Signet Ring Cell Carcinoma Patients Research Articles

Survival benefit of palliative gastrectomy followed by chemotherapy in stage IV gastric signet ring cell carcinoma patients: A large population‐based study

BackgroundStage IV gastric signet ring cell carcinoma (SRCC) is a type of malignant gastric cancer (GC) with poorer survival compared to metastatic non‐SRCC gastric cancer (NOS). However, chemotherapy alone was unable to maintain long‐term survival. This study aimed to evaluate survival benefit of palliative gastrectomy plus chemotherapy (PG+C) for metastatic gastric SRCC.MethodsWe obtained data on gastric cancer patients between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Statistical methods included χ 2 tests, Kaplan‐Meier curves, COX models, propensity score matching (PSM) and subgroup analysis.ResultsAmong 27 240 gastric cancer patients included, 4638 (17.03%) were SRCC patients. The proportion of patients with younger age, female gender, poorly differentiated grade and M1 stage was higher in SRCC than in NOS (P < .001). Multivariate analysis revealed that multiple metastatic sites (HR = 1.39, 95% CI: 1.14‐1.69, P = .001) was associated with increased mortality risk in metastatic SRCC. Median survival time was improved in metastatic SRCC receiving PG+C compared to PG/C alone (13 vs 7 months, P < .001). Notably, in subgroup analysis, 13 of 17 groups of metastatic SRCC patients with PG+C had prolonged overall survival compared to chemotherapy alone, especially for those with only one metastatic site (HR = 0.61, 95% CI: 0.51‐0.73, P < .001).ConclusionsOur results suggested that there exists at least a selective group of stage IV gastric SRCC patients, who could benefit from palliative gastrectomy followed by chemotherapy compared to chemotherapy alone. Further prospective trials are needed to support our conclusion.

Using nomograms to predict prognostic factors in young colorectal mucinous and signet-ring cell adenocarcinoma patients.

Due to insufficient quantitative evaluation of the clinic-pathological features and prognosis of young colorectal cancer (CRC) with mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRC), the aim of our study was to develop a nomogram to identify the prognostic predictors for overall survival (OS) in this patient population. We retrospectively evaluated the patient records of MAC and SRC patients aged ≤ 40 years. Kaplan–Meier analysis and log-rank testing were performed to estimate OS. A nomogram predicting OS was created for risk quantitation and decision tree analysis was performed for patient grouping. With a median follow-up of 36.5 months, we included a total of 90 young CRC patients for analysis. The overall cumulate 5-year OS rate was 57.7% (95% confidence interval (CI): 45.1–68.5%). The estimated 5-year OS was 62.9% (95% CI: 48.5–74.3%) for MAC and 37.3% (95% CI: 14.4–61.2%) for SRC (P=0.021). The recurrence rate was significantly greater in the SRC group compared with the mucinous group (52.4 compared with 26.1%, P=0.047). In the multivariate Cox regression model, preoperative carcinoembryonic antigen (CEA) levels and cycles of adjuvant chemotherapy (CT) were found to be an independent prognostic factor for OS (hazard ratio (HR): 2.43; 95% CI: 1.13–5.62, P=0.024; HR: 0.21; 95% CI: 0.083–0.57, P=0.002, respectively). Nomograms predicting 3- and 5-year OS were established that performed well (concordance index (c-indexes) of 0.636, 95% CI: 0.549–723) for OS. For MAC and SRC disease, a greater proportion of young patients present with advanced disease, and the prognosis for young SRC patients is poorer than MAC. Furthermore, preoperative CEA levels and cycles of adjuvant CT seem to independently affect the OS in this patient population.

