Case 5 -

Epithelioid Hemangioendothelioma Gregg Allen Staerkel M.D. Anderson Cancer Center Houston, TX

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Clinical History This 57-year-old man saw his primary care physician after noting right chest discomfort for a two-month interval. Work-up, at that time, which included a chest x-ray revealed no abnormalities. The patient was in turn followed by a neurologist and received physical therapy treatments for a complaint of back and neck discomfort. When relief was not achieved a chest CT was ordered. This scan revealed a 3 cm mass within the anterior chest wall. Unexpectantly, low-density lesions were seen within the subcapsular region of the right and left lobes of liver, which extended centrally. A subsequent abdominal scan was read as suspicious for metastatic or primary liver neoplasm. At this point, the patient was referred for further evaluation. A review of the patient's past medical, family and social histories were notable for his occupation in a family owned propane gas company, a smoking history of 1-½ packs per day for 8 years (quitting 30 years ago) and a reported use of chewing tobacco, cigars, pipes, snuff, as well as, recreational drugs. The patient underwent an ultrasound of the liver, which confirmed multiple liver masses, described as hyperechoic areas as large as 9 cm in greatest diameter. Again, metastatic disease vs. primary cholangiocarcinoma was suggested. A fine needle aspiration was performed of one of the liver masses. Representative areas are illustrated. Case 5 - Figure 1 - Smears show cohesive (right side) to loosely cohesive (left side) epithelioid cell groups. Mild to focally moderate atypia, hallmarked by nuclear irregularity and intranuclear inclusions, is seen. Nuclei have a tendency to be polarized to one end of the cell. (Papanicolaou, medium power) Case 5 - Figure 2 - Tumor cells (left side) are seen in contrast to normal hepatocytes (right side). The abnormal cells show a greater degree of nuclear enlargement. Because of eccentric nuclear placement, a "hobnail" appearance is created. Occasional single cells demonstrate stretched cytoplasm (top center) and an inconspicuous cytoplasmic vacuole is present (arrow). (Papanicolaou, high power) Case 5 - Figure 3 - This loosely cohesive tumor cell group shows two prominent intranuclear cytoplasmic inclusions and vaguely apparent cytoplasmic clearing/vacuolization (arrow). Nuclei within these latter cells are particularly eccentric. (Papanicolaou, medium power) Case 5 - Figure 4 - Tumor cells show a greater degree of nuclear size variation and irregularity. A more defined cytoplasmic vacuole can be identified (arrow). (Papanicolaou, high power) Cytologic Diagnosis: Neoplastic cells consistent with epithelioid hemangioendothelioma Histologic Diagnosis: Epithelioid hemangioendothelioma Case 5 - Figure 5 - Histologic section shows abundant infiltrating tumor cells in a collagenous matrix. Prominent cytoplasmic vacuoles are noted. ( H & E, low power) Case 5 - Figure 6 - Cytoplasmic vacuoles, representing intracellular vascular lumina, of various sizes are present. Nuclei are eccentrically placed and demonstrate variable degrees of nuclear size and irregularity. Neoplastic cells range from "epithelioid" to "dendritic" in nature. (H & E, high power) Cytologic Findings Each aspiration performed demonstrated scant to few tumor cells admixed with normal hepatic parenchyma, both hepatocytes and bile duct epithelium. Tumor cells presented as single cells and small cell groups. Cell groups appeared cohesive to loosely cohesive which conveyed an epithelioid appearance. Some groups, because of eccentric nuclear placement, showed a distinctive hobnail appearance. Single cells were difficult to differentiate from hepatocytes, except when nuclear irregularity was pronounced or cell cytoplasm was elongated (more dendritic-like and not polygonal). Nuclear atypia ranged from minimal to moderate in degree, hallmarked largely by mild nuclear enlargement, occasional nuclear irregularity and frequent intracytoplasmic nuclear inclusions. Easily overlooked were cells showing cytoplasmic clearing or vacuolization. Mitotic activity and necrotic debris were not identified. Tumor cells stained strongly positive for the vascular marker CD31, via immunochemistry, performed on direct smear preparations. A diagnosis of neoplastic cells consistent with epithelioid hemangioendothelioma was rendered. Histologic and Clinical Follow-up A CT scan of the abdomen and pelvis, with and without contrast, was performed and showed multiple low-density lesions, which were noted to parallel vascular branches. No significant enhancement was noted and no biliary dilation to suggest an unusual cholangiocarcinoma was identified. There was no interval change in the size of the lesions when compared to an outside CT film taken one month ago. Aside from the patient's priorly disclosed pleural-based chest wall mass, no other lesions were disclosed; this included no retroperitoneal, pelvic, inguinal or mesenteric lymphadenopathy or bone metastases. The radiological differential diagnosis was epithelioid hemangioendothelioma vs. atypical presentation of lymphoma. Histologic core biopsies from multiple sites within the liver showed single cells and small cell groups