Molecular and immunophenotypic characterization of SMARCB1 (INI1) - deficient intrathoracic Neoplasms

Abstract

The switch/sucrose-non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeling complex that plays important roles in DNA repair, transcription and cell differentiation. This complex consists of multiple subunits and is of particular interest in thoracic malignancies due to frequent subunit alteration of SMARCA4 (BRG1). Much less is known about SMARCB1 (INI1) deficient intrathoracic neoplasms, which are rare, often misclassified and understudied. In a retrospective analysis of 1479 intrathoracic malignant neoplasms using immunohistochemistry for INI1 (SMARCB1) on tissue micro arrays (TMA) and a search through our hospital sarcoma database, we identified in total nine intrathoracic, INI1 deficient cases (n = 9). We characterized these cases further by additional immunohistochemistry, broad targeted genomic analysis, methylation profiling and correlated them with clinical and radiological data. This showed that genomic SMARCB1 together with tumor suppressor alterations drive tumorigenesis in some of these cases, rather than epigenetic changes such as DNA methylation. A proper diagnostic classification, however, remains challenging. Intrathoracic tumors with loss or alteration of SMARCB1 (INI1) are highly aggressive and remain often underdiagnosed due to their rarity, which leads to false diagnostic interpretations. A better understanding of these tumors and proper diagnosis is important for better patient care as clinical trials and more targeted therapeutic options are emerging.

STK11 loss and SMARCB1 deficiency mutation in a dedifferentiated lung cancer patient present response to neo-adjuvant treatment with pembrolizumab and platinum doublet: A case report

“…The difference of the alteration types might stand as one of potential reasons for the diverse clinical outcomes. Besides, the missence of SMARCB1 p.S67X*10.74% mutation may also contribute to the favorable outcomes in the present case, prognosis of which was consistent to a recent study as mentioned before (16). Histological findings with hematoxylin and eosin-stained biopsy specimen from biopsy on June 6 th , 2022 (A, × 200), and surgery on September 6 th , 2022 (B, × 400).…”

“…Mutation of SMARCB1 was frequently presented in sinonasal carcinoma, gastrointestinal cancer, and pancreatic cancer types, however, rarely reported in lung carcinoma (13,14). According to the former literature, cancer patients with pathologic SMARCB1 mutations were reported resulting in a worse prognosis independently from the conventional treatment strategies including chemotherapy, radiation therapy or surgery (12,15,16).…”

SMARCB1/INI1‐deficient intrathoracic neoplasm with rhabdoid/plasmacytoid cytomorphology in a patient with plasma cell myeloma: A case report

“…Among the cases in the relevant literature, SMARCB1 (INI1)‐deficient intrathoracic neoplasms were previously diagnosed as squamous cell carcinoma, epithelioid sarcoma, mesothelioma, large cell carcinoma, or large cell neuroendocrine carcinoma 5–7 . Haberecker et al classified such tumors into four morphologic subgroups: (1) epithelioid (tumors with discohesive large oval cells with abundant eosinophilic cytoplasm), (2) rhabdoid (tumors with cells harboring distinct hyaline cytoplasmic inclusions and undifferentiated round‐to‐plasmcytoid cells with compressed crescent‐shaped peripheral nuclei), (3) mixed (tumors with both rhabdoid and epithelioid patterns), and (4) solid (tumors with carcinoma‐like solid nests with cellular cohesion).…”

“…The differential diagnoses for the rhabdoid cytomorphology are summarized in Table 1. It is important to properly diagnose tumors with loss of SMARCB1 (INI1) to ensure better patient care given that the effectiveness of target therapies, such as EZH2 inhibitors, has been reported in clinical and preclinical trials 1,5 …”

“…It is important to properly diagnose tumors with loss of SMARCB1 (INI1) to ensure better patient care given that the effectiveness of target therapies, such as EZH2 inhibitors, has been reported in clinical and preclinical trials. 1,5 Plasma cell myeloma is a bone marrow-based multifocal neoplastic proliferation of plasma cells. 15 It is known that serous cavities are involved in lymphomatous processes; however, myelomas caused by malignant effusions are rare, accounting for only 1%-2% of all cases of myeloma.…”