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Published on: October 30, 2012
Recurrent GRHL fusions in a subset of sebaceoma: microscopic and molecular characterisation of eight cases
Mélanie Legrand1, Baptiste Louveau2, Nicolas Macagno3,4
1Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France.
Aims:
Sebaceous neoplasms constitute a group of adnexal tumours, including sebaceous adenoma, sebaceoma and sebaceous carcinoma. Although mismatch repair deficiency may be observed, the nature of the genetic alterations contributing to the development of most of these tumours is still unknown. In the present study, we describe the clinical, microscopic, and molecular features of eight sebaceomas with GRHL gene rearrangement.
Methods And Results:
Among these sebaceomas, four occurred in women and four in men; the median age was 63 years (range = 29-89). The tumours were located in the head and neck area in all cases. Microscopic examination revealed a well-demarcated lesion located in the dermis with focal extension into the subcutaneous tissue (three cases). The neoplasms displayed macronodular (eight cases), cribriform (seven cases) and organoid (six cases) growth patterns, occurring in combination. The tumours were mainly composed of immature basophilic cells associated with scattered mature sebocytes. Numerous small infundibular cysts were present in seven cases. Mitotic activity was low (none/one to four mitoses/mm2). Immunohistochemistry showed positivity for androgen receptor and p63. Preserved expression of MLH1, PMS2, MSH2 and MSH6 was observed in all cases. RNA-sequencing revealed RCOR1::GRHL2 (three cases), BCL6::GRHL1 (two cases), a BCOR::GRHL2 (one case), RCOR1::GRHL1 (one case) and TLE1::GRHL1 (one case) fusion transcript. Methylation analysis demonstrated that GRHL-fused sebaceomas form an independent cluster and highlight the proximity of such tumours with poromas with folliculo-sebaceous differentiation.
Conclusions:
In conclusion, we report recurrent fusions of the GRHL genes in a distinctive subset of sebaceomas harbouring infundibulocystic differentiation, a frequent organoid growth pattern and lack of mismatch repair deficiency.
Insights
Genetic rearrangements involving GRHL genes were identified in a specific group of sebaceomas. These sebaceomas show unique microscopic features and lack mismatch repair deficiency, suggesting a distinct tumor subtype.
Area of Science:
- Dermatopathology
- Oncology
- Molecular Genetics
Background:
- Sebaceous neoplasms, including adenoma, sebaceoma, and carcinoma, are skin adnexal tumors.
- The genetic drivers for most sebaceous neoplasms remain largely unknown, despite potential associations with mismatch repair deficiency.
Purpose of the Study:
- To investigate the clinical, microscopic, and molecular characteristics of sebaceomas associated with GRHL gene rearrangements.
- To identify specific genetic alterations contributing to the development of a subset of sebaceomas.
Main Methods:
- Analysis of eight sebaceomas using clinical, microscopic, and molecular techniques.
- RNA-sequencing to identify gene fusions, including those involving GRHL genes.
- Immunohistochemistry for mismatch repair proteins and methylation analysis.
Main Results:
- Eight sebaceomas (median age 63 years) were identified, all located in the head and neck region.
- Tumors exhibited macronodular, cribriform, and organoid growth patterns with infundibulocystic differentiation and immature sebocytes.
- Recurrent GRHL gene fusions (e.g., RCOR1::GRHL2, BCL6::GRHL1) were detected, forming an independent molecular cluster related to poromas.
Conclusions:
- Recurrent GRHL gene fusions define a distinct subset of sebaceomas.
- These sebaceomas are characterized by infundibulocystic differentiation, organoid growth, and intact mismatch repair.
- The findings suggest a unique molecular pathogenesis for this specific group of sebaceous neoplasms.
