BACKGROUND:Post-colonoscopy colorectal cancer (PCCRC), defined as colorectal cancer (CRC) detected after a cancer-negative colonoscopy, represents a key quality indicator for CRC detection and prevention. While most PCCRC is attributed to missed lesions, few studies examine pathologic and molecular characteristics of PCCRC to assess for possible de novo cancer formation causing PCCRC. AIM:The aim of this study was to identify cases of PCCRC where prior colonoscopy was adequate (A-PCCRC) versus inadequate (I-PCCRC) and compare both subtypes with spontaneous CRC (sCRC) in terms of patient factors, histopathology and molecular characteristics. METHODS:This was a 12-year retrospective population-based study using a data set from the Western Australian Cancer Registry between 2000 and 2011. A-PCCRCs were identified by excluding lesions likely missed due to procedural factors or incomplete prior resection at index colonoscopy performed within 3-36 months of cancer diagnosis. Histopathological review and next-generation sequencing were conducted on subsets of patients with A-PCCRC and sCRC. Statistical analysis included univariable and multivariable regression models and chi-squared and Wilcoxon rank sum tests. RESULTS:A total of 524 (3.81%) cases of PCCRC were identified out of 13 757 cases of CRC; 272 were A-PCCRC (1.98%) and 252 I-PCCRC (1.83%). Female sex, older age and proximal location were associated with A-PCCRC. Mutations in the PIK3CA gene were less common in A-PCCRC compared to sCRC. CONCLUSION:A significant percentage of PCCRC occurred despite adequate prior colonoscopy. Missed sessile serrated lesions may contribute to many of these cases; however, further studies are required to examine possible de novo cancer as a cause of PCCRC that may involve unique biological pathways.

