The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes

Abstract

In 2010, the World Health Organization reclassified the entity originally described as intraductal oncocytic papillary neoplasm as the ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm. Although several key molecular alterations of other intraductal papillary mucinous neoplasm subtypes have been discovered, including common mutations in KRAS, GNAS, and RNF3, those of oncocytic subtype have not been well characterized. We analyzed 11 pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms. Nine pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms uniformly exhibited typical entity-defining morphology of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent, nucleoli, and intraepithelial lumina. The remaining two were atypical. One lacked the arborizing papilla and had flat oncocytic epithelium only; the other one had focal oncocytic epithelium in a background of predominantly intestinal subtype intraductal papillary mucinous neoplasm. Different components of this case were analyzed separately. Formalin-fixed, paraffin-embedded specimens of all cases were microdissected and subjected to high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes in a platform that enabled the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Fresh frozen specimens of two cases were also subjected to whole-genome sequencing. For the nine typical pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms, the number of mutations per case, identified by next-generation sequencing, ranged from 1 to 10 (median = 4). None of these cases had KRAS or GNAS mutations and only one had both RNF43 and PIK3R1 mutations. ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were somatically altered in more than one of these typical ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms but not in the other two atypical ones. In the neoplasm with flat oncocytic epithelium, the only mutated gene was KRAS. All components of the intestinal subtype intraductal papillary mucinous neoplasms with focal oncocytic epithelium manifested TP53, GNAS, and RNF43 mutations. In conclusion, this study elucidates that ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm is not only morphologically distinct but also genetically distinct from other intraductal papillary mucinous neoplasm subtypes. Considering that now its biologic behavior is also being found to be different than other intraductal papillary mucinous neoplasm subtypes, ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm warrants being recognized separately.

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

“…Several other studies have investigated the patterns of mucin protein expression and genetic alterations in IOPNs 10, 14, 37 , including our study analyzing a series of IOPNs by targeted next-generation sequencing 40 , and have shown that IOPNs are genetically distinct from IPMNs. However, to the best of our knowledge, this the first study comparing immunohistochemical profiles of IOPNs and IPMN using a large spectrum of antibodies associated with genetic alterations previously described for DAs and IPMNs as well as antibodies to mucins and differentiation markers.…”

“…Similarly, in a recent study investigating eleven IOPNs by targeted next-generation sequencing for a panel of 300 key cancer-associated genes, our group has confirmed that IOPNs are genetically distinct: None of our typical IOPNs revealed KRAS or GNAS mutations and only one had RNF43, PIK3R1 , and PIK3R3 mutations. Instead, ARHGAP26, ASXL1, EPHA8 , and ERBB4 genes were mutated in more than one IOPN 40 .…”

“…Several other studies have investigated mucin expression and selected gene mutations in IOPNs and showed that IOPNs generally do not have specific patterns of mucin protein expression (except for MUC6 18 ), and they do not harbor the same genetic alterations commonly seen in DAs and IPMNs 14, 22, 33, 37-40 . For example, in their analysis of a single IOPN, Patel et al did not detect mutations at codons 12 and 13 of the KRAS gene 37 .…”

Insights into the Pathogenesis of Pancreatic Cystic Neoplasms

“…Oncocytic variant of IPMN seem to evolve on a completely different pathway. Basturk et al [18] performed high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes on nine typical pancreatic ‘oncocytic subtype’ of IPMN. Interestingly, none of the samples had KRAS or GNAS mutation and only one had RNF43 and PIK3R1 mutations suggesting that the oncocytic subtype is not only morphologically but also genetically distinct.…”

Precursor Lesions of Pancreatic Cancer

“…Several commonly mutated genes in IPMNs, including KRAS , GNAS , and RNF43 , are mutated at low frequency or are not mutated in IOPNs [53,76,77,78,79]. Instead, low-frequency of ARHGAP26 , ASXL1 , EPHA8 and ERBB4 mutations have been reported [76].…”