Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas

Abstract

Intraductal oncocytic papillary neoplasm(IOPN) of the pancreas is classified as a variant of intraductal papillary mucinous neoplasm(IPMN) in the WHO guidelines. However, the neoplastic cells of IOPNs are unique, with distinctive architecture/oncocytic cytoplasm. Although molecular/immunohistochemical features of other IPMN variants have been extensively studied, those of IOPNs have not been well characterized. Expression profile of antibodies associated with genetic alterations previously described for ductal adenocarcinomas(DAs) and IPMNs(SMAD4/β-catenin/p53/mesothelin/claudin-4) as well as with antibodies to mucins and differentiation markers(MUC1/MUC2/MUC5AC/MUC6/CDX2/HepPar-1) was investigated in 24 IOPNs and 22 IPMNs to assess the similarities/differences between these tumors. Expression of mesothelin and claudin-4 were dissimilar between these tumor types: a higher proportion of IOPNs labeled with mesothelin[21/24(87.5%) of IOPNs, 6/22(27%) of IPMNs, p<0.001], while the reverse was true for claudin-4[2/23(9%) of IOPNs, 9/22(41%) of IPMNs, p=0.01]. The results of immunolabeling for SMAD4/β-catenin/p53 were similar in both: None of the cases showed SMAD4 loss in the intraductal components and only 1/21(5%) of IOPNs and 2/22(9%) of IPMNs revealed abnormal β-catenin expression(p=0.49). Nuclear p53 accumulation was seen mostly in architecturally complex/high grade dysplasia areas in both. Immunolabeling for MUC proteins showed that almost all lesions expressed MUC5AC. 12/24(50%) of IOPNs and 6/22(27%) of IPMNs(p=0.11) labeled for MUC1, whereas 7/24(29%) of IOPNs and 10/22(45%) of IPMNs labeled for MUC2(p=0.25). MUC6 was expressed in 8/9(89%) of IOPNs(strong) and 6/21(29%) of IPMNs(weak)(p=0.002). 14/23(61%) of IOPNs and 4/22(18%) of IPMNs labeled for HepPar-1(p=0.003). These results show that IOPNs have distinct immunoprofile and provide support for the proposition that IOPN is a distinct entity developing through a mechanism different from other pancreatic ductal neoplasms.

Intraductal neoplasms of the pancreas: an update

“…IoPN is usually seen during the seventh decade of life (58,121,122) with equal male to female ratio (58,121,122). Patients are either asymptomatic or have non-specific symptoms, similar to IPMNs.…”

“…Intracellular lumens are also seen (38, 121-123, 125, 126). Despite highly complex morphology and atypical cytology, most examples are devoid of invasive carcinoma, and, if present, invasion is usually limited in amount (121,124). The invasive component can be oncocytic, mucinous (colloid-like), sarcomatoid/undifferentiated, or even neuroendocrine type (38,123,125,127,128).…”

“…The invasive component can be oncocytic, mucinous (colloid-like), sarcomatoid/undifferentiated, or even neuroendocrine type (38,123,125,127,128). Similar to IPMNs, features of both invasive and non-invasive components should be documented separately (121).…”

“…The tumor cells usually express MUC1 and MUC6 (61,77,121,129,130), while are negative for MUC2, and CDX2. More importantly, neuroendocrine and acinar differentiation markers are both negative.…”

“…However, survival outcomes are still favorable despite the second resection. Also, even though these intraductal neoplasms may develop invasive carcinoma, usually in the form of invasive oncocytic or mucinous (colloid-like) carcinoma, they still have more indolent course than conventional PDAC (16,31,38,40,71,121,124,126,133).…”