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a rare pancreatic cystic neoplasm which was first described in 1996.1Adsay N.V. Adair C.F. Heffess C.S. et al.Intraductal oncocytic papillary neoplasms of the pancreas.Am J Surg Pathol. 1996; 20: 980-994Crossref PubMed Scopus (241) Google Scholar It occurs in a wide age range, on average in the seventh decade, with males and females equally affected.2Liszka Ł. Pająk J. Zielińska-Pająk E. et al.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.J Hepatobiliary Pancreat Sci. 2010; 17: 246-261Crossref PubMed Scopus (27) Google Scholar 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.3Basturk O. Chung S.M. Hruban R.H. et al.Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas.Virchows Arch. 2016; 469: 523-532Crossref PubMed Scopus (53) Google Scholar,4Basturk O. Tan M. Bhanot U. et al.The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes.Mod Pathol. 2016; 29: 1058-1069Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar For example, IOPN lacks the typical mutations observed in IPMN, including KRAS, GNAS, and RNF43.4Basturk O. Tan M. Bhanot U. et al.The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes.Mod Pathol. 2016; 29: 1058-1069Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar 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.5Marchegiani G. Mino-Kenudson M. Ferrone C.R. et al.Oncocytic-type intraductal papillary mucinous neoplasms: a unique malignant pancreatic tumor with good long-term prognosis.J Am Coll Surg. 2015; 220: 839-844Crossref PubMed Scopus (52) Google Scholar,6Wang T. Askan G. Adsay V. et al.Intraductal oncocytic papillary neoplasms: clinical-pathologic characterization of 24 cases, with an emphasis on associated invasive carcinomas.Am J Surg Pathol. 2019; 43: 656-661Crossref PubMed Scopus (32) Google Scholar 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.7Reid M.D. Cytologic assessment of cystic/intraductal lesions of the pancreatobiliary tract.Arch Pathol Lab Med. 2022; 146: 280-297Crossref PubMed Scopus (5) Google Scholar,8Reid M.D. Stallworth C.R. Lewis M.M. et al.Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: criteria and clinical implications of accurate diagnosis.Cancer Cytopathol. 2016; 124: 122-134Crossref PubMed Scopus (32) Google Scholar 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).1Adsay N.V. Adair C.F. Heffess C.S. et al.Intraductal oncocytic papillary neoplasms of the pancreas.Am J Surg Pathol. 1996; 20: 980-994Crossref PubMed Scopus (241) Google Scholar,2Liszka Ł. Pająk J. Zielińska-Pająk E. et al.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.J Hepatobiliary Pancreat Sci. 2010; 17: 246-261Crossref PubMed Scopus (27) Google Scholar,6Wang T. Askan G. Adsay V. et al.Intraductal oncocytic papillary neoplasms: clinical-pathologic characterization of 24 cases, with an emphasis on associated invasive carcinomas.Am J Surg Pathol. 2019; 43: 656-661Crossref PubMed Scopus (32) Google Scholar 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.1Adsay N.V. Adair C.F. Heffess C.S. et al.Intraductal oncocytic papillary neoplasms of the pancreas.Am J Surg Pathol. 1996; 20: 980-994Crossref PubMed Scopus (241) Google Scholar,2Liszka Ł. Pająk J. Zielińska-Pająk E. et al.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.J Hepatobiliary Pancreat Sci. 2010; 17: 246-261Crossref PubMed Scopus (27) Google Scholar,5Marchegiani G. Mino-Kenudson M. Ferrone C.R. et al.Oncocytic-type intraductal papillary mucinous neoplasms: a unique malignant pancreatic tumor with good long-term prognosis.J Am Coll Surg. 2015; 220: 839-844Crossref PubMed Scopus (52) Google Scholar,6Wang T. Askan G. Adsay V. et al.Intraductal oncocytic papillary neoplasms: clinical-pathologic characterization of 24 cases, with an emphasis on associated invasive carcinomas.Am J Surg Pathol. 2019; 43: 656-661Crossref PubMed Scopus (32) Google Scholar By immunohistochemistry, the lesional cells of IOPNs are positive for MUC6 and EMA/MUC1 with focal positivity for MUC5AC.3Basturk O. Chung S.M. Hruban R.H. et al.Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas.Virchows Arch. 2016; 469: 523-532Crossref PubMed Scopus (53) Google Scholar,9Lüttges J. Zamboni G. Longnecker D. et al.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.Am J Surg Pathol. 2001; 25: 942-948Crossref PubMed Scopus (231) Google Scholar,10Basturk O. Khayyata S. Klimstra D.S. et al.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.Am J Surg Pathol. 2010; 34: 364-370Crossref PubMed Scopus (94) Google Scholar 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. 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. Reports exploring the cytopathological features of IOPN as a distinct entity are rare.8Reid M.D. Stallworth C.R. Lewis M.M. et al.Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: criteria and clinical implications of accurate diagnosis.Cancer Cytopathol. 2016; 124: 122-134Crossref PubMed Scopus (32) Google Scholar,11Monzen M. Shimizu K. Hatori T. et al.Usefulness of cell block cytology for preoperative grading and typing of intraductal papillary mucinous neoplasms.Pancreatology. 2013; 13: 369-378Crossref PubMed Scopus (15) Google Scholar 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.8Reid M.D. Stallworth C.R. Lewis M.M. et al.Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: criteria and clinical implications of accurate diagnosis.Cancer Cytopathol. 2016; 124: 122-134Crossref PubMed Scopus (32) Google Scholar 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.11Monzen M. Shimizu K. Hatori T. et al.Usefulness of cell block cytology for preoperative grading and typing of intraductal papillary mucinous neoplasms.Pancreatology. 2013; 13: 369-378Crossref PubMed Scopus (15) Google Scholar 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.7Reid M.D. Cytologic assessment of cystic/intraductal lesions of the pancreatobiliary tract.Arch Pathol Lab Med. 2022; 146: 280-297Crossref PubMed Scopus (5) Google Scholar,8Reid M.D. Stallworth C.R. Lewis M.M. et al.Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: criteria and clinical implications of accurate diagnosis.Cancer Cytopathol. 2016; 124: 122-134Crossref PubMed Scopus (32) Google Scholar 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.12Singhi A.D. Wood L.D. Parks E. et al.Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct.Gastroenterology. 2020; 158: 573-582.e2Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar 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. The authors state that there are no conflicts of interest to disclose.

Background and study aims Colonic angioectasia are the most common vascular lesions in the gastrointestinal tract and are among the most common causes for chronic or recurrent lower gastrointestinal bleeding. Endoscopic treatment involves a variety of techniques, all of which focus on destruction of the mucosal abnormality. However, recurrent bleeding after endoscopic treatment is common, with more than one treatment frequently necessary. We report a technique for definitive treatment of colonic angioectasia by targeting the feeding submucosal vessel. Patients and methods Analogous to endoscopic mucosal resection, a submucosal injection is made beneath the target lesion which is then removed by electrocautery snare resection of the mucosal lesion. The exposed feeding vessel is then destroyed by application of coagulation current. The resection defect is closed by clips. Results Six patients with a total of 14 colonic angioectasia were treated over the study period. All lesions were destroyed without adverse events. Conclusion Elevation, hot snare resection and coagulation (ESC) of the visible vessel for treating colonic angioectasia appears safe and effective. Larger prospective comparative studies are required to assess its specific role.

