Shinichi Ban

Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas

Objective The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. Design Retrospective multicentre analysis of 283 surgically resected IPMNs. Results Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p=0.0032), age (p=0.00924), ectatic duct size (p=0.0245), detection of mural nodules (p=4.09×10−6), histological grade (p<2.20×10−16), macroscopic types with differential involvement of the pancreatic duct system (p=3.91×10−5), invasive phenotypes (p=3.34×10−12), stage (p<2.20×10−16) and recurrence (p=0.00574). Kaplan–Meier analysis showed significant differences in patient survival by morphological type (p=5.24×10−6). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p=3.68×10−8) followed by the morphological type (p=0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p=0.0089). Conclusion In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis.

Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) may derive from an intraductal papillary mucinous neoplasm (IPMN) of the pancreas or may develop in the pancreatic duct apart from IPMN. The purpose of this study was to define the clinicopathological features of these 2 entities and compare them with those of ordinary PDAC. Methods: Of 765 patients who had surgical resection for IPMN, 122 were diagnosed as having PDAC derived from IPMN and 31 with PDAC concomitant with IPMN. In addition, 7605 patients with PDAC who were registered in the Japan Pancreas Society pancreatic cancer registry were compared with the above patients. Results: Pancreatic ductal adenocarcinomas derived from IPMN and concomitant with IPMN were significantly smaller, less invasive, and less extensive than ordinary PDAC. The median survival of patients with the 2 conditions was significantly longer than for those with ordinary PDAC when compared overall or when limited to TS2 (2.0 cm < tumor size ≤ 4.0 cm) or TS3 (4.0 cm < tumor size ≤ 6.0 cm) cases. Conclusions: These findings suggest that PDAC concomitant with IPMN and PDAC derived from IPMN may have more favorable biological behaviors or be diagnosed earlier than ordinary PDAC.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.

Intraductal papillary mucinous neoplasm (IPMN) is a unique pancreatic neoplasm developing in the ductal system. Two major histologic subtypes have been reported, that is the gastric type and the intestinal type. However, their histopathologic features, especially those of the gastric type, have not been fully described. To evaluate the features of these two types and refine their differences, we analyzed 80 IPMNs including 50 cases of the gastric type and 30 cases of the intestinal type with mucin immunohistochemistry. By defining a main duct-type lesion as predominantly involving the main pancreatic duct with or without branch ducts, and a branch duct-type lesion as exclusively centered on branch ducts or consisting of a collection of small cystic lesions, gastric-type IPMNs were mostly branch duct-type lesions (98%), whereas the intestinal-type IPMNs were usually main duct type (73%). The histologic grade of the intestinal type was generally higher than that of the gastric type. The intestinal type was also characterized by frequent intraluminal nodular growth, and severe atrophy and fibrosis of the surrounding parenchyma with mucous lake formation. In contrast, pyloric glandlike structures at the base of the papillae and pancreatic intraepithelial neoplasia (PanIN)-like complexes were more frequently observed in the gastric type. A significant difference was observed between the gastric type and the intestinal type with regard to all the above features (P<0.05). Seven cases (23%) of the intestinal type were associated with an invasive adenocarcinoma (6 mucinous and 1 ductal), versus only 1 case (2%) of the gastric type (invasive ductal carcinoma). All cases of both gastric and intestinal types expressed MUC5AC; however, high immunolabeling scores for MUC2 were mostly observed in the intestinal type (P<0.05). In conclusion, gastric and intestinal types of IPMNs have distinct histopathologic features and mucin profiles, suggesting that they may follow different biologic pathways.

Endoscopic mucosal resection: an improved diagnostic procedure for early gastroesophageal epithelial neoplasms.

Endoscopic mucosal resection (EMR), which is advocated for the treatment of early (superficial) gastroesophageal neoplasms, has also been alluded to represent a superior diagnostic and staging modality. We compared the diagnostic concordance of preceding biopsies with EMR specimens in 31 gastric and 10 esophageal EMRs consisting of 6 low-grade and 12 high-grade dysplasias, 21 intramucosal adenocarcinomas, and 2 submucosal invasive adenocarcinomas. Discrepancies were considered as either major or minor if the histologic grades differed by 2 or more, or by only 1, respectively. Discrepant and concordant cases were compared with regard to the size of lesion (maximum dimension and surface area), number of biopsy fragments, and extent of biopsy sampling (ratio between lesion size and number of biopsy fragments). These same variables were used to evaluate the differences seen between gastric and esophageal cases. Of the 41 cases, 16 (39%) had discrepant diagnoses, including 14 gastric and 2 esophageal neoplasms. A major discrepancy was seen in 2% of the cases (n = 1, gastric) and a minor discrepancy, in 15 cases. All but 2 of the discrepant cases were found to have a higher grade on EMR. The average number of biopsy fragments was 4.4 in both concordant and discrepant groups. The maximal dimension, surface area, and biopsy sampling ratios of the lesion were significantly greater in the discrepant cases than in the concordant cases. The esophageal cases trended toward having smaller size and a significantly extensive biopsy sampling. We conclude that EMR is superior to biopsy for diagnosing superficial gastroesophageal tumors. Discrepancies between the specimens occur in larger lesions (>10 mm) with less extensive biopsy sampling. EMR can substantially modify the diagnostic grade of a lesion and therefore facilitate optimal therapeutic decisions by avoiding undertreatment and overtreatment based on inaccurate grading and staging.

Intraductal Tubulopapillary Neoplasms of the Pancreas Distinct From Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of “intraductal tubulopapillary neoplasms (ITPNs)” and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of β-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

Buried dysplasia and early adenocarcinoma arising in barrett esophagus after porfimer-photodynamic therapy.

