Clinicopathologic and immunohistochemical correlation in sporadic pancreatic endocrine tumors: possible roles of utrophin and cyclin D1 in malignant progression

Pancreatic endocrine tumors (PETs), both functioning and nonfunctioning, are usually well differentiated and progress slowly. The 2004 World Health Organization (WHO) criteria classify PETs according to clinicopathologic features and Ki-67 proliferative index. A tumor associated with poorer prognostic features may be considered "uncertain" in behavior, but the malignant classifications are reserved for tumors showing clear signs of aggressive behavior. It remains difficult to predict malignant progression in any individual PET. The cytoskeletal protein utrophin is encoded on chromosome 6q, a region frequently lost in malignant PETs. Cyclin D1 is a highly regulated mediator of the cell cycle and is frequently overexpressed in sporadic PETs. Sporadic PETs resected or biopsied from 40 patients were identified and classified using WHO criteria (19 benign/uncertain, 21 malignant). Distinctive patterns of biologic activity in unequivocally malignant PETs were demonstrated by immunohistochemistry for utrophin and cyclin D1. Utrophin localized to cell membranes (76% in malignant versus 21% in benign/uncertain PETs, P < .0006) and cyclin D1 staining showed nuclear positivity (67% in malignant versus 17% in benign/uncertain PETs, P < .003). Membranous utrophin localization was associated with significantly reduced patient survival (P = .045). Both membranous utrophin and nuclear cyclin D1 staining were also associated with higher Ki-67 proliferative indices. In our series, neither utrophin nor cyclin D1 was predictive of malignant progression in uncertain (WHO 1.2) PETs. Further studies are warranted to elucidate the role of utrophin and cyclin D1 in the malignant progression of PETs.