The earliest events in BRAF-mutant colorectal cancer: exome sequencing of sessile serrated lesions with a tiny focus dysplasia or cancer reveals recurring mutations in two distinct progression pathways.

Around 15-30% of colorectal cancers (CRC) develop from sessile serrated lesions (SSLs). After many years of indolent growth, SSLs can develop dysplasia and rapidly progress to CRC through events that are only partially understood. We studied molecular events at the very early stages of progression of SSLs via the MLH1-proficient and deficient pathways to CRC. We collected a cohort of rare SSLs with a small focus (<10 mm) of dysplasia or cancer from the pathology archives of three hospitals. Whole-exome sequencing was performed on DNA from nonprogressed and progressed components of each SSL. Putative somatic driver mutations were identified in known cancer genes that were differentially mutated in the progressed component. All analyses were stratified by MLH1 proficiency. Forty-five lesions with a focus dysplasia or cancer were included, of which 22 (49%) were MLH1-deficient. Lesions had a median diameter of 10 mm (interquartile range [IQR] 8-15), while the progressed component had a median diameter of 3.5 mm (IQR 1.75-4.75). Tumor mutational burden (TMB) was high in MLH1-deficient lesions (23.9 mutations per MB) as compared to MLH1-proficient lesions (6.3 mutations per MB). We identified 34 recurrently mutated genes in MLH1-deficient lesions. Most prominently, ACVR2A and RNF43 were affected in 18/22 lesions, with mutations clustered in three hotspots. Most lesions with RNF43 mutations had concurrent mutations in ZNRF3. In MLH1-proficient lesions APC (10/23 lesions) and TP53 (6/23 lesions) were recurrently mutated. Our results show that the mutational burden is exceptionally high even in the earliest MLH1-deficient lesions. We demonstrate that hotspot mutations in ACVR2A and in the RNF43/ZNRF3 complex are extremely common in the early progression of SSLs along the MLH1-deficient serrated pathway, while APC and TP53 mutations are early events in the the MLH1-proficient pathway. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Histopathological Revision for Gastroenteropancreatic Neuroendocrine Neoplasms in Expert Centers: Does It Make the Difference?

BACKGROUND: The correct histopathological diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is crucial for treatment selection and prognostication. It is also very challenging due to limited experience in nonexpert centers. Revision of pathology is standard of care for most patients who are referred to NEN expert centers. OBJECTIVES: To describe the clinical impact of histopathological revision for GEP-NEN patients referred to an expert center. METHODS: Retrospective multicenter analysis of all GEP-NENs receiving a histopathological revision in 6 European NEN expert centers (January 2016 to December 2016) to evaluate the impact on patient management. RESULTS: 175 patients were included and 14.7% referred for a second opinion. Histological samples were 69.1% biopsies, 23.4% surgical specimens, and 7.5% endoscopic resections. Histopathological changes due to revision included first assessment of Ki67 in 8.6% of cases, change in grading in 11.4% (3.4% G1 to G2; 5.7% G2 to G1; 0.6% G2 to G3; 1.7% G3 to G2), definition of tumor invasion in 10.8%, additional immunohistochemical staining in 2.3%, diagnosis of mixed adenoneuroendocrine carcinoma in 3.4%, exclusion of NEN in 3.4%, first diagnosis of NEN in 2.3%, and tumor differentiation for G3 in 1.7%. The revision had a clinical impact in 36.0% of patients, leading to a new therapeutic indication in 26.3%. The indication to then perform a new imaging test occurred in 21.1% and recommendation to follow-up with no further treatment in 6.3%. CONCLUSIONS: Histopathological revision in expert centers for NENs can change the diagnosis, with a significant clinical impact in about one third of patients.

Value of Laparoscopy for Resection of Small-Bowel Neuroendocrine Neoplasms Including Central Mesenteric Lymphadenectomy.

