Multidisciplinary Approach for the Management of Metastatic Poorly Differentiated Neuroendocrine Carcinoma of the Pancreas: A Case Report of an Exceptional Responder.

ABSTRACT: Poorly differentiated pancreatic neuroendocrine carcinomas (pNECs) are rare, highly aggressive neoplasms. Frequently metastatic at diagnosis, prognosis is poor with median overall survival estimated to be less than 1 year. Although multidisciplinary management, including systemic medications and locoregional therapies aimed at reducing and preventing symptoms caused by mass effect, is the mainstay of treatment for patients with metastatic well-differentiated pancreatic neuroendocrine tumors, rapid progression, organ dysfunction, and poor performance status often preclude initiation of even single-modality palliative chemotherapy for patients with metastatic pNEC, limiting the use of and recommendation for multidisciplinary management.We describe the case of a 51-year-old male patient diagnosed with pNEC metastatic to liver and lymph nodes presenting with impending cholestatic liver failure for whom we were able to successfully initiate and dose-escalate cytotoxic chemotherapy with excellent radiographic response. After multidisciplinary review of his case, the patient underwent pancreaticoduodenectomy and hepatic wedge biopsies, with pathology demonstrating a pathologic complete response to chemotherapy in both the pancreas and liver. Surveillance scans at 2 years from initial diagnosis and 1 year from surgery remain without evidence of locoregional or distant recurrence, highlighting the importance and utility of multidisciplinary management in select cases.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

Artificial Intelligence Enabled Histological Prediction of Remission or Activity and Clinical Outcomes in Ulcerative Colitis.

BACKGROUND & AIMS: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. METHODS: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. RESULTS: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. CONCLUSION: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials.

Constrained multiple instance learning for ulcerative colitis prediction using histological images.

BACKGROUND AND OBJECTIVE: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and the rectum characterized by a remitting-relapsing course. To detect mucosal inflammation associated with UC, histology is considered the most stringent criteria. In turn, histologic remission (HR) correlates with improved clinical outcomes and has been recently recognized as a desirable treatment target. The leading biomarker for assessing histologic remission is the presence or absence of neutrophils. Therefore, the finding of this cell in specific colon structures indicates that the patient has UC activity. However, no previous studies based on deep learning have been developed to identify UC based on neutrophils detection using whole-slide images (WSI). METHODS: The methodological core of this work is a novel multiple instance learning (MIL) framework with location constraints able to determine the presence of UC activity using WSI. In particular, we put forward an effective way to introduce constraints about positive instances to effectively explore additional weakly supervised information that is easy to obtain and enjoy a significant boost to the learning process. In addition, we propose a new weighted embedding to enlarge the relevance of the positive instances. RESULTS: Extensive experiments on a multi-center dataset of colon and rectum WSIs, PICASSO-MIL, demonstrate that using the location information we can improve considerably the results at WSI-level. In comparison with prior MIL settings, our method allows for 10% improvements in bag-level accuracy. CONCLUSION: Our model, which introduces a new form of constraints, surpass the results achieved from current state-of-the-art methods that focus on the MIL paradigm. Our method can be applied to other histological concerns where the morphological features determining a positive WSI are tiny and similar to others in the image.

A novel rat model for the study of postoperative pancreatic fistula.

While over the past several decades mortality after pancreatic surgery has decreased to <5%, postoperative morbidity remains remarkably high, ranging from 15% to 65%. The development of a postoperative pancreatic fistula (POPF) is a significant contributor to morbidity in patients undergoing pancreatic surgery. POPF can lead to life-threatening conditions such as intra-abdominal abscess, uncontrolled hemorrhage, sepsis, and death. Rates of POPF have not significantly changed over time, despite the introduction of multiple technical and pharmacologic interventions aimed at their treatment and prevention. Unfortunately, there are few POPF experimental models that have been described in the literature and existing models are unable to reliably reproduce the clinical sequelae of POPF, limiting the development of new methods to prevent and treat POPF. Herein, we describe a new rat experimental model that reliably creates a POPF via transection of the common pancreatic duct.

