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Pseudomyogenic Hemangioendothelioma (Epithelioid Sarcoma-Like Hemangioendothelioma).

In 1992, Mirra et al (1) described a distinctive soft tissue tumor characterized by multifocal presentation in a single limb, often including osseous involvement, consisting of bland keratin-positive spindle cells with "fibrohistiocytic" or "myoid" cytomorphology. They proposed that this tumor type was a variant of epithelioid sarcoma (ES), the "fibromalike" variant. Of the 5 patients in this series, 2 developed distant metastases.

Later, in 2003, Billings et al (2) described a lesion with some similar characteristics, although with a predominance of epithelioid cytomorphology and without evidence of distant metastases. They demonstrated endothelial differentiation by immunohistochemistry and named it "Epithelioid Sarcoma-Like Hemangioendothelioma" (ESLH). (2) Ultimately, Hornick and Fletcher (3) reported 50 cases of a lesion that appears to belong to the same diagnostic category. They recognized that the neoplasm shares some morphologic features with ES but has predominantly myoid-appearing spindle cells, and they designated it as "Pseudomyogenic hemangioendothelioma" (PMH). After considerable controversy, the general consensus is that ESLH and PMH are the same entity. (4)

This lesion was added to the group of vascular tumors of intermediate malignancy in the last edition (2013) of the World Health Organization Classification of Tumours of Soft Tissue and Bone. (5)

EPIDEMIOLOGY AND PATHOGENESIS

Pseudomyogenic hemangioendothelioma is a rare lesion, with marked male predominance (male to female ratio of 4:1). Its peak incidence is in young adults (mean age, 30 years), with only about 20% of patients being older than 40 years. (5) This tumor usually arises in the soft tissue of the lower limbs and less frequently in the upper limbs and trunk, although other sites have rarely been reported. (2,3) Primary cases of bone have been described, (6) although concurrent soft tissue and bone involvement is present in approximately 25% of cases. (4) The chromosomal translocation t(7;19)(q22;q13) leading to SERPINE1-FOSB gene fusion is a recurrent alteration in PMH. (7-9)

CLINICAL FEATURES

Pseudomyogenic hemangioendothelioma frequently presents as a nodular mass, and about half of the patients have pain. Two-thirds have involvement of multiple tissue planes, (5) most of them present with a cutaneous or subcutaneous lesion, (10) 50% have intramuscular involvement, and 25% have osseous involvement.

Bone lesions are lytic, lobulated, and well circumscribed on computed tomography and radiography (Figure 1).

On magnetic resonance imaging, the lesions are hypointense on T1-weighted images and hyperintense on T2-weighted and stir-weighted images. (6)

Positron emission tomography scan may be useful to visualize clinically occult deep lesions because they are avid for 18F-fluorodeoxyglucose. (5)

GROSS PATHOLOGY

Grossly, the lesion is ill-defined, usually multifocal, with a white-to-brown cut surface (Figure 2). Most tumors are between 1 and 2.5 cm, with only approximately 10% being larger than 3 cm. (5)

HISTOPATHOLOGY

Pseudomyogenic hemangioendothelioma shows infiltrative borders; most lesions exhibit a fascicular pattern and are composed of sheets and loose fascicles of plump spindle or epithelioid cells, with abundant brightly eosinophilic cytoplasm, sometimes mimicking rhabdomyoblasts (5) (Figure 3). Dermal lesions may show a variable degree of epidermal hyperplasia similar to dermatofibroma. (10)

The tumor cells contain vesicular nuclei, often with small nucleoli. The degree of nuclear atypia is usually mild, and mitotic activity is scarce. About 10% of tumors show notable pleomorphism and occasionally contain focally myxoid stroma. About 50% of cases contain prominent stromal neutrophils (Figure 3, inset). Unlike epithelioid hemangioendothelioma (EHE) and angiosarcoma, PMH rarely has intracytoplasmic vascular lumens. (2)

In some cases, intravascular invasion by neoplastic fascicles within entrapped blood vessels may be seen, (3) although this histopathologic finding does not seem to confer a worse prognosis.

ANCILLARY STUDIES

Immunohistochemistry

These tumors show diffuse expression of cytokeratin AE1/ AE3 and the endothelial transcription factors FLI1 and ERG. About 50% of cases are positive for CD31. Focal expression of smooth muscle actin is observed in one-third of tumors.