Abstract 3177: KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor

Abstract Background: Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related death, particularly in China. Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer. Mutations in KRAS are detected in many types of human tumors and have been proved to be associated with development and progression of cancer. In this study, we sought to explore the role of KRAS in signet-ring cell carcinoma. Patients and methods: Genomic data from 393 GC samples from The Cancer Genome Atlas (TCGA) was extracted to analyze mutation status of KRAS. Sanger sequencing for KRAS was applied in 234 FFPE SRCC patient samples. Immunohistochemical(IHC) and Fluorence in situ hybridization(FISH) were performed to detect KRAS expression level and KRAS amplification status in FFPE samples. Patients were evaluated in terms of survival and clinicopathological characteristics, as well as KRAS mutation and expression status in TCGA and in our cohort, respectively. We also explored KRAS mutation and expression level in 4 SRCC cell lines. Drug inhibition rate of MEK/mTOR inhibitors was evaluated by cell viability assay. Results: Thirty-one patients (0.079%) and thirty-seven GC patients (0.094%) in TCGA harbored point mutations and copy number variation (CNV), respectively. Patients with KRAS point mutations and CNV showed higher mRNA level compared to non-mutant cases (P = 0.003 and P &amp;lt; 0.001). No survival difference was observed between KRAS different gene status in TCGA cohort. In our 234 in-house SRCC samples, 15 samples harbored KRAS mutations. We further did analysis on the 75 patients which had enough FFPE samples. Eight patients showed KRAS mutations and two patients showed KRAS amplification. The median overall survival (OS) was 12.5 months for patients with KRAS mutation, and 19.5 months for patients without KRAS mutation (P = 0.045). The majority of SRCC patients are positive with KRAS detected by IHC, which is higher than our intestinal cohort (80% vs 38.6%, P&amp;lt;0.001). However, no difference of overall survival was observed between different KRAS expression level. We further explore the correlation between KRAS status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored KRAS mutation, were hypersensitive to MEK inhibition. However, mTOR inhibitor showed no preference on SRCC cell lines in terms of KRAS status. Conclusion: These data demonstrate the status of KRAS gene in SRCC and uncover the therapeutic potential for targeting of these tumors through MEK inhibition in SRCC. Citation Format: Nandie Wu, Ying Huang, Xiangshan Fan, Yang Yang, Qin Liu, Lixia Yu, Rafael Rosell, Baorui Liu, Jia Wei. KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3177.

Chemotherapy is associated with increased survival from colorectal signet ring cell carcinoma with distant metastasis: A Surveillance, Epidemiology, and End Results database analysis.

BackgroundColorectal signet ring cell carcinoma (SRCC) is a rare histological subtype of colorectal adenocarcinoma with high metastatic frequency compared to non‐SRCC colorectal cancer (NOS). The aim of this study was to analyze prognostic factors of colorectal SRCC with different metastatic sites and evaluate impacts of various therapies for metastatic colorectal SRCC.MethodsPatients with NOS and SRCC were from the Surveillance, Epidemiology, and End Results (SEER) database during 2010‐2014. χ2 tests were used to compare data significance. Kaplan‐Meier and COX models were used to analyze the differences in the survival. Propensity‐matched analyses were used to adjust numerical differences.ResultsAmong the 173 460 patients, 1932 (1.11%) patients had colorectal SRCC. In univariate analysis, older age, male sex, and peritoneum metastasis were associated with higher mortality risk. The peritoneum was both the site with the highest metastatic frequency and the site with the worst prognosis in SRCC. In the COX regression model, peritoneum‐metastatic SRCC patients receiving chemotherapy had better survival than patients treated with surgery.ConclusionsOur study analyzed the unique metastatic pattern of colorectal SRCC toward different sites and found that compared to surgery, chemotherapy was associated with better survival for colorectal SRCC patients with distant metastasis, which provided insights for future SRCC patient treatment.

Postoperative Radiotherapy Improves Survival in Gastric Signet-Ring Cell Carcinoma: a SEER Database Analysis.

