Bone & Soft Tissue Pathology
Case 2 -
University of Washington Medical Center
Click on each slide thumbnail image for an enlarged view
The patient is a 51 year-old man with a history of ulcerative colitis, treated with Imuran. He noted
severe right upper quadrant pain while biking, although he had experienced similar, less intense pain for
approximately 1 year. Workup revealed several liver lesions. Core needle biopsy was followed by total
Case 2 - Figure 1 - Gross specimen showing a section of liver with several circular lesions of varying sizes (arrows).
Case 2 - Figure 2 - There is a prominent angiocentric growth pattern with tumor cells virtually filling the lumen of a small blood vessel.
Case 2 - Figure 3 - Nests and cords of epithelioid cells set in a myxohyaline stroma.
Case 2 - Figure 4 - Occasional cells have vacuolated cytoplasm.
Case 2 - Figure 5 - The lesional cells are diffusely and strongly positive for CD31.
Case 2 - Figure 6 - The infiltrative nature of the lesion can be seen as the lesional cells are negative for cytokeratins AE1/AE3, while the entrapped hepatocytes are strongly positive.
The neoplastic cells were diffusely and strongly positive for CD31 and CD34, and negative for
cytokeratins AE1/AE3 and CAM5.2 and for epithelial membrane antigen.
Epithelioid hemangioendothelioma (EHE) was first described as a distinctive vascular tumor of the soft
tissues in 1982.  In addition to skin and soft tissue, EHE can arise at virtually any anatomic
location. However it is most common in lung,  liver,  and bone.  EHE of
soft tissue most commonly arises in the head and neck but also tends to occur in the extremities,
anogenital region, mediastinum, or abdomen.
EHE of lung, liver, and bone is frequently
multicentric while soft tissue lesions are usually solitary. Liver lesions occur with a striking female
predominance, while EHE at other sites does not show a sex predilection. EHE occurs over a wide age
range with a peak in middle age; it is very rare in children. Presenting symptoms are usually referable
to a mass lesion. However, some lesions are painful and this is thought to be related to vascular
occlusion. According to the latest edition of the WHO Classification of Tumours of Bone and Soft Tissue,
EHE is classified as a malignant soft tissue tumor.  EHE is locally aggressive and capable of
distant metastasis, most commonly to lungs, liver and regional lymph nodes. Death due to EHE does occur,
with reported rates from 13% in soft tissue to 35% in liver and 65% in lung. 
Gross examination reveals a firm ill-defined soft tissue mass. Occasionally, EHE involves a large
vessel with infiltration into the surrounding soft tissues. Liver lesions tend to be circular and more
well-defined. Individual tumor nodules can be up to 10 cm in greatest dimension.
Histologically, EHE exhibits an infiltrative growth pattern with ill defined margins. Approximately
50% involve/arise from blood vessels. When they involve vessels, they expand the vessel, with tumor
cells infiltrating in a whirling pattern through the vessel wall into the surrounding tissue. The vessel
wall is preserved but the lumen is usually filled with necrotic debris and/or collagen. Importantly, EHE
does not usually show vascular differentiation in the form of well-formed blood vessels. It consists of
cords and strands of epithelioid cells that are typically set in a variably myxohyaline stroma. Vascular
differentiation at the light microscopic level occurs in the form of vacuolated cytoplasm that may or may
not possess red blood cells. In some cases, the vacuoles coalesce, giving the impression that the
neoplasm is infiltrating adipose tissue. Usually, there is minimal cellular pleomorphism. However, in
about 25% of cases, pleomorphism is present and the cells may have a spindled appearance. Mitotic
activity is usually less than 1 mitotic figure/10 hpfs and necrosis is uncommon. Occasionally, the
neoplastic cells may form nests or solid sheets. It is not unusual for the stroma to be hyalinized
densely and in these cases, the neoplastic cells can be few and difficult to identify. Metaplastic bone
can also occur in cases that are densely hyalinized.
Immunohistochemically, EHE is positive for a variety of endothelial markers including CD31, CD34, and
Factor VIII-AG. Approximately 25% of cases are positive for cytokeratin.  Electron microscopy
reveals features that are typical of endothelial cells including a well developed basal lamina,
pinocytotic vesicles, and Weibel Palade bodies.
Although the number of cases that have been karyotyped is very small, EHE appears to have a recurrent
chromosomal translocation involving chromosomes 1 and 3 [t(1;3)(p36.3;q25)]. This genetic aberration has
been identified in two cases (liver and thigh) by Mendlick et al.  and we have seen an
additional two cases that involved liver and harbored the identical translocation (unpublished).
Histologic features appear to predict clinical behavior to some extent, with the presence of
significant atypia, mitotic figures >1/10 hpfs, focal spindle cell cytomorphology, and necrosis,
portending a worse prognosis.
However, it is not possible to predict behavior with
absolute certainty based on the above mentioned criteria since lesions without the aforementioned
criteria are still capable of aggressive clinical behavior including the ability to metastasize.
Furthermore, it is possible that there is a histologic continuum between EHE and epithelioid
angiosarcoma; absolutely reliable criteria do not exist to separate "high grade/malignant" EHE from
epithelioid angiosarcoma. At the present time, all EHE should be regarded as malignant for treatment
purposes, with wide local excision being the treatment of choice.
The differential diagnosis of EHE is broad and includes primarily carcinoma, melanoma, epithelioid
sarcoma, and epithelioid angiosarcoma. Carcinoma and melanoma usually show a greater degree of cytologic
pleomorphism and are negative for vascular markers. In contrast to poorly differentiated adenocarcinoma,
the cytoplasmic vacuoles of EHE do not contain mucin. However, it is important to emphasize that
approximately 25% of EHE are positive for cytokeratin, and thus, this is a potential diagnostic pitfall.
Unlike melanoma, which is virtually always positive for S-100, EHE is negative for this antigen.
Epithelioid sarcoma can be difficult to distinguish from EHE, especially in those cases of EHE with
extensive hyalinized stroma. This is further compounded by the immunohistochemical profile of
epithelioid sarcoma, which is usually positive for cytokeratins and CD34. However, epithelioid sarcoma
is negative for CD31 and usually exhibits a granulomatous growth pattern with central caseating necrosis.
As mentioned above, it can be difficult to distinguish higher grade appearing forms of EHE from
epithelioid angiosarcoma since they can both have a sheet like growth pattern and are positive for
endothelial markers. However, in general, epithelioid angiosarcoma exhibits a greater degree of cellular
atypia/pleomorphism, is mitotically active, and frequently has necrosis.
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- Fletcher CDM, Unni KK, Mertens F. (Eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. IARC Press: Lyon 2002.
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- Angervall L, Kindblom L-G, Karlsson K, et al. Atypical hemangioendothelioma of venous origin. A clinicopathologic, angiographic, immunohistochemical, and ultrastructural study of two endothelial tumors within the concept of histiocytoid hemangioma. Am J Surg Pathol 1985;9:504-16.
- Mendlick MR, Nelson M, Pickering D, et al. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J SurgPathol 2001;25:684-87.