SMAD4 Expression in Mucin-Producing Cystic Neoplasms of the Pancreas and Associated Carcinomas
Kristen M Stashek, James J Mezhir, Kevin K Roggin, Andrew M Bellizzi. University of Iowa Hospitals and Clinics, Iowa City, IA; University of Chicago Medicine, Chicago, IL
Background: SMAD4, a tumor suppressor mediating TGF-β superfamily signaling, is inactivated in 55% of ductal adenocarcinomas (DA) by homozygous deletion or inactivating mutation/allelic loss. These mechanisms lead to complete absence of SMAD4 expression (ubiquitously expressed in the nucleus/cytoplasm of non-neoplastic tissue). Loss of expression is well-characterized in DA, and SMAD4 immunohistochemistry (IHC) is often used in the distinction of DA from reactive lesions in small tissue samples. Data regarding expression in DA precursors is limited and, particularly as regards intraductal papillary mucinous neoplasm (IPMN), conflicting. For example, 1 group found intact expression in all non-invasive IPMN's and 97% of invasive carcinomas (inv) ex IPMN, while another found SMAD4 to be absent in 75% of these cancers.
Design: Tissue microarrays (TMA) were made from 13 mucinous cystic neoplasms (MCN), 34 IPMN, and 43 normal pancreata. Effort was made to capture varying dysplasia grades (low [lg], moderate-high [hg]) and inv from a single tumor; different areas were each arrayed in duplicate. Samples included 9 inv (7 DA, 2 colloid), all ex IPMN. SMAD4 IHC was graded as intact, weak, and absent (lost). Cores without intact internal control were excluded. For discrepant cores from the same component of a tumor, grade was based on the "more intact" staining. Given preliminary findings, we also stained whole sections from 10 separate MCN.
Results: No MCN (or normal pancreas) showed absent staining. 5/9 (56%) inv ex IPMN displayed absent SMAD4; all were DA. Loss was also seen in the corresponding hg non-invasive component in all 4 tumors in which it was sampled (overall loss in hg: 4/27; 15%). The rate of loss in IPMN-lg was 13% (2/15), although in 1 of these a corresponding hg area was intact. In fact, on initial blinded review, we were surprised by frequent weak or absent expression in individual lg-appearing cores (e.g., MCN-lg: 29% weak, 8% lost). This prompted evaluation of whole sections, which showed heterogeneous staining (modulating between all 3 scores in a single section) in 8 and uniform, intact staining in 2.
Conclusions: We found a similar rate of SMAD4 loss in carcinoma ex IPMN as has been reported for all DA. Interestingly, this was confined to the ductal subtype. Frequent heterogeneity of staining in our TMA cores, especially in lg lesions, highlights a potential pitfall in similarly sized small biopsies/cytology specimens and underscores the importance of verifying TMA findings in whole sections.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 273, Monday Morning