Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes

Abstract

Pancreatic undifferentiated carcinoma is a heterogeneous group of neoplasms, including pleomorphic giant cell, sarcomatoid, round cell, and rhabdoid carcinomas, the molecular profiles of which have so far been insufficiently characterized. We studied 14 undifferentiated carcinomas with prominent rhabdoid cells, occurring as advanced tumors in seven females and seven males aged 44-96 years (mean: 65 years). Histologically, 10 tumors qualified as pleomorphic giant cell and 4 as monomorphic anaplastic carcinomas. A glandular component, either in the primary or in the metastases, was seen in 5 out of 14 tumors (4 out of 10 pleomorphic giant cell and 1 out of 4 monomorphic anaplastic subtypes, respectively). Osteoclast-like giant cells were absent. Immunohistochemistry revealed coexpression of cytokeratin and vimentin, and loss of membranous b-catenin and E-cadherin staining in the majority of cases. Nuclear SMARCB1 (INI1) expression was lost in 4 out of 14 cases (28%), representing all 4 tumors of the monomorphic anaplastic subtype. FISH and mutation testing of KRAS revealed KRAS amplification in 5 out of 13 (38%) and exon 2 mutations in 6 out of 11 (54%) successfully analyzed cases. A strong correlation was found between KRAS alterations (mutation and/or copy number changes) and intact SMARCB1 expression (7 out of 8; 87%). On the other hand, loss of SMARCB1 expression correlated with the absence of KRAS alterations (3 out of 5 cases; 60%). The results suggest that rhabdoid phenotype in pancreatic undifferentiated rhabdoid carcinomas has a heterogeneous genetic background. SMARCB1 loss is restricted to the anaplastic monomorphic subtype and correlates with the absence of KRAS alterations, whereas the pleomorphic giant cell subtype is characterized by KRAS alterations and intact SMARCB1 expression. Recognition and appropriate subtyping of these rare variants might become necessary for future therapeutic strategies.

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant

“…On the other hand, 1 case with prominent undifferentiated large cell morphology and extensive rhabdoid features showed intact SMARCB1 but complete loss of SMARCA4 in the predominant rhabdoid undifferentiated component. The rhabdoid features seen in this case were identical to what we have reported recently in undifferentiated rhabdoid pancreatic carcinoma associated with SMARCB1 loss [24]. Thus, this case highlights the increasingly recognized close link between the rhabdoid phenotype and loss of different components of the SWI/SNF chromatin remodeling complex, in particular, loss of SMARCB1 or SMARCA4.…”

“…In the current case, the presence of a differentiated SMARCA4-intact endometrioid carcinoma component and the limitation of the SMARCA4 loss to the undifferentiated component indicate a secondary loss in the setting of tumor progression. A true collision tumor is unlikely in our case, and the origin of the dedifferentiated rhabdoid clone from the differentiated endometrioid component is accepted based on (1) focal intermingling of the 2 components, (2) the presence of scattered rhabdoid cells amid the endometrioid glands of the differentiated component, and (3) in the light of previous observation of similar phenomenon in the uterus and other organs [21,[23][24][25]. Loss of E-cadherin [24] associated with variable loss of pancytokeratin [16,24] has been reported in dedifferentiated carcinoma of uterus and other organs.…”

“…Presence of a low-grade endometrioid component justified the term collision tumor [20] or composite rhabdoid tumor [21]. Based on recent observations by us and others, it is increasingly recognized that components of the SWI/SNF complex, particularly SMARCB1, can be involved in the process of secondary dedifferentiation in subsets of gastroenteropancreatic carcinomas, resulting in a rhabdoid phenotypic shift (rhabdoid dedifferentiation) associated with worse prognosis [23,24]. The differentiated component in this setting might be extensive, minor represented by a minute focus of intraepithelial neoplasia, or even completely absent [23,24].…”

“…Based on recent observations by us and others, it is increasingly recognized that components of the SWI/SNF complex, particularly SMARCB1, can be involved in the process of secondary dedifferentiation in subsets of gastroenteropancreatic carcinomas, resulting in a rhabdoid phenotypic shift (rhabdoid dedifferentiation) associated with worse prognosis [23,24]. The differentiated component in this setting might be extensive, minor represented by a minute focus of intraepithelial neoplasia, or even completely absent [23,24]. To the best of our knowledge, this study represents the first analysis of the expression status of the SWI/SNF chromatin remodeling complex components SMARCB1 and SMARCA4 in a consecutive series of poorly differentiated endometrioid adenocarcinoma of the uterus.…”

SMARCA4-deficient undifferentiated carcinoma of the ovary (small cell carcinoma, hypercalcemic type): clinicopathologic and immunohistochemical study of 3 cases

“…9 [3]) indicating a minor component of mucinous carcinoma, at least in that case. Several recent studies convincingly illustrated the origin of SMARCB1-deficient undifferentiated neoplasm from SMARCB1-intact differentiated parent neoplasm in different organs in adults [19][20][21]. The extent of the differentiated component was highly variable ranging from extensive to minor, being just represented by a mere minute focus of intraepithelial neoplasia.…”