Hepatic Epithelioid Hemangioendothelioma

Hepatic EHE shows a predilection for females (male to female ratio, 1:1.5).^4,5  The average age at presentation is 30 to 40 years. Approximately one-quarter of patients are asymptomatic at the time of diagnosis. Makhlouf et al⁶  found that 55 of their 131 consults (42%) with available clinical information reported the hepatic lesions were an incidental finding. Symptomatic patients usually have nonspecific complaints, the most common of which is right upper-quadrant pain. Other findings include abdominal discomfort, weakness, anorexia, fever, nausea/vomiting, weight loss, ascites, fatigability, and hepatomegaly.^4,6,7  Rarely, hepatic EHE may present as Budd-Chiari syndrome, veno-occlusive disease, and/or portal hypertension because of a mass effect or invasive growth of the neoplasm into the surrounding vasculature.^8–10  The most frequently reported laboratory abnormality associated with hepatic EHE is an elevation in alkaline phosphatase, but other liver enzymes (eg, γ-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase) may be elevated as well.

Hepatic EHE currently has no definitive etiology. A number of cases are associated with a documented history of oral contraceptive use, but no statistically significant correlation has been established. Other associations may include alcohol consumption, trauma to the liver, sarcoidosis, Crohn disease, vinyl chloride or asbestos exposure, and hepatitis B and C.^4,6,10,11  In addition, hepatic EHE has been diagnosed in patients with no known history of hepatic insult or systemic disease.

Hepatic EHE routinely presents as multiple nodules involving both lobes of the liver with a predominantly peripheral or subcapsular growth pattern.^4,6,7,12,13  Late in the disease process, the individual lesions may grow and coalesce into larger, more-complex masses. Hepatic EHE is sometimes stratified into nodular and diffuse types, based on those early and late appearances, respectively. The literature reports that 27% to 37% of patients have extrahepatic spread at their time of diagnosis.^4,12,14 

On noncontrast computed tomography imaging, the tumor nodules most commonly have a hypodense appearance, and subcapsular lesions may show associated capsular retraction. Calcifications, compensatory hypertrophy, or cysts are less commonly seen.⁴  After the administration of contrast, smaller nodules (<2 cm) predominantly have homogenous enhancement, whereas larger lesions may show peripheral or heterogeneous enhancement.¹²  Almonari¹³  reported a series of 5 cases in which the computed tomography image had a characteristic “lollipop sign,” caused by an enhancing vein terminating at the periphery of a hypodense mass (Figure 1). Hepatic EHE usually appears hypointense on T1-weighted magnetic resonance imaging and heterogeneous to hyperintense on T2-weighted magnetic resonance imaging.^4,8,12,15 

On gross examination, the tumor nodules appear white, tan, yellow, or yellow-brown and have ill-defined borders.^1,6,11  The nodules feel firm or rubbery on palpation, and the cut surface may have a gritty texture if calcifications are present.⁷  In multifocal disease, nodules range from 0.2 to 18 cm.¹¹  Hepatic EHE that presents as a single nodule can vary widely in size but measures 5.6 cm on average.⁶ 

Hepatic EHE displays an infiltrative growth pattern composed of epithelioid, dendritic, and intermediate cells interspersed in a hyaluronic acid–rich myxoid matrix (Figure 2). On low power, the lesions have variable cellularity. The neoplastic cells tend to grow along vascular structures (with the potential for intravascular growth as well) and infiltrate hepatic sinusoids, causing atrophy and replacement of hepatocytes. A dense, mucopolysaccharide, extracellular matrix is usually present. The portal tracts and terminal hepatic venules remain intact despite destruction of the hepatic plates.⁶  Older lesions may become sclerotic, necrosed, and/or calcified.^1,6,7  Some nodules become completely scarred over with no identifiable cellular component. A variable amount of mixed inflammatory infiltrates may be seen at an inverse proportion to the amount of sclerosis. Ishak et al¹  hypothesized that this progressive fibrosis may explain why hepatic EHE can have such an indolent course. Although the neoplastic cells recapitulate primitive vessels, the dense sclerosis created by the lesion may destroy and/or occlude the native hepatic vasculature, and the tumor cells may eventually be deprived of blood.

The neoplastic cells are composed of epithelioid endothelial cells and dendritic cells as well as intermediate cells that have features of both. The epithelioid cells contain rounded vesicular nuclei with eosinophilic cytoplasm. Some cells have a signet ring–like appearance with intracytoplasmic vacuoles or lumina. The intracytoplasmic spaces resemble early angiogenesis and may contain erythrocytes.²  These cells appear to be epithelial on hematoxylin-eosin stain; however, electron microscopy and IHC stains reveal that they are of vascular origin. The dendritic cells have elongated, stellate nuclei, with pale cytoplasm, which may contain a single or multiple closely associated vacuoles, with or without intraluminal erythrocytes. Mitotic activity can vary, with most cases having little or none.⁶  Nuclear atypia is usually mild to moderate.

