ZD, Rabin L, Stromeyer FW. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of

32 cases. Hum Pathol 1984;15:839-852.

2. Clements D, Hubscher S, West R, Elias E, McMaster P Epithelioid haemangioendothelioma: a case report. J Hepatol. 1986;2:441-449.

3. Cobden I, Johri S, Terry G, et al. Hepatic epithelioid haemangioendothelioma: difficult name, difficult diagnosis? Postgrad Med J. 1988;64:128-131. 4. Dean Pi, Haggitt RC, O'Hara Cl. Malignant epithelioid hemangioendothelioma of the liver in young women: relationship to oral contraceptive use. Am J Surg Pathol. 1985;9:695-704.

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6. Eckstein RP, Ravich RB. Epithelioid hemangioendothelioma of the liver: report of two cases histologically mimicking veno-occlusive disease. Pathology 1986;18:459-462.

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8. Kelleher MB, Iwatsuki S, Sheahan DG. Epithelioid hemangioendothelioma of liver: clinicopathological correlation of 10 cases treated by orthotopic liver transplantation. Am] Surg PathoL 1989;13:999-1008.

9. Marino IK, Todo S, Tzakis AG, et al. Treatment of hepatic epithelioid hemangioendothelioma with liver transplantation. Cancer 1988;62:2079-2084. 10. Radin DR, Craig JR, Colletti PM, Rails PW, Halls JM. Hepatic epithelioid hemangioendothelioma. Radiology. 1988;169:145-148.

11. Treg R, Bruguera M, Campo E, Hojman R, Levi D, Podesta A. Epithelioid hemangioendothelioma of the liver: report of two cases. Liver 1988;8:105-110. 12. Schluger LK, Cubukcu O, Klion F, Thung SN. Unexplained Budd-Chiari syndrome in a young man. Hepatology.1995;21:584-588.

13. Demetris A), Minervini M, Raikow RB, Lee RG. Hepatic epithelioid hemangioendothelioma: biologic questions based on pattern of recurrence in an allograft and tumor immunophenotype. Am J Surg Pathol. 1997;21:263-270.

Accepted for publication April 28, 1998. From the The Lillian and Henry M. Stratton-Hans Popper Department of Pathology (Drs Walsh, Hytiroglou, Thung, and Fiel) and Division of Liver Diseases (Dr Siegel), Department of Medicine, and Division of Abdominal Organ Transplant, Department of Surgery (Dr Emre), The Mount Sinai School of Medicine, City University of New York (NY); and the Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC (Dr Ishak).

Reprints: Swan N. Thung, MD, Department of Pathology, Box 1194, Mount Sinai School of Medicine, One Gustave L. Levy PI, New York, NY 10029.

Copyright College of American Pathologists Sep 1998
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