with focal cytoplasmic vacuoles, representing intracellular vascular lumens, with rare erythrocytes. Nuclei were eccentrically placed demonstrating mild to moderate enlargement and irregularity. Epithelioid and dendritic cell forms were observed. Tumor cells were noted within collagenous stroma. Focally, associated chronic inflammation and bile ductule proliferation was present. Immunohistochemical stains for CD31, CD34, and Factor VIII were positive in neoplastic cells while a pan-cytokeratin was negative. A special stain for mucin was also negative. A diagnosis of epithelioid hemangioendothelioma was made. The patient's chest wall mass was resected. Histologic sections revealed a S-100 positive, CD31 negative spindle cell neoplasm consistent with cellular schwannoma. Resection of the patient's epithelial hemangioendothelioma was not an option due to the anatomy of his disease, i.e., involving, diffusely, both the right and left lobes of the liver. Liver transplantation was proposed as therapy. However, in light of the asymptomatic nature of the patient's disease, a period of observation was decided upon, despite the possibility for metastasis. To date, one year later, there has been no interval change in the patient's abdominal/pelvic CT scans. Discussion Primary malignant mesenchymal tumors of the liver are extremely rare. However, within this group, epithelioid hemangioendothelioma, as well as, angiosarcoma are the most common. Epithelioid hemangioendothelioma can occur at a variety of body sites including liver, lung, bone, soft tissue, breast, brain, meninges and lymph nodes. Those lesions within the liver, at the time of presentation, are seen in patients ranging in age from 12 to 86 years with a 62% female predominance. As in this case, epithelial hemangioendotheliomas of the liver are frequently disclosed as incidental findings (42%), but can be associated with abdominal pain, nausea/vomiting, decrease appetite, weakness, jaundice, hepatosplenomegaly, hemoperitoneum, Budd-Chiari syndrome, portal hypertension or liver failure. Both the etiology and pathogenesis of epithelioid hemangioendothelioma are unknown. However, it is accepted to be a malignant neoplasm of endothelial cell origin with a biologic behavior in between benign hemangioma and angiosarcoma. Approximately 28% of these tumors will metastasize. However, the presence of metastases does not necessarily correlate with prognosis. Mitoses, capsular invasion and nuclear atypia have not been shown to predict behavior. Only high cellularity and to a lesser degree tumor necrosis are indicators of poor clinical outcome. Liver epithelioid hemangioendotheliomas almost always present as multifocal lesions involving the entire liver. At first glance, this presentation, when seen on imaging studies, may suggest metastatic disease, however, the trained reviewer can make additional observations that strongly suggest the correct diagnosis. Many lesions will have a peripheral location, extending to the liver capsule. Flattening or retraction of the liver capsule over tumor deposits, due to lesional fibrosis and/or compensatory hypertrophy of adjacent liver segments is frequently seen. Other primary liver tumors and metastases, that have not undergone the shrinking effects of tumor cell death and fibrosis resulting from chemotherapy, tend to bulge the liver capsule. Larger lesions exhibit a central low density (corresponding to areas of sclerosed tumor) and a frequent peripheral zone of contrast enhancement (occurring because of tumor growth within vascular structures which in turn reduces blood flow and shunts blood and contrast to the surrounding uninvolved areas of liver). Lastly, foci of tumor calcification can be identified. With this radiological information, only obtaining representative tissue for pathologic review and immunochemistry staining for vascular markers, such as, CD34, CD31 and Factor VIII remains to make the diagnosis (it should be noted that epithelioid hemangioendotheliomas have been reported to infrequently express cytokeratins). However, without clinical and radiologic assistance, cytologic review of cells acquired may raise concern for cholangiocarcinoma, angiosarcoma, metastatic adenocarcinoma (e.g., signet ring cell carcinoma, if cytoplasmic vacuoles and single cells are prominent) or melanoma. To avoid these misdiagnoses, keep in mind that when there is an absence of a single dominant mass and/or negative keratin staining, presence of spindled (not epithelioid) cells showing considerable pleomorphism and no intracellular lumens, no known primary tumor outside the liver and/or negative mucin or keratin stains, and negative staining for melanoma markers (e.g., HMB-45, Melan-A), respectively, an alarm should go off leading one to acquire additional history and/or expand one's selection of immunochemistry stains and thereby arrive at the correct diagnosis. Epithelioid hemangioendothelioma of the liver has characteristic cytology and radiologic findings that should allow for its diagnosis in an adequately obtained specimen. It's infrequent nature, however, results in a lack of exposure and resulting knowledge for the reviewing cytopathologist that may lead to this entity never being considered as a possibility. 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