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Data on the age-specific incidence of esophageal cancer are lacking. Our aim was to investigate the age-stratified incidence, treatment, and survival trends of esophageal cancer in the Netherlands, with a focus on adults <50 years. Patients diagnosed with esophageal cancer were included from the nationwide Netherlands Cancer Registry (1989–2018). Follow-up data were available until 31 December 2018. Annual percentage changes of incidence were analyzed according to age group (<50, 50–74, and ≥75 years) and histology type: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Treatment trends and relative survival rates (RSR) were estimated by age and stage grouping. A total 59,584 patients were included. In adults <50 years, EAC incidence tripled (mean increase per year: males 1.5%, females 3%), while the incidence of ESCC decreased (mean decrease per year: males −5.3%, females −4.3%). Patients <50 years more often presented with advanced disease stages compared to older patients and were more likely to receive multimodality treatments. Most patients <50 years with potentially curable disease were treated with neoadjuvant chemoradiotherapy followed by surgery compared to patients 50–74 and ≥75 years (74% vs. 55% vs. 15%, respectively; p <.001), and received more frequent systemic therapy once staged with palliative disease (72% vs. 54% vs. 19%, respectively; p <.001). The largest RSR improvement was seen in patients <50 years with early-stage (five years: +47%), potentially curable (five years: +22%), and palliative disease (one year: +11%). Over time, a trend of increasing survival difference was seen between patients <50 and ≥75 years with potentially curable (five-year difference: 17% to 27%) and palliative disease (one-year difference: 11% to 20%). The incidence of EAC is increasing in adults <50 years in the Netherlands. Differences in the use of multimodality treatments with curative or life-prolonging intent in different age categories may account for increasing survival gaps. [ABSTRACT FROM AUTHOR]

PURPOSE: Neuroendocrine carcinomas and mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (NE GBC) are rare and highly aggressive entities. The cell of origin of NE GBC has been a matter of controversy. Here, we performed a comparative histopathologic and molecular analysis of NE GBC cases and, if present, associated precancerous lesions. PATIENTS AND METHODS: We selected cases diagnosed between 2000 and 2019 in the Netherlands. Precursors and carcinomas were immunohistochemically compared and analyzed for mutations, gene amplifications, microsatellite instability, and tumor mutational burden using an next-generation sequencing panel containing 523 cancer-related genes. In addition, presence of fusion genes was analyzed using a panel of 55 genes. RESULTS: Sixty percent of neuroendocrine cases (6/10) presented with a precursor lesion, either intracholecystic papillary neoplasm (n = 3) or biliary intraepithelial neoplasia (n = 3). Immunohistochemically, neuroendocrine components were different from the epithelial precursor lesions. Molecular profiling, however, revealed TP53 mutations shared between different components in five of six cases, indicating a clonal relation. Furthermore, 40% of cases (4/10) harbored at least one potentially actionable alteration. This included (likely) pathogenic mutations in RAD54L , ATM , and BRCA2 ; amplifications of ERBB2 and MDM2 ; and a gene fusion involving FGFR3-TACC3. All cases were microsatellite-stable and had a tumor mutational burden of < 10 mutations/Mb. CONCLUSION: Our data provide insight into the development of NE GBC and suggest a common origin of precancerous epithelial lesions and invasive neuroendocrine components, favoring the hypothesis of lineage transformation. Moreover, nearly half of the NE GBCs carried at least one potentially actionable molecular alteration, highlighting the importance of molecular testing in this highly lethal cancer. [ABSTRACT FROM AUTHOR]

With increasing interest in organ-preserving strategies for potentially curable esophageal cancer, real-world data is needed to understand the impact of pathological tumor response after neoadjuvant chemoradiotherapy (CRT) on patient outcome. The objective of this study is to assess the association between pathological tumor response following CROSS neoadjuvant CRT and long-term overall survival (OS) in a nationwide cohort. All patients diagnosed in the Netherlands with potentially curable esophageal cancer between 2009 and 2017, and treated with neoadjuvant CRT followed by esophagectomy were included. Through record linkage with the nationwide Dutch Pathology Registry (PALGA), pathological data were obtained. The primary outcome was pathological tumor response based on ypTNM, classified into pathological complete response (ypT0N0) and incomplete responders (ypT0N+, ypT+N0, and ypT+N+). Multivariable logistic and Cox regression models were used to identify predictors of pathological complete response (pCR) and survival. A total of 4946 patients were included. Overall, 24% achieved pCR, with 19% in adenocarcinoma and 42% in squamous cell carcinoma. Patients with pCR had a better estimated 5-year OS compared to incomplete responders (62% vs. 38%, p<.001). Of the patients with incomplete response, ypT+N+ patients (32% of total population) had the lowest estimated 5-year OS rate, followed by ypT0N+ and ypT+ N0 (22%, 47%, and 49%, respectively, p<.001). Adenocarcinoma, well to moderate differentiation, cT3-4, cN+, signet ring cell differentiation and lymph node yield (≥15) were associated with lower likelihood of pCR. In this population-based study, pathological tumor response based on the ypTNM-stage was associated with different prognostic subgroups. A quarter of patients achieved ypT0N0 with favorable long-term survival, while one-third had an ypT+N+ response