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Background We sought to determine the sites of recurrence and identify predicting factors for recurrence and survival in patients who underwent gastrectomy for adenocarcinoma at an institution where preoperative therapy is commonly used for advanced gastric cancer. Methods We collected clinicopathologic data and sites of recurrence from a prospectively maintained database of patients who underwent potentially curative resection of gastric or gastroesophageal adenocarcinoma at our institution in 1995–2014, and we assessed associations between these characteristics and recurrence patterns and survival. Results We identified 488 patients who underwent R0 resection of localized gastric cancer. The median age was 63 years (interquartile range 53–71 years), and 60% were male. The most common T and N categories, per endoscopic ultrasonography, were T3 (58%) and N0 (61%). Preoperative treatment was used in 61% of patients. A total of 125 (26%) patients experienced recurrence during follow-up. Recurrences were locoregional in 19 patients (15%), peritoneal in 61 (49%), and nonperitoneal distant in 67 (54%). The peritoneum also was the most common organ of recurrence (49%), followed by the liver (21%). The median time from primary resection to recurrence was 2.7 years for locoregional, 1.3 years for peritoneal, and 0.6 years for nonperitoneal distant recurrence ( p  = 0.01). Median overall survival was markedly shorter after peritoneal and nonperitoneal distant recurrences than after locoregional recurrences. Conclusions The peritoneum was a common site of recurrence after curative resection of gastric cancer and was associated with poor survival. Prophylactic treatment targeting the peritoneal cavity might improve survival of advanced gastric cancer.

Background This study aimed to identify the yield of staging laparoscopy with peritoneal lavage cytology for gastric cancer patients and to track it over time. Methods The medical records of patients with gastric or gastroesophageal adenocarcinoma who underwent pretreatment staging laparoscopy at the authors’ institution from 1995 to 2012 were reviewed. The yield of laparoscopy was defined as the proportion of patients who had positive findings on laparoscopy, including those with macroscopic carcinomatosis, positive cytology, or other clinically important findings. To compare the yield of laparoscopy over time, the patients were divided into three 6-year ranges based on the date of diagnosis. Associations between clinicopathologic factors and peritoneal disease were examined using uni- and multivariate analyses. Results The study included 711 patients. Among these patients, 43.5 % had gastroesophageal junction tumors, 72.9 % had poorly differentiated adenocarcinoma, and 53 % had signet ring cell morphology. Endoscopic ultrasound had most commonly identified T3 (83.9 %) and N-positive (66.4 %) tumors. At laparoscopy, 148 (20.8 %) patients had been found to have macroscopic peritoneal carcinomatosis. Among 514 macroscopically negative patients who underwent peritoneal lavage cytologic analysis, 68 (13.2 %) had positive cytology results for malignancy. The total laparoscopy yield was 36 %, which did not change over time ( p = 0.58). Multivariate analysis demonstrated that positive cytology or carcinomatosis was associated with poorly differentiated histology, linitis plastica, and equivocal computed tomography findings. Conclusions Laparoscopy remains a useful staging procedure to evaluate for peritoneal spread when treatment or surgery is considered, even with the current availability of high-quality imaging.

Background Linitis plastica due to gastric adenocarcinoma is a condition with a long history, but still lacks a standardized definition and is commonly confused with Borrmann type IV, Lauren diffuse, and signet-cell type gastric cancer. The absence of a clear definition is a problem when investigating its biological characteristics and role as a possible independent factor for prognosis. Nevertheless, the biological behavior for linitis plastica, which is unique, may be valuable in risk stratification and have implications for treatment. A definition of linitis plastica based on molecular or genomic criteria could represent a useful starting point for investigating new targeted therapies. Main body This literature review of linitis plastica will focus on the current classifications for gastric cancer, illustrating how the concept of linitis plastica relates to them in most cases and identifying a clear and reproducible definition. Moreover, the review will highlight the diagnostic challenges associated with linitis plastica, its prognostic implications, and the therapeutic options available. Future perspectives for its management are also addressed. Conclusion Linitis plastica is a carcinoma with a scirrhous stroma, involving the submucosal and muscular layers of the stomach even in the absence of mucosal alteration. In most cases, the primary cancer cells are signet-ring cells or scattered cells in the context of a poorly differentiated carcinoma. Diagnosis is challenging. Staging should be thorough, including diagnostic laparoscopy in all cases due to the high incidence of peritoneal involvement. The prognostic significance of linitis plastica is still controversial. Curative-intent surgery, when feasible, should be performed, with a multimodality treatment approach. Cancer-stroma interactions are important features of this disease, and represent attaining potential target for future therapies. Future pathologic assessments of gastric cancer should report the stromal reaction in order to allow better characterization of the tumor.