Colorectal Cancer Is Associated with the Presence of Cancer Driver Mutations in Normal Colon.

Although somatic mutations in colorectal cancer are well characterized, little is known about the accumulation of cancer mutations in the normal colon before cancer. Here, we have developed and applied an ultrasensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without colorectal cancer. This testing platform revealed that normal colon from patients with and without colorectal cancer carries mutations in common colorectal cancer genes, but these mutations are more abundant in patients with cancer. Oncogenic KRAS mutations were observed in the normal colon of about one third of patients with colorectal cancer but in none of the patients without colorectal cancer. Patients with colorectal cancer also carried more TP53 mutations than patients without cancer and these mutations were more pathogenic and formed larger clones, especially in patients with early-onset colorectal cancer. Most mutations in the normal colon were different from the driver mutations in tumors, suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals who develop colorectal cancer. These results indicate that somatic evolution contributes to clonal expansions in the normal colon and that this process is enhanced in individuals with cancer, particularly in those with early-onset colorectal cancer. SIGNIFICANCE: This work suggests prevalent somatic evolution in the normal colon of patients with colorectal cancer, highlighting the potential of using ultrasensitive gene sequencing to predict disease risk.

PICaSSO virtual electronic chromendoscopy accurately reflects combined endoscopic and histological assessment for prediction of clinical outcomes in ulcerative colitis.

BACKGROUND AND AIMS: A composite endoscopic-histologic remission is increasingly explored as an important endpoint in ulcerative colitis (UC). We investigated combined endoscopic-histologic remission for predicting clinical outcomes at 12 months compared with endoscopic remission alone using the high definition virtual chromoendoscopy (VCE) Paddington International virtual ChromoendoScopy ScOre (PICaSSO) and histology scores. METHODS: Ulcerative colitis patients, prospectively enrolled from 11 international centres, underwent VCE with targeted biopsies and followed up for 12 months. Endoscopic activity was assessed by Mayo Endoscopic Score (MES), Ulcerative Colitis Endoscopic Index Severity (UCEIS) followed by VCE-PICaSSO. Robarts Histopathological Index|Robarts Histological index≤3 without neutrophils in mucosa, and Nancy Histological index (NHI)≤ 1 were used to define histologic remission. Combined endoscopic-histologic remission was compared with endoscopic remission alone by Cox proportional hazards model and by two- and three-proportion analysis using pre-specified clinical outcomes. RESULTS: 307 patients were recruited and 302 analysed. There was no difference in survival without specified clinical outcomes between PICaSSO defined endoscopic remission alone and endoscopic plus histologic remission in the rectum (HR 0.42, 95%CI 0.16-1.11 and HR 1.03, 95%CI 0.42-2.52 for Robarts Histological index and NHI respectively) at 12 months. There was however a significant survival advantage without specified clinical outcome events for UCEIS combined with histology compared with UCEIS alone (HR 0.30, 95%CI 0.12-0.75, p = 0.02) at 12 months (but not combined with NHI). For MES there was no advantage for predicting specified clinical outcomes at 12 months for endoscopy alone versus endoscopy plus histology, but there were differences in two and three proportion analysis at 6 months. CONCLUSION: Endoscopic remission by VCE-PICaSSO alone was similar to combined endoscopic and histologic remission for predicting specified clinical outcomes at 12 months. Larger studies with specific therapeutic interventions are required to further confirm the findings.

PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity. METHODS: Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies. RESULTS: PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy. CONCLUSIONS: PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

An International Multicenter Real-Life Prospective Study of Electronic Chromoendoscopy Score PICaSSO in Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. METHODS: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. RESULTS: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission. CONCLUSION: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC.

Fecal Calprotectin Thresholds to Predict Endoscopic Remission Using Advanced Optical Enhancement Techniques and Histological Remission in IBD Patients.

