GLI1 -Rearranged Tumors of the Gynecologic Tract : A Detailed Clinicopathologic Study of 10 Cases

GLI1 -rearranged tumors of the gynaecologic tract are rare, but likely under-recognised, neoplasms, which have recently been reported in the ovary and uterus. It is important to identify these neoplasms due to their malignant potential and possible responsiveness to tyrosine kinase inhibition in the metastatic setting. We present the largest series to date of GLI1 -rearranged tumours of the gynaecologic tract with comprehensive clinicopathologic analysis. Ten cases (7 primary ovarian tumors and 3 primary uterine corpus tumours) with GLI1 rearrangements were identified in the case files of the contributing authors, and clinical findings, histomorphology, and immunophenotype were reviewed. Patients ranged in age from 26 to 60 years of age. Three of the 10 tumours in our series recurred, including one late recurrence 180 months postoperatively. The 10 cases, in keeping with previous reports in the literature, showed 2 main morphologic patterns: (i) variable admixture of trabecular, nested and tubular/microfollicular growth, akin to sex cord-stromal morphology; and (ii) cytologically bland, elongated spindle cells with abundant admixed blood vessels and variably myxoid matrix, morphologically suggestive of a low-grade mesenchymal neoplasm such as low-grade endometrial stromal sarcoma. In both scenarios, the immunophenotype was not supportive of the morphologic impression (with the sex cord-like tumours typically showing negative staining for calretinin, inhibin, and WT-1, whereas the tumours resembling low-grade endometrial stromal sarcomas were consistently hormone receptor-negative), and the diagnosis was ultimately made after next-generation sequencing. GLI1 fusion partners included PTCH1 (4 cases), ACTB (4 cases), CHD4 (1 case), and TXNIP (1 case). Morpho-molecular correlation suggested that tumours with PTCH1::GLI1 fusions were enriched in sex cord-like morphology, whereas tumours with ACTB::GLI1 fusions were enriched in low-grade endometrial stromal sarcoma-like morphology. Given that our cases were identified in a relatively short time period, it is likely that GLI1 -rearranged tumours are more common in the female genital tract than is realised and a high index of suspicion is required to initiate appropriate testing and establish the diagnosis. In the absence of readily available appropriate molecular testing, GLI1 immunohistochemistry can serve as an acceptably accurate surrogate biomarker for GLI1 rearrangement, since we found that GLI1 immunohistochemistry showed strong, diffuse nuclear staining in 6 GLI1 -rearranged gynaecologic tumours stained for this study, whereas this was consistently negative, or at most weak/focal, in an array of 135 morphologic mimics.