Fine-needle aspiration cytology of hepatic EHE has not been extensively reported in the literature and mainly consists of case studies. From this limited sampling, hepatic EHE has been described as paucicellular to moderately cellular, with spindled and epithelial cells seen singly and in clusters.¹⁶  The cytoplasm ranges from absent to abundant, and vacuoles (sometimes containing erythrocytes or erythrocyte fragments) and streaming may be seen. The nuclei are generally round to oval, with multiple, small nucleoli. Additionally, intranuclear inclusions, hyperchromasia, and multinucleation were reported in some specimens. Prognostic risk stratification of EHE in soft tissue has shown a correlation between mitotic activity and size and a propensity for malignant behavior; no such definitive link between histology and clinical course has been identified in lesions in the liver.^6,17 

Hepatic EHE stains positive for endothelial markers by IHC. Factor VIII–related antigen is positive in almost 100% of cases, but the degree of staining between cells within a lesion can be highly variable (Figure 3).^1,6  CD34 and CD31 are positive in 94% and 86% of cases, respectively (Figures 4 and 5). Other IHC stains that can be positive include factor XIIIa, vimentin, and type IV collagen. More recently, Fujii et al¹⁸  demonstrated that positive podoplanin (D2-40) staining can help differentiate hepatic EHE from other angiomatous lesions. Tumors may occasionally stain positive for cytokeratin markers and/or smooth muscle actin (Figure 6). The stroma of early lesions stain with variable intensity for mucicarmine and periodic acid–Schiff.¹  Over time, there is increased staining with Masson trichrome, which corresponds with the increased sclerosis seen on hematoxylin-eosin.

Electron microscopy provided valuable historic evidence for the endothelial origin of the tumor cells. Weiss and Enzinger²  identified multiple endothelial structures on electron microscopy, including elaborate junctional attachments, pinocytotic vesicles, investing basal lamina, and Weibel-Palade bodies.

Molecular studies have helped provide a more-definitive characterization of hepatic EHE and may have the long-term benefit of understanding the disease process and building targeted therapies. In 2001, Mendlick et al¹⁹  described translocation t(1;3)(p36.3;q25) in 2 patients (1 with hepatic EHE, and the other with soft tissue EHE) by karyotype. Ten years later, Errani et al¹⁷  analyzed 17 cases of EHE (2 of which were from the liver) using florescence in situ hybridization and demonstrated the rearrangement was a translocation between CAMTA1 on band 1p36.23 and WWTR1 on band 3q25.1. CAMTA1 is a calmodulin-binding transcription activator, and WWTR1 is a transcriptional coactivator.²⁰  In 3 of these cases, there was frozen tissue available for reverse transcription-polymerase chain reaction, which was used to confirm the fusion product. This rearrangement was found in all 17 cases of EHE and was not present in any of their control cases (epithelioid hemangioma and epithelioid angiosarcoma). The exact breakpoint for those translocations varied from patient to patient, and Errani et al²¹  went on to evaluate the breakpoint present in different lesions of patients who present with multifocal disease within a single organ. Before that 2013 study, the dominant theory of the tendency of hepatic EHE to present with multifocal disease was that each nodule represented a primary tumor that arose independent of the others. In evaluating the breakpoint of 6 nodules from 2 different patients with EHE of the liver, they were able to demonstrate that the multinodular presentation of hepatic EHE more likely represented local metastatic disease arising from a single clonal population.

Past attempts to use IHC to identify CAMTA1 overexpression in EHE have been unsuccessful. However, a recent study by Doyle et al²²  evaluated an IHC marker made from a polyclonal antibody that attached to the C-terminus of CAMTA1, rather than within it. They found that 51 of 59 cases (86%) of EHE had positive nuclear staining and that all but 1 (an epithelioid angiosarcoma that may have been a misdiagnosis) of the other 145 epithelioid mesenchymal were negative. Further investigation is required, but having an IHC stain that can assist with properly classifying this entity would be beneficial.