BACKGROUND: Fecal calprotectin (FC) is a common surrogate marker of mucosal healing (MH) in patients with ulcerative colitis (UC) and Crohn's disease (CD). We investigated the optimum FC thresholds for defining endoscopic remission (ER) and histological remission (HR) using advanced endoscopic techniques. PATIENTS AND METHODS: In this cross-sectional study, we collected clinical, endoscopic, histological data, and FC from 76 UC and 41 CD patients. Receiver operating characteristic curves were created to evaluate the optimum cut-off of FC to predict ER evaluated by Mayo Endoscopic Score (MES), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and modified PICaSSO (Paddington International Virtual Chromoendoscopy Score) for UC patients and Simple Endoscopic Score (SES-CD) in CD patients; and HR was scored by the Robarts Histology Index (RHI) and Nancy Index for UC and modified Riley for CD. RESULTS: In UC patients, the best thresholds of FC to identify ER calculated with MES, UCEIS, and modified PICaSSO were 112, 148, and 161 mcg/g with accuracy of 86.9% 86.8%, and 81.6%, respectively. The best value of FC to predict HR was 112 mcg/g and 172 mcg/g with accuracy of 84.2% and 81.6% for RHI and Nancy Index, respectively.In CD patients, the best cut-off of FC to predict ER was 96 mcg/g with accuracy of 82.9%. The HR was best predicted by an FC value of 225 mcg/g with accuracy of 75.6%. CONCLUSIONS: The FC value threshold between 112 and 172 mcg/g could identify ER and HR in UC patients, whereas a value under 225 mcg/g should be considered for CD patients.

Interobserver agreement in pathologic evaluation of bile duct biopsies.

Intraductal biopsy is commonly used for preoperative evaluation of the etiology of biliary strictures. Interpretation of intraductal biopsies is frequently challenging. The diagnosis often suffers from interobserver disagreement, which has not been studied in the literature. We sought to assess interobserver concordance in the interpretation of intraductal biopsies. Eighty-five biopsies were retrieved, falling into five diagnostic categories: negative for dysplasia (NED), indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma (CA). Eight gastrointestinal pathologists blindly reviewed all the slides. Agreement among pathologists was analyzed using Fleiss κ and weighted concordance coefficient S∗. A face-to-face consensus/training session was held to discuss the classification criteria, followed by a second round review. The overall interobserver agreement was fair in the first round review (κ = 0.39; S∗ = 0.56) and improved to moderate in the second round review (κ = 0.48; S∗ = 0.69). The agreement before and after consensus meeting was substantial to nearly perfect for CA (κ = 0.65, S∗ = 0.83; and κ = 0.80, S∗ = 0.91), fair for HGD (κ = 0.28, S∗ = 0.69; and κ = 0.40, S∗ = 0.63), and moderate for NED (κ = 0.47, S∗ = 0.50; and κ = 0.47, S∗ = 0.53). Agreement improved from fair to moderate for LGD (κ = 0.36, S∗ = 0.61; and κ = 0.49, S∗ = 0.71) and slight to fair for IND (κ = 0.16, S∗ = 0.51; and κ = 0.33, S∗ = 0.50). Compared with Hollande's fixed specimens, the agreement was higher in almost all diagnostic categories in formalin-fixed biopsies. Overall, interobserver concordance was improved after a consensus/training session. Interobserver reproducibility was high at the end of the diagnostic spectrum (CA) but fair to moderate for other diagnostic categories.

Macroscopic and microscopic characteristics of low grade appendiceal mucinous neoplasms (LAMN) on appendectomy specimens and correlations with pseudomyxoma peritonei development risk.

