Case 4 -

Epithelioid Hemangioendothelioma David A. Owen, University of British Columbia, Vancouver, BC, Canada

Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:



under each thumbnail image below. You must have Aperio ImageScope installed on your PC.

If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy:

Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.

If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.

Clinical History The patient is a 44 year old woman who presented with several masses in the liver. Clinically, they were assumed to represent metastatic carcinoma, but a needle biopsy did not confirm the diagnosis. The patient remained well for the next 10 years with no active medical treatment. At this time the masses were slowly enlarging and because of vague upper abdominal pain a surgical resection was performed. A representative section of these masses is provided. Pertinent Laboratory Data: At surgery, three liver masses were encountered with the largest measuring 10.0 X 6.0 X 6.0cm. The masses were poorly circumscribed and were rubbery in consistency. The largest mass extended to the inner margin of the liver capsule but not on to the serosal surface. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Case 4 - Figure 2 Case 4 - Figure 3 Case 4 - Figure 4 CK7 Case 4 - Figure 5 CD34 Case 4 - Figure 6 CD31 Case 4 - Figure 7 FactorVIII Introduction: Hepatic hemangioendothelioma is a rare primary neoplasm. A majority of cases have no known clinical cause. In a small minority of cases there is an association with exposure to vinyl chloride, hepatitis B, hepatitis C and oral contraceptives. However, it is not clear whether this association is coincidental or causative. Clinical Features Approximately two thirds of neoplasms occur in women. The average age at presentation is in the fifth decade (range 12 to 86 years) and only 5% of cases involve individuals <20 years old. Most vascular tumors that occur in infants and children are examples of infantile hemangioma (formerly called infantile hemangioendothelioma) which despite the similarity in name is a completely different entity. The most common presentation is with abdominal pain but patients may also complain of nausea and vomiting. Examination reveals hepatosplemomegaly with occasional jaundice and ascites. In 10% of cases the neoplasm is discovered incidentally. Because the tumors are multifocal within the liver, surgical resection of individual masses may not be possible. Hepatic transplantation is now considered appropriate if the disease is advancing and simple surgical excision is impractical. Conventional imaging studies demonstrate multiple hepatic masses that may or may not have central calcification. MRI imaging shows nodules with a multilayered targetoid appearance corresponding to peripheral thrombosed vascular channels. Morphologic and Immunophenoptypic Features Epithelioid hemangioendotheliomas are typically multifocal and the nodules may vary considerably in size. They are circumscribed but not encapsulated. When they are found in a subcapsular location the nodules are commonly umbilicated. Slicing into the tumor masses reveals a uniform whitish or pale cream appearance with a rubbery texture. The histologic features of this tumor are characteristic. The center of the tumor is sparsely cellular with abundant hyalinised fibrous tissue that often has a bluish appearance resembling cartilage because of the production of mucopolysaccharides. As the lesion progress this cartilage-like tissue becomes progressively eosinophilic and fibrotic. Eventually calcification may occur. Within this central area small groups and individual tumor cells may be found. Three types of cell are encountered: vacuolated cells, dendritic cells and intermediate cells. Typically, vacuolated cells have a recognizable lumen. This lumen pushes the nucleus to one side resulting in a "signet ring" formation. If larger lumina are present they may contain red blood cells. The dendritic cells have a spindle cell or stellate morphology. Intermediate cells have mixed features. At the edges of the tumor nodules there is considerably more cellularity and tumor cells infiltrate the liver parenchyma along sinusoids. At this location the tumor has a more obvious vascular nature with endothelial cells having abundant pale eosinophilic cytoplasm (epithelioid differentiation). Tumor cells are invariably stain negative for mucin but commonly demonstrate immunohistochemical features of epithelial differentiation (CK7 is positive in 50% of tumors, AE1/AE3 is positive in 35% and pan keratin is positive in 12%). Other unusual positive immunohistochemical markers include smooth muscle actin (positive in 30% of cases), and CD117 (positive in 15% of cases). The key to the diagnosis is to recognize the vascular nature of the neoplasm and confirm it with appropriate immunostains such as Factor XIIIA (positive in virtually 100% of cases), CD31 (positive in 90% of cases) and CD34 (positive in 80% of cases). Prognostic Significance The case demonstrated is a woman aged 43 years at the time of her clinical presentation with masses in the liver. Metastatic tumor was suspected but a needle biopsy demonstrated epithelioid hemangioendothelioma. No active treatment was recommended. Ten years later the tumors had enlarged and were causing significant abdominal distress. Orthotopic hepatic translation was carried out. She remained well for four years when she developed two masses in the left lung. These were excised surgically and proved to represent metastatic hemangioendothelioma. She remains well and tumor free the present time: seventeen years after first presentation and seven years after hepatic transplantation. Epithelioid hemangioendotheliomas are very slow growing neoplasms. The five year survival is estimated at 43-55%. Surgery