BackgroundProgrammed death ligand 1 (PD-L1) is a key protein upregulated by tumor cells to suppress immune responses. Tumor-associated macrophages (TAMs) play a major role in this immunosuppression, but the relationship between PD-L1 expression and TAMs remains unclear in gastric adenocarcinoma (GAC). We simultaneously examined expression of PD-L1 and TAMs in GAC.MethodsWe performed immunohistochemical staining for PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) in 217 GAC samples using a tissue microarray. Expression of PD-L1 and CD68- and CD163-positive cells was evaluated using the Cytoplasmic V2.0 algorithm in Aperio ImageScope software, and logistic regression analysis was used to compare expression patterns between groups.ResultsThirty-one samples (14%) were positive for PD-L1 expression. The mean (± standard error) rates of infiltration were 6.83 ± 0.38% for CD68-positive cells and 6.16 ± 0.29% for CD163-positive cells. The mean rate of CD163-positive cell infiltration was significantly higher in diffuse GAC than in intestinal GAC (diffuse n = 111, 6.91%; intestinal n = 91, 5.26%; p = 0.006), but the mean rate of CD68-positive cell infiltration was similar between these types (p = 0.38). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive GAC were significantly higher than in PD-L1-negative GAC (CD68 p = 0.0002; CD163 p < 0.0001). In multivariate logistic regression analyses, CD163-positive cell infiltration was associated with PD-L1 expression (odds ratio 1.13; 95% confidence interval 1.02–1.25; p = 0.021).ConclusionM2-like macrophage infiltration is highly associated with PD-L1 expression in GAC cells, suggesting that macrophage infiltration can serve as a potential therapeutic target.

BackgroundThe American Joint Committee on Cancer (AJCC) recently released its 8th edition staging system, which created a separate staging system for gastric cancer patients who have undergone preoperative therapy (ypStage). The objective of this retrospective study was to apply the new ypStage to patients who have undergone preoperative therapy and potentially curative gastrectomy.MethodsWe collected data from a prospectively maintained institutional database of gastric cancer patients who underwent potentially curative gastrectomy after preoperative therapy (1995–2015). Kaplan–Meier survival estimations and log-rank tests were performed to compare survival. Univariable and multivariable analyses were performed to determine risk factors for overall survival.ResultsA total of 354 patients met our criteria. Most patients completed planned preoperative therapy (94%; 332/354) and received chemoradiation therapy (75%; 265/354). Although clinical stage (cStage) provided a poor discrimination of survival, postneoadjuvant pathological stage (ypStage) identified significant variation in survival (p < 0.001). Multivariable analysis showed the following factors were associated with survival after adjustment for ypStage: Asian race (HR 0.52; p = 0.028), linitis plastica (HR 1.66; p = 0.037), and R1 resection (HR 1.91; p = 0.016). Survival was not longer in ypT0N0 patients than in ypStage I patients (HR 1.29; p = 0.377).ConclusionsThe AJCC 8th edition staging system for gastric cancer demonstrated reasonable survival prediction by ypStage, but not cStage, in patients who had undergone preoperative therapy. ypT0N0 patients, although not defined in the 8th edition, may be considered for inclusion in the ypStage I group.

Background The prognosis of patients with linitis plastica (LP) gastric cancer is reported to be poor. The purpose of our retrospective study was to characterize the clinicopathologic features and survival outcomes of patients with LP, using a univocal definition. Methods We defined LP as gastric cancer that involves more than 1/3 of the gastric wall macroscopically. We reviewed a prospectively maintained institutional database of gastric cancer patients and summarized and compared clinicopathologic factors of patients with and without LP who had undergone gastrectomy. Patients were matched 1:1 using propensity score matching, and their overall survival (OS) rates and durations were compared. Multivariable Cox regression analyses were conducted, using gastrectomy as a time-varying covariate. Results We identified 740 patients with radiographically non-metastatic gastric cancer, 157 (21.2%) of whom had LP. Most patients with LP had advanced-stage disease (75.8% had stage IV disease, mainly due to peritoneal involvement). Patients with LP had significantly shorter OS durations than did those without LP in the entire cohort (median OS, 14.0 vs. 33.5 months; p value < 0.001) and in the surgical cohort (median OS after gastrectomy, 21.8 vs. 91.0 months; p < 0.001), as well as in the propensity-matched surgical cohort. In the LP cohort, chemotherapy (hazard ratio [HR] = 0.594; p = 0.076), chemoradiation therapy (HR = 0.346; p = 0.001), and gastrectomy (HR = 0.425; p = 0.003) were associated with a longer OS. Conclusions LP is a phenotype of gastric cancer that often presents at an advanced stage, with a high rate of peritoneal involvement. The survival durations of patients with LP were poor in our study, even in the surgical cohort. The use of preoperative chemotherapy, chemoradiation therapy, and gastrectomy appeared to be important in carefully selected patients with localized LP.

