A Distinct Malignant Epithelioid Neoplasm With GLI1 Gene Rearrangements, Frequent S100 Protein Expression, and Metastatic Potential

Abstract

ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as "pericytoma with the t(7;12) translocation." In addition, GLI1 oncogenic activation through a related MALAT1-GLI1 gene fusion has been recently reported in 2 unrelated gastric tumors, namely plexiform fibromyxoma and gastroblastoma. Triggered by unexpected targeted RNA-sequencing results detecting GLI1-related fusions in a group of malignant neoplasms with round to epithelioid morphology, and frequently strong S100 protein immunoreactivity, we investigated their clinicopathologic features in relation to other known pathologic entities sharing similar genetics. On the basis of a combined approach of targeted RNA sequencing and fluorescence in situ hybridization screening, we identified 6 cases with GLI1 gene fusions, including 4 fused to ACTB, 1 with MALAT1 and 1 with PTCH1 gene. Patients had a mean age of 36 years at diagnosis (range, 16 to 79 y) and slight female predilection all except 1 tumor originated in the soft tissue. Microscopically, the tumors had a monomorphic epithelioid phenotype arranged in a distinctive nested or cord-like architecture, separated by thin septae and delicate capillary network. All except 2 cases were strongly positive for S100 protein, whereas being negative for SOX10, SMA, and EMA. Only 1 tumor showed focal cytokeratin positivity in rare cells. Although the tumors showed some resemblance to pericytic/glomus tumors or myoepithelial tumors, the immunoprofile was not supportive of either lineage. Moreover, in contrast to the benign course of so-called pericytoma with t(7;12), 3 patients in this series developed metastatic disease to either lymph nodes or lung. In fact the only patient with lung metastases showed a novel PTCH1-GLI1 gene fusion. It remains to be determined whether these tumors represent a clinically and immunohistologically distinct subset of pericytoma, or an altogether novel soft tissue sarcoma. Our findings open new opportunities for targeted therapy, as tumors with GLI1 oncogenic activation, and subsequent PTCH1 overexpression, might be sensitive to sonic hedgehog pathway inhibitors.

Gastroblastoma in old age

“…Interestingly, the cord‐like arrangement of mesenchymal, cytokeratin‐negative neoplastic cells (reported only once in the non‐epithelial component of gastroblastoma) was only focal at relapse, but constituted the majority of the primary tumour, in the absence of an epithelial, cytokeratin‐positive component, which manifested only in the recurring neoplasm. Therefore, in its first presentation, the lesion reported herein strongly resembled most of the extragastric ‘malignant epithelioid neoplasms with GLI1 gene rearrangements’ reported by Antonescu et al . It is of note that MALAT1 was the fusion partner of GLI1 in only one case of the six studied in that series.…”

“…The recently reported consistent finding of a MALAT1 – GLI1 fusion gene in gastroblastoma allows a solid differential diagnosis with other biphasic neoplasms such as synovial sarcoma, carcinosarcoma, and teratoma. Intriguingly, the same genetic defect has been detected in some plexiform fibromyxomas, which are gastric mesenchymal tumours that are definitely benign, lack biphasic morphology and are most likely unrelated to gastroblastoma . Table summarises the features of the gastroblastomas published so far.…”

“…8 Finally, a series of six extragastric tumours harbouring GLI1 rearrangements has been published, showing focal cytokeratin positivity and scattered tubular structures in one case (bearing an ACTB-GLI1 fusion), leading to the proposal of an entity defined as 'malignant epithelioid neoplasm with GLI1 fusions'. 9 All reported canonical gastroblastomas occurred within the third decade of life, except for one in a patient aged 56 years. Grossly, gastroblastomas form multinodular/lobulated, often partly cystic/haemorrhagic, masses involving the gastric wall layers.…”

“…Intriguingly, the same genetic defect has been detected in some plexiform fibromyxomas, which are gastric mesenchymal tumours that are definitely benign, lack biphasic morphology and are most likely unrelated to gastroblastoma. 6,9 Table 1 summarises the features of the gastroblastomas published so far.…”

“…The present report is relevant not only because it constitutes a solid example of gastroblastoma, which is an exceedingly rare neoplasm, but also: (i) extends the known age range of this tumour; (ii) is the fifth case confirmed by MALAT1-GLI1 fusion gene detection; and (iii) possibly constitutes the hitherto missing link between gastroblastoma and 'malignant epithelioid neoplasms with GLI1 gene rearrangements'. 9…”