PurposeTo identify the potential therapeutic role of postoperative radiotherapy (RT) in patients with locally advanced (stage II and stage III) gastric signet ring cell carcinoma (SRC).Materials and methodsPatients with locally advanced gastric SRC from the Surveillance, Epidemiology, and End Results program database between 2004 and 2012 were included in our study. Univariate and multivariate Cox proportional models were performed, and survival curves were generated to evaluate the prognostic effect of postoperative RT and surgery alone on SRC patients. Propensity score matching (PSM) was used to avoid selection bias among the study cohorts.ResultsWe found that patients with postoperative RT had better probability of survival compared with those who did not receive RT (overall survival [OS], P<0.001; cancer-specific survival [CSS], P<0.001). After PSM, analysis of both overall and CSS showed that patients who underwent postoperative RT had better prognosis than those receiving surgery alone in the matched cohort (OS, P=0.00079; CSS, P=0.0036). Multivariate Cox proportional model indicated that postoperative RT had better effect on prognosis compared with surgery alone with respect to both overall (hazard ratio [HR], 0.716; 95% confidence interval [95% CI], 0.590–0.87; P=0.001) and CSS (HR, 0.713; 95% CI, 0.570–0.890; P=0.003).ConclusionsPostoperative RT had better prognosis compared with surgery alone for both overall and CSS for patients with locally advanced gastric SRC.

PS02.242: SIGNET-RING CELL PERCENTAGE MAY INFLUENCE PATHOLOGICAL RESPONSE TO CHEMOTHERAPY IN ESOPHAGO-GASTRIC JUNCTION SIGNET RING CELL CARCINOMA

Abstract Background Like in gastric cancer, the incidence of signet-ring cell carcinoma (SRCC) is rising also in esophago-gastric junction (EGJ) adenocarcinoma Siewert type I and II. SRCC is much more studied in gastric cancer and WHO classification divides poorly cohesive gastric cancer in two subtypes, depending on the percentage of signet-ring cells: real SRCC (percentage of signet-ring cell more than 50%) and poorly cohesive non-SRCC (less than 50%). Real SRCC seems to have higher chemosensitivity and better prognosis than poorly cohesive non-SRCC. Recently, a new classification for SRCC has been proposed, which subdivides SRCC based on different cut-off percentages of signet ring cells (less than or equal to 90% vs more than 90%). Aim of this study was to compare pathological response in patients with EGJ SRCC treated with neoadjuvant chemotherapy. Methods Study population comprised 11 patients with Siewert I and II EGJ SRCC treated with neoadjuvant chemotherapy and surgery. We analyzed differences in pathological response to therapy between ‘pure’-SRCC (more than 90% of SRC) and ‘non-pure’-SRCC (less than or equal to 90%). Tumor regression grade (TRG) was used to define response to treatment, with TRG 1–2 defining good response to treatment and TRG 3–5 poor or absent response to treatment. Results Among the 11 patients with EGJ SRCC, 6 had ‘pure’-SRCC histology and 5 ‘non-pure’-SRCC. Response to treatment in ‘pure’-SRCC patients was equally splint into good and poor responders: 3 had good response to treatment (TRG 1–2) and 3 poor or absent response (TRG 3–5). On the contrary most of ‘non-pure’-SRCC had poor or absent response: 4 out of 5 patients had TRG 3–5. Conclusion Although the case series was too small to perform statistical analyses, our results suggest that signet-ring cell percentage may influence the outcome of neoadjuvant therapy. Probably a larger case series would allow to better define cut-offs of percentage of signet-ring cell carcinoma of the EGJ. Moreover it would allow to inspect other factors related to response to treatment. This is only a preliminary investigation and further studies are needed to better understand the characteristics of these rising in incidence types of cancer. Disclosure All authors have declared no conflicts of interest.

Prognosis and efficiency of adjuvant therapy in resected colon signet-ring cell carcinoma

