Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma

Abstract

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in‐frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well‐delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests (‘cell balls’) was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20‐positive Merkel cells were detected. RNA sequencing (RNA‐seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT‐qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA‐seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

SSTR2A is a diagnostic marker of trichogerminoma

“…Of the 25 TG cases included, 16 cases were reported in a previous study. 2 For the nine previously unreported TG cases, all specimens were sharply circumscribed dermal nodules with frequent extension to the subcutaneous tissue (n = 6/9). The neoplasms displayed a prominent, macro-and micro-nodular architecture and were composed of basophilic epithelial cells.…”

“…Since the initial description by Sau et al in 1992, 1 only 52 cases have been reported in the literature. 2 Recently, applying whole transcriptome analysis our group identified recurrent FOXK1::GRHL1/2 and GPS2::GRHL1/2/3 gene fusions in this tumour entity. 2,3 Further investigation of this transcriptomic data set evidenced high level of Somatostatin Receptor 2 (SSTR2) expression in TG.…”