Mutations of tumor suppressor genes TP53, p16 INK4 and DPC4 in chronic pancreatitis — a rare but significant event in a minority of cases

Abstract

Based on clinical and molecular studies, pancreatic ductal carcinoma seems to follow a multistep progression sequence from low-grade dysplasia to high-grade dysplasia and eventually to invasive carcinoma; however, until recently, it was difficult to compare studies investigating dysplasia in pancreatic ducts due to the lack of consensus regarding the terminology and criteria for grading. In 2001, the term pancreatic intra-epithelial neoplasia (PanIN) was proposed for these lesions, and the criteria were established.Accordingly, grading of PanINs follows a progressive increase of cytological and architectural atypia from PanIN/L-1A that are characterized by lack of cytological atypia to PanIN-1B characterized by increased crowding of cells with early papillary projections, to PanIN-2 characterized by similar architectural appearance with PanIN-1B but with mild to moderate nuclear atypia, and to PanIN-3 which resemble carcinoma, at a cytological level, demonstrating severe atypia, necrosis, tufting and mitotic activity.Molecular evidence also supports that this progression is characterized by gradual accumulation of genetic alterations in cancer-associated genes that translates into inactivation of tumour suppressor genes and overexpression or aberrant activation of oncoproteins. These alterations can be categorized as ‘early’ such as k-ras mutation, HER-2/neu, prostate stem cell antigen, MUC5 and fascin overexpression; ‘intermediate’ such as p16 inactivation, MUC1 and cyclin D1 overexpression; and finally as ‘late’ such as p53 and deleted in pancreatic carcinoma locus 4 inactivation, BRCA2 mutation, and overexpression of ki-67, 14-3-3σ and mesothelin.In terms of current pathology practice, it should be mentioned that PanINs-1 and -2 are common incidental findings and are generally not reported. If they are reported, this is followed by a note indicating their ‘inconsequential’ nature. PanIN-3, on the other hand, is strongly suspected to be a significant process that may require therapy. It is generally recommended that PanIN-3 should be documented in the surgical pathology report, especially in the absence of invasive carcinoma, keeping in mind that there are such cases on record that developed invasive carcinoma in follow-up.Histopathologically, PanINs may be mimicked, on the one hand, by other incidental and significant ductal changes (reactive atypia, transitional/squamous metaplasia) and on the other hand by colonization/cancerization of native ducts by invasive carcinoma. It is also important to distinguish PanINs, both conceptually and diagnostically, from intraductal papillary mucinous neoplasias; the latter involve ducts >1 cm, typically form a cystic or nodular (intraductal papillary) mass and may have a different biology.The recognition of PanIN is becoming increasingly important for cancer researchers and for clinical practice.