Abstract

Angiosarcoma and anaplastic carcinoma are the most lethal neoplasms of the thyroid worldwide and share some similarities, which have led to a longstanding controversy on their etiopathological relationship. Thyroid angiosarcomas are characterized by vessel formation and an immunophenotype common to endothelial cells, while anaplastic carcinomas are partially or wholly composed of mesenchymal-like cells that have lost the morphologic and functional features of normal thyroid follicular cells. To investigate whether angiosarcomas represent the endothelial extreme of the differentiation spectrum of carcinomas or they are bona fide vascular neoplasms, we studied the clinico-morphologic and genetic characteristics of a series of 10 angiosarcomas and 22 anaplastic carcinomas. Immunohistochemically, among the endothelial markers, CD31 and ERG were the most consistently expressed in angiosarcomas. Among the markers of thyroid origin, PAX8 was the most reliable in anaplastic carcinomas, while TTF-1 reactivity was found in only 5% of anaplastic carcinomas and thyroglobulin was always negative. Pankeratin reacted with most angiosarcomas and anaplastic carcinomas and is therefore not useful in the differential diagnosis. Interestingly a mutated pattern of p53 immunostaining prompted a diagnosis of anaplastic carcinoma. To compare the genetic profile, we used the NGS approach to sequence hotspot regions within a panel of 57 genes. As a result, only a few mutations were found in angiosarcomas and all of them were single events (no TP53 or TERT mutation). On the other hand, anaplastic carcinomas were characterized by a higher number of mutations, and TP53 and TERT promoter mutations were the most frequent genetic alterations. The lack in angiosarcomas of the common mutations identified in anaplastic carcinomas supports a different genetic origin and strongly suggests that, in spite of a shared sarcomatous morphology and a similar clinical aggressiveness, angiosarcomas and anaplastic carcinomas rely on a completely different set of genetic alterations during their evolution.

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References

  1. 1.

    Wick MR, Eusebi V, Lamovec J, Ryska A. Angiosarcoma. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J, editors. WHO Classification of tumors of endocrine organs, Lyon: IARC; 2017. p. 129–32.

  2. 2.

    Eckert F, Schmid U, Gloor F, hedinger C. Evidence of vascular differentiation in anaplastic tumours of the thyroid--an immunohistological study. Virchows Arch. 1986;410:203–15.

  3. 3.

    Krisch K, Holzner JH, Kokoschka R, jakesz R, Niderle B, Roka R. Hemangioendothelioma of the thyroid gland-true endothelioma or anaplastic carcinoma? Pathol Res Pract. 1980;170:230–42.

  4. 4.

    Mills SE, Gaffey MJ, Watts JC, Swanson PE, Wick MR, LiVolsi VA et al. Angiomatoid carcinoma and ‘angiosarcoma’ of the thyroid gland. A spectrum of endothelial differentiation. Am J Clin Pathol. 1994;102:322–30.

  5. 5.

    Mills SE, Stallings RG, Austin MB. Angiomatoid carcinoma of the thyroid gland. Anaplastic carcinoma with follicular and medullary features mimicking angiosarcoma. Am J Clin Pathol. 1986;86:674–8.

  6. 6.

    Chan YF, Ma L, Boey JH, Yeung HY. Angiosarcoma of the thyroid. An immunohistochemical and ultrastructural study of a case in a Chinese patient. Cancer. 1986;57:2381–8.

  7. 7.

    Eusebi V, Carcangiu ML, Dina R, Rosai J. Keratin-positive epithelioid angiosarcoma of thyroid. A report of four cases. Am J Surg Pathol. 1990;14:737–47.

  8. 8.

    Lamovec J, Zidar A, Zidanik B. Epithelioid angiosarcoma of the thyroid gland. Report of two cases. Arch Pathol Lab Med. 1994;118:642–6.

  9. 9.

    Maiorana A, Collina G, Cesinaro AM, Fano RA, Eusebi V. Epithelioid angiosarcoma of the thyroid. Clinicopathological analysis of seven cases from non-Alpine areas. Virchows Arch. 1996;429:131–7.

  10. 10.

    Tanda F, Massarelli G, Bosincu L, Cossu A. Angiosarcoma of the thyroid: a light, electron microscopic and histoimmunological study. Hum Pathol. 1988;19:742–5.

  11. 11.

