Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients ...the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well‐defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz–Jeghers syndrome, juvenile polyposis, Li–Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.
Aim
Currently, screening of colorectal cancers (CRC) by assessing mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is used to identify Lynch syndrome (LS) patients. Advanced ...adenomas are considered immediate precursor lesions of CRC. In this study we investigate the relevance of screening of advanced adenomas for LS in population screening.
Methods and results
Advanced adenomas (n = 1572) were selected from the Dutch colorectal cancer population screening programme, based on one or more of the criteria: tubulovillous (n = 848, 54%) or villous adenoma (n = 118, 7.5%), diameter ≥ 1 cm (n = 1286, 82%) and/or high‐grade dysplasia (n = 176, 11%). In 86 cases (5%), all three criteria were fulfilled at the same time. MMR–IHC and/or MSI analyses were performed on all cases. Only five advanced adenomas (0.3%) showed dMMR and MSI, including two cases with hypermethylation. In at least two patients a germline event was suspected based on allelic frequencies. No pathogenic explanation was found in the last case.
Conclusion
Timely testing of precursor lesions would be preferable to detect new LS patients before CRC development. However, standard assessment of dMMR of advanced adenomas from the population screening is not effective.
Around 10–20% of gastric cancer patients have relatives with a diagnosis of GC and in 1–3% of patients a genetic cause can be confirmed. Histopathologically, GC is classified into intestinal-type, ...with glandular growth, and diffuse-type with poorly cohesive growth pattern often with signet ring cells. Familial or hereditary GC is classified into hereditary diffuse GC (HDGC), familial intestinal GC (FIGC) and polyposis forms. This review focuses on recent research findings and new concepts of hereditary GC.
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.
Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse ...events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.
Detailed information on metastatic patterns in of patients with esophageal and gastric cancer is limited. Early recognition of metastases is important to avoid futile locoregional treatments. ...Furthermore, knowledge on metastatic patterns is necessary for further development of personalized treatment modalities.
To gain insight into the metastatic pattern of gastroesophageal cancer.
A nationwide retrospective autopsy study of 3876 patients with adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the esophagus or stomach between 1990 and 2017 was performed. Only patient with metastases were included for analysis. The metastatic pattern was analyzed according to the primary tumor location and histological subtype.
Metastatic disease was found in 268 esophageal and 331 gastric cancer patients. In esophageal cancer, the most common metastatic locations were liver (56%), distant lymph nodes (53%) and lung (50%). Esophageal AC showed more frequently metastases to the peritoneum and bone compared with esophageal SCC. In gastric cancer, the most common metastatic locations were distant lymph nodes (56%), liver (53%) and peritoneum (51%). Intestinal-type AC of the stomach showed metastases to the liver more frequently, whereas metastases to the bone, female reproductive organs and colorectum were observed more frequently in diffuse-type gastric AC.
This study showed differences in metastatic patterns of patients with esophageal and gastric cancer according to the primary tumor location and histological subtype.
Aims
Lymph node metastases (LNM) are one of the most important prognostic indicators in solid tumours and a major component of cancer staging. Neoadjuvant therapy might influence nodal status by ...induction of regression. Our aim is to determine the prevalence and role of regression of LNM on outcomes in patients with rectal cancer.
Methods and results
Four independent study populations of rectal cancer patients treated with similar regimens of chemoradiotherapy were pooled together to obtain a total cohort of 469 patients. Post‐treatment nodal status (ypN) and signs of tumour regression (Reg) were incorporated to form three‐tiered (ypN− Reg+, ypN− Reg− and ypN+) and four‐tiered (ypN− Reg+, ypN− Reg−, ypN+ Reg+ and ypN+ Reg−) classifications. In our cohort, 31% of patients presented with ypN+ rectal cancer. As expected, we found significantly worse overall survival (OS) in ypN+ patients compared to ypN− patients (P = 0.002). The percentage of ypN− patients with lymph nodes with complete regression was 20% in our cohort. While node‐negative patients with and without regression had similar OS (P = 0.09), disease‐free survival (DFS) was significantly better in node‐negative patients with regression (P = 0.009).
Conclusions
Regression in lymph nodes is frequent, and node‐negative patients with evidence of lymph node regression have better DFS compared to node‐negative patients without such evidence.
As well as the primary tumour, lymph nodes can respond to neoadjuvant treatment. Lymph node regression impacts survival: patients with complete response in lymph nodes have the longest life expectancy.
Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, ...surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused ...by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.
Aims
Tumour deposits (TDs) are clusters of cancer cells in the soft tissue that are discontinuous from the primary tumour. In this review we are exploring their relevance for prognosis in patients ...with gastric cancer.
Methods and results
A literature search was performed to identify studies providing data on TDs and prognosis in gastric cancer patients. Eight papers were included in the meta‐analysis, which was carried out in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). Of 7445 patients, 1551 had TDs (20.9%). TDs were associated with a decreased overall survival (OS) in univariate (HR = 2.82, 95% CI = 1.9–4.3) and multivariate analyses (HR = 1.65, 95% CI = 1.3–2.1). TDs were also associated with known prognostic factors such as synchronous metastatic disease (RR = 9.5), invasion depth (RR = 1.8), lymph node metastasis (RR = 1.7), lymphatic invasion (RR = 1.7), vascular invasion (RR = 2.6) and poor differentiation (RR = 1.2).
Conclusions
We found a strong indication that TDs are independent predictors of prognosis in patients with gastric cancer; hence, TDs should be included in the staging of gastric cancers.
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