Recently, diffuse nuclear immunoreactivity for FOSB was demonstrated in 96% of PMH. Of note, its most relevant histologic mimics were negative, with the exception of isolated cases of EHE or angiosarcoma. (7)

Staining for cytokeratin MNF-116, EMA, S100 protein, CD34, and desmin is consistently negative. In contrast to ES, INI1 expression is retained in tumor cells. (3)

Electron Microscopy

The cytoplasm contains prominent rough endoplasmic reticulum and aggregates of intermediate filaments. (1-3) Subplasmalemmal pinocytic vesicles are numerous in some cells, and scattered desmosome-like junctions are often seen. An external lamina is prominent in some cases.

Genetics

As mentioned above, PMH harbors a t(7;19)(q22;q13) translocation that leads to the SERPINE1-FOSB gene fusion. (8,9)

SERPINE1 encodes the plasminogen activator inhibitor-1, which is highly expressed in endothelial cells. (11) FOSB encodes a transcription factor belonging to the FOS family of proteins, a major component of the Activating Protein 1 (AP-1) complex.

The role of SERPINE1 in this gene fusion is probably to provide a strong promoter for FOSB. FOSB fusions were also found in a subset of epithelioid hemangiomas, and although they do not show significant morphologic overlap with PMH, this lends credence to the idea that FOSB oncogenic activation is an important event in some benign and intermediate-grade vascular neoplasms. (12) Notably, SERPINE1-FOSB is not the only fusion gene in PMH, because 3 cases have been found to harbor FOSB rearrangements without SERPINE1 involvement. (12)

DIFFERENTIAL DIAGNOSES

Because of the presence of epithelioid cells and the diffuse expression of cytokeratins in a multifocal lesion, a metastatic carcinoma might be considered. The clinical context (usually young patients with no history of cancer) and, more importantly, the expression of FOSB, FLI1, and CD31 in a tumor that does not show significant nuclear atypia, argue against carcinoma.

The presence of rhabdomyoblast-like cells might suggest a rhabdomyosarcoma; however, the expression of FOSB, CD31, ERG, and FLI1, and the absence of desmin or myogenin expression help to rule it out.

Epithelioid hemangioendothelioma is a malignant angiocentric vascular neoplasm (Figure 4) that commonly arises in the superficial or deep soft tissues of the extremities, although it may involve virtually any part of the body. (13) It consists of epithelioid endothelial cells that display frequent intracytoplasmic vacuoles/lumina, occasionally containing erythrocytes ("blister cells"; Figure 4, inset). (13,14) These vacuolated endothelial cells, coupled with their arrangement in short cords or strands recapitulating the primitive angiogenic cords of the yolk sac, have become pathognomonic features of this lesion. The matrix is also quite distinctive and consists of a dense myxochondroid or hyaline material. (13,14)

Epithelioid hemangioendothelioma may acquire a spindled appearance similar to that of PMH. This usually occurs in more aggressive forms, in which there is a shift to an extremely high nuclear grade tumor with increased mitotic activity. Epithelioid hemangioendothelioma also expresses typical vascular markers, including CD31, CD34, FLI1, and ERG. (13) A subset of EHE also expresses epithelial antigens, such as CK7, CK8, CK18, and EMA, although their expression is usually focal, and rarely intense and diffuse, as seen in PMH. (15) Importantly, EHE has a t(1;3)(p36;q23-25) translocation that leads to WWTR1-CAMTA1 fusion in virtually all cases. (16) Nuclear expression of CAMTA1 by immunohistochemistry or identification of the fusion by fluorescent in situ hybridization is extremely helpful in confirming the diagnosis. (17) A small subset of EHE has a YAP1-TFE3 fusion. Unlike conventional EHE and PMH, these tumors show evidence of variable mature vaso-formation, often with a solid or pseudoalveolar growth pattern. (18)

