MP28-08 DPC4 LOSS OF EXPRESSION IN INVASIVE UROTHELIAL CARCINOMAS: AN IMMUNOHISTOCHEMICAL STUDY

Abstract

INTRODUCTION AND OBJECTIVES: DPC4 (SMAD4) is a tumor suppressor gene that encodes for a critical transcription factor involved in the TGF-beta signal pathway. Genetic inactivation of the DPC4 gene has been described in pancreatic and extrahepatic biliary adenocarcinomas, and loss of DPC4 expression by immunohistochemistry is considered a relatively specific marker of tumors originating from those sites. However, the status of DPC4 has not been previously studied in urothelial carcinomas (UC). We evaluated DPC4 expression in a set of invasive UC of the bladder and the upper urinary tract (UT). METHODS: Formalin-fixed paraffin-embedded tissues from 13 invasive UC of the upper UT (12 high grade and 1 low grade) and 18 invasive high grade UC of the bladder were retrieved from our surgical pathology archives and used to build 2 tissue microarrays. Paired tumor and non-neoplastic tissue were spotted 4 times each. DPC4 expression was evaluated using standard immunohistochemistry (DPC4: clone B8, Santa Cruz, CA). DPC4 expression in each case was categorized as intact (positive DPC4) or lost (at least focal negative DPC4). Only spots with positive internal control were considered. Intact labeling was defined as uniform expression of DPC4 in the cytoplasm of tumor cells per spot, with at least focal nuclear expression of DPC4. DPC4 loss was defined as lack of both cytoplasmic and nuclear expression in any subset of tumor cells in the presence of positive internal control staining. Several cut off values were used to reflect the extent of DPC4 loss ( 75% of the tumor cells). RESULTS: We found varying extent of DPC4 loss in 14 cases of invasive UC. Among the bladder carcinomas, 7/18 (39%) cases had some extent of DPC4 loss. Among the upper UT carcinomas, 7/13 (54%) cases had some extent of DPC4 loss, as detailed in table 1. Intact DPC4 staining was observed in 11/18 cases (61%) of invasive UC of the bladder and in 6/13 cases (46%) of invasive UC of upper UT. CONCLUSIONS: Our findings reveal that loss of DPC4 expression can be observed in UC. The current TMA based findings merrit further evaluation in whole sections of UC using immunohistochemistry. If confirmed, our findings suggest that urothelial carcinoma should be considered in the differential diagnosis of a metastatic carcinoma of unknown primary, when loss of DPC4 is seen. Sequencing analysis to assess DPC4 gene status in UC is also warranted.