Pancreatic Specific Transcription Factors and CK19 in Pancreatic Endocrine Tumors
L Albarello, A Zerbi, V Capitanio, L Piemonti, V Di Carlo, C Doglioni. San Raffaele Scientific Institute, Milan, Italy
Background: The role of transcription factors (TFs) Isl-1, Pax6, Nkx2.2, Nkx6.1, MafB and Pdx-1 in pancreas development was recently described. They regulate commitment to individual cell lineages and maintain terminally differentiated phenotype. Their disruption results in impaired development of pancreatic endocrine structures. Few data are available about their expression in pancreatic endocrine tumors (PETs). PETs are classified in WHO categories as tumors with benign behaviour (WDET-B), uncertain behavior (WDET-U), well differentiated carcinomas (WDEC) and poorly differentiated carcinomas (PDEC). No absolute histopathological criteria are available to predict clinical course. Therefore, identification of immunohistochemical markers that could predict the biological behavior would be extremely helpful in surgical management and adjuvant therapy of PET. The expression of the intermediate filament cytokeratin 19 (CK19) has been recently proposed as predictor of survival in PETs.
Design: To evaluate in a large series of PETs the expression of TFs (Isl-1, Pax6, Nkx2.2, Nkx6.1, MafB, Pdx-1) and CK19 and analize their correlation with WHO categories. TFs expression was immunohistochemically evaluated in a series of 131 PET (48 WDET-B, 32 WDET-U, 41 WDEC and 10 PDEC); TF score was defined as follows: Low (LS), 0-3 TFs immunopositive per case; High (HS), 4-6 TFs immunopositive per case. The same series was evaluated for CK19 expression and its correlation with WHO categories and TFs expression investigated.
Results: HS for TFs (4 or more) was observed in 90% of WDET-B, in 69% of WDET-U, and in 49% of WDEC; all PDEC showed LS (p<0.05). Nkx6.1 was the most frequently TF associated with WDET-B (79%) in contrast to WDET-U with 50% of positive cases. Low reactivity was observed for Nkx6.1 in WDEC (20%) and PDEC (10%) (p<0.05). CK19 expression was higher in WDEC (83%) than in WDET-B and WDET-U tumors (56%) (p<0.05).
Conclusions: Endocrine specific TFs are coexpressed in most WDET-B and WDET-U; on the contrary, a progressive loss of expression is detected in WDEC and PDEC: the TFs biological role in pancreatic endocrine specification is maintained in PET and run in parallel with WHO PET categories. Among these TFs, Nkx6.1 is the most sensitive marker of tumor differentiation, with very limited reactivity in WDEC and PDEC. These changes in TFs expression in PET are inversely correlated with CK 19 expression. The combined analysis of TFs and CK19 could offer a better prognostic index in the clinico-pathologic evaluation of PET.
Tuesday, March 10, 2009 8:30 AM
Platform Session: Section H1, Tuesday Morning