Background Sarcomatoid carcinoma of unknown primary (SCUP) is a rare entity of either poorly differentiated carcinoma with sarcoma-like differentiation or a true mixed lineage neoplasm. Limited data regarding clinicopathological profile and management exists. Methods We retrospectively reviewed the MD Anderson Cancer of Unknown Primary database and tumor registry to identify 48 SCUP patients between 2001 and 2017. Patient characteristics, pathology, molecular diagnostics, treatments, and outcomes were obtained. Kaplan-Meier method was used to estimate overall survival (OS) and compared using log rank test. Results Median age at diagnosis was 59 years (range 27–86). Majority of patients were female (58%) and presented with ≥3 metastatic sites (52%), commonly lymph node (50%), bone (42%), lung (27%), and liver (21%). First line treatment included chemotherapy (35%), surgery (27%), and radiation (24%). Gemcitabine and docetaxel (18%) was the most common chemotherapy regimen. Median OS for entire cohort was 11 months (95% CI: 5.6 to 16.4). Poor performance status (PS), > 1 metastatic site, elevated lactate dehydrogenase (LDH), and high neutrophil-to-lymphocyte ratio (NLR) were significantly associated with worse OS on univariate analyses. On multivariate analyses, poor PS (HR 8.7; 95%CI: 3.0–25.0; p  <  0.001) and high NLR (HR 3.4; 95%CI: 1.3–8.8; p  = 0.011) emerged as independent prognostic factors for OS. Conclusions SCUP is a rare presentation with an aggressive clinical course and limited survival. Diagnosis is difficult to make and requires careful review and synthesis of histology, immunohistochemistry, and molecular diagnostics. Chemotherapy resistance remains a challenge. Early mutational profiling is warranted, and clinical trial participation should be encouraged for this subset.

Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant preclinical models. Here, we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, did not drive or accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss did not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, owing to promiscuity of the Cre promoter used, hepatocellular carcinomas and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate that the context of a human genome is essential for tumorigenesis. This article has an associated First Person interview with the first author of the paper.

BackgroundThe benefit of preoperative chemoradiation (CXRT) over preoperative chemotherapy alone (“chemotherapy” hereafter) is unknown. By analyzing the National Cancer Database (NCDB), we investigated whether preoperative CXRT improves the incidence of primary tumor pathologic complete response (ypT0) and overall survival (OS) compared with preoperative chemotherapy in patients with gastric cancer.MethodsPatients with non-metastatic gastric adenocarcinoma who underwent CXRT or chemotherapy followed by gastrectomy were included. Propensity score matching with a ratio of 1:1 was implemented to reduce selection bias. A conditional logistic regression model was used to compare incidences of ypT0 between groups, and Cox proportional hazards model was used to compare OS.ResultsWe identified 8464 patients. Median patient age was 63 years; 76% were male and 79% were white. ypT0 was observed in 16.1% of patients in the CXRT group and 6.6% in the chemotherapy group (p < 0.001). After propensity score matching, a total of 2408 patients were matched. CXRT was associated with a higher incidence of ypT0 (OR 2.28, 95% CI 1.76–2.95; p < 0.0001) and higher frequency of R0 resection (92 vs. 86%; p < 0.001). However, CXRT was not associated with longer OS (HR 1.03, 95% CI 0.92–1.15; p = 0.63). Safety profiles (30-day mortality, 30-day readmission, and length of hospital stay) were equivalent between groups.ConclusionsIn this study of gastric cancer patients from the NCDB, CXRT was associated with a higher incidence of ypT0 and R0 resection compared with chemotherapy, although it was not associated with a longer OS.