BACKGROUND: Literature on laparoscopic resection of small-bowel neuroendocrine neoplasms consists of single case descriptions or small selected case-series only, likely because of challenging mesenteric lymphadenectomy. OBJECTIVE: We evaluated an institutional change in approach from open to laparoscopic resection of small-bowel neuroendocrine neoplasm independent from lymph node involvement. DESIGN: This is a retrospective comparative cohort study. SETTING: This study was conducted at a tertiary referral center. PATIENTS: Patients with small-bowel neuroendocrine neoplasms were included. INTERVENTIONS: Laparoscopic or open segmental bowel resection with central mesenteric lymphadenectomy was the studied intervention. MAIN OUTCOME MEASURES: Complexity of lymphadenectomy was assessed by determining the distance between suspect lymph nodes and main mesenteric branches on preoperative CT. Number of (tumor-positive) lymph nodes, conversion to open surgery, and postoperative complications according to Clavien-Dindo classification and length of stay were measured. RESULTS: A total of 34 patients were identified, of whom 11 (32%) underwent open and 23 (68%) laparoscopic surgery. Distances between lymph nodes and main mesenteric branches and number of examined and tumor-positive lymph nodes did not differ significantly. Laparoscopy was converted in 7 patients (30%). Major postoperative complications (grades 3-5) occurred in 1 patient (9%) in the open surgery group (grade 5) and 2 patients (9%) in the laparoscopic surgery group (grade 3b). The length of stay was 8 days (range, 6-18 d) in the open surgery group and 4 days (4-8 d) in the laparoscopic group (p = 0.036). LIMITATIONS: Long-term outcomes could not reliably be assessed because of the relatively short follow-up time of the laparoscopy group. CONCLUSIONS: Laparoscopic bowel resection with central mesenteric lymphadenectomy for small-bowel neuroendocrine neoplasm appears safe and associated with similar pathologic outcome and shorter length of stay in the setting of a tertiary referral center. See Video Abstract at http://links.lww.com/DCR/B512. VALOR DE LA LAPAROSCOPIA PARA LA RESECCIN DE NEOPLASIAS NEUROENDOCRINAS DEL INTESTINO DELGADO, INCLUIDA LA LINFADENECTOMA MESENTRICA CENTRAL: ANTECEDENTES:La literatura sobre la resección laparoscópica de neoplasias neuroendocrinas del intestino delgado consiste en descripciones de casos únicos o en series de pequeños casos seleccionados, probablemente debido a la dificultad de la linfadenectomía mesentérica.OBJETIVO:Evaluamos un cambio institucional en el enfoque de la resección abierta a laparoscópica de SB-NEN independientemente de la afectación de los ganglios linfáticos.DISEÑO:Este es un estudio de cohorte comparativo retrospectivo.AJUSTE:Este estudio se realizó en un centro de referencia terciario.PACIENTES:Pacientes con neoplasias neuroendocrinas de intestino delgado.INTERVENCIONES:Resección intestinal segmentaria laparoscópica o abierta con linfadenectomía mesentérica central.PRINCIPALES MEDIDAS DE RESULTADO:La complejidad de la linfadenectomía se evaluó determinando la distancia entre los ganglios linfáticos sospechosos y las principales ramas mesentéricas en la TC preoperatoria. Número de ganglios linfáticos (tumor positivos), conversión a cirugía abierta, complicaciones postoperatorias según Clavien-Dindo y duración de la estancia.RESULTADOS:Se identificaron 34 pacientes, de los cuales 11 (32%) fueron sometidos a cirugía abierta y 23 (68%) laparoscópica. Las distancias entre los ganglios linfáticos y las principales ramas mesentéricas y el número de ganglios linfáticos examinados y con tumores positivos no difirieron significativamente. La laparoscopia se convirtió en 7 pacientes (30%). Se produjeron complicaciones posoperatorias importantes (grados 3-5) en un paciente (9%) en el grupo de cirugía abierta (grado 5) y en 2 (9%) pacientes en el grupo de cirugía laparoscópica (grado 3b). La estancia intrahospitalaria fue de 8 días (rango 6-18) en el grupo de cirugía abierta y 4 días (4-8) en el grupo laparoscópico (p = 0.036).LIMITACIONES:Los resultados a largo plazo no se pudieron evaluar de manera confiable debido al seguimiento relativamente corto del grupo de laparoscopia.CONCLUSIONES:La resección intestinal laparoscópica con linfadenectomía mesentérica central para SB-NEN parece segura y se asocia con un resultado patológico similar y una estadía más corta en el contexto de un centro de referencia terciario. Consulte Video Resumen en http://links.lww.com/DCR/B512.