The restoration of squamous epithelium after photodynamic therapy (PDT) for Barrett esophagus (BE) and its related neoplasms has been noted. It may result in the development of buried neoplasms and/or BE underneath restored squamous epithelium which maintain their potential for malignant transformation. The purpose of this study was to evaluate the prevalence, endoscopic, and histologic characteristics and also response to further treatment of buried neoplastic epithelium developing after PDT. Fifty-two BE patients with high-grade dysplasia (n=19), intramucosal adenocarcinoma (n=28), and invasive adenocarcinoma (n=5) were treated with porfimer PDT. Buried neoplasms completely covered by squamous epithelium were seen in 1 patient before and in 13 patients after PDT. Their prevalence was 0.6% and 7.4% of pre and post-PDT biopsy levels positive for neoplasia (P=0.001). Buried neoplasms, representing the highest grade of residual neoplasm, were noted in a series of 11 post-PDT endoscopies (7.1% of 155 post-PDT endoscopies with neoplastic diagnoses) of 8 patients. Their occurrence after PDT was neither associated with the length of BE, the diffuseness of neoplasms nor the presence of buried lesions before treatment. There was no prevalent location for these lesions in relation to the original segment of BE, although the majority of both surface and buried neoplasms were found in the prior neoplastic sites. Patients with buried neoplasms responded to further treatment similarly to those with only surface neoplasms (8 of 13 vs. 17 of 24) (P=0.33). In conclusion, buried neoplasms are not uncommon after PDT. Thorough endoscopic surveillance with extensive biopsies, especially of the sites previously positive for neoplasia is important to avoid overlooking buried neoplasms that may progress.

Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett's esophagus.

The efficacy of photodynamic therapy (PDT) is currently evaluated for the treatment of superficial neoplasms arising in Barrett’s esophagus (BE). An accurate assessment of this technique requires the evaluation of biopsies before and after treatment. However, despite the importance of pathology, only a limited number of studies have systematically assessed the mucosal changes after PDT. To evaluate mucosal changes after PDT, and pathologic variables that may impact on the success of this therapy, we analyzed the pre- and post-PDT biopsies of a cohort of patients treated by this modality. Thirty-three patients (mean age, 71 years) with high-grade dysplasia (HGD) and/or intramucosal carcinoma (IMC) arising in BE and followed up after PDT using Porfimer sodium form the basis of this study. In all patients, a review of all pre- and post-PDT biopsies was performed. The variables recorded included the histologic grade and architecture of neoplasms, the distribution of neoplasms, and squamous re-epithelialization. IMC and HGD coexisted in the pre-PDT biopsies of 18 patients (54.5%). IMC and HGD showed a prominent tubular proliferation in 14 patients and displayed a papillary pattern (at least partially) in 19 patients. In post-PDT, patches of specialized columnar epithelium were buried under squamous epithelium in 17 patients (51.5%), and foci of dysplasia/carcinoma covered by squamous epithelium were found in 9 patients (27.3%). HGD and/or IMC were eradicated in 17 patients (eradicated group) and persisted in 16 patients (persistent group). In the persistent group, grade and architecture were unchanged after PDT in 62.5% and 87.5% of patients, respectively. The persistent group was characterized by: 1) a more frequent papillary architecture (P < 0.05), and 2) a diffuse distribution of the neoplasms on pre-PDT biopsies (P = 0.05). Singularly, the persistent neoplastic lesions were observed in the distal esophagus (P < 0.05). A systematic histopathologic evaluation allowed us to draw attention to the fact that distally located and papillary-type neoplasia seem resistant to PDT. The higher than expected incidence of buried residual neoplastic epithelium should also be emphasized since it represents a risk for undetected growth of malignancy.

Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas.

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P=0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P=0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P<0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P<0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients’ prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

Endoscopic mucosal resection for gastric epithelial neoplasms: a study of 39 cases with emphasis on the evaluation of specimens and recommendations for optimal pathologic analysis.

Endoscopic mucosal resection of gastric neoplasms is a curative technique that avoids surgery and its potential complications. Infrequently performed in the West, the limitations, pitfalls and challenges provided by this new therapeutic modality are not well known by general surgical pathologists. We evaluated a series of 39 endoscopic mucosal resections and assessed the correlation between original biopsies and final diagnoses, depth of excision, status of deep and lateral margins, artifactual changes and recurrence rate. The tumors consisted of 24 intramucosal carcinomas, six high-grade dysplasias, eight low-grade dysplasias and one submucosal invasive carcinoma. The preresection diagnoses corresponded to the final evaluation in 63% of the cases with previous biopsies. In 37% of the cases, the biopsies under-diagnosed the neoplasia. The rate of positive margins was 38%. Iatrogenic changes, that is, intramucosal hemorrhage and electrodiathermic burn, were noted in 44% of the cases but hindered the pathologic evaluation in only 10% of the cases. Persistence or recurrence was observed in only seven cases and there was no progression to advanced adenocarcinoma. Based on our experience, we offer some recommendations in order to provide optimal pathologic analysis of endoscopic mucosal resection specimens.

Prospective study of the evaluation of the usefulness of tumor typing by narrow band imaging for the differential diagnosis of gastric adenoma and well-differentiated adenocarcinoma.

Background and Aim:  Presently, the differential diagnosis of gastric adenoma and well‐differentiated adenocarcinoma by endoscopy is very difficult. We carried out magnifying endoscopy with narrow band imaging (NBI) in lesions that required discrimination between gastric adenoma and well‐differentiated adenocarcinoma, and prospectively evaluated whether the tumor typing that we propose is useful for their differential diagnosis.