AIMS: The formal pathogenesis of salivary carcinosarcoma (SCS) remained unclear, both with respect to the hypothetical development from either preexisting pleomorphic adenoma (PA) or de novo and the clonal relationship between highly heterogeneous carcinomatous and sarcomatous components. METHODS AND RESULTS: We performed clinicopathological and molecular (targeted RNA sequencing) analyses on a large series of 16 cases and combined this with a comprehensive literature search (111 cases). Extensive sampling (average 11.6 blocks), combined with immunohistochemistry and molecular studies (PA-specific translocations including PLAG1 or HMGA2 proven in 6/16 cases), enabled the morphogenetic identification of PA in 15/16 cases (93.8%), by far surpassing a reported rate of 49.6%. Furthermore, we demonstrated a multistep (intraductal/intracapsular/extracapsular) adenoma-carcinoma-sarcoma-progression, based on two alternative histogenetic pathways (intraductal, 56.3%, versus myoepithelial pathway, 37.5%). Thereby, early intracapsular stages are identical to conventional carcinoma ex PA, while later extracapsular stages are dominated by secondary, frequently heterologous sarcomatous transformation with often large tumour size (>60 mm). CONCLUSION: Our findings strongly indicate that SCS (almost) always develops from PA, with a complex multistep adenoma-carcinoma-sarcoma-sequence, based on two alternative histogenetic pathways. The findings from this novel approach strongly suggest that SCS pathogenetically is a rare (3-6%), unique, and aggressive variant of carcinoma ex PA with secondary sarcomatous overgrowth. In analogy to changes of terminology in other organs, the term "sarcomatoid carcinoma ex PA with/without heterologous elements" might be more appropriate.

D and R Institute of Pathology Medical University of Graz Graz Austria

Dental School Ludwig Maximilians University Munich Germany

Department of Head Neck Oral Pathology Guy's and St Thomas' NHS Foundation Trust London UK

Department of Pathology East Kent Hospitals University NHS Foundation Trust Ashford UK

DERMPATH Muenchen Munich Germany

Fingerland Department of Pathology Charles University Faculty of Medicine and University Hospital Hradec Kralove Hradec Králové Czech Republic

Institute of Pathology Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Institute of Pathology Friedrich Alexander University Erlangen Nürnberg University Hospital Erlangen Erlangen Germany

Institute of Pathology Ludwig Maximilians University Munich Germany

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Stephen J, Batsakis JG, Luna MA, von der Heyden U, Byers RM. True malignant mixed tumors (carcinosarcoma) of salivary glands. Oral Surg. Oral Med. Oral Pathol. 1986; 61; 597-602.

Tortoledo ME, Luna MA, Batsakis JG. Carcinomas ex pleomorphic adenoma and malignant mixed tumors. Histomorphologic indexes. Arch. Otolaryngol. 1984; 110; 172-176.

Staffieri C, Marioni G, Ferraro SM, Marino F, Staffieri A. Carcinosarcoma de novo of the parotid gland. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2007; 104; e35-e40.

Carson HJ, Tojo DP, Chow JM, Hammadeh R, Raslan WF. Carcinosarcoma of salivary glands with unusual stromal components. Report of two cases and review of the literature. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1995; 79; 738-746.

Garner SL, Maves MD, Robinson RA, Barnes CH. Salivary gland carcinosarcoma: true malignant mixed tumor. Ann. Otol. Rhinol. Laryngol. 1989; 98; 611-614.

Gnepp DR. Malignant mixed tumors of the salivary glands: a review. Pathol. Annu. 1993; 28; 279-328.

King OH Jr. Carcinosarcoma of accessory salivary gland. First report of a case. Oral Surg. Oral Med. Oral Pathol. 1967; 23; 651-659.

Harada H. Histomorphological investigation regarding to malignant transformation of pleomorphic adenoma (so-called malignant mixed tumor) of the salivary gland origin: special reference to carcinosarcoma. Kurume Med. J. 2000; 47; 307-323.

Dardick I, Hardie J, Thomas MJ, Peter Nostrand AWV. Ultrastructural contributions to the study of morphological differentiation in malignant mixed (pleomorphic) tumors of salivary gland. Head Neck 1989; 11; 5-21.

Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch. A Pathol. Anat. Histopathol. 1986; 409; 93-103.

El-Naggar AK, JKC C, Grandis JR, Takata T, Slootweg PJ. WHO classification of head and neck Tumours. Lyon: International Agency for Research on Cancer, 2017.