Update on Incidence, Prevalence, Treatment and Survival of Patients with Small Bowel Neuroendocrine Neoplasms in the Netherlands.

BACKGROUND: Small bowel neuroendocrine neoplasms (SB-NEN) are rare cancers, population-based studies are needed to study this rare indolent disease. The aim of this study was to explore trends in epidemiology, treatment and survival outcomes of patients with SB-NEN based on Dutch nationwide data. PATIENTS AND METHODS: Patients with grade 1 or 2 SB-NEN diagnosed between 2005 and 2015 were retrieved from the Netherlands Cancer Registry and linked to The Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands. Age-adjusted incidence rates were calculated based using the direct standardization method. Survival analyses were performed with the Kaplan-Meier method. RESULTS: A total of 1132 patients were included for epidemiological analyses. The age-adjusted incidence rate of SB-NEN increased from 0.52 to 0.81 per 100.000 person-years between 2005 and 2015. Incidence was higher for males than females (0.93 vs. 0.69 in 2015). Most patients had grade 1 tumours (83%). Surgery was performed in 86% of patients, with resection of the primary tumour in 99%. During the study period, administration of somatostatin analogues (SSAs) increased from 5 to 22% for stage III and from 27 to 63% for stage IV disease. Mean follow-up was 61 (standard deviation 38) months. Survival data were complete for 975/1132 patients and five-year overall survival was 75% for stage I-II, 75% for stage III and 57% for stage IV. CONCLUSIONS: This study shows an increase in the incidence of SB-NEN in the Netherlands. A predominant role of surgery was found in all disease stages. Use of SSAs has increased over time.

Transmission of breast cancer by a single multiorgan donor to 4 transplant recipients.

We report 4 cases of breast cancer transmission to transplant recipients from a single organ donor that occurred years after donation. The diagnosis of breast cancer was occult at the time of donation. All of the recipients developed a histologically similar type of breast cancer within 16 months to 6 years after transplantation. Three out of 4 recipients died as a result of widely metastasized disease. One of the recipients survived after transplant nephrectomy followed by cessation of immunosuppression and chemotherapy. This extraordinary case points out the often fatal consequences of donor-derived breast cancer and suggests that removal of the donor organ and restoration of immunity can induce complete remission.

A New Scoring System to Predict Recurrent Disease in Grade 1 and 2 Nonfunctional Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The aim of this study was to predict recurrence in patients with grade 1 or 2 nonfunctioning pancreatic neuroendocrine tumors (NF-pNET) after curative resection. BACKGROUND: Surgical resection is the preferred treatment for NF-pNET; however, recurrence occurs frequently after curative surgery, worsening prognosis of patients. METHODS: Retrospectively, patients with NF-pNET of 3 institutions were included. Patients with distant metastases, hereditary syndromes, or grade 3 tumors were excluded. Local or distant tumor recurrence was scored. Independent predictors for survival and recurrence were identified using Cox-regression analysis. The recurrence score was developed to predict recurrence within 5 years after curative resection of grade 1 to 2 NF-pNET. RESULTS: With a median follow-up of 51 months, 211 patients with grade 1 to 2 NF-pNET were included. Thirty-five patients (17%) developed recurrence. The 5- and 10-year disease-specific/overall survival was 98%/91% and 84%/68%, respectively. Predictors for recurrence were tumor grade 2, lymph node metastasis, and perineural invasion. On the basis of these predictors, the recurrence score was made. Discrimination [c-statistic 0.81, 95% confidence interval (95% CI) 0.75-0.87] and calibration (Hosmer Lemeshow Chi-square 11.25, P = 0.258) indicated that the ability of the recurrence score to identify patients at risk for recurrence is good. CONCLUSIONS: This new scoring system could predict recurrence after curative resection of grade 1 and 2 NF-pNET. With the use of the recurrence score, less extensive follow-up could be proposed for patients with low recurrence risk. For high-risk patients, clinical trials should be initiated to investigate whether adjuvant therapy might be beneficial. External validation is ongoing due to limited availability of adequate cohorts.

Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned.

LESSONS LEARNED: Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible. BACKGROUND: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. METHODS: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. RESULTS: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. CONCLUSION: Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.

OBJECTIVE: Accurate endoscopic differentiation would enable to resect and discard small and diminutive colonic lesions, thereby increasing cost-efficiency. Current classification systems based on narrow band imaging (NBI), however, do not include neoplastic sessile serrated adenomas/polyps (SSA/Ps). We aimed to develop and validate a new classification system for endoscopic differentiation of adenomas, hyperplastic polyps and SSA/Ps <10 mm. DESIGN: We developed the Workgroup serrAted polypS and Polyposis (WASP) classification, combining the NBI International Colorectal Endoscopic classification and criteria for differentiation of SSA/Ps in a stepwise approach. Ten consultant gastroenterologists predicted polyp histology, including levels of confidence, based on the endoscopic aspect of 45 polyps, before and after participation in training in the WASP classification. After 6 months, the same endoscopists predicted polyp histology of a new set of 50 polyps, with a ratio of lesions comparable to daily practice. RESULTS: The accuracy of optical diagnosis was 0.63 (95% CI 0.54 to 0.71) at baseline, which improved to 0.79 (95% CI 0.72 to 0.86, p<0.001) after training. For polyps diagnosed with high confidence the accuracy was 0.73 (95% CI 0.64 to 0.82), which improved to 0.87 (95% CI 0.80 to 0.95, p<0.01). The accuracy of optical diagnosis after 6 months was 0.76 (95% CI 0.72 to 0.80), increasing to 0.84 (95% CI 0.81 to 0.88) considering high confidence diagnosis. The combined negative predictive value with high confidence of diminutive neoplastic lesions (adenomas and SSA/Ps together) was 0.91 (95% CI 0.83 to 0.96). CONCLUSIONS: We developed and validated the first integrative classification method for endoscopic differentiation of small and diminutive adenomas, hyperplastic polyps and SSA/Ps. In a still image evaluation setting, introduction of the WASP classification significantly improved the accuracy of optical diagnosis overall as well as SSA/P in particular, which proved to be sustainable after 6 months.

Incidence of colonic neoplasia in patients with serrated polyposis syndrome who undergo annual endoscopic surveillance.

BACKGROUND & AIMS: Patients with serrated polyposis syndrome (SPS) are advised to undergo endoscopic surveillance for early detection of polyps and prevention of colorectal cancer (CRC). The optimal surveillance and treatment regimen is unknown. We performed a prospective study to evaluate a standardized endoscopic treatment protocol in a large cohort of patients with SPS. METHODS: We followed a cohort of patients with SPS who received annual endoscopic surveillance at the Academic Medical Centre in Amsterdam, The Netherlands from January 2007 through December 2012. All patients underwent clearing colonoscopy with removal of all polyps ≥3 mm. After clearance, subsequent follow-up colonoscopies were scheduled annually. The primary outcomes measure was the incidence of CRC and polyps. Secondary outcomes were the incidence of complications and the rate of preventive surgery. RESULTS: Successful endoscopic clearance of all polyps ≥3 mm was achieved in 41 of 50 (82%) patients. During subsequent annual surveillance, with a median follow-up time of 3.1 years (interquartile range, 1.5-4.3 years), CRC was not detected. The cumulative risks of detecting CRC, advanced adenomas, or large (≥10 mm) serrated polyps after 3 surveillance colonoscopies were 0%, 9%, 34%, respectively. Twelve patients (24%) were referred for preventive surgery; 9 at initial colonoscopy and 3 during surveillance. Perforations or severe bleeding did not occur. CONCLUSIONS: Annual surveillance with complete removal of all polyps ≥3 mm with timely referral of selected high-risk patients for prophylactic surgery prevents development of CRC in SPS patients without significant morbidity. Considering the substantial risk of polyp recurrence, close endoscopic surveillance in SPS seems warranted. www.trialregister.nl ID NTR2757.

