Epithelioid hemangioendothelioma

EHE is a soft tissue sarcoma and is generally considered a vascular cancer insofar as the ‘lesional’ cells have surface markers typical of endothelial cells (cells lining the interior of blood vessels). EHE was originally described as occurring most commonly in the veins of the extremities (arms and legs) and two organs, the liver and lungs. It has since been described in organs throughout the body. In addition to liver and lungs, bones and skin have been the most frequent organs.

Before the initial description of Weiss, the tumor had been reported under a variety of other names, including histiocytoid hemangioendothelioma, intravascular bronchoalveolar tumor (in the lung), and sclerosing cholangiocarcinoma. In the lung and liver, common sites of metastatic tumor, it was most likely to be confused with carcinoma a far more common type of tumor.

EHE typically occurs in the 20 – 40 age range although the overall age range involved is much broader and a modest predilection for females over males. It often has an indolent course, and many affected people have survived for decades with multi-organ disease.^[1]:601 The extent and number of organs involved apparently has little effect on longevity.

Genetics

The cytogenetics of EHE gave some of the first clues of an underlying genetic alteration. A balanced, reciprocal translocation t(1;3)(p36.3;q25) in EHE tumor cells was first described by Mendlick et al. in 2001. This led to the landmark paper by Tanas et al. in 2011 describing the specific genes involved in the translocation associated with the most common forms of EHE. This alteration results in the fusion of genes coding for two transcription co-activators (transcriptional regulators): TAZ (transcriptional co-activator with PDZ-binding motif) also known as WWTR1 (WW domain-containing transcription regulator protein 1) and CAMTA1 (calmodulin-binding transcription activator 1). The names in parentheses are not relevant to casual (or even science) readers but are included to help distinguish them from other genes. For instance, another gene with an entirely different function, Tafazzin, is unrelated to EHE but confusingly, also referred to as TAZ. In any case, the EHE translocation results in an abnormal ‘fusion gene’ that expresses an abnormal mRNA resulting in synthesis of a fusion protein variant of TAZ that is always turned on. This form of TAZ always resides in the nucleus and therefore is constitutively active. It binds and turns on a very important member of the TEAD family of transcription factors and this causes cells to proliferate. It is this production of the TAZ-TEAD transcriptome that causes the affected endothelial cells to grow into tumors. In normal cells, TAZ is considered a major negative transducer of the Hippo pathway, a signaling system that regulates organ size by causing cells to stop growing when they touch each other (contact inhibition). Many upstream inputs regulate the Hippo signal which normally functions to turn off or de-activate TAZ by keeping it in the cytoplasm and out of the nucleus. In EHE cells, the abnormal fusion TAZ is ‘immune’ to this input and just stays in the nucleus, and continuing to stimulate cell growth.

Note that about 10% of EHE patients harbor a different translocation. This one similarly results in the constitutive activation of YAP, an orthologue of TAZ (i.e., a gene that has sequence and function that are very similar to TAZ). This also results in persistent, unregulated growth of the affected cells and therefore causes EHE-type tumors.