Epithelioid angiosarcoma tends to localize in deep soft tissues and presents as large masses composed of sheets of epithelioid endothelial cells of uniformly high nuclear grade (Figure 5). In contrast to PMH, this neoplasm forms distinct multicellular vascular channels within a hemorrhagic backdrop (Figure 5, inset). (19,20) The vast majority behave as high-grade sarcomas, resulting in death in more than 50% of patients in a median interval of 11 months. (20) Epithelioid angiosarcomas also express vascular markers, such as CD31, FLI1 and ERG, with CD34 positivity in about 50% of cases. (21) Expression of cytokeratins (CKAE1/AE3, CK7, and CK8) has been demonstrated in up to one-third of cases. (21,22) FOSB is positive in only 5% of cases. (7)

Perhaps the most challenging differential diagnosis, considering the overlapping clinical and histologic features, is ES. Both tumors usually occur in young adults, may present with multifocal disease (or develop multiple lesions in the course of the disease), and, histologically, show epithelioid, cytokeratin-positive cells. Epithelioid sarcoma tends to grow in distinct, cohesive nodules, having central areas of hyalinization and necrosis (Figure 6), as opposed to the sheets and fascicles of PMH. (2) Immunohistochemistry plays a critical role in the distinction of these 2 lesions. CD31 and FOSB are expressed by PMH and are negative in ES, whereas many cases of ES, but not PMH, express CD34. It is important to mention that there may be expression of ERG and FLI1 in ES, which can cause diagnostic confusion. (23,24) The most useful finding is the loss of INI1 expression that is observed in more than 90% of both conventional and proximal-type ES but is not seen in most of its mimickers. (25) These differential diagnoses are summarized in the Table.

In bone lesions, besides the above-mentioned epithelioid neoplasms, other pitfalls may be osteoblastoma or fibrous dysplasia, due to the abundance of reactive woven bone (Figure 7). The presence of the spindled or epithelioid cells of PMH in the intertrabecular tissue, as single cells (Figure 7, inset) or arranged in fascicles, is an important diagnostic clue because they are absent in osteoblastoma and fibrous dysplasia.

PROGNOSIS AND TREATMENT

Approximately 60% of patients with this tumor experience local recurrences (often multiple) or develop additional nodules in the same anatomic region. (1-3) The interval between excision of the primary tumor and recurrence is usually 1 to 2 years. The relationship between margin status and recurrence has not been established. Of the 62 cases described by Mirra et al, (1) Billings et al, (2) and Hornick and Fletcher, (3) only 1 patient presented with a regional lymph node metastasis, and 3 developed distant metastases. Two patients died of disease.

The treatment of choice has been surgery (wide resection), with certain cases receiving radiotherapy or chemotherapy. (3) Recently, high expression of mTOR has been demonstrated by immunohistochemistry, and 2 cases treated with mTOR inhibitors showed clinical improvement. (26-28)

CONCLUSIONS

Pseudomyogenic hemangioendothelioma is an uncommon vascular lesion that affects mainly young men and is characterized by multifocal lesions in the extremities, usually involving different tissue planes. Nonvascular lesions, such as metastatic carcinoma, rhabdomyosarcoma, or ES, represent potential diagnostic pitfalls. Among vascular tumors, PMH can be confused with epithelioid vascular lesions, such as EHE and epithelioid angiosarcoma. Pseudomyogenic hemangioendothelioma usually has an indolent behavior, with minimal risk of metastasis, in contrast with most of its mimickers. Therefore, correct recognition is extremely important to establish adequate prognosis and treatment.

References

(1.) Mirra JM, Kessler S, Bhuta S, Eckardt J. The fibroma-like variant of epithelioid sarcoma: a fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer. 1992;69(6):1382-1395.

(2.) Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol. 2003;27(1):48-57.

(3.) Hornick JL, Fletcher CD. Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol. 2011;35(2):190-201.

(4.) Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma (pseudomyogenic hemangioendothelioma). Am J Surg Pathol. 2011; 35(7):1088; author reply 1088-1089.

(5.) Hornick JL, Mertens F, Fletcher CD. Pseudomyogenic haemangioendothelioma. In: Fletcher CD, Bridge JA, Hogendoorn PCW, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press; 2013: 153-154. World Health Organization Classification of Tumours; vol 5.

(6.) Inyang A, Mertens F, Puls F, et al. Primary pseudomyogenic hemangioendothelioma of bone. Am J Surg Pathol. 2016;40(5):587-598.

(7.) Hung YP, Fletcher CD, Hornick JL. FOSB is a useful diagnostic marker for pseudomyogenic hemangioendothelioma. Am J Surg Pathol. 2016;41(5):596-606.