with very poor survival. The association between pathological tumor response and long-term survival could help in more accurate assessments of individual prognosis and treatment decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: Appropriate reporting of pathological findings is required for optimal patient care and to perform high-quality research. The aim of our study was to assess the completeness of pathology reports of gallbladder cancer (GBC) in a large nation-wide patient cohort from the Netherlands. Results showed that reports were often incomplete; information on essential items that can predict prognosis were often missing. Whereas certain items were often missing in the report, they could be retrospectively detected in a large proportion of patients during pathology review. Our findings showed that significant improvements could be made in the reporting of gallbladder cancer in the Netherlands. To this end, the added value of standardized (synoptic) reporting should be explored, of which the beneficial effects have already been demonstrated in other tumor types. Adequate reporting of pathological findings is essential for optimal patient management and to perform high-quality research. The aim of this study was to assess the completeness of pathology reports of gallbladder cancer (GBC) at the nationwide level to assess guideline adherence and make recommendations for improvement. A retrospective population-based cohort of GBC patients diagnosed in the Netherlands from 2000 to 2019 was collected using data from the Dutch Cancer Registry and the nationwide network and registry of histology. Pathology reports were scored on the presence and content of essential and optional items according to the Dutch consensus-based guideline on biliary tract cancer. By histopathological review of cases, we compared findings with the conclusion of the corresponding pathology report. All pathology reports (n = 849) had a narrative, nonstructured format. Overall completeness was low. Information on key prognostic factors, such as tumor side (hepatic vs. serosal), status of cystic duct and liver surgical margins and venous and perineural invasion, was frequently lacking (80%, 23%, 59%, 74% and 74% missing, respectively). Whereas certain items were often missing from the report, they could be retrospectively detected in a substantial proportion of cases during pathology review (n = 738). In conclusion, significant improvements could be made in the reporting of GBC in the Netherlands. Synoptic reporting could greatly enhance the completeness of reports, as already demonstrated for tumor types. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate interobserver variability between individual pathologists and a panel of pathologists in the histopathological assessment of advanced colorectal neoplasms in the Dutch bowel cancer screening population., Methods and Results: Histological slides of adenomas with high-grade dysplasia and early colorectal carcinomas (CRC) from 20 different laboratories were reviewed by the pathology panel of the Dutch bowel screening programme. Interobserver variability was reported by descriptive statistics. In addition, potential clinical consequences of discrepancies were evaluated. A total of 104 cases of adenomas with high-grade dysplasia and 83 early CRCs were reviewed. Discrepancies were observed in 41 of 104 (39.4%) adenoma cases, which potentially had clinical consequences in 16 (15.4%) cases. For CRC, discrepancies were shown in 44 of 83 cases (53.0%) and would have potentially led to alternative treatment strategies in 25 (30.1%) cases. Most frequently, discrepancies were observed in the assessment of lymphovascular invasion (23 of 73 cases, 31.5%)., Conclusion: This study showed that considerable interobserver variability is present in the histopathological assessment of advanced colorectal neoplasia, which may impact upon treatment choices. Additional stains and education, as well as intercollegial consultation, might decrease this variability., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background & Aims: Colorectal cancers (CRCs) are rare in adolescents and adults ages 25 years or younger. We analyzed clinical, pathology, and molecular features of colorectal tumors from adolescents and young adults in an effort to improve genetic counseling, surveillance, and, ultimately, treatment and outcomes., Methods: We analyzed clinical data and molecular and genetic features of colorectal tumor tissues from 139 adolescents or young adults (age, ≤25 y; median age, 23 y; 58% male), collected from 2000 through 2017; tumor tissues and clinical data were obtained from the nationwide network and registry of histopathology and cytopathology and The Netherlands Cancer Registry, respectively. DNA samples from tumors were analyzed for microsatellite instability, mutations in 56 genes, and genome-wide somatic copy number aberrations., Results: Mucinous and/or signet ring cell components were observed in 33% of tumor samples. A genetic tumor risk syndrome was confirmed for 39% of cases. Factors associated with shorter survival time included younger age at diagnosis, signet ring cell carcinoma, the absence of a genetic tumor risk syndrome, and diagnosis at an advanced stage of disease. Compared with colorectal tumors from patients ages 60 years or older in the Cancer Genome Atlas, higher proportions of tumors from adolescents or young adults were microsatellite stable with nearly diploid genomes, or contained somatic mutations in TP53 and POLE, whereas lower proportions contained mutations in APC., Conclusions: We found clinical, molecular, and genetic features of CRCs in adolescents or young adults to differ from those of patients older than age 60 years. In 39% of patients a genetic tumor risk syndrome was identified. These findings provide insight into the pathogenesis of CRC in young patients and suggest