Petersson F, Loh KS. Carcinosarcoma ex non-recurrent pleomorphic adenoma composed of TTF-1 positive large cell neuroendocrine carcinoma and myofibrosarcoma: Apropos a rare case. Head Neck Pathol. 2013; 7; 163-170.

Katsakhyan L, LiVolsi VA, Chalian AA, Zhang PJ. Giant cell carcinosarcoma of the parotid gland with a PLAG 1 translocation in association with a pleomorphic adenoma with HMGA2 translocation. Am. J. Clin. Pathol. 2020; 154; 811-815.

Vékony H, Leemans CR, Ylstra B, Meijer GA, van der Waal I, Bloemena E. Salivary gland carcinosarcoma: Oligonucleotide array CGH reveals similar genomic profiles in epithelial and mesenchymal components. Oral Oncol. 2009; 45; 259-265.

WHO Classification of Tumours Editorial Board. WHO classification of tumours series. In Head and Neck Tumours. Vol. 9. 5th ed. Lyon: International Agency for Research on Cancer, 2022 Beta version ahead of print. Available from: https://tumourclassification.iarc.who.int/chapters/52.

Nagao T, Gaffey TA, Serizawa H et al. Sarcomatoid variant of salivary duct carcinoma: clinicopathologic and immunohistochemical study of eight cases with review of the literature. Am. J. Clin. Pathol. 2004; 122; 222-231.

Henley JD, Seo IS, Dayan D, Gnepp DR. Sarcomatoid salivary duct carcinoma of the parotid gland. Hum. Pathol. 2000; 31; 208-213.

Thompson L, Chang B, Barsky SH. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am. J. Surg. Pathol. 1996; 20; 277-285.

Weiler C, Zengel P, van der Wal JE et al. Carcinoma ex pleomorphic adenoma with special reference to the prognostic significance of histological progression: a clinicopathological investigation of 41 cases. Histopathology 2011; 59; 741-750.

Ihrler S, Guntinas-Lichius O, Agaimy A, Wolf A, Mollenhauer M. Histological, immunohistological and molecular characteristics of intraductal precursor of carcinoma ex pleomorphic adenoma support a multistep carcinogenic process. Virchows Arch. 2017; 470; 601-609.

Katabi N, Gomez D, Klimstra DS, Carlson DL, Lee N, Ghossein R. Prognostic factors of recurrence in salivary carcinoma ex pleomorphic adenoma, with emphasis on the carcinoma histologic subtype: a clinicopathologic study of 43 cases. Hum. Pathol. 2010; 41; 927-934.

di Palma S, Skálová A, Vanìèek T, Simpson RH, Stárek I, Leivo I. Non-invasive (intracapsular) carcinoma ex pleomorphic adenoma: recognition of focal carcinoma by HER-2/neu and MIB1 immunohistochemistry. Histopathology 2005; 46; 144-152.

Griffith CC, Thompson LDR, Assaad A et al. Salivary duct carcinoma and the concept of early carcinoma ex pleomorphic adenoma. Histopathology 2014; 65; 854-860.

Olsen KD, Lewis JE. Carcinoma ex pleomorphic adenoma: a clinicopathologic review. Head Neck 2001; 23; 705-712.

Rito M, Fonseca I. Carcinoma ex-pleomorphic adenoma of the salivary glands has a high risk of progression when the tumor invades more than 2.5 mm beyond the capsule of the residual pleomorphic adenoma. Virchows Arch. 2016; 468; 297-303.

Ihrler S, Weiler C, Hirschmann A et al. Intraductal carcinoma is the precursor of carcinoma ex pleomorphic adenoma and is often associated with dysfunctional p53. Histopathology 2007; 51; 362-371.

Skálová A, Stenman G, Simpson RHW et al. The role of molecular testing in the differential diagnosis of salivary gland carcinomas. Am. J. Surg. Pathol. 2018; 42; e11-e27.

Agaimy A, Ihrler S, Baněčková M et al. HMGA2-WIF1 rearrangements characterize a distinctive subset of salivary pleomorphic adenomas with prominent trabecular (canalicular adenoma-like) morphology. Am. J. Surg. Pathol. 2022; 46; 190-199.

Robinson JT, Thorvaldsdóttir H, Winckler W et al. Integrative genomics viewer. Nat. Biotechnol. 2011; 29; 24-26.

Feng D, Fidele NB, Agustin MM et al. Carcinosarcoma of parotid gland (malignant mixed tumor). Ann Maxillofac Surg 2015; 5; 240-243.

Proceedings of the North American Society of Head and Neck Pathology Companion Meeting, New Orleans, LA, March 12, 2023: Classification of Salivary Gland Tumors: Remaining Controversial Issues?