SWI/SNF‐deficiency defines highly aggressive undifferentiated endometrial carcinoma

Abstract

Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two‐thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF‐deficient DDEC/UEC in comparison to SWI/SNF‐intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF‐deficient DDEC/UEC (2 POLE‐mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co‐loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF‐intact DDEC/UEC (4 POLE‐mutated). The average age at diagnosis was 61 years for patients with SWI/SNF‐deficient tumors and 64 years for SWI/SNF‐intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF‐deficient and 50% of SWI/SNF‐intact tumors. At initial presentation, 55% of patients with SWI/SNF‐deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF‐intact tumors. The 2‐year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF‐intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF‐deficient tumors compared to 36 months for SWI/SNF‐intact tumors (p = 0.0003). All six patients with POLE‐mutated tumors, including one with stage IV SWI/SNF‐deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF‐deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane‐based) and all except the patient with a POLE‐mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF‐deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane‐based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

Loss of ARID1B and SMARCB1 expression are specific for the diagnosis of dedifferentiated/undifferentiated carcinoma in tumours of the upper gynaecological tract and cervix

“…23,28 Furthermore, the clinical behaviour of SWI/SNF-intact DDEC/UEC more closely parallels other high-grade endometrial carcinomas, such as FIGO grade 3 endometrioid or serous carcinomas, and it is likely that some SWI/SNF-intact DDEC/UEC may actually represent FIGO grade 3 endometrioid carcinomas, serous carcinomas or carcinosarcomas with a prominent or exclusively solid growth pattern. 28 ARID1B, SMARCA4 and SMARCB1 immunohistochemistry therefore could enable pathologists to appropriately identify highly aggressive DDEC/UEC. Histologically, undifferentiated carcinoma does not exhibit glandular differentiation, including villoglandular, cribriform, papillary or tubulocystic architecture that is seen in endometrioid, serous or clear cell carcinomas.…”

“…Recent studies have shown that 40% of clinically stages I-II patients and nearly 100% of stages III-IV patients with SWI/SNF-deficient DDEC/ UEC succumb to progressive disease within a year after initial diagnosis despite the use of conventional platinum/taxane-based chemotherapy, with a median disease-specific survival of less than 6 months. 23,28 Appropriate recognition of this aggressive tumour is therefore important to ensure timely surgical management and/or consideration for non-conventional systemic therapy through clinical trials or other drug access programmes. However, both over-and underdiagnosis can occur, 13,29 and this could be minimised with the appropriate use of specific and sensitive diagnostic markers.…”

“…DDEC/UEC are clinically aggressive, particularly when characterised by core SWI/SNF protein deficiency, including co‐inactivation/loss of ARID1A and ARID1B or inactivation/loss of SMARCA4 or SMARCB1. Recent studies have shown that 40% of clinically stages I–II patients and nearly 100% of stages III–IV patients with SWI/SNF‐deficient DDEC/UEC succumb to progressive disease within a year after initial diagnosis despite the use of conventional platinum/taxane‐based chemotherapy, with a median disease‐specific survival of less than 6 months 23,28 . Appropriate recognition of this aggressive tumour is therefore important to ensure timely surgical management and/or consideration for non‐conventional systemic therapy through clinical trials or other drug access programmes.…”

“…We thus recommend immunohistochemical analysis of ARID1B, SMARCA4 and SMARCB1 expression in tumours where DDEC/UEC is under diagnostic consideration, given the high specificity of loss of staining in these tumours. The sensitivity of this panel is more limited, as not all histologically defined DDEC/UEC demonstrate loss of expression of these core SWI/SNF proteins, but it is important to note that histologically defined tumours lacking ARID1B, SMARCA4 or SMARCB1 deficiency appear to be less aggressive clinically 23,28 . Furthermore, the clinical behaviour of SWI/SNF‐intact DDEC/UEC more closely parallels other high‐grade endometrial carcinomas, such as FIGO grade 3 endometrioid or serous carcinomas, and it is likely that some SWI/SNF‐intact DDEC/UEC may actually represent FIGO grade 3 endometrioid carcinomas, serous carcinomas or carcinosarcomas with a prominent or exclusively solid growth pattern 28 .…”

“…The sensitivity of this panel is more limited, as not all histologically defined DDEC/UEC demonstrate loss of expression of these core SWI/SNF proteins, but it is important to note that histologically defined tumours lacking ARID1B, SMARCA4 or SMARCB1 deficiency appear to be less aggressive clinically 23,28 . Furthermore, the clinical behaviour of SWI/SNF‐intact DDEC/UEC more closely parallels other high‐grade endometrial carcinomas, such as FIGO grade 3 endometrioid or serous carcinomas, and it is likely that some SWI/SNF‐intact DDEC/UEC may actually represent FIGO grade 3 endometrioid carcinomas, serous carcinomas or carcinosarcomas with a prominent or exclusively solid growth pattern 28 . ARID1B, SMARCA4 and SMARCB1 immunohistochemistry therefore could enable pathologists to appropriately identify highly aggressive DDEC/UEC.…”