    Totsch M, Dobler G, Feichtinger H, Sandbichler P, Ladurner D, Schmid KW. Malignant hemangioendothelioma of the thyroid. Its immunohistochemical discrimination from undifferentiated thyroid carcinoma. Am J Surg Pathol. 1990;14:69–74.

  12. 12.

    Goh SG, Chuah KL, Goh HK, Chen YY. Two cases of epithelioid angiosarcoma involving the thyroid and a brief review of non-Alpine epithelioid angiosarcoma of the thyroid. Arch Pathol Lab Med. 2003;127:E70–73.

  13. 13.

    Rotellini M, Vezzosi V, Bianchi S. Epithelioid angiosarcoma of the thyroid: report of a case from an Italian non-alpine area and review of the literature. Endocr Pathol. 2015;26:152–6.

  14. 14.

    Ryska A, Ludvikova M, Szepe P, Böör A. Epithelioid haemangiosarcoma of the thyroid gland. Report of six cases from a non-Alpine region. Histopathology. 2004;44:40–46.

  15. 15.

    Papotti M, Arrondini M, Tavaglione V, Veltri A, Volante M. Diagnostic controversies in vascular proliferations of the thyroid gland. Endocr Pathol. 2008;19:175–83.

  16. 16.

    Papotti M, Volante M, Negro F, Eusebi V, Bussolati G. Thyroglobulin mRNA expression helps to distinguish anaplastic carcinoma from angiosarcoma of the thyroid. Virchows Arch. 2000;437:635–42.

  17. 17.

    Ritter JH, Mills SE, Nappi O, Wick MR. Angiosarcoma-like neoplasms of epithelial organs: true endothelial tumors or variants of carcinoma? Semin Diagn Pathol. 1995;12:270–82.

  18. 18.

    Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. 2009;16:17–44.

  19. 19.

    Kuhn E, Kurman RJ, Vang R, Sehdev AS, Han G, Soslow R, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions. J Pathol. 2012;226:421–6.

  20. 20.

    Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, et al. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst. 2012;104:1503–13.

  21. 21.

    Lococo F, Gandolfi G, Rossi G, Pinto C, Rapicetta C, Cavazza A, et al. Deep sequencing analysis reveals that KRAS mutation is a marker of poor prognosis in patients with pulmonary sarcomatoid carcinoma. J Thorac Oncol. 2016;11:1282–92.

  22. 22.

    Gandolfi G, Ragazzi M, de Biase D, Visani M, Zanetti E, Torricelli F, et al. Genome-wide profiling identifies the THYT1 signature as a distinctive feature of widely metastatic papillary thyroid carcinomas. Oncotarget. 2018;9:1813–25.

  23. 23.

    Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest. 2016;126:1052–66.

  24. 24.

    De Felice F, Moscatelli E, Orelli S, Bulzonetti N, Musio D, Tombolini V. Primary thyroid angiosarcoma: a systematic review. Oral Oncol. 2018;82:48–52.

  25. 25.

    Dibelius G, Mehra S, Clain JB, Urken ML, Wenig BM. Noninvasive anaplastic thyroid carcinoma: report of a case and literature review. Thyroid. 2014;24:1319–24.

  26. 26.

    Pichardo-Lowden A, Durvesh S, Douglas S, Todd W, Bruno M, Goldenberg D. Anaplastic thyroid carcinoma in a young woman: a rare case of survival. Thyroid. 2009;19:775–9.

  27. 27.

    Patel SH, Hayden RE, Hinni ML, Wong WW, Foote RL, Milani S, et al. Angiosarcoma of the scalp and face: the Mayo Clinic experience. JAMA Otolaryngol Head Neck Surg. 2015;141:335–40.

  28. 28.

    Krishnan H, Rayes J, Miyashita T, Ishii G, Retzbach EP, Sheehan SA, et al. Podoplanin: an emerging cancer biomarker and therapeutic target. Cancer Sci. 2018;109:1292–9.

  29. 29.

    Ciarrocchi A, Piana S, Valcavi R, Gardini G, Casali B. Inhibitor of DNA binding-1 induces mesenchymal features and promotes invasiveness in thyroid tumour cells. Eur J Cancer. 2011;47:934–45.

  30. 30.

    Gugnoni M, Sancisi V, Gandolfi G, Manzotti G, Ragazzi M, Giordano D, et al. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene. 2017;36:667–77.

