Benign Etiology for High-Risk Intraductal Papillary Mucinous Neoplasm: A Case Report and Literature Review.

Intraductal papillary mucinous neoplasms are relatively common and entail a variable risk of malignant potential. The Fukuoka guidelines present criteria for the risk of malignant transformation and are used for risk stratification and treatment decision-making. However, these guidelines entail some fallibility with limited sensitivity and specificity. In this case, we present an individual who had many of the hallmarks of malignant transformation but was found to have no evidence of malignancy or high-grade dysplasia. We discuss the suspected etiology of this individual's condition and how it might arise in others, as well as a brief review of the literature on risk factors in intraductal papillary mucinous neoplasms.

Deep learning classification of ex vivo human colon tissues using spectroscopic optical coherence tomography.

Screening for colorectal cancer (CRC) with colonoscopy has improved patient outcomes; however, it remains the third leading cause of cancer-related mortality, novel strategies to improve screening are needed. Here, we propose an optical biopsy technique based on spectroscopic optical coherence tomography (OCT). Depth resolved OCT images are analyzed as a function of wavelength to measure optical tissue properties and used as input to machine learning algorithms. Previously, we used this approach to analyze mouse colon polyps. Here, we extend the approach to examine human biopsied colonic epithelial tissue samples ex vivo. Optical properties are used as input to a novel deep learning architecture, producing accuracy of up to 97.9% in discriminating tissue type. SOCT parameters are used to create false colored en face OCT images and deep learning classifications are used to enable visual classification by tissue type. This study advances SOCT toward clinical utility for analysis of colonic epithelium.

Critical updates in neuroendocrine tumors: Version 9 American Joint Committee on Cancer staging system for gastroenteropancreatic neuroendocrine tumors.

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

Novel endoscopic scoring system for immune mediated colitis: a multicenter retrospective study of 674 patients.

BACKGROUND AND AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084). CONCLUSIONS: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Differential spatial distribution of HNF4α isoforms during dysplastic progression of intraductal papillary mucinous neoplasms of the pancreas.

Hepatocyte Nuclear Factor 4-alpha (HNF4α) comprises a nuclear receptor superfamily of ligand-dependent transcription factors that yields twelve isoforms in humans, classified into promoters P1 or P2-associated groups with specific functions. Alterations in HNF4α isoforms have been associated with tumorigenesis. However, the distribution of its isoforms during progression from dysplasia to malignancy has not been studied, nor has it yet been studied in intraductal papillary mucinous neoplasms, where both malignant and pre-malignant forms are routinely clinically identified. We examined the expression patterns of pan-promoter, P1-specific, and P2-specific isoform groups in normal pancreatic components and IPMNs. Pan-promoter, P1 and P2 nuclear expression were weakly positive in normal pancreatic components. Nuclear expression for all isoform groups was increased in low-grade IPMN, high-grade IPMN, and well-differentiated invasive adenocarcinoma. Poorly differentiated invasive components in IPMNs showed loss of all forms of HNF4α. Pan-promoter, and P1-specific HNF4α expression showed shifts in subnuclear and sub-anatomical distribution in IPMN, whereas P2 expression was consistently nuclear. Tumor cells with high-grade dysplasia at the basal interface with the stroma showed reduced expression of P1, while P2 was equally expressed in both components. Additional functional studies are warranted to further explore the mechanisms underlying the spatial and differential distribution of HNF4α isoforms in IPMNs.

ACAA2 is a novel molecular indicator for cancers with neuroendocrine phenotype.

BACKGROUND: Neuroendocrine phenotype is commonly associated with therapy resistance and poor prognoses in small-cell neuroendocrine cancers (SCNCs), such as neuroendocrine prostate cancer (NEPC) and small-cell lung cancer (SCLC). Expression levels of current neuroendocrine markers exhibit high case-by-case variability, so multiple markers are used in combination to identify SCNCs. Here, we report that ACAA2 is elevated in SCNCs and is a potential molecular indicator for SCNCs. METHODS: ACAA2 expressions in tumour xenografts, tissue microarrays (TMAs), and patient tissues from prostate and lung cancers were analysed via immunohistochemistry. ACAA2 mRNA levels in lung and prostate cancer (PC) patients were assessed in published datasets. RESULTS: ACAA2 protein and mRNA levels were elevated in SCNCs relative to non-SCNCs. Medium/high ACAA2 intensity was observed in 78% of NEPC PDXs samples (N = 27) relative to 33% of adeno-CRPC (N = 86), 2% of localised PC (N = 50), and 0% of benign prostate specimens (N = 101). ACAA2 was also elevated in lung cancer patient tissues with neuroendocrine phenotype. 83% of lung carcinoid tissues (N = 12) and 90% of SCLC tissues (N = 10) exhibited medium/high intensity relative to 40% of lung adenocarcinoma (N = 15). CONCLUSION: ACAA2 expression is elevated in aggressive SCNCs such as NEPC and SCLC, suggesting it is a potential molecular indicator for SCNCs.