(8.) Trombetta D, Magnusson L, Von Steyern FV, Hornick JL, Fletcher CD, Mertens F. Translocation (7;19)(q22;q13)--a recurrent chromosome aberration in pseudomyogenic hemangioendothelioma? Cancer Genet. 2011;204(4):211-215.

(9.) Walther C, Tayebwa J, Lilljebjorn H, et al. A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol. 2014;232(5):534-540.

(10.) Requena L, Santonja C, Martinez-Amo JL, Saus C, Kutzner H. Cutaneous epithelioid sarcoma-like (pseudomyogenic) hemangioendothelioma: a little-known low-grade cutaneous vascular neoplasm. JAMA Dermatol. 2013;149(4): 459-465.

(11.) Ghosh AK, Vaughan DE. PAI-1 in tissue fibrosis. J Cell Physiol. 2012;227(2): 493-507.

(12.) Antonescu CR, Chen HW, Zhang L, et al. ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features. Genes Chromosomes Cancer. 2014;53(11):951-959.

(13.) Weiss SW, Antonescu CR, Bridge JA, Deyrup AT. Epithelioid hemangioendothelioma. In: Fletcher CD, Bridge JA, Hogendoorn PCW, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press; 2013:155-156. World Health Organization Classification of Tumours; vol 5.

(14.) Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970-981.

(15.) Gray MH, Rosenberg AE, Dickersin GR, Bhan AK. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol. 1990;21(2):212-217.

(16.) Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 2011;50(8):644-653.

(17.) Doyle LA, Fletcher CD, Hornick JL. Nuclear expression of CAMTA1 distinguishes epithelioid hemangioendothelioma from histologic mimics. Am J Surg Pathol. 2016;40(1):94-102.

(18.) Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013;52(8):775-784.

(19.) Fletcher CD, Beham A, Bekir S, Clarke AM, Marley NJ. Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm. Am J Surg Pathol. 1991;15(10):915-924.

(20.) Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol. 1998;22(6):683-697.

(21.) Miettinen M. Immunohistochemistry of soft tissue tumours-review with emphasis on 10 markers. Histopathology. 2014;64(1):101-118.

(22.) Wei S, Henderson-Jackson E, Qian X, Bui MM. Soft tissue tumor immunohistochemistry update: illustrative examples of diagnostic pearls to avoid pitfalls. Arch Pathol Lab Med. 2017;141(8):1072-1091.

(23.) Miettinen M, Wang Z, Sarlomo-Rikala M, AbdullaevZ, Pack SD, Fetsch JF. ERG expression in epithelioid sarcoma: a diagnostic pitfall. Am J Surg Pathol. 2013;37(10):1580-1585.

(24.) Stockman DL, Hornick JL, Deavers MT, Lev DC, Lazar AJ, Wang WL. ERG and FLI1 protein expression in epithelioid sarcoma. Mod Pathol. 2014;27(4):496-501.

(25.) Hollmann TJ, Hornick JL. INI1-deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol. 2011;35(10):47-63.

(26.) Joseph J, Wang WL, Patnana M, et al. Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma. Clin Sarcoma Res. 2015; 5:22.

(27.) Ozeki M, Nozawa A, Kanda K, et al. Everolimus for treatment of pseudomyogenic hemangioendothelioma. J Pediatr Hematol Oncol. 2017;39(6): 328-331.

(28.) Gabor KM, Sapi Z, Tiszlavicz LG, et al. Sirolimus therapy in the treatment of pseudomyogenic hemangioendothelioma. Pediatr Blood Cancer. 2018;65(2). doi: 10.1002/pbc.26781.

Gustavo A. Caballero, MD; Pablo D. Roitman, MD

Accepted for publication December 12, 2018.

Published online April 24, 2019.

From the Pathology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: Gustavo A. Caballero, MD, Pathology Department, Hospital Italiano de Buenos Aires, Gascon 450, Juan D.l Peron 4190, Buenos Aires, Buenos Aires C1199ABB, Argentina (email: gustavo.caballero@hospitalitaliano.org.ar).

Caption: Figure 1. Radiograph shows multiple lytic lesions in the proximal femur.

Caption: Figure 2. Grossly, multiple yellowish, partially hemorrhagic lesions are seen.