Narrow-band imaging for the detection of polyps in patients with serrated polyposis syndrome: a multicenter, randomized, back-to-back trial.

BACKGROUND: Serrated polyposis syndrome (SPS) is characterized by the presence of multiple serrated polyps spread throughout the colon. Patients with SPS are considered to be at risk of colorectal cancer and are advised to undergo endoscopic surveillance. Narrow-band imaging (NBI) may improve the detection of polyps during these surveillance colonoscopies. OBJECTIVE: To compare polyp miss rates between NBI and high-resolution white-light endoscopy (HR-WLE). DESIGN: Multicenter, randomized, crossover study. SETTING: Four tertiary referral institutions. PATIENTS: A total of 52 patients with SPS undergoing surveillance colonoscopy. INTERVENTION: All patients underwent back-to-back colonoscopies with HR-WLE and NBI in a randomized order. MAIN OUTCOME MEASUREMENTS: Polyp miss rates of HR-WLE and NBI. RESULTS: In the HR-WLE group, 116 polyps were detected during the first inspection. A second inspection with NBI added 47 polyps, resulting in an overall polyp miss rate of 29% with HR-WLE (95% confidence interval, 22-36). In the NBI group, a total of 128 polyps were detected during the first inspection. Subsequent inspection with HR-WLE added 32 polyps, resulting in an overall polyp miss rate of NBI of 20% (95% confidence interval, 15-27). Comparison of the overall polyp miss rates of HR-WLE and NBI showed no significant difference (P = .065). LIMITATIONS: Small sample size; second inspection was performed by the same endoscopist. CONCLUSIONS: The results of our study suggest that NBI does not reduce polyp miss rates in patients with SPS compared with HR-WLE. Further multinational studies with larger numbers of patients are warranted to verify these results. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR2497.).

Yield of screening colonoscopy in first-degree relatives of patients with serrated polyposis syndrome.

GOALS: We aimed to evaluate the diagnostic yield of screening colonoscopies in first-degree relatives (FDRs) of patients with serrated polyposis syndrome (SPS). BACKGROUND: Patients with SPS are at an increased risk for colorectal cancer. Although inheritance patterns are unknown, FDRs of these patients have an increased risk for both colorectal cancer and SPS. Prospective studies evaluating the yield of screening colonoscopies in this group are however scarce. This information would be useful to evaluate a possible mode of inheritance and to investigate whether screening colonoscopies are justified in this group. STUDY: FDR of patients with SPS were invited to undergo colonoscopy. The diagnostic yield was expressed by the number of FDRs with at least 1 significant polyp relative to the total number of included FDRs. Significant polyps were defined adenomas, traditional serrated adenomas, sessile serrated adenoma/polyp, or proximal hyperplastic polyp. Tissue specimens were reviewed by one expert pathologist. RESULTS: Seventy-seven FDRs underwent colonoscopy (median age 52 y; interquartile range, 41 to 60). Colorectal cancer was not diagnosed. One or more significant polyps were detected in 43% of FDRs. No differences based on age, gender, or familial relationship were observed in the detection of polyps. Seven first-degree (9%) relatives had multiple polyps (≥5). Eleven (14%) FDRs fulfilled SPS WHO-criterion 2, of whom 1 sibling also met SPS WHO-criterion 3. CONCLUSIONS: The yield of a single screening colonoscopy in FDRs of patients with serrated polyposis is substantial, warranting a colonoscopy screening program for these individuals.

Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite-instable colorectal cancers.

Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite-stable and microsatellite-instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes. We studied a cohort of 23 SSLs with a small focus (<10 mm) of dysplasia or cancer, 10 of which were MLH1 deficient and 13 MLH1 proficient. By comparing, for each SSL, the methylation status of (1) the region of dysplasia or cancer (SSL-D), (2) the nondysplastic SSL (SSL), and (3) adjacent normal mucosa, differentially methylated probes (DMPs) and regions (DMRs) were assessed both genome-wide as well as in a tumor-suppressor gene-focused approach. By comparing DNAm of MLH1-deficient SSL-Ds with their corresponding SSLs, we identified five DMRs, including those annotating for PRDM2 and, not unexpectedly, MLH1. PRDM2 gene promotor methylation was associated with MLH1 expression status, as it was largely hypermethylated in MLH1-deficient SSL-Ds and hypomethylated in MLH1-proficient SSL-Ds. Significantly increased DNAm levels of PRDM2 and MLH1, in particular at 'critical' MLH1 probe sites, were to some extent already visible in SSLs as compared to normal mucosa (p = 0.02, p = 0.01, p < 0.0001, respectively). No DMRs, nor DMPs, were identified for SSLs destined to evolve into MLH1-proficient SSL-Ds. Our data indicate that, within both arms of the serrated CRC pathway, the majority of the epigenetic alterations are introduced early during SSL formation. Promoter hypermethylation of PRDM2 and MLH1 on the other hand specifically initiates in SSLs destined to transform into MLH1-deficient CRCs suggesting that the fate of SSLs may not necessarily result from a stochastic process but possibly is already imprinted and predisposed.

The role of high-resolution endoscopy and narrow-band imaging in the evaluation of upper GI neoplasia in familial adenomatous polyposis.

BACKGROUND: The Spigelman classification stratifies cancer risk in familial adenomatous polyposis (FAP) patients with duodenal adenomatosis. High-resolution endoscopy (HRE) and narrow-band imaging (NBI) may identify lesions at high risk. OBJECTIVE: To compare HRE and NBI for the detection of duodenal and gastric polyps and to characterize duodenal adenomas harboring advanced histology with HRE and NBI. DESIGN: Prospective, nonrandomized, comparative study. Retrospective image evaluation study. SETTING: Tertiary-care center. PATIENTS: Thirty-seven FAP patients undergoing surveillance upper endoscopies. INTERVENTION: HRE endoscopy was followed by NBI. The number of gastric polyps and Spigelman staging were compared. Duodenal polyp images were systematically reviewed in a learning and validation phase. MAIN OUTCOME MEASUREMENTS: Number of gastric and duodenal polyps detected by HRE and NBI and prevalence of specific endoscopic features in duodenal adenomas with advanced histology. RESULTS: NBI did not identify additional gastric polyps but detected more duodenal adenomas in 16 examinations, resulting in upgrades of the Spigelman stage in 2 cases (4.4%). Pictures of 168 duodenal adenomas (44% advanced histology) were assessed. In the learning phase, 3 endoscopic features were associated with advanced histology: white color, enlarged villi, and size ≥1 cm. Only size ≥1 cm was confirmed in the validation phase (odds ratio 3.0; 95% confidence interval, 1.2-7.4). LIMITATIONS: Nonrandomized study, scant number of high-grade dysplasia adenomas. CONCLUSION: Inspection with NBI did not lead to a clinically relevant upgrade in the Spigelman classification and did not improve the detection of gastric polyps in comparison with HRE. The only endoscopic feature that predicted advanced histology of a duodenal adenoma was size ≥1 cm.

Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution white-light endoscopy and narrow-band imaging.

