A Case Series of Metastatic Malignant Gastrointestinal Neuroectodermal Tumors and Comprehensive Genomic Profiling Analysis of 20 Cases

Abstract

Malignant gastrointestinal neuroectodermal tumor (GNET) is an ultra-rare soft tissue sarcoma, therefore often misdiagnosed and has no available standard treatment. Here, we report 3 cases of metastatic GNET with variable clinical courses. Our small case series as well as extensive literature review, further support that GNET is a spectrum of diseases with variable inherent biology and prognosis. Surgical management in the setting of recurrent/metastatic disease may be appropriate for GNET with indolent nature. Response to systemic treatments including chemotherapy and targeted treatments is variable, likely related to heterogenous biology as well. Furthermore, we retrospectively identified 20 additional GNET cases from Foundation Medicine’s genomic database and expanded on their clinicopathological and genomic features. Comprehensive genomic profiling (CGP) with DNA and RNA sequencing of this cohort, in the course of clinical care, demonstrated recurrent EWSR1 chromosomal rearrangements and a sparsity of additional recurrent or driver genomic alterations. All cases had low tumor mutational burden (TMB) and were microsatellite stable.

Inflammatory and Nested Testicular Sex Cord Tumor

“…23,24 This is apparently the case for neoplasms driven by EWSR1::ATF1, a fusion that has been identified in multiple tumor types, including clear cell sarcoma of soft tissue, malignant gastrointestinal neuroectodermal tumor (also known as clear cell sarcoma-like tumor of the gastrointestinal tract), clear cell carcinoma of salivary gland, hyalinizing clear cell carcinoma of the thymus and lung, clear cell odontogenic carcinoma, myoepithelial tumors, intracranial myxoid mesenchymal tumor, primary pulmonary myxoid sarcoma, and subsets of mesothelioma, angiosarcoma, and angiomatoid fibrous histiocytoma. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] These entities span a wide morphologic, biological, and clinical spectrum that comprises indolent entities with little malignant potential (angiomatoid fibrous histiocytoma), to low-grade malignancies (clear cell carcinoma of salivary gland), to aggressive neoplasms with poor outcomes (clear cell sarcoma of soft tissue, malignant gastrointestinal neuroectodermal tumor). IN-TSCTs seem to belong in the latter end of the spectrum, as they demonstrate a tendency for early metastatic spread to lymph nodes and visceral sites, with poor response to systemic therapy.…”

“…The phenotypic and biological features of tumors driven by gene fusions are likely determined by multiple factors, such as the cell of origin, the tumor microenvironment, and the presence of concurrent genomic and epigenomic alterations 23,24. This is apparently the case for neoplasms driven by EWSR1::ATF1 , a fusion that has been identified in multiple tumor types, including clear cell sarcoma of soft tissue, malignant gastrointestinal neuroectodermal tumor (also known as clear cell sarcoma-like tumor of the gastrointestinal tract), clear cell carcinoma of salivary gland, hyalinizing clear cell carcinoma of the thymus and lung, clear cell odontogenic carcinoma, myoepithelial tumors, intracranial myxoid mesenchymal tumor, primary pulmonary myxoid sarcoma, and subsets of mesothelioma, angiosarcoma, and angiomatoid fibrous histiocytoma 25–41. These entities span a wide morphologic, biological, and clinical spectrum that comprises indolent entities with little malignant potential (angiomatoid fibrous histiocytoma), to low-grade malignancies (clear cell carcinoma of salivary gland), to aggressive neoplasms with poor outcomes (clear cell sarcoma of soft tissue, malignant gastrointestinal neuroectodermal tumor).…”

The Malignant Gastrointestinal Neuroectodermal Tumor (GNET): A Distinct Entity and the Challenging Differential Diagnosis with Mesenchymal, Lymphoid, and Melanic Tumors: A Case Report and Brief Review of the Literature

“…Kandler T. et al claim that although the median age at diagnosis ranges from 33 to 36 years [ 1 , 7 , 10 , 11 , 12 , 13 ], GNET patients exhibit a wide range of age distribution and show no predilection for either gender.…”

“…Through their 16-case series, Stockman et al, who promoted treating GNET as a separate tumor entity rather than a variety of CCS, coined the term “GNET” in 2012 [ 10 ]; ( Table 3 ). Only 111 cases were reported as of December 2021, according to Kandler T. et al [ 11 ]; ( Table 3 ), making it challenging to use the limited clinical, prognosticative, tumor staging, pharmacological, and treatment data that was available.…”

“…As the hypothesis progressed, Stockman et al [ 10 ] established this specific type of tumor as “GNET”, validating the EWSR1 gene rearrangement using molecular biology techniques and the absence of melanogenesis using ultrastructural data. To date, at this moment, 111 cases have thus far been documented in the literature [ 10 , 11 ]. GNET’s histological characteristics can be partially superimposed with other types of gastrointestinal tract lesions.…”