  31. 31.

    Ferru A, Fromont G, Gibelin H, Guilhot J, Savagner F, Tourani JM, et al. The status of CDKN2A alpha (p16INK4A) and beta (p14ARF) transcripts in thyroid tumour progression. Br J Cancer. 2006;95:1670–7.

  32. 32.

    Pita JM, Figueiredo IF, Moura MM, Leite V, Cavaco BM. Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014;99:E497–507.

  33. 33.

    Ginter PS, Mosquera JM, MacDonald TY, D'Alfonso TM, Rubin MA, Shin SJ. Diagnostic utility of MYC amplification and anti-MYC immunohistochemistry in atypical vascular lesions, primary or radiation-induced mammary angiosarcomas, and primary angiosarcomas of other sites. Hum Pathol. 2014;45:709–16.

  34. 34.

    Sakr HI, Chute DJ, Nasr C, Sturgis CD. cMYC expression in thyroid follicular cell-derived carcinomas: a role in thyroid tumorigenesis. Diagn Pathol. 2017;12:71.

  35. 35.

    Enomoto K, Zhu X, Park S, Zhao L, Zhu YJ, Willingham MC, et al. Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. J Clin Endocrinol Metab. 2017;102:2268–80.

  36. 36.

    Bonhomme B, Godbert Y, Perot G, Al Ghuzlan A, Bardet S, Belleannée G, al. Molecular pathology of anaplastic thyroid carcinomas: a retrospective study of 144 cases. Thyroid. 2017;27:682–92.

  37. 37.

    Collini P, Barisella M, Renne SL, Pizzi N, Mattavelli D, Stacchiotti S, et al. Epithelioid angiosarcoma of the thyroid gland without distant metastases at diagnosis: report of six cases with a long follow-up. Virchows Arch. 2016;469:223–32.

  38. 38.

    Deeken-Draisey A, Yang GY, Gao J, Alexiev BA. Anaplastic thyroid carcinoma: an epidemiologic, histologic, immunohistochemical and molecular single institution study. Hum Pathol. 2018. https://doi.org/10.1016/j.humpath.2018.07.027.

  39. 39.

    Jeon MJ, Chun SM, Kim D, Kwon H, Jang EK, Kim TY, et al. Genomic alterations of anaplastic thyroid carcinoma detected by targeted massive parallel sequencing in a BRAF(V600E) mutation-prevalent area. Thyroid. 2016;26:683–90.

  40. 40.

    Oishi N, Kondo T, Ebina A, Sato Y, Akaishi J, Hino R, et al. Molecular alterations of coexisting thyroid papillary carcinoma and anaplastic carcinoma: identification of TERT mutation as an independent risk factor for transformation. Mod Pathol. 2017;30:1527–37.

  41. 41.

    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–62.

  42. 42.

    Murali R, Chandramohan R, Moller I, Scholz SL, Berger M, Huberman K, et al. Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway. Oncotarget. 2015;6:36041–52.

  43. 43.

    Liau JY, Tsai JH, Yang CY, lee JC, Liang CW, Hsu HH, et al. Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas. Hum Pathol. 2015;46:1360–6.

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Author notes

  1. These authors contributed equally: Elisabetta Kuhn, Moira Ragazzi

Affiliations

  1. Pathology Unit, Arcispedale Santa Maria Nuova, Azienda USL-IRCCS, Reggio Emilia, Italy

    • Elisabetta Kuhn
    • , Moira Ragazzi
    • , Eleonora Zanetti
    • , Alessandra Bisagni
    •  & Simonetta Piana
  2. Laboratory of Translational Research, Arcispedale Santa Maria Nuova, Azienda USL-IRCCS, Reggio Emilia, Italy

    • Alessia Ciarrocchi
    •  & Federica Torricelli
  3. Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) - Molecular Pathology Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy

    • Dario de Biase
  4. Department of Anatomic Pathology, Azienda Ospedaliero-Universitaria, Modena, Italy

    • Stefania Corrado
  5. Department of Medicine and Surgery, University of Insumbria, Varese, Italy

    • Silvia Uccella
  6. Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland

    • Stefano La Rosa
    •  & Massimo Bongiovanni
  7. National Cancer Institute G. Pascale, Naples, Italy

    • Simona Losito

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Correspondence to Simonetta Piana.

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https://doi.org/10.1038/s41379-018-0199-z