Low grade appendiceal mucinous neoplasm (LAMN) is the primary source of pseudomyxoma peritonei (PMP). PMP may develop after seemingly complete resection of primary tumor by appendectomy, which is unpredictable due to lack of reliable prognostic indicators. We retrospectively reviewed 154 surgically resected LAMNs to explore if any of the macroscopic and microscopic characteristics may be associated with increasing risk of PMP development. Our major findings include: (1) As compared to those without PMP, the cases that developed PMP were more frequent to have (a) smaller luminal diameter (<1 cm) and thicker wall, separate mucin aggregations, and microscopic perforation/rupture, all suggestive of luminal mucin leakage; (b) microscopic acellular mucin presenting on serosal surface and not being confined to mucosa; and (c) neoplastic epithelium dissecting outward beyond mucosa, however, with similar frequency of neoplastic cells being present in muscularis propria. (2) Involvement of neoplastic cells or/and acellular mucin at surgical margin did not necessarily lead to tumor recurrence or subsequent PMP, and clear margin did not absolutely prevent PMP development. (3) Coexisting diverticulum, resulted from neoplastic or non-neoplastic mucosa being herniated through muscle-lacking vascular hiatus of appendiceal wall, was seen in a quarter of LAMN cases, regardless of PMP. The diverticular portion of tumor involvement was often the weakest point where rupture occurred. In conclusion, proper evaluation of surgical specimens with search for mucin and neoplastic cells on serosa and for microscopic perforation, which are of prognostic significance, should be emphasized.

Dysregulation of IL6/IL6R-STAT3-SOCS3 signaling pathway in IBD-associated colorectal dysplastic lesions as compared to sporadic colorectal adenomas in non-IBD patients.

BACKGROUND: IL6-IL6R-STAT3-SOCS3 signaling pathway is known to play important roles in regulating intestinal epithelial homeostasis, in pathogenesis of inflammatory bowel disease (IBD), and in tumorigenesis of colorectal neoplasia. We studied the expressions of these factors in IBD-associated dysplasia and compared to sporadic colorectal adenomas in non-IBD individuals. MATERIALS AND METHODS: The expression of IL6, IL6R, STAT3, and SOCS3 within dysplastic as well as background non-dysplastic epithelial cells was evaluated by immunohistochemistry in 26 sporadic colorectal adenomas in non-IBD patients, 32 adenoma-like and 30 non-adenoma-like dysplastic lesions in IBD (41 ulcerative colitis, 21 Crohn's disease) patients. The level of expression of each factor was arbitrarily scored as 0, 1, 2, and 3. RESULTS: In both IBD and non-IBD lesions, neoplastic epithelium showed a higher expression of all factors, except the IL6R, as compared to non-neoplastic epithelium. For non-neoplastic epithelium between IBD and non-IBD settings, the colitic epithelium showed a similar IL6, lower IL6R, higher STAT3, and higher SOCS3 expression. As compared to non-IBD adenomas, IBD-associated dysplasia showed a significantly lower IL6, lower IL6R, higher STAT3, and lower SOCS3 expression. Most notably, a parallel-elevation pattern of STAT3/SOCS3 expressions was seen in non-IBD adenomas but an inverse-expression pattern of STAT3/SOCS3 seen in IBD dysplastic lesions. No significant differences existed between adenoma-like and non-adenoma-like lesions. CONCLUSIONS: IL6/IL6R-STAT3-SOCS3 signaling pathway does not seem to be preferentially associated with IBD-associated dysplasia. However, the STAT3-SOCS3 interaction appears dysregulated in IBD, characterized by a loss of STAT3/SOCS3 balance,i.e., loss of the normal negative regulation of SOCS3.

Chronic inflammation and other changes are significant components of clinically fibrotic strictures in Crohn's disease: a histological study of resected strictures clinically characterized as noninflamed.

