Recurrent GRHL fusions in a subset of sebaceoma: microscopic and molecular characterisation of eight cases

Abstract

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.

Figure 1

Microscopical features of GRHL sebaceomas. Microscopic features of the eight cases included in the present study. The tumours were well circumscribed, often without epidermal connection and localised in the dermis with occasional extension into the subcutaneous tissue. The neoplasm consisted in macronodular, cribriform nests or cords of medium sized tumour cells with a basophilic cytoplasm. Focal clear changes and mature sebocytes were observed. Follicular differentiation and ducts were seen. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Microscopic features of TLE1::GRHL1 sebaceoma (case 5). Case 5 consists of a well‐circumscribed non‐ulcerated tumour with an epidermal connection and expanding into the dermis and subcutaneous tissue. The tumour is organised in macronodular, cribriform and cords of monotonous medium cells. Focal hyalinised stroma was also present. Tumour cells were characterised by enlarged, indented or folded nuclei with a small basophilic cytoplasm. Focal clear cell and mature sebocytes were observed. Ducts and exceptional follicular differentiation were seen. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Immunohistochemical features of a GRHL‐rearranged sebaceoma. Focal expression of CK7 and EpCam was observed. CEA and EMA staining revealed ductal formations. EMA also demonstrated the presence of sebocytes. Tumour cells expressed p63 in a diffuse manner. The majority expressed androgen receptor. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

DNA methylation‐based classification of 3 GRHL‐fused sebaceomas in comparison to other adnexal tumours including trichogerminoma and poroma with folliculo‐sebaceous differentiation with PAK2 fusion. Methylation profiling employing the MethylationEPIC BeadChip was performed with DNA extracted from three GRHL‐fused sebaceomas and 65 other adnexal tumours. This depicted is unsupervised clustering using t‐SNE dimensionality reduction. GRHL‐fused sebaceoma: shades of brown; NCOR2::GRHL1 trichogerminoma: shades of yellow; trichogerminoma: shades of purple; PAK‐fused poroma: shades of pink; poroma: shades of blue; trichoblastoma: shades of orange; basal cell carcinoma: shades of black. [Color figure can be viewed at wileyonlinelibrary.com]