GLI1-Rearranged Enteric Tumor

Abstract

GLI1 encodes a transcription factor that targets cell cycle regulators affecting stem cell proliferation. GLI1 gene fusions were initially described in pericytomas with a t[7;12] translocation and more recently in gastric plexiform fibromyxomas and gastroblastomas. This study describes the clinicopathologic, immunohistochemical, and molecular features of three intestinal-based neoplasms harboring GLI1 gene fusions. We studied three unique mesenchymal small bowel tumors. Paraffin embedded tumor tissues from these cases and 62 additional tumor samples that included a plexiform fibromyxoma were sequenced using a targeted RNAseq method to detect fusion events. The study patients included two women and one man who were 52, 80, and 22 years of age at the time of diagnosis. The tumors involved the submucosa and muscularis propria of the duodenum, jejunum, and ileum. All 3 tumors contained a proliferation of monotonous oval or spindle cells with scattered, somewhat dilated vessels. Two cases showed epithelioid structures such as glands, tubules, or nests. Immunohistochemical analysis revealed cytokeratin expression in the epithelioid components of both tumors displaying these features, and variable numbers of mesenchymal cells. Diffuse CD56 positivity was seen in the mesenchymal component of 2 tumors and desmin and smooth muscle actin staining in the other tumor. Immunostains for S-100 protein, DOG-1, and CD117 were negative in all cases. GLI1 fusions with different partner genes were detected in all tumors, and in the plexiform fibromyxoma, used as a control. Validation by fluorescence in situ hybridization was performed. None of the tumors have recurred or metastasize after surgery. We describe novel GLI1 fusions in 3 mesenchymal neoplasms of the small intestine, including 2 with biphenotypic features. Thus far, all cases have pursued indolent clinical courses. We propose the term “GLI1-rearranged enteric tumor” to encompass this group of unique neoplasms of the small intestine that harbor GLI1 gene fusions and expand the spectrum of gastrointestinal neoplasms with these alterations.

Superficial GLI1‐amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology

“…13,14 CD56 expression in our cases is in line with previous findings in the head and neck, as well as, enteric tumors with GLI1-alterations, in which all tumors displayed CD56 immunoreactivity. 15,27 STAT6 expression in 2/3 of the present cases and in previous series and case reports 13,26 may not come as a surprise and suggests that the STAT6 gene be coamplified in a subset of GLI1amplified neoplasms because of gene proximity. In general, the variable STAT6 expression may be related to the stability and extension of the amplicon, which is not homogeneous between and within tumors because of various cytogenetic phenomena.…”

“…Overall, out of 68 cases with GLI1 alterations (18 amplified, 47 rearranged, and 3 with both amplification/rearrangement) reported since 2004, 45.7% were negative for S100-protein. [4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27][28][29] When describing amplified or rearranged tumors, 52.5% of the GLI1-amplified tumors revealed S100-protein positivity (predominantly focal staining), 13,17 on the other hand 53.7% of the GLI1-rearranged tumors showed S100-protein expression. [4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27]…”

“…[4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27][28][29] When describing amplified or rearranged tumors, 52.5% of the GLI1-amplified tumors revealed S100-protein positivity (predominantly focal staining), 13,17 on the other hand 53.7% of the GLI1-rearranged tumors showed S100-protein expression. [4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27][28][29] The latter were mainly located i...…”

“…44 Prognosis, behavior, and histopathologic predictors are puzzling issues in tumors with GLI1 alterations and are still under debate. Various series of tumors with GLI1 alterations 4,[11][12][13][15][16][17]24,27 describe that many of the cases behave in a benign, indolent or low-grade fashion, but metastases and/or local recurrences have also been reported.…”

“…Out of 47 cases with GLI1 fusions reported since 2004, metastases were documented (to lung, soft tissue, colonic mesentery, bone, or lymph node) in seven cases; all patients were alive with disease with a mean follow-up of 98.4 months. [4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][21][22][23][24][26][27][28][29] Out of the 21 cases with GLI1 amplification (three with concurrent rearrangement) two patients developed metastasis and two local recurrence. In one case the patient developed lung metastasis and was alive with disease after 26 months of follow-up, 13,16,17 whereas in the second case the patient developed pelvic recurrence with brain metastasis and died of disease 36 months after initial diagnosis.…”