If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Intraductal oncocytic papillary neoplasms of the pancreas and bile ducts: a description of five new cases and review based on a systematic survey of the literature.
Previously, IOPN was classified as a variant of intraductal papillary mucinous neoplasm (IPMN), however it has recently been reclassified as a separate entity by the World Health Organization, as it is now known to be biologically and molecularly distinct from IPMN.
More recently, recurrent gene fusions have been described in genes encoding Protein Kinase A (PRKACA and PRKACB) in these tumours, but not any of their clinicopathological differential diagnoses, further cementing their distinction as a separate entity. As might be expected, the clinical behaviour is also distinct, with a much better prognosis than is seen in IPMN, even in the setting of metastasis and recurrence.
The important treatment and prognostic implications of preoperative diagnosis, therefore, necessitate careful clinical, radiological, and cytopathological correlation for accurate diagnosis and risk stratification of pancreatic cystic lesions.
Histologically, IOPN is characterised by neoplastic intraductal arborising papillary structures, lined by variably stratified and pseudostratified oncocytic cells (demonstrating granular eosinophilic cytoplasm and round nuclei with eccentric nucleoli).
Intraductal oncocytic papillary neoplasms of the pancreas and bile ducts: a description of five new cases and review based on a systematic survey of the literature.
Occasional goblet cells and intraepithelial lumina lead to a variably cribriform appearance. Typically, there is high grade dysplasia, and a component of invasive carcinoma is frequently observed.
Intraductal oncocytic papillary neoplasms of the pancreas and bile ducts: a description of five new cases and review based on a systematic survey of the literature.
The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma.
Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis.
Only a few reports on the cytopathological features and use of cytopathology in preoperative diagnosis of these distinct lesions are available in the literature. Herewith, we present two cases of IOPN for which preoperative cytopathological assessment was performed. In both cases imaging did not show high risk features such as solid elements or mural nodules; however, preoperative cytopathological diagnosis prompted surgical management.
The first case was a 59-year-old male with a known history of perianal Crohn disease, found to have an incidental cystic lesion in the head of pancreas. The lesion was detected on magnetic resonance enterography performed for exclusion of small bowel involvement. Imaging showed a 43×29×29 mm multilocated, thin-walled cystic lesion arising in the uncinate process of the pancreas and indenting the duodenum, with no solid areas or septation. No biliary dilatation was seen. The lesion was thought to represent a branch duct IPMN on initial imaging.
The patient underwent endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of the largest locule of the lesion, yielding 12 mL of clear but viscous fluid, from which smears and a cell block were prepared. The supernatant was also analysed for lipase and CEA levels, and polymerase chain reaction (PCR) with pyrosequencing for KRAS mutations was performed.
Prepared smears demonstrated proteinaceous background material and degenerate cells including macrophages and epithelial cells with moderately large nuclei and a moderate increase in nuclear:cytoplasmic ratio. Overall, the nuclear atypia was felt to represent low grade, with a few cells with possible high grade dysplasia. A few clustered papillary-like aggregates were seen. Concomitant cyst fluid biochemistry revealed low levels of lipase and CEA (3 U/L and 6 μg/L, respectively). No mutation in exons 2 or 3 of the KRAS gene was detected in DNA extracted from the cyst fluid. Overall, the preoperative cytopathology was reported as a neoplastic cyst, but a more specific diagnosis was not made at the time.
The patient underwent a planned enucleation of the cystic lesion, and a frozen section of the resection margin was performed (Fig. 1A). Intraoperative touch imprint and frozen sections of the cystectomy resection margin demonstrated neoplastic tissue with oncocytic features (Fig. 1B). Highly cellular touch imprint preparations showed strips, cohesive papillary-like aggregates, and singly dispersed neoplastic cells, ranging from polygonal to columnar in shape. Lesional cell nuclei were round with occasional membrane irregularity, moderate anisonucleosis, coarsely granular chromatin, and prominent peripheral nucleoli (Fig. 1C). Moderate to abundant granular, eosinophilic cytoplasm was noted.
Fig. 1(A) A cystic lesion with papillary areas was evident macroscopically. (B) Neoplastic cells with oncocytic features seen at frozen section. (C) Touch imprint smears show the characteristic cytomorphological features of IOPN: papillary-like clusters of oncocytic cells with round nuclei showing anisonucleosis and peripheral nucleoli, and abundant granular eosinophilic cytoplasm. (D) The arborising papillary architecture is seen in the in situ component (bottom) with focal invasion featuring a desmoplastic reaction and small, irregular, angulated ducts (top).