Deep learning classification of ex vivo human colon tissues using spectroscopic OCT.

Screening programs for colorectal cancer (CRC) have had a profound impact on the morbidity and mortality of this disease by detecting and removing early cancers and precancerous adenomas with colonoscopy. However, CRC continues to be the third leading cause of cancer-related mortality in both men and woman, partly because of limitations in colonoscopy-based screening. Thus, novel strategies to improve the efficiency and effectiveness of screening colonoscopy are urgently needed. Here, we propose to address this need using an optical biopsy technique based on spectroscopic optical coherence tomography (OCT). The depth resolved images obtained with OCT are analyzed as a function of wavelength to measure optical tissue properties. The optical properties can be used as input to machine learning algorithms as a means to classify adenomatous tissue in the colon. In this study, biopsied tissue samples from the colonic epithelium are analyzed ex vivo using spectroscopic OCT and tissue classifications are generated using a novel deep learning architecture, informed by machine learning methods including LSTM and KNN. The overall classification accuracy obtained was 88.9%, 76.0% and 97.9% in discriminating tissue type for these methods. Further, we apply an approach using false coloring of en face OCT images based on SOCT parameters and deep learning predictions to enable visual identification of tissue type. This study advances the spectroscopic OCT towards clinical utility for analyzing colonic epithelium for signs of adenoma.

Debating Deposits, Redux: Substantial Interobserver Agreement Exists in Distinguishing Tumor Deposits From Nodal Metastases in Small Bowel Neuroendocrine Tumors.

CONTEXT.­: Recent data suggest mesenteric tumor deposits (MTDs) indicate poor prognosis in small bowel well-differentiated neuroendocrine tumors (SB-NETs), including compared to positive lymph nodes, making their distinction crucial. OBJECTIVE.­: To study interobserver agreement in distinguishing SB-NET MTDs from positive nodes. DESIGN.­: Virtual slides from 36 locally metastatic SB-NET foci were shared among 7 gastrointestinal pathologists, who interpreted each as an MTD or a positive node. Observers ranked their 5 preferred choices among a supplied list of potentially useful histologic features, for both options. Diagnostic opinions were compared using Fleiss multirater and Cohen weighted κ analyses. RESULTS.­: Preferred criteria for MTD included irregular shape (n = 7, top choice for 5), perineural invasion/nerve entrapment (n = 7, top choice for 2), encased thick-walled vessels (n = 7), and prominent fibrosis (n = 6). Preferred criteria for positive nodes included peripheral lymphoid follicles (n = 6, top choice for 4), round shape (n = 7, top choice for 2), peripheral lymphocyte rim (n = 7, top choice for 1), subcapsular sinuses (n = 7), and a capsule (n = 6). Among 36 foci, 10 (28%) each were unanimously diagnosed as MTD or positive node. For 13 foci (36%), there was a diagnosis favored by most observers (5 or 6 of 7): positive node in 8, MTD in 5. Only 3 cases (8%) had a near-even (4:3) split. Overall agreement was substantial (κ = .64, P < .001). CONCLUSIONS.­: Substantial interobserver agreement exists for distinguishing SB-NET MTDs from lymph node metastases. Favored histologic criteria in making the distinction include irregular shape and nerve/vessel entrapment for MTD, and peripheral lymphocytes/lymphoid follicles and round shape for positive nodes.

Heterogeneity of glycan biomarker clusters as an indicator of recurrence in pancreatic cancer.

Introduction: Outcomes following tumor resection vary dramatically among patients with pancreatic ductal adenocarcinoma (PDAC). A challenge in defining predictive biomarkers is to discern within the complex tumor tissue the specific subpopulations and relationships that drive recurrence. Multiplexed immunofluorescence is valuable for such studies when supplied with markers of relevant subpopulations and analysis methods to sort out the intra-tumor relationships that are informative of tumor behavior. We hypothesized that the glycan biomarkers CA19-9 and STRA, which detect separate subpopulations of cancer cells, define intra-tumoral features associated with recurrence. Methods: We probed this question using automated signal thresholding and spatial cluster analysis applied to the immunofluorescence images of the STRA and CA19-9 glycan biomarkers in whole-block sections of PDAC tumors collected from curative resections. Results: The tumors (N = 22) displayed extreme diversity between them in the amounts of the glycans and in the levels of spatial clustering, but neither the amounts nor the clusters of the individual and combined glycans associated with recurrence. The combined glycans, however, marked divergent types of spatial clusters, alternatively only STRA, only CA19-9, or both. The co-occurrence of more than one cluster type within a tumor associated significantly with disease recurrence, in contrast to the independent occurrence of each type of cluster. In addition, intra-tumoral regions with heterogeneity in biomarker clusters spatially aligned with pathology-confirmed cancer cells, whereas regions with homogeneous biomarker clusters aligned with various non-cancer cells. Conclusion: Thus, the STRA and CA19-9 glycans are markers of distinct and co-occurring subpopulations of cancer cells that in combination are associated with recurrence. Furthermore, automated signal thresholding and spatial clustering provides a tool for quantifying intra-tumoral subpopulations that are informative of outcome.