BACKGROUND: Strictures related to Crohn's disease due to fibrosis are a result of an exaggerated tissue remodelling response to inflammation, characterized by accumulation of collagen-rich extracellular matrix produced by mesenchymal cells. OBJECTIVES: The objective of this study was to characterize histological changes seen in resected 'fibrotic' strictures to better understand individual components of intestinal stenosis. METHODS: We identified patients undergoing surgery for ileal Crohn's disease secondary to symptomatic stricturing disease (Montreal B2) using the histopathology database at Queen Elizabeth Hospital in Birmingham, UK, between 2012 and 2017. Phenotypic data were recorded and resection specimens reviewed. Two independent pathologists applied the semiquantitative scoring system previously developed by us to the microscopic images. Data were analyzed using the possible maximum total score (%PMTS). RESULTS: Forty-eight patients (M = 25) were included. with median disease duration of 7 years (range 0.25-39 years); nearly two-thirds had ileocolonic distribution (L3). In this cohort, despite presurgery diagnosis of noninflamed fibrosis, chronic inflammation was noted to be a prominent component of all strictures. The histological scoring showed presence of several other prominent findings such as muscular hyperplasia and volume expansion.There was statistically significant positive correlation between chronic inflammation and fibrosis and muscular hyperplasia. CONCLUSION: The histological features of Crohn's disease-related strictures show multiple changes in multiple layers and not simply fibrosis. In our cohort, despite the observation prior to surgery that strictures were clinically considered fibrotic, the finding of chronic inflammation as a dominant component at a histological level in the resection is important. The findings might suggest that one of the main drivers of progressive fibrosis is the inflammatory component, which probably is never fully resolved.

Revisiting the distinct histomorphologic features of inflammatory bowel disease-associated neoplastic precursor lesions in the SCENIC and post-DALM Era.

Distinct histomorphologic features of colitis-associated dysplasia (CAD) or neoplastic precursors in inflammatory bowel disease (IBD) have never been clearly identified. In this study, we tried to further explore the differentiating morphologic features of CAD by retrospectively reviewing the lesions that were clearly associated with carcinomas (carcinoma-related lesions) and by comparing between endoscopically nonpolypoid (non-adenoma-like) lesions and polypoid (adenoma-like) lesions and sporadic conventional adenomas found in the noncolitic mucosa and in patients without IBD. Our study results have revealed that (1) precursor lesions related to IBD-associated colorectal carcinomas were almost always nonpolypoid in macroscopic/endoscopic appearance; (2) nearly half of the carcinoma-related lesions and nonpolypoid lesions were similarly nonadenomatous (nonconventional) lesions, largely serrated type, with no or only mild/focal adenomatous dysplasia, and commonly had mixed adenomatous and nonadenomatous features; (3) carcinoma-related and nonpolypoid adenomatous dysplastic lesions frequently showed some peculiar histocytologic features that we observed and described for the first time, including mixed features of inflammatory pseudopolyps or granulation tissue, pleomorphic and disarrayed nuclei, micropapillary or hobnailing surface epithelial cells, and microvesicular or bubbling cytoplasm of dysplastic cells; and (4) polypoid lesions in the colitic mucosa were identical to sporadic adenomas in the noninflamed mucosa and in patients without IBD, and they lacked the aforementioned features. The seemingly distinctive morphologic characteristics that we proposed here, although still not absolutely specific or unique, can be used as the features of inclusion for identifying CAD on endoscopic biopsies when the endoscopy images are not readily available to pathologists and thus to alert clinicians for a closer follow-up.

Assessment of Endoscopic Healing by Using Advanced Technologies Reflects Histological Healing in Ulcerative Colitis.

BACKGROUND: Several studies have reported that ulcerative colitis [UC] patients with endoscopic mucosal healing may still have histological inflammation. We investigated the relationship between mucosal healing defined by modified PICaSSO [Paddington International Virtual ChromoendoScopy ScOre], Mayo Endoscopic Score [MES] and probe-based confocal laser endomicroscopy [pCLE] with histological indices in UC. METHODS: A prospective study enrolling 82 UC patients [male 66%] was conducted. High-definition colonoscopy was performed to evaluate the activity of the disease with MES assessed with High-Definition MES [HD-MES] and modified PICaSSO and targeted biopsies were taken; pCLE was then performed. Receiver operating characteristic [ROC] curves were plotted to determine the best thresholds for modified PICaSSO and pCLE scores that predicted histological healing according to the Robarts Histopathology Index [RHI] and ECAP 'Extension, Chronicity, Activity, Plus' histology score. RESULTS: A modified PICaSSO of ≤ 4 predicted histological healing at RHI ≤ 3, with sensitivity, specificity, accuracy and area under the ROC curve [AUROC] of 89.8%, 95.7%, 91.5% and 95.9% respectively. The sensitivity, specificity, accuracy and AUROC of HD-MES to predict histological healing by RHI were 81.4%, 95.7%, 85.4% and 92.1%, respectively. A pCLE ≤ 10 predicted histological healing with sensitivity of 94.9%, specificity of 91.3%, accuracy of 93.9% and AUROC of 96.5%. An ECAP of ≤ 10 was predicted by modified PICaSSO ≤ 4 with accuracy of 91.5% and AUROC of 95.9%. CONCLUSION: Histological healing by RHI and ECAP is accurately predicted by HD-MES and modified virtual electronic chromoendoscopy PICaSSO, endoscopic score; and the use of pCLE did not improve the accuracy any further.

