Salivary carcinosarcoma: insight into multistep pathogenesis indicates uniform origin as sarcomatoid variant of carcinoma ex pleomorphic adenoma with frequent heterologous elements

Abstract

Salivary carcinosarcoma: insight into multistep pathogenesis indicates uniform origin as sarcomatoid variant of carcinoma ex pleomorphic adenoma with frequent heterologous elements 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 (PAspecific 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.

Expanding the histological spectrum of salivary gland neoplasms with HMGA2::WIF1 fusion emphasising their malignant potential: a report of eight cases

“…To date, including the cases presented in this series, a total of 28 salivary gland tumours with HMGA2::WIF1 fusions have been reported in the English literature (summarised in Table 2). [3][4][5][6][7] While the majority of these tumours are benign (n = 22, 79%), the rate of malignancy is not insignificant, being reported in six (21%) patients, including a case of malignant transformation from PA to CA ex PA at the time of second recurrence and five cases of primary carcinomas. The reported histotypes of these malignant tumours include CA ex PA in five cases and a high-grade carcinoma with basaloid features in one.…”

“…Molecularly, the fusion occurs between HMGA2 exons 3, 4 or 5 and WIF1 exons 3, 4, 8, 9 or 10. [3][4][5][6][7] As HMGA2 translocation has only been reported in PA, CA ex PA, myoepithelioma (case 5) and myoepithelial carcinoma de novo among all salivary gland neoplasms, 1,11,12 the detection of HMGA2::WIF1 fusion implies a diagnosis of PA, CA ex PA, myoepithelioma or myoepithelial carcinoma. In this study, we exclusively utilised RNA sequencing; however, other ancillary tools such as fluorescence in-situ hybridisation (FISH) and immunohistochemistry for HMGA2 may be considered as screening tools for this tumour.…”

“…Among salivary gland neoplasms, pleomorphic adenoma (PA) and carcinoma ex PA adenoma (CA ex PA) are characterised by diagnostic translocations involving PLAG1 or HMGA2 genes. 1,2 In 2007, HMGA2::WIF1 fusion was first described in a PA and a CA ex PA by Queimado et al 3 Afterwards, HMGA2::WIF1 fusion was reported in two additional malignant cases: the first was reported by Persson et al as a malignant transformation of a recurrent PA to CA ex PA 4 and the second was reported by Ihrler et al as an adenoid cystic carcinoma with sarcomatoid transformation ex PA. 5 However, the histological features and immunoprofile of the three documented malignant cases were not provided. To date, HMGA2::WIF1 fusion has been reported in 20 cases of salivary gland neoplasms in the English literature, [3][4][5][6][7] most of which had a diagnosis of PA (17 of 20, 85%).…”

“…as a malignant transformation of a recurrent PA to CA ex PA 4 and the second was reported by Ihrler et al . as an adenoid cystic carcinoma with sarcomatoid transformation ex PA 5 . However, the histological features and immunoprofile of the three documented malignant cases were not provided.…”

“…However, the histological features and immunoprofile of the three documented malignant cases were not provided. To date, HMGA2::WIF1 fusion has been reported in 20 cases of salivary gland neoplasms in the English literature, 3–7 most of which had a diagnosis of PA (17 of 20, 85%).…”