Cytomorphologic observations on the sclerosing variant of well-differentiated pancreatic neuroendocrine tumors: Towards making specific diagnoses early.

BACKGROUND: The recently described sclerosing variant of pancreatic neuroendocrine tumor (spNET) shows prominent stromal fibrosis and decreased tumor cellularity in surgical pathology specimens. Although prognostic data are currently ambivalent, some studies have reported metastatic disease in small primary tumors, highlighting the need for early diagnosis. The aim of our study is to evaluate cytology specimens of spNET to determine its characteristic cytomorphologic features to expedite an early diagnosis. METHODS: Twenty-five cytology cases of spNET from 23 patients and 29 cytology cases of typical pancreatic neuroendocrine tumor (tpNET) from 29 patients diagnosed as such by surgical pathology evaluation were reviewed by two pathologists to assess adequacy of diagnostic material, cellularity and fibrosis. Radiographic findings and outcome data were collected. RESULTS: With only 13 of 25 specimens deemed as diagnostic, spNET specimens were more often non-diagnostic (p < .01) and less often hypercellular (p = .03) compared to tpNET counterparts. While at least focal fibrosis was observed in both groups, a subset of spNET cases showed small tumor cell groups entrapped in large fibrotic fragments. Importantly, spNETs tended to be metastatic at diagnosis (both regionally and distant), with a smaller average tumor size. CONCLUSION: The hypocellular nature of spNET cytology samples makes this variant difficult to diagnose. However, when adequate sample is available, a subset of spNET show characteristic cytomorphology that enables us to consider this specific diagnosis at first diagnostic sampling. It is crucial to diagnose this variant early given the propensity of small tumors with regional lymph node involvement and liver metastases.

Venous Invasion in Pancreatic Neuroendocrine Tumors Is Independently Associated With Disease-free Survival and Overall Survival.

In this study, we evaluated venous invasion and its association with survival in patients with resected pancreatic neuroendocrine tumor (PanNET). Surgical Pathology Archives were searched for pancreatectomies performed for PanNET between October 1, 2005, and December 31, 2019. Hematoxylin and eosin (H&E)-stained slides were evaluated for venous invasion, and Movat's stain was performed in all cases with no venous invasion detected on H&E stains. Pathology reports and electronic medical records were also reviewed. Venous invasion was identified in 23 of 145 (15.9%) cases on H&E stains, and Movat's stain identified additional 34 cases with venous invasion (39.3% overall). Orphan arteries with adjacent well-defined tumor nodules or subtle hyalinizing nodules in hyalinizing tumors are highly specific for venous invasion. In stage I-III cases (n=122), venous invasion was associated with larger tumor size, higher World Health Organization (WHO) tumor grade, perineural invasion, extrapancreatic extension, lymph node metastasis, and liver metastasis ( P <0.05). In univariate analyses, tumor size, WHO grade, venous invasion, perineural invasion, T stage, and lymph node metastasis all correlated with disease-free survival; however, only venous invasion was associated with worse disease-free survival in multivariate analyses ( P <0.01). In all-stage cases, venous invasion was the only attributor associated with worse overall survival in multivariate analyses ( P =0.03). In summary, venous invasion in PanNET can be histologically subtle, and Movat's stain can greatly increase the detection rate. More importantly, enhanced venous invasion by Movat's stain correlates independently with disease-free survival in patients with stage I-III tumors and overall survival in all-stage patients.

Clinicopathologic features of non-type 1/2 gastric neuroendocrine tumors and their associated mucosal changes.