BACKGROUND: Sessile serrated adenomas/polyps (SSAs/Ps) are premalignant lesions susceptible to being easily overlooked by endoscopists. A detailed description of the endoscopic appearance of SSAs/Ps might help endoscopists to recognize these lesions to improve the effectiveness of colonoscopy. OBJECTIVE: To identify various endoscopic features of SSAs/Ps using high-resolution white-light endoscopy (HR-WLE) and narrow-band imaging (NBI). DESIGN: Retrospective image evaluation study. SETTING: Single tertiary referral center. PATIENTS: Forty-5 patients with serrated polyposis syndrome undergoing surveillance colonoscopies. INTERVENTION: HR-WLE and NBI images of 150 polyps (50 SSAs/Ps, 50 hyperplastic polyps [HPs], and 50 adenomas) were systematically assessed by 5 experts using various endoscopic descriptors. MAIN OUTCOME MEASUREMENTS: The prevalence of specific endoscopic features observed in SSAs/Ps versus HPs. RESULTS: Multivariate analysis demonstrated that indistinct borders (OR, 3.11; 95% CI, 1.57-6.15) and a cloud-like surface (OR, 2.65; 95% CI, 1.21-5.78) were associated with SSA/P histology on HR-WLE. On NBI, a cloud-like surface (OR, 4.91; 95% CI, 2.42-9.97), indistinct borders (OR, 2.38; 95% CI, 1.14-4.96), irregular shape (OR, 3.17; 95% CI, 1.59-6.29), and dark spots inside the crypts (OR, 2.05; 95% CI, 1.02-4.11) were found to be endoscopic predictors of SSA/P histology. The sensitivity, specificity, and accuracy of NBI for differentiating serrated polyps containing either none or all 4 endoscopic SSA/P features were, respectively, 89%, 96%, and 93%. LIMITATIONS: Retrospective, image evaluation analysis. CONCLUSIONS: The current study demonstrates that SSAs/Ps possess several specific endoscopic features compared with HPs. Recognition of these characteristics might assist endoscopists in the differentiation of these lesions and could possibly facilitate endoscopic detection of these rather subtle lesions.

A serrated colorectal cancer pathway predominates over the classic WNT pathway in patients with hyperplastic polyposis syndrome.

Hyperplastic polyposis syndrome (HPS) is characterized by the presence of multiple colorectal serrated polyps and is associated with an increased colorectal cancer (CRC) risk. The mixture of distinct precursor lesion types and malignancies in HPS provides a unique model to study the canonical pathway and a proposed serrated CRC pathway in humans. To establish which CRC pathways play a role in HPS and to obtain new support for the serrated CRC pathway, we assessed the molecular characteristics of polyps (n = 84) and CRCs (n = 19) in 17 patients with HPS versus control groups of various sporadic polyps (n = 59) and sporadic microsatellite-stable CRCs (n = 16). In HPS and sporadic polyps, APC mutations were exclusively identified in adenomas, whereas BRAF mutations were confined to serrated polyps. Six of 19 HPS CRCs (32%) were identified in a serrated polyp. Mutation analysis performed in the CRC and the serrated component of these lesions showed identical BRAF mutations. One HPS CRC was located in an adenoma, both components harboring an identical APC mutation. Overall, 10 of 19 HPS CRCs (53%) carried a BRAF mutation versus none in control group CRCs (P = 0.001). Six BRAF-mutated HPS CRCs (60%) were microsatellite unstable owing to MLH1 methylation. These findings provide novel supporting evidence for the existence of a predominant serrated CRC pathway in HPS, generating microsatellite-stable and microsatellite-instable CRCs.

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas.

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.

Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis.

BACKGROUND & AIMS: MYH-associated polyposis (MAP) is a disorder caused by a bi-allelic germline MYH mutation, characterized by multiple colorectal adenomas. These adenomas typically harbor G:C-->T:A transversions in the APC and K-ras genes caused by MYH deficiency. Occasional hyperplastic polyps (HPs) have been described in MAP patients but a causal relationship has never been investigated. We examined the presence of HPs and sessile serrated adenomas (SSAs) in 17 MAP patients and studied the occurrence of G:C-->T:A transversions in the APC and K-ras gene in these polyps. METHODS: MAP patients were analyzed for the presence of HPs/SSAs. APC-mutation cluster region and K-ras codon 12 mutation analysis was performed in adenomas (n = 22), HPs (n = 63), and SSAs (n = 10) from these patients and from a control group of sporadic adenomas (n = 17), HPs (n = 24), and SSAs (n = 17). RESULTS: HPs/SSAs were detected in 8 of 17 (47%) MAP patients, of whom 3 (18%) met the criteria for hyperplastic polyposis syndrome. APC mutations were detected only in adenomas and comprised exclusively G:C-->T:A transversions. K-ras mutations were detected in 51 of 73 (70%) HPs/SSAs in MAP patients, compared with 7 of 41 (17%) sporadic HPs/SSAs in the control group (P < .0001). In HPs/SSAs, 48 of 51 (94%) K-ras mutations showed G:C-->T:A transversions, compared with 2 of 7 (29%) sporadic HPs/SSAs in the control group (P < .0001). CONCLUSIONS: HPs and SSAs are a common finding in MAP patients. The detection of almost exclusively G:C-->T:A transversions in the K-ras gene of HPs/SSAs strongly suggests that these polyps are related causally to MYH deficiency. This implies that distinct pathways, that is, APC-gene related in adenomas and nonrelated in HPS/SSAs, appear to be operational in MAP.