new strategies for clinical management. Performing genetic and molecular analyses for every individual diagnosed with CRC at age 25 years or younger would aid in this optimization., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preoperative differentiation between neoplastic and nonneoplastic gallbladder polyps, and the subsequent indication for cholecystectomy remains a clinical dilemma. The current 1 cm size threshold for neoplasia is unspecific. The aim of this study was to improve diagnostic work-up for gallbladder polyps using sonographic and MRI characteristics of neoplastic and nonneoplastic polyps., Methods: A prospective, exploratory study including patients undergoing cholecystectomy for gallbladder polyp(s) was conducted. Patients underwent targeted transabdominal ultrasound (TAUS) and MRI. Outcomes were sensitivity and specificity for polyp diagnosis, and the radiological characteristics of neoplastic and nonneoplastic polyp types. Histopathology after cholecystectomy was used as reference standard., Results: Histopathology demonstrated gallbladder polyps in 20/27 patients (74%): 14 cholesterol polyps, three adenomyomatosis, two adenomas and one gastric heterotopia. Sensitivity of polyp identification were 72% (routine TAUS) and 86% (targeted TAUS and MRI). Both adenomas were identified as neoplastic on targeted TAUS and MRI. Sonographic presentation as multiple, pedunculated polyps, either heterogeneous or with hyperechoic foci, or as single polyps containing cysts were limited to nonneoplastic polyps. On MRI hyperintense polyps on T1-weighted image were cholesterol polyps. An adenoma with high-grade dysplasia showed foci of decreased ADC values. We propose a checklist for polyp evaluation by targeted TAUS and a flowchart for radiological work-up of gallbladder polyps., Conclusions: The presented checklist and flowchart could aid diagnostic work-up for gallbladder polyps compared to current routine ultrasound, by elimination of nonneoplastic polyps and ultimately improve treatment decision for patients with gallbladder polyps., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Traditionally, surgical pathology reports are narrative. These report types are prone to error and missing data; therefore, structured standardized reporting was introduced. However, the effect of synoptic reporting on the completeness of esophageal and gastric carcinoma pathology reports is not yet established., Materials and Methods: A population-based retrospective nationwide cohort study in the Netherlands was conducted over a period of 2012-2016, utilizing the Netherlands Cancer Registry for patient data and the nationwide network and registry of histology for pathology data., Results: In total, 1148 narrative and 1311 synoptic pathology reports were included. Completeness was achieved in 56.4% of the narrative reports versus 97.0% of the synoptic reports (p < 0.01). Out of 21 standard items, 15 were significantly more frequently reported in synoptic reports., Conclusion: Synoptic reporting improves surgical pathology reporting quality and should be implemented in standard patient care.

Background & Aims: The risk of esophageal adenocarcinoma (EAC) in patients with non-dysplastic Barrett's esophagus (NDBE) is low, so there is debate over the role of ongoing surveillance for patients with NDBE. It is important to identify patients at low risk for progression. We assessed cancer risk based on the subsequent number of endoscopies showing persistence of NDBE in a nationwide study in the Netherlands., Methods: In a population-based study, patients with a first diagnosis of NDBE were selected from the Dutch nationwide registry of histopathology. We calculated incidence rates and incidence rate ratios (IRR) for high-grade dysplasia (HGD) and EAC to determine whether the number of endoscopies negative for dysplasia and the persistence of NDBE over time associate with progression to malignancy., Results: We identified 12,728 patients with NDBE during 2003 and 2013. HGD or EAC developed in 436 patients (3.4%) during 64,537 person-years of follow up (median, 4.9 years). The rate of progression to HGD or EAC was 0.68 (95% CI, 0.61-0.74) per 100 person-years. In patients with 2 consecutive endoscopies showing NDBE, the rate of progression to HGD or EAC decreased to 0.55 (95% CI, 0.46-0.64) per 100 person-years (IRR, 0.72; 95% CI, 0.60-0.87). Overall, the incidence of HGD or EAC decreased by 14% for each year of progression-free follow-up (IRR, 0.86; 95% CI, 0.81-0.92)., Conclusion: In a population-based study in the Netherlands, we found patients with stable NDBE to have a low risk of progression to HGD or EAC. These findings indicate that surveillance intervals might be lengthened or even discontinued in subgroups patients with persistent NDBE., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

IL-12Rβ1 deficiency, also known as immunodeficiency 30 (IMD30, OMIM 614891), is a rare immunodeficiency syndrome caused by biallelic mutations in IL12RB1. Three second-degree relatives of a patient with this syndrome, all women, developed intestinal-type gastric cancer (GC). In the Netherlands the incidence of non-cardia GC in women is only 7 per 100,000 person years. Both relatives that were available for testing proved to be heterozygous for the familial IL12RB1 mutation, suggesting there might be a causal relation. Testing 29 index patients from families with early onset and/or a familial history of GC for germline mutations in both IL12RB1 and IL12RB2, that encodes the binding partner of IL-12Rβ1, did not reveal other germline mutations in these genes. Therefore heterozygous inactivating mutations in IL12RB1 and IL12RB2 are unlikely to be frequently involved in GC predisposition. Additional research in families with IL12RB1 mutations is required to determine whether carriers of IL12RB1 mutations have an increased (gastric) cancer risk.