Antonescu et al²³  discovered a second recurrent translocation, t(11;X)(q13;p11), when they evaluated a 10-patient subset who tested negative for the t(1;3) translocation. Their evaluation was based on a novel case of pulmonic EHE that tested negative for the CAMTA1-WWTR1 fusion but was strongly positive for transcription factor E3 (TFE3) expression by IHC. All 10 cases had a break-apart signal at TFE3 by florescence in situ hybridization, and in 8 of the 10 cases (80%), there was a concurrent YAP1 rearrangement. In a follow-up study by Flucke et al,²⁰  the CAMTA1-WWTR1 and YAP1-TFE3 fusions were found in 33 of 35 cases (94%) and 2 of 35 cases (6%), respectively, of their successful florescence in situ hybridization analyses.

Hepatic EHE is misidentified in approximately 60% to 80% of cases.⁴  Metastatic carcinoma, angiosarcoma, sclerosing variant of hepatocellular carcinoma (HCC), and cholangiocarcinoma are the most common entities with which EHE is confused.^1,2,4,6 

Epithelioid hemangioendothelioma resembles metastatic carcinoma, especially signet ring adenocarcinoma, with its abundant eosinophilic cytoplasm and prominent vacuolization.⁶  Vascular structures may mimic glandular or tubular structures. One clue on hematoxylin-eosin staining, which differentiates the 2 entities, is that hepatic EHE leaves the portal tracts intact and tends toward intravascular growth, whereas metastatic carcinoma does not. Immunohistochemical and special stains can be helpful in differentiating the two as well (Table).

Angiosarcoma and EHE can have a similar hematoxylin-eosin appearance and IHC staining profiles. However, on low power, angiosarcoma causes more parenchymal destruction with less sclerosis than hepatic EHE.¹  On higher power, angiosarcoma has more nuclear pleomorphism, atypia, and mitotic activity. Both entities stain for factor VIII, CD31, and CD34; however, angiosarcoma more frequently loses expression of vascular markers as it dedifferentiates. D2-40 may be helpful because it is more consistently expressed in EHE than it is in angiosarcoma.

Intrahepatic cholangiocarcinoma typically has abundant desmoplastic stroma and gland formation or nested neoplastic cells. The fibrolamellar or sclerosing forms of HCC also have fibrosis and eosinophilic cells with vesicular nuclei similar to that of hepatic EHE, although those cells are usually more oncocytic. High-power examination to assess for the presence of intracytoplasmic lumina containing red blood cells should prompt the investigating pathologist to order special studies for vascular markers. Cholangiocarcinoma and HCC usually have negative staining for CD31, CD34, and factor VIII. However, the sinusoids in HCC may be positive for CD34 if the tumor has undergone sinusoidal capillarization. In those cases, the pattern of staining will be distinctly different from that of hepatic EHE, which will show positivity in the individual and clustered neoplastic cells as well as those invading along the sinusoids.²⁴  Hepatocellular carcinoma will only have positivity along the sinusoids that have been used for angiogenesis. Epithelioid hemangioendothelioma is usually negative for cytokeratin markers with occasional exception. Additional stains that may be positive in HCC and not in hepatic EHE include HepPar-1, arginase, as well as canalicular staining with polyclonal carcinoembryonic antigen and CD10.

There is no well-defined treatment strategy for hepatic EHE. The disease is classically described as having behavior intermediate between hemangioma and angiosarcoma, but the clinical course can vary.²  In a meta-analysis of treatment outcomes performed by Mehrabi et al,⁴  the 1-, 3-, and 5-year survival rates for all 253 diagnosed individuals with survival information available, regardless of treatment, were 211 (83.4%), 141 (55.7%), and 104 (41.1%), respectively. The most common treatment modalities used were liver transplantation, liver resection, chemotherapy and/or radiation therapy, and surveillance, which had 5-year survival rates of 54.5%, 75%, 30%, and 4.5%, respectively. Partial liver resection may not be a viable option for many patients because of the multinodular presentation of the disease. Individuals with hepatic EHE may be good candidates for liver transplantation, even if extrahepatic disease is present. Chemotherapeutic agents employed include doxorubicin, vincristine, interferon-α, 5-fluorouricil, thalidomide, and monoclonal antibodies against vascular endothelial growth factor.^15,25 

Hepatic EHE is a rare, low-grade, vascular tumor that usually presents as an incidental finding and has an unpredictable clinical course. Histologically, it can be mistaken for other benign and malignant vascular and epithelial tumors but is differentiated by its characteristic histologic findings and positive IHC staining for factor VIII–related antigen, CD31, and CD34. The CAMTA1-WWTR1 fusion product is the most commonly identified genetic abnormality in EHE, with YAP1-TFE3 fusions also reported. It is important for pathologists to be aware of this entity to avoid misdiagnosis as a more aggressive process.

We thank Janet Shaw, MD, of the Joint Pathology Center for her expertise and helpful comments.