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Molecular Profiling for IPMN/IPMC

Intraductal papillary mucinous neoplasms (IPMN) are pancreatic precancerous lesions composed of dilated main or branch ducts lined by mucin producing atypical epithelium, which usually proliferates in a papillary fashion [1]. Based on their increasing architectural and nuclear atypia IPMN are divided into three groups: intraductal papillary mucinous adenoma (IPMA), borderline IPMN (IPMB), and intraductal papillary mucinous carcinoma (IPMC) [1].

According to the absence or presence of neoplastic cells invading the pancreatic tissue surrounding the involved ducts, IPMC are separated into invasive and noninvasive types [2]. IPMN are precancerous lesions and disclose a progression pattern similar to the "adenoma-carcinoma sequence" in colorectal cancer [3-6].

Most IPMN are slow growing and less aggressive compared with conventional ductal adenocarcinoma. Borderline lesions and carcinoma are accompanied by less atypical lesions in the vicinity, and transition from adenoma to adenocarcinoma has been described. The overall incidence of invasive carcinoma associated with an IPMN is 20% to 40% [7] and invasiveness seems to be the strongest prognostic factor [4].

The prognosis of patients with non-invasive IPMN consisting of adenoma, adenocarcinoma in situ, or minimally invasive adenocarcinoma is excellent, and the 5 year survival rate was reported to be 77% to 100% [4, 8-10]. However, invasive IPMC that macroscopically involves the pancreatic parenchyma comprises 16% to 43% of all IPMN lesions, and the 5 year survival rate for patients with these lesions varied widely from 0% to 64% in several reported series [4, 8, 9, 11-13].

A significant proportion of the patients with completely resected noninvasive IPMN may develop pancreatic adenocarcinoma in the pancreatic remnant and die of disseminated disease. Other studies have also reported recurrences of invasive carcinoma in completely resected noninvasive IPMN [5, 6], some of which demonstrated only moderate dysplasia (borderline IPMN).

The genetic progression of IPMN/IPMC has not been completely defined. IPMN/IPMC are known to harbor mutations of KRAS [14, 15], p16 [16], p53 [15], and DPC4/SMAD4/MADH4 [17], but the prevalence of the mutations is lower than in ductal pancreatic adenocarcinoma. In fact, Dpc4/Smad4/Madh4 expression in IPMN is virtually normal unless associated with invasive ductal adenocarcinoma [18].

Our team has shown the STK11/LKB1 is more frequently inactivated in IPMN/IPMC than PanIN/PDA [19, 20]. Oncogenic PIK3CA plays an important role in the tumorigenesis of IPMN/IPMC, but not in PanIN/PDA [21]. Oncogenic BRAF is involved in the tumorigenesis of IPMN/IPMC, but at a much lower frequency than KRAS and PIK3CA [22, 23]. We also have reported that EGFR and ERBB2 (HER2) mutations are very infrequent in IPMN/IPMC, suggesting the limited possibility of targeting mutated ERBB2 and EGFR for therapy of these lesions [24]. KRAS, BRAF and PIK3CA, however, could represent interesting targets for future therapies in these lesions.

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