Clinical evaluation of endoscopic trimodal imaging for the detection and differentiation of colonic polyps.

BACKGROUND & AIMS: Endoscopic trimodal imaging (ETMI) incorporates high-resolution endoscopy (HRE) and autofluorescence imaging (AFI) for adenoma detection, and narrow-band imaging (NBI) for differentiation of adenomas from nonneoplastic polyps. The aim of this study was to compare AFI with HRE for adenoma detection and to assess the diagnostic accuracy of NBI for differentiation of polyps. This was a randomized trial of tandem colonoscopies. The study was performed at the Academic Medical Center in Amsterdam. METHODS: One hundred patients underwent colonoscopy with ETMI. Each colonic segment was examined twice for polyps, once with HRE and once with AFI, in random order per patient. All detected polyps were assessed with NBI for pit pattern and with AFI for color, and subsequently removed. Histopathology served as the gold standard for diagnosis. The main outcome measures of this study were adenoma miss-rates of AFI and HRE, and diagnostic accuracy of NBI and AFI for differentiating adenomas from nonneoplastic polyps. RESULTS: Among 50 patients examined with AFI first, 32 adenomas were detected initially. Subsequent inspection with HRE identified 8 additional adenomas. Among 50 patients examined with HRE first, 35 adenomas were detected initially. Successive AFI yielded 14 additional adenomas. The adenoma miss-rates of AFI and HRE therefore were 20% and 29%, respectively (P = .351). The sensitivity, specificity, and overall accuracy of NBI for differentiation were 90%, 70%, and 79%, respectively; corresponding figures for AFI were 99%, 35%, and 63%, respectively. CONCLUSIONS: The overall adenoma miss-rate was 25%; AFI did not significantly reduce the adenoma miss-rate compared with HRE. Both NBI and AFI had a disappointing diagnostic accuracy for polyp differentiation, although AFI had a high sensitivity.

Increased cyclooxygenase-2 expression in juvenile polyposis syndrome.

BACKGROUND & AIMS: Gastrointestinal juvenile polyps may occur in juvenile polyposis syndrome (JPS) or sporadically. JPS is an autosomal-dominant condition caused by a germline defect in SMAD4 or BMPR1A in 50% to 60% of cases, and is characterized by multiple juvenile polyps, predominantly in the colorectum. JPS has an increased risk of gastrointestinal malignancy but sporadic juvenile polyps do not. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal tumorigenesis and familial adenomatous polyposis. Inhibition of COX-2 leads to regression of colorectal adenomas in familial adenomatous polyposis patients and inhibits gastrointestinal tumorigenesis. To investigate the role of COX-2 in juvenile polyps, we compared the expression of COX-2 in juvenile polyps from a well-defined group of juvenile polyposis patients and sporadic juvenile polyps. METHODS: COX-2 expression was assessed in 24 genetically well-defined JPS patients and 26 patients with sporadic juvenile polyps using tissue microarray analysis. Two additional markers, Hu-antigen R, a stabilizer of messenger RNA, and CCAAT/enhancer-binding protein beta, a transcription factor, both associated with increased COX-2 expression, also were investigated. RESULTS: Increased COX-2 expression in JPS patients was noted compared with patients with sporadic juvenile polyps (P < .001). Also, JPS patients with a BMPR1A germline defect had higher COX-2 expression than did JPS patients in whom no germline mutation was detected. High COX-2 levels correlated with increased cytoplasmic Hu-antigen R expression in JPS polyps (P = .022), but not in sporadic juvenile polyps. CONCLUSIONS: Juvenile polyposis and sporadic juvenile polyps show distinctive expression profiles of COX-2 that may have clinical implications.