offers the main hope for cure and chemotherapy or radiotherapy are generally not effective. Differential Diagnosis : Angioma with thrombosis and re-organization Cholangiocarcinoma Metastatic adenocarcinoma (stomach or pancreas) Infantile hemangioma (hemangioendothelioma) Angiosarcoma Amyloid tumor Diagnostic problems are unlikely to arise in cases where the neoplasm is adequately sampled. However, needle biopsies taken from the center of the lesion may reveal only small gland-like structures set in a dense fibrous background. Positive immunostaining for CK 7 may lead to an erroneous diagnosis of cholangiocarcinoma or metastatic upper GI adenocarcinoma. Epithelioid hemangioendotheliomas are invariably negative with mucin stains such as PASD and mucicarmine indicating that these simple special stains are still diagnostically valuable!! However, beware of the presence of entrapped non-neoplastic bile ductules in any fibrosing hepatic neoplasm. As may be seen in the present case, surviving non-neoplastic ductules may be found in the center of epithelioid hemangioendotheliomas. CD31 and CD 34 stains are positive in the cells lining the gland-like spaces. However, as the present case demonstrates positivity may be scattered and weak. The dendritic cells are positive for Factor XIII and X111A and usually these immunostains are useful and reliable. Intermediate cells may be negative for all immunohistochemical markers. Infantile hemangioma is usually not a difficult diagnosis as most cases are diagnosed in the first two years of life. Generally patients do not present with liver disease but do suffer from the effects of arterio-venous blood shunting: typically cardiac failure and consumptive coagulopathy with thrombocytopenia (Kassabach-Merritt syndrome). The most common histologic finding is an obviously vascular neoplasm composed of intercommunicating channels lined by a single layer of bland endothelium and separated by fine fibrous bands. Dilated cyst-like vessels represent tumor involution. Infantile hemangiomas express GLUT1 and this immunostain can be used to differentiate them from congenital vascular malformations. Infantile hemangiomas do not metastasize although they may be multifocal (spleen, lungs and bone). If the infant survives any hemodynamic complications, the tumors tend to regress and rarely require surgical resection. Hemangiomas of the liver are common. Most of them occur in adults and are cavernous in type. They usually present no diagnostic difficulty for pathologists although radiologic distinction from other solid hepatocellular tumors may be difficult. Diagnostic problems can arise if an angioma undergoes thrombosis with re-organization. This can be a particular problem with small biopsies where distinguishing granulation tissue from a well differentiated angiosarcoma may not be straightforward. Reliance has to be placed on finding pleomorphism and atypical mitoses in a sarcoma. Angiosarcoma can be a difficult diagnosis to exclude. Generally poorly differentiated angiosarcomas appear as obvious malignant neoplasms. They do not express epithelial markers and the diagnostic challenge is to differentiate them from other types of sarcoma. Well differentiated angiosarcomas spread by growth along the sinusoids. Generally they have recognizable nuclear pleomorphism and mitotic activity. There is little tendency for angiosarcomas to develop central areas of hyaline connective tissue. Amyloid deposition in the liver is generally diffuse and present in the space of Disse. Occasionally, however, it may be found in a globular form (amyloid tumor) that can mimic the cartilage-like fibrosis encountered in epithelioid hemangioendothelioma. Plump vessels may be seen in the center of nodular amyloid and these could be confused with a sclerosing vascular neoplasm. Final Diagnosis: Epithelioid Hemangioendothelioma Conclusions: Epithelioid hemangioendothelioma with characteristic morphologic, immunohistochemical and clinical features. References Ishak KG, Sesterhen, Goodman ZD, Rabin L, Stromeyer FW. Epithelioid hemangioendothelioma of the liver: a clinico-pathologic and follow-up study of 32 cases. Hum Pathol 1984;15:839-852 Demetris AJ, Minervini M, Raikow RB, Lee RG. Hepatic epithelioid hemangioendothelioma. Biological questions based on pattern of recurrent allograft and tumor phenotype. Am J Surg Pathol 1997;21:263-270. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: A clinicopathologic study of 137 cases. Cancer 1999;85:562-582. Ben-Haim M, Roayaie S, Ye MQ, Thung SN, Emre S, Fishbein TA, et al. Hepatic epithelioid hemangioendothelioma: resection or transplantation, which and when? Liver Transpl Surg 1999;5:526-531 Miettinen M, Fetsch JF. Distribution of keratins in normal endothelial cells and a spectrum of vascular tumors: Implications in tumor diagnosis. Hum Pathol 2000;31:1062-1067. Uchimura K, Nakamuta M, Osoegawa M, Takeaki S, Nishi H, Iwamoto H, et al. hepatic epithelioid hemangioendothelioma. J Clin Gastroenterol 2001;32:431-434 Selby DM, Stocker JT, Waclawiw MA, Hitchcock CL, Ishak KG. Infantile hemangioendothelioma of the liver. Hepatology 1994;20:39-45 Kim TJ, Lee YS, Song YS, Park CK, et al. Infantile hemangioendothelioma with elevated alpha fetoprotein: A report of two cases with immunohistochemical analysis. Hum Pathol 2010;41:763-7. Mo JQ, Dimashkieh HH, Bove KE. Glut1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation. Hum Pathol 2004;35:200-209. Makhlouf HR, Iahak KG. Sclerosed hemangioma and sclerosing hemangioma of the liver: a comparative clinicopathologic and immunohistochemical study with emphasis on the role of mast cells in their histogenesis. Liver 2002;22:70-78. Kojiro M, Nakashima T, Ito Y, et al.Thorium dioxide related angiosarcoma of the liver: Pathomorphologic study of 29 autopsy cases. Arch Pathol Lab Med 1985;109:853-857