Background: Colon signet-ring cell carcinoma (SRCC) is associated with poor survival compared with other histologic subtypes such as adenocarcinoma (AC) and mucinous adenocarcinoma (MC). This present study analyzed the prognosis factors of SRCC and assessed whether the adjuvant therapy could supply benefit for SRCC with different regimens. Methods: Data on 82,606 colon cancer patients who received surgery in the period 1992–2005 was included in this population-based study. The survival benefit was evaluated using a Cox proportional hazards model and propensity score (PS)-matched techniques. Results: SRCC was found in 779 (0.9%) patients who were more frequently in stage III and IV colon cancer than other subtypes. The 5-year survival of SRCC patients were 30.1% (95% CI, 26.7–33.5) which was significantly lower compared with 51.6% (95% CI, 51.3–52.0) for AC and 48.8% (95% CI, 47.8–49.8) for MC. For patients in stage II, there was no significantly difference between chemo group and no-chemo group in all histologic subtypes. The results in stage III showed that 5-FU based adjuvant chemotherapy for AC and SRCC patients could improve overall survival (OS) which could be further enhanced by adding oxaliplatin. The similar benefit was found in stage IV patients. However, there was no significantly difference between different therapy regimens in stage IV SRCC patients. Conclusions: Although the prognosis of patients with colon SRCC was pessimistic, the effective role of adjuvant therapy for OS was still observed in stage III SRCC patients who received surgery. Similarly, patients with stage IV SRCC could also gain benefit from systemic therapy.

Differences in clinicopathological characteristics and computed tomography findings between signet ring cell carcinoma and nonsignet ring cell carcinoma in early and advanced gastric cancer.

Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics. SRC's clinicopathological characteristics and prognosis are still controversial. Our study is to describe the clinicopathological features and multidetector computed tomography (MDCT) findings of patients with SRC of the stomach in comparison with nonsignet ring cell adenocarcinoma (NSRC). We retrospectively analyzed data from 241 patients who had undergone curative gastrectomy, including 62 SRC and 179 NSRC. Clinicopathological outcomes and MDCT findings were evaluated, and we investigated whether these variables were correlated with histopathological type. In early gastric carcinoma, patients with SRC were younger (50.2 vs. 60.2 years; P = 0.000) and more likely to be observed in the middle and lower third stomach (P = 0.010). Early SRC had a tendency to be confined to the mucosa (82.1%). There were significant differences in degree of enhancement between early SRC and NSRC on MDCT imaging (P < 0.001). In advanced gastric carcinoma, SRC was more likely to be stage T3‐4 (100%). SRC patients had thicker tumors (P = 0.001) and a higher frequency of diffusely infiltrative gross appearance (P < 0.001). SRC was more likely to have high‐degree contrast enhancement than were NSRC (P = 0.001). The maximal diameter of SRC tumor on MDCT imaging correlated with lymph node metastasis (sensitivity 93.9%, specificity 74.1%) and serosal invasion (sensitivity 89.5%, specificity 78.0%) of SRC. In conclusion, SRC differs significantly from NSRC in clinicopathological features at presentation. MDCT could help differentiate advanced gastric SRC from NSRC based on the thickened stomach wall, high‐degree contrast enhancement, and a higher frequency of diffusely infiltrative gross appearance, particularly in combination.

Neural Invasion is a Significant Contributor to Peritoneal Recurrence in Signet Ring Cell Gastric Carcinoma.

Gastric signet ring cell carcinoma (SRC) has shown a favorable outcome in early stages but has a worse prognosis than non-SRC in advanced stages. However, the cause for this stage-dependent prognostic impact has not been determined. This study aimed to compare clinicopathologic features and recurrence patterns between gastric SRC and non-SRC in a cohort of Eastern patients. This study reviewed the prospectively collected data of 764 patients undergoing curative resection for gastric cancer from 2005 to 2008. The demographics, clinicopathologic characteristics, disease-specific survival (DSS) rate, and recurrence-free survival (RFS) rate of the patients were analyzed. The SRC patients (n=176) had a worse prognosis than the non-SRC patients (n=588), especially in stages T3 and T4. Peritoneal recurrence and the incidence of neural invasion (NI) were significantly increased in the SRC patients, albeit only in stages T3 and T4. In the T3 and T4 patients with NI, peritoneal recurrence occurred more frequently in SRC than in non-SRC (28.7% vs. 13.7%; p=0.001), but not in the T3 and T4 patients without NI. Only in the patients with NI, SRC led to a significantly shorter DSS (67.6 vs. 90.7months; p=0.008) and RFS (67.1 vs. 80.3months; p=0.036) than non-SRC. This report is the first to present the relationship between NI and peritoneal recurrence as the cause of stage-dependent prognoses for SRC. A better understanding of NI may lend insight into cancer spread and recurrence, especially in gastric SRC.