Introduction: We have previously reported our initial experience with prolonged initial chemotherapy with gemcitabine/abraxane followed by radiotherapy with concurrent infusional 5-FU. Continued application of this treatment approach has now resulted in 18 patients with unresectable pancreatic adenocarcinoma being resected (17 achieving R0 resections) with significantly prolonged survival times. Patients with tri-modality therapy showed a 45% four year survival. Methods: An electronic database search was carried out to identify all cases of locally advanced pancreatic cancer treated between 2 institutions. Case records, pathology, radiology and multidisciplinary team meeting records were then examined to determine type and dose of chemotherapy given together with radiological, pathological and survival outcomes. Patients were deemed unresectable if at multidisciplinary team meeting, they were shown to have vascular involvement >180 degrees and considered by the surgical, endoscopic ultrasound and radiological team to be not suitable for vascular reconstruction. Patients were then treated with up to 8 cycles of gemcitabine plus nab-paclitaxel followed by external beam radiotherapy 54Gy in 30 fractions. Follow-up with tumour markers and serial CT scanning was used to determine response and case records were examined for follow-up and survival data. Results: 89 patients were identified who fulfilled these criteria. 18 patients responded well enough to be deemed resectable at subsequent MDT meetings. These patients underwent Whipple's pancreatico duodenectomy. 3 pathological complete responses were seen and 17 of 18 patients achieved an R0 resection. Toxicity was related mainly to neuropathy from oxaliplatin and cytopenia. No treatment related deaths were seen. Medium length of stay following surgery was 18 days and there were no perioperative deaths. Median survival for those receiving or 3 modalities of therapy was greater than 2 years compared to less than 2 years for those not undergoing surgery and 10 months for those not undergoing surgery or proceeding with radiotherapy. Conclusion: Our data suggests that prolonged initial chemotherapy with up to 8 cycles of gemcitabine/nab-paclitaxel followed by radiotherapy with concurrent infusional 5-FU results in a significant number of patients being down staged from unresectable to resectable. Those undergoing tri-modality therapy have particularly impressive survival times.

BACKGROUND & AIMS: Transplantation of peripheral blood stem cells has been successful therapy for small numbers of patients with Crohn's disease (CD), but requires prior myeloconditioning. Mesenchymal stromal cells (MSCs) escape immune recognition, so myeloconditioning is not required before their administration. We investigated the efficacy of allogeneic MSCs in patients with luminal CD. METHODS: Our phase 2, open-label, multicenter study included 16 patients (21-55 y old; 6 men) with infliximab-or adalimumab-refractory, endoscopically confirmed, active luminal CD (CD activity index [CDAI], >250). Subjects were given intravenous infusions of allogeneic MSCs (2 x 10(6) cells/kg body weight) weekly for 4 weeks. The primary end point was clinical response (decrease in CDAI >100 points) 42 days after the first MSC administration; secondary end points were clinical remission (CDAI, <150), endoscopic improvement (a CD endoscopic index of severity [CDEIS] value, <3 or a decrease by > 5), quality of life, level of C-reactive protein, and safety. RESULTS: Among the 15 patients who completed the study, the mean CDAI score was reduced from 370 (median, 327; range, 256-603) to 203 (median, 129) at day 42 (P < .0001). The mean CDAI scores decreased after each MSC infusion (370 before administration, 269 on day 7, 240 on day 14, 209 on day 21, 182 on day 28, and 203 on day 42). Twelve patients had a clinical response (80%; 95% confidence interval, 72%-88%; mean reduction in CDAI, 211; range 102-367), 8 had clinical remission (53%; range, 43%-64%; mean CDAI at day 42, 94; range, 44-130). Seven patients had endoscopic improvement (47%), for whom the mean CDEIS scores decreased from 21.5 (range, 3.3-33) to 11.0 (range, 0.3-18.5). One patient had a serious adverse event (2 dysplasia-associated lesions), but this probably was not caused by MSCs. CONCLUSIONS: In a phase 2 study, administration of allogeneic MSCs reduced CDAI and CDEIS scores in patients with luminal CD refractory to biologic therapy.

The objective of this study was to develop a triage algorithm to optimize diagnostic yield from cytology, carcinoembryonic antigen (CEA), and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) testing on different components of a single pancreatic cyst fluid specimen. The authors also sought to determine whether cell block supernatant was suitable for CEA and KRAS testing.

EUS-guided FNA (EUS-FNA) is a safe and well-established technique for the diagnosis and staging of pancreatic cancer.1 Reports of tumor seeding are exceedingly rare compared with percutaneous FNA.2,3 We report a case of tumor seeding at the gastric wall after EUS-FNA of a pancreatic tail mass.