Newly recognized non-adenomatous lesions associated with enteric carcinomas in inflammatory bowel disease - Report of six rare and unique cases.

It is the current view that the inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous (with classic cytologic dysplasia) and non-adenomatous (without frank cytologic dysplasia), and the latter ones are in various histomorphologies including serrated, mucinous, eosinophilic (goblet cell deficient), and differentiated (dysplasia with terminal epithelial differentiation) types. By retrospectively reviewing the surgically resected IBD-associated colorectal and ileal carcinomas (×53), analyzing the background epithelial changes/lesions in the mucosa surrounding and adjacent to invasive carcinomas, and testing the key molecular profile (KRAS, BRAF, PIK3CA, NRAS, p53, mismatch repair proteins, and SAT-B2) known to be involved in colorectal carcinogenesis, we identified 6 representative, rare and unique cases, in which non-adenomatous lesions were clearly in vicinity and in transition to invasive carcinomas. Furthermore, we identified certain colonic carcinoma-related molecular alterations, and thus further confirmed the neoplastic nature of various non-adenomatous lesions. It was also revealed that non-adenomatous lesions are heterogeneous in both morphology and molecular alterations, and that it is common to have more than one type of lesions be associated with a carcinoma. Moreover, mixed focal adenomatous dysplasia was common, which may be the necessary step in the malignant transformation of the non-adenomatous lesions.

Histological and molecular diversity and heterogeneity of precancerous lesions associated with inflammatory bowel diseases.

AIMS: Inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous or non-adenomatous with various histomorphologies. We aim to validate the newly proposed classification, to explore the neoplastic nature of the non-adenomatous lesions and to elucidate the molecular mechanisms underlying the different histomorphologies. METHODS: 44 background precursor lesions identified in 53 cases of surgically resected IBD-associated colorectal and ileal carcinomas were reviewed for the histomorphological features (classified into adenomatous, mucinous, sessile serrated adenoma (SSA)-like, traditional serrated adenoma-like, differentiated, eosinophilic and serrated not otherwise specified (NOS)) and analysed for a key panel of colonic cancer-related molecular markers. RESULTS: Approximately 60% of the lesions were adenomatous, of which some had mixed serrated, mucinous or eosinophilic changes. The remaining non-adenomatous lesions, including all other types except SSA-like type, mostly showed mixed features and focal adenomatous dysplasia. KRAS mutation and p53 mutant-type expression were found in about half cases across all types, while PIK3CA mutation only in some of adenomatous and eosinophilic lesions and MLH1/PMS2 loss in a subset of adenomatous, mucinous and eosinophilic but not in differentiated and serrated lesions. SAT-B2 or PTEN loss and IMP3 overexpression were seen in a small subset of lesions. No BRAF, NRAS or EGFR gene mutation was detected in any type. Certain molecular-morphological correlations were demonstrated; however, no single or combined molecular alteration(s) was specific to any particular morphological type. CONCLUSIONS: IBD-associated precancerous lesions are heterogeneous both histologically and molecularly. True colitis-associated adenomatous lesions are unlikely conventional adenomas. Non-adenomatous lesions without frank cytologic dysplasia should also be regarded as neoplastic.