E-Cadherin (CDH1) Is Frequently Mutated in Urothelial Carcinoma with Signet-Ring Cell and Plasmacytoid Morphology
Hikmat Al-Ahmadie, Gopa Iyer, Rohit Mehra, Yingbei Chen, Anuradha Gopalan, Samson W Fine, Satish K Tickoo, Michael F Berger, Dean F Bajorin, Guido Dalbagni, David B Solit, Victor E Reuter. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: A minority (<1%) of urothelial carcinomas (UC) exhibit a diffuse growth pattern without significant stromal reaction to the invasive tumor. Such tumors have been referred to as signet-ring cell carcinoma (SRC), plasmacytoid carcinoma (PC), and/or lymphoma-like carcinoma. They typically present at advanced stage and have been associated with significantly worse cancer specific survival than classical UC. Tumors possessing this morphology have also been observed in other organs such as diffuse gastric cancer and lobular breast carcinoma. In both of these locations, inactivating mutations in E-cadherin (CDH1) have been reported in the majority of cases with loss of E-cadherin expression by immunohistochemistry (IHC). We analyzed the mutation status of CDH1 in a cohort of urothelial SRC and PC by Sanger sequencing and compared the results to E-cadherin expression by IHC.
Design: Twenty cases of primary bladder SRC and/or PC with matched normal tissue were selected. DNA was extracted from formalin-fixed paraffin-embedded tissue and all coding exons of CDH1 were sequenced. IHC for E-cadherin expression was performed for all cases. For comparison, we assessed CDH1 status in a separate cohort of 50 high grade UC without PC/SRC morphology.
Results: Mutations in CDH1 were present in 15 of 20 SRC and or PC cases (75%). All mutations were confirmed to be somatic. PC morphology was present in 16 (80%) cases and SRC morphology in 10 (50%) cases. Both morphologies were present in 8 (40%) cases. In tumors with CDH1 mutations, E-cadherin expression was retained as a diffuse membranous expression in 6 (40%) cases, completely lost in 4 (27%) cases and decreased (weak cytoplasmic staining) in 5 (33%) other cases. In the 5 cases with PC/SRC morphology but without mutation in CDH1, E-cadherin expression was completely lost in the tumor. Only 1 of the 50 UC cases without SRC or PC morphology harbored a CDH1 mutation.
Conclusions: Mutations in CDH1 are frequently present in urothelial carcinoma with signet-ring cell and plasmacytoid morphology and appear to be specific to this distinct subset. The functional role of these aberrations has yet to be defined in this aggressive subtype of UC. The presence of mutations does not always correlate with loss of E-cadherin expression by IHC. Clinical correlations with patient outcome and both mutation status and loss of expression of E-cadherin are ongoing in a larger cohort.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 2:30 PM
Proffered Papers: Section A, Tuesday Afternoon