The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes.
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.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Olca
O
Basturk
Department of Surgery, University of South Alabama, Mobile, AL, USA.
Marcus
M
Tan
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Umesh
U
Bhanot
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.
Peter
P
Allen
Department of Pathology, Emory University, Atlanta, GA, USA.
Volkan
V
Adsay
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Sasinya N
SN
Scott
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Ronak
R
Shah
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Michael F
MF
Berger
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Gokce
G
Askan
Department of Molecular Diagnostics, New York Genome Center, New York, USA.
Esra
E
Dikoglu
Department of Molecular Diagnostics, New York Genome Center, New York, USA.|Department of Pathology, Columbia University Medical Center, New York, USA.
Vaidehi
V
Jobanputra
Department of Molecular Diagnostics, New York Genome Center, New York, USA.
Kazimierz O
KO
Wrzeszczynski
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Carlie
C
Sigel
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
Christine
C
Iacobuzio-Donahue
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
David S
DS
Klimstra
D014408:Biomarkers, Tumor / Q000235:genetics*; D002864:Chromogranins / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000145:classification / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics; D024862:Oxyphil Cells / Q000145:classification / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D000073336:Whole Genome Sequencing
D014408:Biomarkers, Tumor; D002864:Chromogranins; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D015513:Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras)