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Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.

Background There is ongoing debate concerning the necessity of routine histopathological examination following cholecystectomy. In order to reduce the pathology workload and save costs, a selective approach has been suggested, but evidence regarding its oncological safety is lacking. Methods In this multicentre, prospective, cross-sectional study, all gallbladders removed for gallstone disease or cholecystitis were systematically examined by the surgeon for macroscopic abnormalities indicative of malignancy. Before sending all specimens to the pathologist, the surgeon judged whether histopathological examination was indicated. The main outcomes were the number of patients with hypothetically missed malignancy with clinical consequences (upper limit two-sided 95 per cent c.i. below 3:1000 considered oncologically safe) and potential cost savings of selective histopathological examination. Results Twenty-two (2.19:1000) of 10 041 specimens exhibited malignancy with clinical consequences. In case of a selective policy, surgeons would have held back 7846 of 10041 (78.1 per cent) gallbladders from histopathological examination. Malignancy with clinical consequences would have been missed in seven of 7846 patients (0.89:1000, upper limit 95% c.i. 1.40:1000). No patient benefitted from the clinical consequences, while two were harmed (futile additional surgery). Of 15 patients in whom malignancy with clinical consequences would have been diagnosed, one benefitted (residual disease radically removed), two potentially benefitted (palliative systemic therapy), and four experienced harm (futile additional surgery). Estimated cost savings established by replacing routine for selective histopathological examination were €703 500 per 10 000 patients. Conclusion Selective histopathological examination following cholecystectomy is oncologically safe and could reduce pathology workload, costs, and futile re-resections.

ObjectiveDespite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group.DesignThis prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries. Consecutive Lynch syndrome patients ≥18 years undergoing surveillance colonoscopy were randomised (1:1) and stratified by centre for inspection with either LCI or HD-WLE. Primary outcome was the polyp detection rate (PDR).ResultsBetween January 2018 and March 2020, 357 patients were randomised and 332 patients analysed (160 LCI, 172 HD-WLE; 6 excluded due to incomplete colonoscopies and 19 due to insufficient bowel cleanliness). No significant difference was observed in PDR with LCI (44.4%; 95% CI 36.5% to 52.4%) compared with HD-WLE (36.0%; 95% CI 28.9% to 43.7%) (p=0.12). Of the secondary outcome parameters, more adenomas were found on a patient (adenoma detection rate 36.3%; vs 25.6%; p=0.04) and a colonoscopy basis (mean adenomas per colonoscopy 0.65 vs 0.42; p=0.04). The median withdrawal time was not statistically different between LCI and HD-WLE (12 vs 11 min; p=0.16).ConclusionLCI did not improve the PDR compared with HD-WLE in patients with Lynch syndrome undergoing surveillance. The relevance of findings more adenomas by LCI has to be examined further.Trial registration numberNCT03344289.

Background and Aims Proctitis after subtotal colectomy with ileostomy for ulcerative colitis [UC] is common, but its impact on short- and long-term outcome after pouch surgery is unknown. The aim of this study was to determine the incidence of proctitis after subtotal colectomy and its impact on postoperative morbidity and pouchitis. Methods The distal margin of the rectal stump of all consecutive patients undergoing completion proctectomy and pouch procedure for UC, between 1999 and 2017, was revised and scored for active inflammation according to the validated Geboes score, and for diversion proctitis. Pathological findings were correlated to complications after pouch surgery and pouchitis [including therapy-refractory] using multivariate analyses. Results Out of 204 included patients, 167 [82%] had active inflammation in the rectal stump and diversion colitis was found in 170 specimens [83%]. Overall postoperative complications and anastomotic leakage rates were not significantly different between patients with and without active inflammation in the rectal stump [34.7% vs 32.4%, p = 0.79, and 10.2% vs 5.4%, p = 0.54, respectively]. Active inflammation of the rectal stump was significantly associated with the development of pouchitis [54.3% vs 25.5%, plog = 0.02], as well as with therapy refractory pouchitis [14% vs 0%, plog = 0.05]. Following multivariate analysis, active inflammation was an independent predictor for the development of pouchitis. Diversion proctitis showed no association with these outcome parameters. Conclusions Active inflammation in the rectal stump after subtotal colectomy occurs in 80% of UC patients and is a predictor for the development of pouchitis and therapy-refractory pouchitis.

Background Routine histopathological examination after cholecystectomy is costly, but the prevalence of unsuspected gallbladder cancer (incidental GBC) is low. This study determined whether selective histopathological examination is safe. Methods A comprehensive search of PubMed, Embase, Web of Science and the Cochrane Library was performed. Pooled incidences of incidental and truly incidental GBC (GBC detected during histopathological examination without preoperative or intraoperative suspicion) were estimated using a random‐effects model. The clinical consequences of truly incidental GBC were assessed. Results Seventy‐three studies (232 155 patients) were included. In low‐incidence countries, the pooled incidence was 0·32 (95 per cent c.i. 0·25 to 0·42) per cent for incidental GBC and 0·18 (0·10 to 0·35) per cent for truly incidental GBC. Subgroup analysis of studies in which surgeons systematically examined the gallbladder revealed a pooled incidence of 0·04 (0·01 to 0·14) per cent. In high‐incidence countries, corresponding pooled incidences were 0·83 (0·58 to 1·18), 0·44 (0·21 to 0·91) and 0·08 (0·02 to 0·39) per cent respectively. Clinical consequences were reported for 176 (39·3 per cent) of 448 patients with truly incidental GBC. Thirty‐three patients (18·8 per cent) underwent secondary surgery. Subgroup analysis showed that at least half of GBC not detected during the surgeon's systematic examination of the gallbladder was early stage (T1a status or below) and of no clinical consequence. Conclusion Selective histopathological examination of the gallbladder after initial macroscopic assessment by the surgeon seems safe and could reduce costs., This meta‐analysis found that the incidence of truly incidental gallbladder cancer (GBC) was less than 0·5 per cent and decreased to less than 0·1 per cent when the surgeon performed a systematic macroscopic examination. At least 50 per cent of GBC that was not detected before or during surgery was of early stage and with no clinical consequences. Particularly in non‐endemic regions, selective histopathological examination after initital macroscopic assessment of the gallbladder by the surgeon seems safe and will likely result in significant cost and time savings. Open and palpate it

We report a case of intestinal lesions in a patient with a history of lupus nephritis and renal transplantation. Biopsy revealed an EBV-driven post-transplant lymphoproliferative disease (PTLD). An EBV-driven PTLD is a major complication after renal transplantation and is an important differential diagnostic consideration in the follow-up of renal transplant recipients.

Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034). Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.

Background Resections for Crohn’s disease should be limited and only resect macroscopically affected bowel. However, recent studies suggest microscopic inflammation at resection margins as a predictor for postoperative recurrence. The clinical impact remains unclear, as non-uniform pathological criteria have been used. The aim of this study was to assess the predictive value of pathological characteristics at ileocecal resection margins for recurrence. Methods Both resection margins of 106 consecutive patients undergoing ileocecal resection for Crohn’s disease between 2002 and 2009 were revised and scored for active inflammation, myenteric plexitis, and granulomas. Pathological findings were correlated to recurrence, defined as recurrent disease activity demonstrated by endoscopy (modified Rutgeerts score ≥i2) requiring upscaling medical treatment, using multivariate analysis. Results Active inflammation was found at the proximal and distal resection margin in 27% and 15% of patients, respectively, myenteric plexitis in 37% and 32%, respectively, and granulomas in 4% and 6%, respectively. In total, 47 out of 106 patients developed recurrence. Only active inflammation at the distal colonic resection margin was an independent significant predictor for recurrence (88% vs 43% vs 51% for distal, proximal, and no involved margins, respectively; P < 0.01). Conclusion Active inflammation at the distal colonic resection margin after ileocecal resection identifies a patient group at high risk for postoperative recurrence both at the anastomotic site and the colon because it identifies undiagnosed L3 disease. These patients have a different and more aggressive natural history and require more intense medical treatment. Therefore, pathological evaluation of the distal resection margin should be implemented in daily practice.

Background: Optical diagnosis can replace histopathology of diminutive (1 – 5 mm) polyps if surveillance intervals based on optical diagnosis of polyps have ≥ 90 % agreement with intervals based on polyp histology and if the negative predictive value (NPV) for predicting neoplastic histology in the rectosigmoid is ≥ 90 %. This study aims to assess whether small (6 – 9 mm) polyps can be included in optical diagnosis strategies. Method: This is a post-hoc analysis of a prospective multicenter study in which 27 endoscopists, all performing endoscopies for the Dutch screening program, were trained in optical diagnosis. For 1 year, endoscopists recorded the predicted histology for all lesions detected using narrow-band imaging during 3144 consecutive colonoscopies after a positive fecal immunochemical test, along with confidence levels. Surveillance interval agreement and NPV were calculated for high confidence predictions for polyps of 1 – 9 mm and compared with histopathology. Surveillance interval agreement was calculated using the European Society of Gastrointestinal Endoscopy surveillance guideline. Results: Surveillance interval agreement was 95.4 % (confidence interval [CI] 94.2 % – 96.4 %), and NPV for predicting neoplastic histology in the rectosigmoid 90.0 % (CI 87.3 % – 92.2 %). The reduction in histology (45.9 % vs. 30.5 %) and the proportion of patients who could have received direct surveillance advice (15.6 % vs. 7.3 %) was higher when small polyps were included (P Conclusion: Including small polyps in the optical diagnosis strategy improves its efficacy while maintaining performance thresholds. However, there is a small risk of missing T1 cancers when small polyps are included in the optical diagnosis strategy.

Simple Summary Colon cancer is one of the leading causes of cancer-related death worldwide. Therefore, the development of new therapeutic strategies is of the utmost importance. Previously, we identified a subset of colon cancers that are characterised by DNA methylation and have a poor prognosis. In this study, we therefore treated ten colon cancer patients with a demethylating agent, decitabine, to investigate if reversal of methylation is feasible and can be used as a novel therapy. Unfortunately, this study revealed that while decitabine treatment is effective in vitro, it only marginally decreased global methylation in patients and had no effect on the specific regions of DNA methylation in the tumours. Future studies should therefore focus on optimisation of treatment schedules in patients with highly methylated tumours. Abstract DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre- and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved.

Contains fulltext : 238983.pdf (Publisher’s version ) (Open Access) BACKGROUND: In pancreatoduodenectomy specimens, dissection method may affect the assessment of primary tumour origin (i.e. pancreatic, distal bile duct or ampullary adenocarcinoma), which is primarily determined macroscopically. This is the first study to prospectively compare the two commonly used techniques, i.e. axial slicing and bivalving. METHODS: In four centres, a randomized controlled trial was performed in specimens of patients with a suspected (pre)malignant tumour in the pancreatic head. Primary outcome measure was the level of certainty (scale 0-100) regarding tumour origin by four independent gastrointestinal pathologists based on macroscopic assessment. Secondary outcomes were inter-observer agreement and R1 rate. RESULTS: In total, 128 pancreatoduodenectomy specimens were randomized. The level of certainty in determining the primary tumour origin did not differ between axial slicing and bivalving (mean score 72 [sd 13] vs. 68 [sd 16], p = 0.21), nor did inter-observer agreement, both being moderate (kappa 0.45 vs. 0.47). In pancreatic cancer specimens, R1 rate (60% vs. 55%, p = 0.71) and the number of harvested lymph nodes (median 16 vs. 17, p = 0.58) were similar. CONCLUSION: This study demonstrated no differences in determining the tumour origin between axial slicing and bivalving. Both techniques performed similarly regarding inter-observer agreement, R1 rate, and lymph node harvest.

A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3β. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.

IntroductionGrowing evidence is showing that complicated and uncomplicated appendicitis are two different entities that may be treated differently. A correct diagnosis of the type of appendicitis is therefore essential. The Scoring system of Appendicitis Severity (SAS) combines clinical, laboratory and imaging findings. The SAS rules out complicated appendicitis in 95% (negative predictive value, NPV) and detects 95% (sensitivity) of patients with complicated appendicitis in adults suspected of acute appendicitis. However, this scoring system has not yet been validated externally. In this study, we aim to provide a prospective external validation of the SAS in a new cohort of patients with clinical suspicion of appendicitis. We will optimise the score when necessary.Methods and analysisThe SAS will be validated in 795 consecutive adult patients diagnosed with acute appendicitis confirmed by imaging. Data will be collected prospectively in multiple centres. The predicted diagnosis based on the SAS score will be compared with the combined surgical and histological diagnosis. Diagnostic accuracy for ruling out complicated appendicitis will be calculated. If the SAS does not reach a sensitivity and NPV of 95% in its present form, the score will be optimised. After optimisation, a second external validation will be performed in a new group of 328 patients. Furthermore, the diagnostic accuracy of the clinical perspective of the treating physician for differentiation between uncomplicated and complicated appendicitis and the patient’s preferences for different treatment options will be assessed.Ethics and disseminationEthical approval was granted by the Amsterdam UMC Medical Ethics Committee (reference W19_416 # 19.483). Because of the observational nature of this study, the study does not fall under the scope of the Medical Research Involving Human Subjects Act. Results will be presented in peer-reviewed journals. This protocol is submitted for publication before analysis of the results.

Background Owing to substantial costs and increasing interest in the nonoperative management of appendicitis, the necessity of routine histopathologic examination of appendectomy specimens is being questioned. The aim of this study was to determine whether routine histopathologic examination after appendectomy for suspected appendicitis should still be performed. Methods PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies listing the histopathologic diagnoses after appendectomy for suspected appendicitis. Main outcomes were the incidence of histopathologically proven aberrant findings, the ability of surgeons to recognize unexpected appendiceal pathology intraoperatively, and the percentage of aberrant findings resulting in a change of postoperative management. A meta-analysis was performed using a random-effects model. Results Twenty-five studies with 57,357 patients were included. The pooled percentage of aberrant findings was 2.52% (95% confidence interval 1.81–3.51). Neoplasms were found in 0.71% (95% confidence interval 0.54–0.94). Findings of the intraoperative assessment by the surgeon were reported for 82 of the 2,718 (3.0%) unexpected diagnoses, with great variation between studies. The impact on postoperative management was described for 237 of 2,718 (8.7%) aberrant findings. Of these, 166 (70.0%) resulted in a change of postoperative management. Conclusion Based on current evidence, it remains unclear how many of the unexpected appendiceal pathologies with clinical consequences can be identified intraoperatively by the surgeon. Until reliable data on the safety and potential cost savings of a selective policy becomes available, we advise sending appendectomy specimens routinely for histopathologic examination.

Clinical significance of the pT4 category in colon cancer is increasing with several therapeutic implications. The aim of this study was to evaluate variability in diagnosing pT4a colon cancer. Twelve pathologists classified 66 preselected scanned Hematoxylin/Eosin-stained slides with tumor cells at a distance of 25–1500 μm (n = 22), 0–25 μm (n = 22), or on (n = 22) the peritoneal surface. Inter- and intraobserver variability were calculated using Kappa statistics. For interlaboratory variability, pathology reports of pT3 and pT4a colon cancer were extracted from the Dutch Pathology Registry between 2012 and 2015. The proportion of pT4a (pT4a/(pT3+pT4a)) was compared between 33 laboratories. Potential risk of understaging was assessed by determining the average number of blocks taken from pT3 and pT4a N0-2M0 tumors with metachronous peritoneal metastasis. Interobserver variability among 12 pathologists was 0.50 (95%CI 0.41–0.60; moderate agreement). Intraobserver variability (8 pathologists) was 0.71 (substantial agreement). A total of 7745 reports with pT3 or pT4aN0-2M0 colon cancer from 33 laboratories were included for interlaboratory analysis. Median percentage of pT4a was 15.5% (range 3.2–24.6%). After adjustment for case mix, 8 labs diagnosed pT4a significantly less or more frequently than the median lab. Metachronous peritoneal metastases were histologically verified in 170 of 6629 pT3 and in 129 of 1116 pT4a tumors, with a mean number of blocks of 4.03(SD 1.51) and 4.78 (SD 1.76) taken from the primary tumors, respectively (p

The worldwide implementation of bowel cancer screening programmes (BCSPs) results in a growing number of early T1 colorectal cancers (T1 CRCs). Successful treatment of T1 CRCs starts with accurately recognising these lesions during endoscopy. This study performed in the Dutch BCSP showed that endoscopists correctly diagnosed T1 CRCs in only 39% of 92 cases (95% CI 30 to 49) and that this limited diagnostic accuracy of optical diagnosis resulted in different treatment outcomes. In patients with T1 CRCs that were optically not diagnosed as cancer and treated locally, adjuvant surgery was performed in 41% of cases, compared with 11% of patients with T1 CRCs that were correctly optically diagnosed (p=0.02). In this prospective multicentre study (trial registration number: NTR4635, NCT02407925), endoscopists accredited for fecal immunochemical test (FIT)-positive colonoscopies within the Dutch BCSP were trained in optical diagnosis with our validated National Institute for Health and Care Excellence (NICE)-WASP (Workgroup serrAted polypS and Polyposis) module (online supplementary material 1 for full methods).1 2 A total of 27 endoscopists completed the training successfully and entered the prospective study, in which the endoscopists as well as pathologists reported their findings in a predefined structure. This facilitated high-quality data collection and ensured collection of exact data on all aspects of each detected lesion as location, size, Paris morphology, optical diagnosis (colorectal cancer (CRC), adenoma, hyperplastic polyp, sessile serrated lesion or other), endoscopic treatment method (biopsy, cold or hot snare polypectomy, endoscopic mucosal resection, biopsy for diagnosis or no treatment), completeness of resection and whether a tattoo was placed. Participating endoscopists recorded optical diagnosis using narrow band imaging in all consecutive FIT-positive colonoscopies for the Dutch BCSP during 1 year. Local treatment was defined as endoscopic resection or transanal endoscopic microsurgery. For all patients initially diagnosed with T1 CRCs, the original H&E staining slides were collected …

Background and study aims Colorectal polyps involving the appendiceal orifice (AO) are difficult to resect with conventional polypectomy techniques and therefore often require surgical intervention. These appendiceal polyps could potentially be removed with endoscopic full-thickness resection (eFTR) performed with a full-thickness resection device (FTRD). The aim of this prospective observational case study was to evaluate feasibility, technical success and safety of eFTR procedures involving the AO. Patients and methods This study was performed between November 2016 and December 2017 in a tertiary referral center by two experienced endoscopists. All patients referred for eFTR with a polyp involving the AO that could not be resected by EMR due to more than 50 % circumferential involvement of the AO or deep extension into the AO were included. The only exclusion criterion was lesion diameter > 20 mm. Results Seven patients underwent eFTR for a polyp involving the AO. All target lesions could be reached with the FTRD and retracted into the device. Technical success with an endoscopic radical en-bloc and full-thickness resection was achieved in all cases. Histopathological R0 resection was achieved in 85.7 % of patients (6/7). One patient who previously underwent an appendectomy developed a small abscess adjacent to the resection site, which was treated conservatively. Another patient developed secondary appendicitis followed by a laparoscopic appendectomy. Conclusion This small exploratory study suggests that eFTR of appendiceal polyps is feasible and can offer a minimally invasive approach for radical resection of these lesions. However, more safety and long-term follow-up data are needed to evaluate this evolving technique.

Solid malignancies have been speculated to depend on cancer stem cells (CSCs) for expansion and relapse after therapy. Here we report on quantitative analyses of lineage tracing data from primary colon cancer xenograft tissue to assess CSC functionality in a human solid malignancy. The temporally obtained clone size distribution data support a model in which stem cell function in established cancers is not intrinsically, but is entirely spatiotemporally orchestrated. Functional stem cells that drive tumour expansion predominantly reside at the tumour edge, close to cancer-associated fibroblasts. Hence, stem cell properties change in time depending on the cell location. Furthermore, although chemotherapy enriches for cells with a CSC phenotype, in this context functional stem cell properties are also fully defined by the microenvironment. To conclude, we identified osteopontin as a key cancer-associated fibroblast-produced factor that drives in situ clonogenicity in colon cancer.

BACKGROUND AND AIMS: Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) because of microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients with a matched control population.METHODS: We collected data of Lynch syndrome patients with a proven germline mutation who underwent colonoscopy between January 2011 and April 2016 in 2 tertiary referral hospitals. Control subjects undergoing elective colonoscopy from 2011 and onward for symptoms or surveillance were selected from a prospectively collected database. Patients were matched 1:1 for age, gender, and index versus surveillance colonoscopy. An expert pathology review of serrated polyps was performed. The primary outcomes included the detection rates and distribution of SSLs.RESULTS: We identified 321 patients with Lynch syndrome who underwent at least 1 colonoscopy. Of these, 223 Lynch syndrome patients (mean age, 49.3; 59% women; index colonoscopy, 56%) were matched to 223 control subjects. SSLs were detected in 7.6% (95% confidence interval, 4.8-11.9) of colonoscopies performed in Lynch syndrome patients and in 6.7% (95% confidence interval, 4.1-10.8) of control subjects (P = .86). None of the detected SSLs in Lynch syndrome patients contained dysplasia.CONCLUSIONS: The detection rate of SSLs in Lynch syndrome patients undergoing colonoscopy is comparable with a matched population. These findings suggest that the role of the serrated neoplasia pathway in CRC development in Lynch syndrome seems to be comparable with that in the general population.

A pancreatoduodenectomy specimen is complex, and there is much debate on how it is best approached by the pathologist. In this review, we provide an overview of topics relevant for current clinical practice in terms of gross dissection, and macro- and microscopic assessment of the pancreatoduodenectomy specimen with a suspicion of suspected pancreatic cancer. Tumor origin, tumor size, degree of differentiation, lymph node status, and resection margin status are universally accepted as prognostic for survival. However, different guidelines diverge on important issues, such as the diagnostic criteria for evaluating the completeness of resection. The macroscopic assessment of the site of origin in periampullary tumors and cystic lesions is influenced by the grossing method. Bi-sectioning of the head of the pancreas may offer an advantage in this respect, as this method allows for optimal visualization of the periampullary area. However, a head-to-head comparison of the assessment of clinically relevant parameters, using axial slicing versus bi-sectioning, is not available yet and the gold standard to compare both techniques prospectively might be subject of debate. Further studies are required to validate the various dissection protocols used for pancreatoduodenectomy specimens and their specific value in the assessment of pathological parameters relevant for prognosis.

Colorectal cancer (CRC) is a heterogeneous disease, which can be categorized into distinct consensus molecular subtypes (CMSs). These subtypes differ in both clinical as well as biological properties. The gold-standard classification strategy relies on genome-wide expression data, which hampers widespread implementation. Here we describe an immunohistochemical (IHC) Mini Classifier, a practical tool that, in combination with microsatellite instability testing, delivers objective and accurate scoring to classify CRC patients into the main molecular disease subtypes. It is a robust immunohistochemical-based assay containing four specific stainings (FRMD6, ZEB1, HTR2B, and CDX2) in combination with cytokeratin. We also describe an online tool for classification of individual samples based on scoring parameters of these stainings.

Although it is known that B-cell lymphomas occur more frequently in immunocompromised patients, thus far such an association has not been clearly established for T-cell lymphomas. Of the 251 patients who were diagnosed with a T-cell non-Hodgkin lymphoma in our center between 1999 and 2014, at least 25 were identified in immunocompromised patients. Herein, we retrospectively analyzed the clinical and pathological characteristics of these 25 cases. In addition, we searched the literature and present an overview of 605 previously published cases. The actual number of patients with B-cell chronic lymphocytic leukemia and patients on immunosuppressive drugs for inflammatory bowel disease or rheumatoid arthritis in the total cohort of 251 patients diagnosed with T-cell non-Hodgkin lymphoma was much higher than the number of patients expected to have these diseases in this cohort, based on their prevalence in the general population. This, together with the large number of additional cases found in the literature, suggest that the risk of developing T-cell non-Hodgkin lymphoma is increased in immunocompromised patients. Compared to T-cell non-Hodgkin lymphoma in the general population, these lymphomas are more often located extranodally, present at a younger age and appear to have a poor outcome. The observations made in the study herein should raise awareness of the possible development of T-cell non-Hodgkin lymphoma in immunodeficient patients, and challenge the prolonged use of immunosuppressive drugs in patients who are in clinical remission of their autoimmune disease.

Background and Aims The objective of this study was to examine the modulating effect of an appendectomy on the disease course of therapy-refractory ulcerative colitis [UC] patients, and to analyse appendiceal pathological characteristics predictive of pathological response. Methods Patients with therapy-refractory UC, and referred for proctocolectomy, were invited to undergo laparoscopic appendectomy first. The primary end points were clinical response after 3 and 12 months. Secondary end points were endoscopic remission, failure, and pathologic response. Appendiceal specimens, and pre- and post-operative biopsies were histologically graded according to the validated Geboes score. Results Thirty patients [53% male] with a median age of 40 (interquartile range [IQR], 33–47) underwent appendectomy, with a median preoperative total Mayo score of 9 [IQR, 8–11]. After 12 months, 9 patients [30%] had lasting clinical response, of whom 5 [17%] were in endoscopic remission. Pathological evaluation was possible in 28 patients. After a median of 13.0 weeks [range 7–51], pathological response was seen in 13 patients [46%], with a median decrease of 2 points [range 1–3]. Appendiceal inflammation was highly predictive of pathological response when compared with no inflammation or extensive ulcerations [85% vs 20%, p = 0.001]. Conclusions Appendectomy was effective in one-third of therapy-refractory UC patients, with a substantial proportion of patients demonstrating complete endoscopic remission after 1 year. Pathological response was seen in almost 50% of patients and was related to active inflammation in the appendix, limited disease, and shorter disease duration. These early results suggest that there is a UC patient group that may benefit from appendectomy.

IntroductionRoutine histopathological examination following appendicectomy and cholecystectomy has significant financial implications and comprises a substantial portion of the pathologists’ workload, while the incidence of unexpected pathology is low. The aim of the selective histopathological examination Following AppeNdicectomy and CholecystectomY (FANCY) study is to investigate the oncological safety and potential cost savings of selective histopathological examination based on macroscopic assessment performed by the surgeon.Methods and analysisThis is a Dutch multicentre prospective observational study, in which removed appendices and gallbladders will be systematically assessed by the operating surgeon for macroscopic abnormalities suspicious for malignant neoplasms. After visual inspection and digital palpation of the removed specimen, the operating surgeon will report whether macroscopic abnormalities suspicious for a malignant neoplasm are present, and if he or she believes additional microscopic examination by the pathologist is indicated. Regardless of the surgeon’s assessment, all specimens will be sent for histopathological examination. In this way, routine histopathological examination can be compared with a hypothetical situation in which specimens are routinely examined by surgeons and only sent to the pathologist on indication. The two main outcomes are oncological safety and potential cost savings of a selective policy. Oncological safety of selective histopathological examination will be assessed by calculating the number of patients in whom a histopathological diagnosis of an appendiceal neoplasm or gallbladder cancer with clinical consequences benefitting the patient would have been missed. A cost analysis will be performed to quantify the potential cost savings.Ethics and disseminationThe study protocol was reviewed by the Institutional Review Board of the Amsterdam UMC, location AMC, which decided that the Dutch Medical Research Involving Human Subjects Act is not applicable. In all participating centres, approval for execution of the FANCY study has been obtained from the local Institutional Review Board before the start of inclusion of patients. The study results will be disseminated through peer-reviewed publications and conference presentations. Guidelines will be revised according to the findings of the study.Trial registration numberNCT03510923.

ObjectiveAfter prophylactic colectomy, adenomas continue to develop in the remaining intestine of patients with familial adenomatous polyposis (FAP). There is a lack of standard clinical recommendation for chemoprevention in patients with FAP. Because of promising in vivo studies, the aim of this pilot study was to investigate the safety of sirolimus and its effect on progression of intestinal adenomas.DesignPatients with FAP with InSiGHT Polyposis Staging System 3 of the retained rectum or pouch received sirolimus for 6 months, dosed at plasma concentration levels of 5–8 µg/L. Primary outcomes were safety and change in marked polyp size. Secondary outcomes were change in number of polyps and effect on proliferation and apoptosis assessed by immunohistochemistry.ResultsEach of the included four patients reported 4 to 18 adverse events (toxicity grades 1–3). One patient prematurely terminated the study because of adverse events. Marked polyp size decreased in 16 (80%)/20 and remained the same in 4 (20%)/20 patients. The number of polyps decreased in all patients (MD −25.75, p=0.13). Three out of four patients showed substantial induction of apoptosis or inhibition of proliferation.ConclusionSix months of sirolimus treatment in four patients with FAP showed promising effects especially on the number of polyps in the rectal remnant and ileal pouch, although at the cost of numerous adverse events.Trial registration numberClinicalTrials.gov ID NCT03095703.

AimsCD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required.Methods and resultsWe conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair ( = 0.12-0.35 for CD30-positive tumour cell percentage and = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity ( = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal ( = 0.35-0.60).ConclusionsLack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response.

Background and Aims: Large non-pedunculated rectal polyps are most commonly resected by endoscopic mucosal resection (EMR) or transanal endoscopic microsurgery (TEM). Despite pre-procedural diagnostics, unexpected rectal cancer is incidentally encountered within the resected specimen. This study aimed to compare the diagnostic assessment and procedural characteristics of lesions with and without unexpected submucosal invasion. Methods: A post-hoc analysis of a multicenter randomized trial (TREND study) was performed in which patients with a non-pedunculated rectal polyp of >= 3 cm without endoscopic suspicion of invasive growth were randomized between EMR and TEM. Results: Unexpected rectal cancer was detected in 13% (27/203) of patients; 15 after EMR and 12 after TEM. Most consisted of low-risk T1 cancers (78%, n = 18). There were no differences in the diagnostic assessment between lesions with and without unexpected submucosal invasion. Diagnostic biopsies revealed similar rates of high-grade dysplasia (28%[7/25] vs 18% [26/144]). When compared with EMR of adenomas, EMR procedures of unexpected cancers had a lower success rate of submucosal lifting (60% vs 93%, P

BACKGROUND: Optical diagnosis of diminutive (1 to 5 mm) polyps could result in a more cost-effective colonoscopy practice. Previous optical diagnosis studies did not incorporate the differentiation of sessile serrated polyps (SSPs). This study aimed to evaluate the impact of optical diagnosis of diminutive SSPs on the overall performance of endoscopic polyp differentiation in daily colonoscopy practice.METHODS: Endoscopy data were prospectively collected between 2011 and 2014 in a colonoscopy center. Each endoscopist reported a real-time optical diagnosis (SSP, adenoma or hyperplastic polyp) for all lesions in a structured colonoscopy reporting system, using narrow band imaging at their discretion. Study outcomes were accuracy of optical diagnosis, surveillance interval agreement and negative predictive value for diminutive rectosigmoid neoplastic histology based on the optical diagnosis of diminutive polyps compared to histopathology.RESULTS: Of 2853 removed diminutive polyps, 202 (7.1%) were histologically proven SSPs. Optical diagnosis of diminutive SSPs was accurate in 24.4%. Diminutive SSPs determined 6.9% of postpolypectomy surveillance assignments. Inaccurate optical diagnosis of diminutive SSPs led to lower surveillance interval agreement (78.1% vs. 53.3%, PCONCLUSIONS: Endoscopic characterization of diminutive SSPs is difficult, impairing overall performance of optical diagnosis in patients with diminutive SSPs. Future optical diagnosis studies should use validated trainings and classification algorithms that include differentiation of SSPs.

Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin, but their clinicopathologic features are still ill defined. Differentiation from primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is important, as MTX-associated B-LPD may show spontaneous regression after withdrawal of MTX therapy. In the present study, the clinicopathologic and phenotypical features of 10 patients with MTX-associated B-LPD first presenting in the skin, including 5 EBV(+) and 5 EBV(-) cases, were investigated. Six patients had skin-limited disease. Clinically, abrogation of MTX therapy resulted in a complete response in 4 cases and a partial response in another 2. The 5-year disease-specific survival was 90%. MTX-associated B-LPD differed from primary cutaneous follicle center lymphoma by the presence of ulcerating and/or generalized skin lesions, an infiltrate composed of centroblasts/immunoblasts rather than large centrocytes, reduced staining for CD79a, and expression of BCL2, IRF4, and FOXP1 in most cases. EBV(+) MTX-associated B-LPD differed from PCLBCL-LT by the presence ulcerative skin lesions, marked tumor cell polymorphism, reduced staining for CD79a, and expression of CD30 and EBV. EBV(-) cases showed morphologic and immunophenotypical similarities to PCLBCL-LT but differed by presentation with generalized skin lesions in 4 of 5 cases. The results of this study, showing a relatively good clinical outcome and spontaneous disease regression after only withdrawal of MTX in a considerable proportion of patients, underscores the importance of a careful wait-and-see policy before considering more aggressive therapies in patients with MTX-associated B-LPD of the skin.

Primary bone lymphoma (PBL) comprises 5 % of all extranodal non-Hodgkin's lymphomas (NHLs). Diffuse large B-cell lymphoma (DLBCL) accounts for the majority of cases, which is the most heterogeneous group of lymphomas. Previous studies suggested that besides the tumor cell phenotype, phosphatidylinositol 3-kinase/acutely transforming retrovirus/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway activity and the composition of the immune-microenvironment of DLBCL influence the clinical behavior of the disease. The aim of our study was to determine the relationship between clinical factors, tumor cell phenotype, microenvironment, PI3K/AKT/mTOR pathway activity, and disease outcome in primary bone diffuse large B-cell lymphoma (PB-DLBCL). We constructed tissue-microarrays from 41 cases of PB-DLBCL. To characterize tumor cell phenotype, T-cell subsets, macrophages, and PI3K/AKT/mTOR pathway activity immunohistochemical stainings were evaluated. Kaplan–Meier survival analysis provided evidence that age (≤65), CD3 and CD8+ T cell infiltrations >5 %, low BCL2 expression of the tumor cells (≤30 %), and low proliferation index (Ki67 ≤ 57 %) were associated with favorable outcome of PB-DLBCL patients. Multivariate analysis revealed that CD8+ T cell infiltration >5 % and low BCL2 expression (≤30 %) were independent predictors of survival. Increased macrophage infiltration (>10 %) showed tendency toward an adverse prognostic effect. International prognostic index, tumor cell phenotype (GCB or ABC), MYC protein expression, and activation of PI3K/AKT/mTOR pathway had no significant impact on survival. However, mTOR activity showed a significant correlation with activated B-cell phenotype. We conclude that CD8 and BCL2 expressions are potential prognostic markers for PB-DLBCL patients and the PI3K/AKT/mTOR pathway appears to be an additional therapeutic target in PB-DLBCL with activated-B-cell phenotype.

Background Numbers of programmed death-1 (PD-1) positive T cells have prognostic significance in some types of nodal B-cell lymphomas, but data on PD-1 expression in cutaneous B-cell lymphoma (CBCL) are few. In this study we determined the expression and distribution of PD-1 on neoplastic B cells and reactive T cells in skin sections from primary CBCLs. Methods By means of immunohistochemical staining, PD-1 expression was investigated in skin biopsies from 10 patients with primary cutaneous marginal zone lymphoma (PCMZL), 18 patients with primary cutaneous follicle center lymphoma (PCFCL) and 12 patients with primary cutaneous diffuse large B-cell lymphoma–leg type (PCDLBCL–LT). Results Neoplastic B cells were negative for PD-1 in all cases, except for two cases of PCDLBCL–LT. The frequency of PD-1+ T cells was significantly higher in PCFCL than in PCMZL and PCDLBCL–LT, accounting for 20, 10 and 3% of the total number of infiltrating cells, and 60, 20 and 15% of the total number of CD3+ T cells, respectively. Conclusions PD-1 is rarely expressed by the neoplastic B cells in CBCL. High percentages of PD-1+ T cells, particularly if found outside germinal centers, support a diagnosis of PCFCL.

Langerhans cell histiocytosis (LCH) is a neoplastic myeloid disorder with a thus far poorly understood immune component. Tertiary lymphoid structures (TLS) are lymph node-like entities which create an immune-promoting microenvironment at tumor sites. We analyzed the presence and clinical relevance of TLS in n = 104 H&E-stained, therapy-naive LCH lesions of non-lymphoid origin and applied immunohistochemistry to a smaller series. Lymphoid-follicular aggregates were detected in 34/104 (33%) lesions. In line with the lymphocyte recruitment capacity of MECA-79+ high endothelial venules (HEVs), MECA-79+-expressing-LCH lesions (37/77, 48%) contained the most CD3+ T-lymphocytes (p = 0.003). TLS were identified in 8/15 lesions and contained T-and B-lymphocytes, Follicular Dendritic Cells (FDC), HEVs and the chemokines CXCL13 and CCL21 representing key cellular components and TLS-inducing factors in conventional lymph nodes (LN). Lymphoid-follicular aggregates were most frequently detected in patients presenting with unifocal LCH (24/70, 34%) as compared to patients with poly-ostotic or multi-system LCH (7/30, 23%, p = 0.03). In addition, patients with lymphoid-follicular aggregates-containing lesions had the lowest risk to develop new LCH lesions (p = 0.04). The identification of various stages of TLS formation within LCH lesions may indicate a key role for the immune system in controlling aberrant histiocytes which arise in peripheral tissues.

Background and Aims: Traditionally large, complex colorectal polyps were managed by surgical resection (SR), and in recent years endoscopic resection (ER) has progressed significantly. However, to what extent ER has replaced SR remains largely unknown. We performed a multicenter retrospective cohort study to assess the volume and volume changes of SR for benign colorectal polyps over the past decade. Methods: Patients who underwent SR for a benign colorectal polyp in the Netherlands between 2005 and 2015 were selected from the prospective nationwide Dutch Pathology Registry (PALGA database). Clinical characteristics were obtained from the charts of patients who underwent SR in the province of Noord-Holland. Results: A total of 5937 patients were treated with SR for a colorectal polyp and the absolute (454-739 per year) and relative volumes (0.20%-0.37% per colonoscopy per year) of SR remained stable. In the province of Noord-Holland, 928 patients (15.6%) underwent SR. In these patients, submucosal lifting and ER were attempted in 19.9% (n = 175) and 15.0% (n = 134). After 2010, patients were more likely to undergo lifting (27.7% vs 11.4%, P