Following the intraoperative assessment findings, the patient proceeded to pancreaticoduodenectomy, and a diagnosis of IOPN was rendered on the final resection specimen, with complex arborising papillae comprising multilayered oncocytic epithelial cells lining delicate fibrovascular cores (Fig. 1D). An associated invasive component was seen, comprising small, irregular, angulated tubular structures lined by a single layer of neoplastic oncocytic epithelium surrounded by desmoplastic stroma, with a maximum extent of 6 mm. By immunohistochemistry the neoplastic cells were positive for MUC6, with variable MUC1 (EMA) and MUC5AC positivity, and negative MUC2. Comprehensive next generation sequencing of 33 genes was performed on formalin-fixed, paraffin-embedded tissue using the AmpliSeq for Illumina (USA) custom DNA panel. No variants of clinical significance were detected in either of KRAS or GNAS.
The second case was a 40-year-old male with an episode of unexplained pancreatitis 6 months prior, who was found to have a 4 cm head of pancreas cyst. Subsequent magnetic resonance cholangiopancreatography showed a stable lobular multiseptated cystic lesion within the uncinate process, which communicated with the main pancreatic duct through a dilated accessory branch. EUS-FNA was performed, yielding 2 mL of mucoid material, from which smears and a cell block were prepared, with the supernatant analysed for lipase and CEA (11,400 U/L and 8 μg/L, respectively).
The smears demonstrated background thick, proteinaceous, colloid-like mucin, and abnormal cells arranged in small groups and a few medium-sized sheets (Fig 2A), without any appreciable papillary architecture. The cells showed small to medium sized nuclei with scattered large nuclei, stippled chromatin, and nucleoli which were difficult to appreciate on Diff-Quik stained smears. The patient went on to undergo a pancreaticoduodenectomy, with the subsequent histopathology confirming a high grade IOPN without an invasive component (Fig. 2B). The neoplastic cells were positive for CK7, MUC6, and MUC5AC, with focal CDX2 and MUC2 positivity. Immunohistochemistry for MUC1 was negative.
Fig. 2(A) Smaller clusters of oncocytic cells were seen on this EUS-FNA smear, with subtle peripheral nucleolation on Diff-Quik staining. (B) Histopathology of the resection demonstrates a clear papillary architecture with cribriforming and oncocytic cytomorphology.
Reid et al. describe the cytopathological features as demonstrated in five EUS-FNA biopsies, with hypercellular smears characterised by a papillary architecture showing punched out intercellular spaces, and cells showing abundant granular cytoplasm, rounded nuclei, and eccentric nucleoli.
Two cases of IOPN (amongst ‘other’ subtypes of IPMN) were successfully diagnosed on cell block cytology (as compared with subsequent histopathology of the resection specimens) by Monzen et al. from pancreatic juice.
Again, the authors describe thick branching complex papillae with arborising columnar cells showing abundant eosinophilic cytoplasm and rounded nuclei with peripheral nucleoli.
Intraductal tubulopapillary neoplasm, oncocytic pancreatic neuroendocrine tumour, acinar cell carcinoma, and metastases with oncocytic features (such as hepatocellular carcinoma and oncocytic thyroid neoplasms) should be differentiated if a diagnosis of IOPN is considered on cytomorphological features.
Confirmation would require ancillary studies including cyst fluid biochemistry and molecular analysis if available. Of note is the identification of recurrent gene fusions involving PRKACA and PRKACB in IOPN, which a recent retrospective study demonstrated as a distinguishing feature when compared to clinicopathological differential diagnoses which did not demonstrate these fusions.
Furthermore, in cases which underwent preoperative EUS-FNA, these fusions were demonstrable in stored DNA and RNA from preoperative cyst fluid, highlighting the promising role of molecular studies in preoperative diagnosis of these lesions.
The cases we describe demonstrate some of the distinctive cytopathological features which are similarly described in the limited available literature, as well as the value of ancillary testing.
In summary, awareness of the entity, correct identification of the oncocytic nature of the lesional cells and availability of supportive biochemical and molecular results are the key to accurate preoperative cytological diagnosis of IOPN. In light of the considerable difference in prognosis compared with possible differentials, we emphasise the importance of considering IOPN when these cytopathological features are present. Importantly, both of these cases did not show high risk features at imaging.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
References
Adsay N.V.
Adair C.F.
Heffess C.S.
et al.
Intraductal oncocytic papillary neoplasms of the pancreas.
Intraductal oncocytic papillary neoplasms of the pancreas and bile ducts: a description of five new cases and review based on a systematic survey of the literature.
The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma.
Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis.
00091-0&id=gr1.jpg){kind=link}
00091-0&id=gr2.jpg){kind=link}