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Open Access 01-12-2014 | Research

Epithelioid Hemangioendothelioma: clinicopathologic, immunhistochemical, and molecular genetic analysis of 39 cases

Authors: Uta Flucke, Rob JC Vogels, Nicolas de Saint Aubain Somerhausen, David H Creytens, Robert G Riedl, Joost M van Gorp, Anya N Milne, Clement J Huysentruyt, Marian AJ Verdijk, Monique M van Asseldonk, Albert JH Suurmeijer, Johannes Bras, Gabriele Palmedo, Patricia JTA Groenen, Thomas Mentzel

Published in: Diagnostic Pathology | Issue 1/2014

Abstract

Background

Epithelioid hemangioendothelioma is a malignant, often indolent vascular tumor which occurs at various anatomic sites. Based on a reciprocal translocation t (1;3)(p36;q25), a consistent WWTR1-CAMTA1 fusion gene has been found. An alternate YAP1-TFE3 fusion has been detected in a small and distinct subset of cases.

Methods

Thirty-nine tumors, from 24 females and 15 males with an age range 9–85 years, were located in soft tissue (head and neck [8], trunk [5], upper extremities [3], lower extremities [2], mediastinal [1], and paratesticular [1]), lymph node (1), breast (1), skin (2), bone (6), lung (7), and liver (2). The cases were investigated using a panel of immunohistochemical markers. The aforementioned fusion-genes were examined using RT-PCR and/or FISH in order to validate their diagnostic value.

Results

Follow-up available for 17 patients ranged from 3 months to 7 years (median interval 1.5 years). Eleven patients were alive without disease, 2 patients were alive with disease after 1.5 and 2 years, respectively. Four patients died of disease after 4 months (n = 1), 5 months (n = 2), and 1.5 years (n = 1).

The size, known for 30 lesions, was >3 cm in 9 of them. Histologically, all lesions had classical features, at least focally. Four tumors counted >3 mitoses/50 HPF.

Immunohistochemically, all cases tested stained positive for ERG (21), FLI1 (5) and CD31 (39). CD34 and D2-40 positivity was seen in 81% and 71% of the examined cases, respectively. 11/35 cases expressed pan-keratin and 6/20 cases CK8.18. TFE3 showed a nuclear reaction in 21/24 cases, irrespective of TFE3 rearrangement.

Molecular genetically, 35/35 cases revealed one of the fusion genes by FISH and/or RT-PCR with WWTR1-CAMTA1 in 33 cases and YAP1-TFE3 in 2 cases.

Conclusions

These results demonstrate the high diagnostic value of FISH and RT-PCR in detecting the fusion genes of EHE. The immunohistochemical utility of TFE3 appears questionable in this study.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4010279141259481

Weiss SW, Enzinger FM: Epithelioid hemangioendothelioma. a vascular tumor often mistaken for a carcinoma. Cancer. 1982, 50: 970-981.PubMedCrossRef

Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD: Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol. 1997, 21: 363-374.PubMedCrossRef

Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara G, Rosenthal H, Bridge JA: Translocation t (1;3) (p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol. 2001, 25: 684-687.PubMedCrossRef

Deyrup AT, Tighiouart M, Montag AG, Weiss SW: Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol. 2008, 32: 924-927.PubMedCrossRef

Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopolous C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP: Identification of disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med. 2011, 3: 98ra82

Jinghong X, Lirong C: Pulmonary epithelioid hemangioendothelioma accompanied by bilateral multiple calcified nodules in the lung. Diagn Pathol. 2011, 6: 21-PubMedPubMedCentralCrossRef

Li XM, Lin XY, Xu HT, Yu JH, Wang L, Fan CF, Liu Y, Wang EH: Mediastinal epitheloid hemangioendothelioma with abundant spindle cells and osteoclast-like giant cells mimicking malignant fibrous histiocytoma. Diagn Pathol. 2013, 8: 103-PubMedPubMedCentralCrossRef

Billings SD, Folpe AL, Weiss SW: Epithelioid sarcoma-like hemangioenothelioma. Am J Surg Pathol. 2003, 27: 48-57.PubMedCrossRef

Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki R, Healey JH, Antonescu CR: A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 2011, 50: 644-653.PubMedPubMedCentralCrossRef

10.

Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen CL, Chen HW, Pathan N, Krausz T, Dickson BC, Weinreb I, Rubin MA, Hameed M, Fletcher CD: Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013, 52: 775-784.PubMedPubMedCentralCrossRef

11.

Mitelman F, Johansson B, Mertens F: The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007, 7: 233-245.PubMedCrossRef

12.

Cheah AL, Goldblum JR, Billings SD: Molecular diagnostics complementing morphology in superficial mesenchymal tumors. Semin Diagn Pathol. 2013, 30: 95-109.PubMedCrossRef

13.

Haq R, Fisher DE: Biology and clinical relevance of the microophtalmia family of transcription factors in human cancer. J Clin Oncol. 2011, 29: 3474-3482.PubMedCrossRef

14.

Chan JK, Frizzera G, Fletcher CD, Rosai J: Primary vascular tumors of lymph nodes other than Kaposi’s sarcoma. Am J Surg Pathol. 1992, 16: 335-350.PubMedCrossRef

15.

Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Dal Cin P, Bridge J: The der (17) t (X;17) (p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001, 20: 48-57.PubMedCrossRef

16.

Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M: Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001, 159: 179-192.PubMedPubMedCentralCrossRef

17.

Argani P, Aulmann S, Illei P, Netto G, Ro J, Cho HY, Dogan S, Ladanyi M, Martignoni G, Goldblum JR, Weiss SW: A distinctive subset of PEComas harbor TFE3 gene fusions. Am J Surg Pathol. 2010, 34: 1395-1406.PubMedCrossRef

18.

Malinowska I, Kwiatkowski DJ, Weiss SW, Martignoni G, Netto G, Argani P: Perivascular epithelioid cell tumors (PEComas) harboring TFE3 gene rearrangements lack the TSC2 alterations characteristic of conventional PEComas: further evidence for a biologic distinction. Am J Surg Pathol. 2012, 36: 783-784.PubMedPubMedCentralCrossRef

19.

Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M: Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol. 2003, 27: 750-761.PubMedCrossRef

20.

Folpe AL, Chand EM, Goldblum JR, Weiss SW: Expression of Fli-1, a nuclear transcriptionfactor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol. 2001, 25: 1061-1066.PubMedCrossRef

21.

Miettinen M, Wang ZF, Paetau A, Tan SH, Dobi A, Srivastava S, Sesterhenn I: ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol. 2011, 35: 432-441.PubMedCrossRef

22.

Brenn T, Fletcher CD: Cutaneous epithelioid angiomatous nodule: a distinct lesion in the morphologic spectrum of epithelioid vascular tumors. Am J Dermatopathol. 2004, 26: 14-21.PubMedCrossRef

23.

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

24.

Hornick JL, Fletcher CD: Pseudomyogenic hemangioendothelioma: a distinctive, often muticentric tumor with indolent behavior. Am J Surg Pathol. 2011, 35: 190-201.PubMedCrossRef

25.

Fetsch JF, Sesterhenn IA, Miettinen M, Davis CJ: Epithelioid hemangioma of the penis. a clinicopathologic and immunohistochemical analysis of 19 cases, with special reference to exuberant examples often confused with epithelioid hemangioendothelioma and epithelioid angiosarcoma. Am J Surg Pathol. 2004, 28: 523-533.PubMedCrossRef

26.

Errani C, Zhang L, Panicek DM, Healey JH, Antonescu CR: Epithelioid hemangioma of bone and soft tissue. Clin Orthoped Relat Res. 2012, 470: 1498-1506.CrossRef

27.

Nielsen GP, Srivastava A, Kattapuram S, Deshpande V, O’Connell JX, Mangham CD, Rosenberg AE: Epithelioid hemangioma of bone revisited. a study of 50 cases. Am J Surg Pathol. 2009, 33: 270-277.PubMedCrossRef

28.