OBJECTIVES: The pathogenesis for non-type 1/2 gastric neuroendocrine tumors (G-NETs) remains unclear. The aim of this study was to examine the clinicopathologic features of G-NETs and associated mucosal changes. METHODS: The electronic health records of patients with non-type 1/2 G-NETs were reviewed. H&E slides were reviewed for pathologic features and mucosal changes. The t test and Fisher exact test were used for statistical analysis. RESULTS: In total, 33 patients were assigned to either group 1 (n = 23) or group 2 (n = 10). Group 1 included patients with a history of proton pump inhibitor (PPI) use, increased gastrin levels, or significant PPI effect (PPI/gastrin-associated). All other patients were assigned to group 2. There was no significant difference in age and sex between the 2 groups. Group 2 tumors were more likely to be larger, invade deeper, and develop metastases (P < .05). Tumors in patients with cirrhosis tended to be larger. Peritumoral mucosal changes included loss of oxyntic glands, foveolar hyperplasia, and intestinal metaplasia. Background mucosa in group 1 patients showed PPI effect and neuroendocrine hyperplasia or dysplasia. CONCLUSIONS: Although PPI/gastrin-associated non-type 1/2 G-NETs were smaller and more indolent than typical type 3 G-NETs, tumors in patients with cirrhosis tended to be larger. Additionally, peritumoral mucosal changes could mimic chronic atrophic gastritis.

Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification.

The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor κB (TNF-NFκB) and cell cycle (cycling S and cycling G2-M) programs occurred with relative prominence in PB and INT subtypes, respectively. Together, this study delineates markers of high-risk IPMN and insights into malignant progression.

Heterogeneity of Glycan Biomarker Clusters as an Indicator of Recurrence in Pancreatic Cancer.

Outcomes following tumor resection vary dramatically among patients with pancreatic cancer. A challenge in defining predictive biomarkers is to discern within the complex tumor tissue the specific subpopulations and relationships that drive recurrence. Multiplexed immunofluorescence is valuable for such studies when supplied with markers of relevant subpopulations and analysis methods to sort out the intra-tumor relationships that are informative of tumor behavior. We hypothesized that the glycan biomarkers CA19-9 and STRA, which detect separate subpopulations of cancer cells, define intra-tumoral features associated with recurrence. We probed this question using automated signal thresholding and spatial cluster analysis applied to the immunofluorescence images of the STRA and CA19-9 glycan biomarkers in whole-block tumor sections. The tumors (N = 22) displayed extreme diversity between them in the amounts of the glycans and in the levels of spatial clustering, but neither the amounts nor the clusters of the individual and combined glycans associated with recurrence. The combined glycans, however, marked divergent types of spatial clusters, alternatively only STRA, only CA19-9, or both. The co-occurrence of more than one cluster type within a tumor associated significantly with disease recurrence, in contrast to the independent occurrence of each type of cluster. In addition, intra-tumoral regions with heterogeneity in biomarker clusters spatially aligned with pathology-confirmed cancer cells, whereas regions with homogeneous biomarker clusters aligned with various non-cancer cells. Thus, the STRA and CA19-9 glycans are markers of distinct and co-occurring subpopulations of cancer cells that in combination are associated with recurrence. Furthermore, automated signal thresholding and spatial clustering provides a tool for quantifying intra-tumoral subpopulations that are informative of outcome.

Practice patterns for reporting digestive system neuroendocrine neoplasms: results from a large, comprehensive international survey.

AIMS: Criteria for the interpretation of digestive system neuroendocrine neoplasms (NENs) continue to evolve. Although there are some literature recommendations regarding workup and diagnosis of these lesions, different practice patterns exist among pathologists when signing out these specimens. The aim of this study was to assess practice trends among pathologists worldwide when reporting these neoplasms. METHODS AND RESULTS: We created an online survey with multiple questions pertaining to digestive NENs. The results were analysed based on type of practice setting, years of sign-out experience, and practice location. Respondents included 384 practicing pathologists: 70% academic, 30% private practice; 63% gastrointestinal (GI) pathology-subspecialised, 37% not; 39% North American, 42% European, 19% others; 45% with ≤10 years in practice; 55% with >10 years. Some question responses were chosen by the majority (e.g. 85% use both mitotic count and Ki67 index for grading NENs, 82% complete a synoptic, and Ki67 stain even for small incidental appendiceal neuroendocrine tumours [NETs], and 96% utilize the diagnosis of grade 3 NET). However, some questions showed varying responses, including counting mitotic figures, Ki67 stain interpretation, and pancreatic grade 3 NEN workup. Pathologists also had some variability in interpreting regional metastatic foci of small bowel NETs and in choosing blocks for Ki67 staining in multifocal lesions. CONCLUSION: There existed scenarios wherein practice patterns varied despite recommendations in the literature, and there were also scenarios lacking clear guidelines wherein pathologists used varying judgement. This survey highlights current key grey areas in digestive system NEN evaluation, leading to variation in practice patterns.

Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising.

Histopathological tumour response scoring in resected pancreatic cancer following neoadjuvant therapy: international interobserver study (ISGPP-1).

BACKGROUND: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. METHODS: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. RESULTS: The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. CONCLUSION: Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT.