SMARCA4-deficient undifferentiated carcinoma. EndoTODAY 이준행

[Gastric cancer 935. SMARCA4-deficient undifferentiated carcinoma]

001 | 101 | 201 | 301 | 401 | 501 | 601 | 701 | 801 | 901 | 1000

SMARCA4-deficient undifferentiated carcinoma

Sarcoma로 간주되다가 epithelial malignacy로 분류가 바뀐 드문 역사를 가지고 있는 병이다.

Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex는 tumor suppressor function을 한다. SMARCA4, also known as Brahma-related gene-1 (BRG1), is a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex regulates transcription and promotes cell differentiation. An inactivating gene mutation or loss of protein expression in several subunits of this complex is reportedly present in about 20% of all malignancies.

Immunohistochemical screening has identified loss of SMARCA4 protein expression in 0.5% to 3.4% of gastroesophageal cancers.

Histologic characterization has described SMARCA4-deficient gastroesophageal carcinomas to exhibit undifferentiated and rhabdoid morphology.

Literature review (Front Oncol 2024)

We retrieved data for “(SMARCA4) AND (gastric carcinoma)” on PubMed and found 29 reported patients described in nine studies, namely, 22 (76%) men and seven (24%) women aged 30?75 years (average: 62.3 years). The neoplasm sites (excluding seven patients with no description) from most to least common were the body (10/22), antrum (7/22), fundus (1/22), cardia (1/22), and angle (1/22); the remaining two involved several sites, including the cardia, fundus, and body. Tumor size ranged from 4 cm to 14 cm (average: 7.3 cm), and nine cases were not described. Metastatic lymph nodes were found in 81% (22/27), and other metastases in 30% (7/23). There were 78% (18/29) stage III or IV cases. The median overall survival was 9 months (2?190.1 months). The histomorphology varied and included diffuse sheets, nests, abortive gland lumens, and tubules of anaplastic epithelioid cell sand scattered rhabdoid multinucleated giant cells. The tumors with sheets were predominant, presenting an undifferentiated pattern in 50% (12/24). Partly glandular or mixed and dedifferentiated carcinoma occurred in 25% (6/24). Tumors with pure nests or diagnosed tubular adenocarcinoma and solid adenocarcinoma occurred in 25% (6/24). These tumors were classified according to histomorphology. Although they were not significantly different in clinical characteristics by existing limited data, they had different histomorphology and immunophenotypes. Interestingly, we found SMARCA2 only strongly expressed in adenocarcinoma, irrespective of subtype.

[Selected literatures]

Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors' institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course. (Am J Surg Pathol 2021)

Deficiency of SMARCA4, a member of the SWI/SNF chromatin remodeling complex, has been described in a subset of undifferentiated gastroesophageal carcinomas with an aggressive clinical course. The full spectrum and frequency of SMARCA4 mutations in gastroesophageal cancer are unknown. We interrogated our institutional database and identified patients with gastroesophageal carcinomas who underwent cancer next-generation sequencing. We classified SMARCA4 mutations, assessed histologic features, and correlated SMARCA4 mutations with SMARCA4 protein expression by immunohistochemistry. SMARCA4 mutations were identified in gastroesophageal carcinomas from 107 (9.1%) of 1174 patients. Forty-nine SMARCA4 mutations, including 26 missense variants and 23 protein-truncating variants, were interpreted as pathogenic in 42 (3.6%) of 1174 patients. Thirty (71%) of 42 cancers with pathogenic SMARCA4 mutations were located in the esophagus or esophagogastric junction, and 12 cancers (29%) were located in the stomach. Sixty-four percent of carcinomas with pathogenic truncating SMARCA4 variants were poorly differentiated or undifferentiated compared with 25% of carcinomas with pathogenic missense variants. Eight of 12 carcinomas with truncating SMARCA4 variants and none of the 7 carcinomas with pathogenic SMARCA4 missense variants showed loss of SMARCA4 expression by immunohistochemistry. Four carcinomas with pathogenic truncating SMARCA4 variants were associated with Barrett esophagus. SMARCA4-mutated gastroesophageal cancers were enriched for APC (31%) and CTNNB1 (14%) mutations and exhibited similar frequency of TP53 (76%) and ARID1A (31%) mutations compared with gastroesophageal cancers without pathogenic SMARCA4 mutations. The median overall survival was 13.6 months for patients who presented with metastasis at diagnosis and 22.7 months for patients without metastasis. Overall, SMARCA4-mutated gastroesophageal cancers exhibit a spectrum of histologic grade, an association with Barrett esophagus, and a concurrent mutational pattern similar to SMARCA4-wild-type gastroesophageal adenocarcinomas. Although SMARCA4-deficient gastroesophageal carcinomas are associated with poorly differentiated and undifferentiated histology, the spectrum of histologic and molecular features suggests overlapping pathogenic pathways with conventional gastroesophageal adenocarcinomas. (Mod Pathol 2023)

Thoracic SMARCA4-deficient undifferentiated tumor is a newly recognized disease entity characterized as a high-grade malignant neoplasm with an undifferentiated or rhabdoid phenotype. The tumor was initially identified as a subtype of thoracic sarcoma with SMARCA4 loss, but further investigation resulted in its classification as a subtype of epithelial malignancies in the current World Health Organization classification. SMARCA4-deficient undifferentiated tumor is highly aggressive and has a poor prognosis. Because of its rarity, an optimal treatment strategy has not yet been identified. (Jpn J Clin Oncol 2024)