Walther C, Tayebwa J, Lilljebjorn H, Magnusson L, Nilsson J, Vult von Steyern F, Ora I, Domanski H, Fioretos T, Nord KH, Fletcher CDM, Mertens F: A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol. 2014, 232: 534-540.PubMedCrossRef

29.

Hornick JL, Fletcher CD: Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2003, 27: 1183-1196.PubMedCrossRef

30.

Antonescu CR, Zhang L, Chang NE, Pawel BR, Travis W, Katabi N, Edelman M, Rosenberg AE, Nielsen GP, Dal Cin P, Fletcher CD: EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. a molecular analysis of sixty-six cases, including soft tissue, bone and visceral lesions showing common involvement of EWSR1 gene rearrangement. Genes Chromosomes Cancer. 2010, 49: 1114-1124.PubMedPubMedCentralCrossRef

31.

Bahrami A, Dalton JD, Krane JF, Fletcher CD: A subset of cutaneous and soft tissue mixed tumors are genetically linked to their salivary gland counterpart. Genes Chromosomes Cancer. 2012, 51: 140-148.PubMedPubMedCentralCrossRef

32.

Flucke U, Palmedo G, Blankenhorn N, Slootweg PJ, Kutzner H, Mentzel T: EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases. Mod Pathol. 2011, 24: 1444-1450.PubMedCrossRef

33.

Antonescu CR, Zhang L, Shao SY, Mosquera JM, Weinreb I, Katabi N, Fletcher CD: Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation. Genes Chromosomes Cancer. 2013, 52: 675-682.PubMedPubMedCentralCrossRef

34.

Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom LG: Extraskeletal myxoid chondrsarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol. 1999, 23: 636-650.PubMedCrossRef

35.

Hisaoka M, Hashimoto H: Extraskeletal myxoid chondrosarcoma: updated clinicopathological and molecular genetic characteristics. Pathol Int. 2005, 55: 453-463.PubMedCrossRef

36.

Chase DR, Enzinger FM: Epithelioid sarcoma. diagnosis, prognostic indicators, and treatment. Am J Surg Pathol. 1985, 9: 241-263.PubMedCrossRef

37.

Flucke U, Hulsebos TJ, van Krieken JH, Mentzel T: Myxoid epithelioid sarcoma: a diagnostic challenge. a report on six cases. Histopathology. 2010, 57: 753-759.PubMedCrossRef

38.

Hornick JL, Dal Cin P, Fletcher CD: Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009, 33: 542-550.PubMedCrossRef

39.

Den Bakker MA, Flood SJ, Kliffen M: CD31 staining in epithelioid sarcoma. Virch Arch. 2003, 443: 93-97.CrossRef

40.

Miettinen M, Wang Z, Sarlomo-Rikala M, Abdullaev Z, Pack SD, Fetsch JF: ERG expression in epithelioid sarcoma. Am J Surg Pathol. 2013, 37: 1580-1585.PubMedPubMedCentralCrossRef

41.

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

42.

Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F: WHO classification of tumours of soft tissue and bone. 2013, Lyon: IARC, 39-264.

43.

Ordóñez NG: Mesothelioma with signet ring cell features: report of 23 cases. Mod Pathol. 2013, 26: 370-384.PubMedCrossRef

Title: Epithelioid Hemangioendothelioma: clinicopathologic, immunhistochemical, and molecular genetic analysis of 39 cases
Authors: Uta Flucke
Rob JC Vogels
Nicolas de Saint Aubain Somerhausen
David H Creytens
Robert G Riedl
Joost M van Gorp
Anya N Milne
Clement J Huysentruyt
Marian AJ Verdijk
Monique M van Asseldonk
Albert JH Suurmeijer
Johannes Bras
Gabriele Palmedo
Patricia JTA Groenen
Thomas Mentzel
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Diagnostic Pathology / Issue 1/2014
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/1746-1596-9-131

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Epithelioid Hemangioendothelioma: clinicopathologic, immunhistochemical, and molecular genetic analysis of 39 cases

Abstract

Background

Methods

Results

Conclusions

Virtual Slides

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Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Virtual Slides

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