Caption: Figure 3. Plump, epithelioid cells arranged in sheets and ill-defined fascicles (inset). Neutrophils are also evident (inset) (hematoxylineosin, original magnification X400).

Caption: Figure 4. Cords of epithelioid cells in a myxohyaline background. Angiocentric growth pattern. Occasional "blister" cells are present (inset) (hematoxylin-eosin, original magnification x400).

Caption: Figure 5. Highly atypical epithelioid cells arranged in solid sheets, with hemorrhage and hemosiderin deposition. Irregular, infiltrative vascular channels (inset) (hematoxylin-eosin, original magnification x400).

Caption: Figure 6. Nodular growth pattern with geographic necrosis. Sheets of epithelioid cells (inset) (hematoxylin-eosin, original magnifications x100 and x400 [inset]).

Caption: Figure 7. Pseudomyogenic hemangioendothelioma in bone. Extensive reactive woven bone and marrow fibrosis. Isolated tumoral cells may be seen between trabeculae (inset) (hematoxylin-eosin, original magnifications x100 and x400 [inset]).
Pseudomyogenic Hemangioendothelioma and Its Differential Diagnoses

                           Pseudomyogenic            Epithelioid
                        Hemangioendothelioma     Hemangioendothelioma

Clinical features      Males. Young adults.     No age or sex
                         Superficial or deep      predilection.
                         soft tissue of           Superficial or deep
                         extremities              soft tissue of
                                                  extremities.
                                                  Visceral
Histologic features
  Growth pattern       Ill-defined nodules      Cords. Myxochondroid
                         and fascicles.           or hyaline stroma
                         Desmoplastic stroma
  Vasoformation        Not present              Frequent
                                                  intracytoplasmic
                                                  lumens
  Nuclear atypia       Mild to moderate         Mild to moderate
Immunohistochemistry   [CD34.sup.-],            [CD34.sup.+],
                         [CD31.sup.+],            [CD31.sup.+],
                         [Fli-1.sup.+],           [Fli-1.sup.+],
                         [ERG.sup.+],             [ERG.sup.+],
                         [FOSB.sup.+],            [FOSB.sup.-],
                         [CKs.sup.+],             [CKs.sup.+],
                         [CAMTA1.sup.-],          [CAMTA1.sup.+],
                         INI-1 retained           INI-1 retained
Genetics               SERPINE1-FOSB fusion     WWTR1-CAMTA1 fusion
Behavior               Usually indolent, but    Local recurrences,
                         with 60% of cases        with metastases in
                         showing local or         20%-30% of cases
                         regional
                         recurrences.
                         Metastases are
                         extremely rare

                            Epithelioid              Epithelioid
                            Angiosarcoma               Sarcoma

Clinical features      Males. Mostly older      Males. Young adults.
                         adults. Deep soft        Superficial soft
                         tissue of                tissue of
                         extremities              extremities
Histologic features
  Growth pattern       Sheets. Necrosis. Old    Nodules, often with
                         and recent               central necrosis
                         hemorrhage
  Vasoformation        Vascular channels.       Not present
                         Intracytoplasmic
                         lumens
  Nuclear atypia       Moderate to marked       Mild to moderate
Immunohistochemistry   [CD34.sup.+] (50%),      [CD34.sup.+] (50%),
                         [CD31.sup.+],            [CD31.sup.-],
                         [Fli-1.sup.+],           [Fli-1.sup.-] and
                         [ERG.sup.+],             [ERG.sup.-] (in most
                         [FOSB.sup.-],            cases),
                         [CKs.sup.+],             [FOSB.sup.-],
                         [CAMTA1.sup.-],          [CKs.sup.+],
                         INI-1 retained           [CAMTA1.sup.-],
                                                  INI-1 lost
Genetics               Complex cytogenetic      Inactivation of
                         aberrations              suppressor gene
                                                  SMARCB1/INI1
Behavior               Local recurrences and    High risk of local
                         metastases. More         recurrences (75%)
                         than 50% of patients     and metastases (45%)
                         die of disease

Abbreviation: CKs, cytokeratins.
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Author:Caballero, Gustavo A.; Roitman, Pablo D.
Publication:Archives of Pathology & Laboratory Medicine
Date:Apr 1, 2020
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