Prognostic Stratification of Advanced Gastric Signet Ring Cell Carcinoma by Clinicopathological Factors and GALNT14 Genotype.

Background: Gastric signet ring cell carcinoma (SRCC) is a histologic variant characterized by abundant intracytoplasmic mucin. Although it has been recognized that gastric adenocarcinoma harboring this feature has poorer prognosis, prognostic stratification within gastric SRCCs themselves has not been clearly defined. N-acetylgalactosaminyltransferase14 (GALNT14) genotype has been associated to poorer treatment outcome in mucinous type colorectal cancer. Here we incorporated clinicopathological factors and GALNT14 genotype to stratify prognosis of advanced gastric SRCC.Methods: Totally 347 gastric SRCC patients were retrospectively enrolled for GALNT14 genotyping. Clinicopathological factors were included for prognosis stratification.Results: Of the 347 patients, 341 underwent radical-intent gastrectomy and 6 received palliative gastrectomy. Kaplan-Meier analysis for overall survival indicated that Tumor-Node-Metastasis staging could only stratify the patients into three prognosis-distinguishable groups: group-1 (stage IA); group-2 (stage IB/IIA) and group-3 (the remaining Tumor-Node-Metastasis stages combined). Multivariate Cox-proportional hazard models for group-3 patients revealed GALNT14 “TT” genotype (P = 0.0482). Tumor size (P = 0.0009), node status (P <0.0001), metastasis status (P = 0.0096), and perineural invasion (P = 0.037) independently associated with unfavorable OS. Exploratory subgroup analysis showed that GALNT14”TT” genotype was associated with unfavorable OS in SRCCs with more aggressive phenotypes: node status >0 (P = 0.0013), lymphatic invasion (P = 0.021), vascular invasion (P = 0.0076) and perineural invasion (P = 0.0161). Accordingly, a scoring system was established capable of stratifying advanced gastric SRCC patients into three distinguishable prognostic subgroups.Conclusions: Gastric SRCC could be stratified into different prognostic subgroups by combining clinicopathological factors and GALNT14 genotype.

Prognosis of Signet Ring Cell Carcinoma of the Colon and Rectum and their Distinction of Mucinous Adenocarcinoma with Signet Ring Cells. A Comparative Study

Signet ring cell carcinoma (SRCC) of the colorectum is very rare, comprising between <1% and 2.4% cases of colorectal cancer. Patients' prognoses are poor. Several case reports had described as SRCC cases that are mucinous adenocarcinomas (MAC) with signet ring cells (SRC). In order to clearly delineate between MAC with SRC and SRCC, we performed a retrospective study at a national cancer referral center in which survival and clinicopathological characteristics between these two forms were comparedand also SRCC were characterized by immunohistochemistry. We retrieved 32 cases that had been classified as either SRCC or MAC with SRC subtypes. It was noted that SRCC patients presented at older ages, demonstrated more advanced clinical stages, lymphovascular invasion, lymph node metastases, and higher carcinoembrionic levels than MAC with SRC patients. Regarding SRCC immunophenotype, 50% showed loss of CDX2 expression, 33% were CK20 negative, 41.7% were CK7 positive, and 25% were negative for both CK7 and CK20. For the MAC with SRC and SRCC groups, the median disease-specific survival (DSS) was 46.1months (95% CI 36.9-55.25) and 22.4months (95% CI 5.1-39.7 [p=0.039]), respectively. The 3-year DSS was 80.7% and 28.6% (p=0.017) for the MAC and SRCC patients, respectively. Univariate and multivariate analyses showed that SRCC was associated with decreased survival. SRCC had several clinicopathological features that permitted differentiation of MAC with SRC from SRCC patients, who had a poor DSS. A differential diagnosis for metastatic gastric cancer is only possible with a good clinicopathological correlation.

Predictive factors for lymph node metastasis in early gastric cancer with signet ring cell histology: a meta-analysis.

Less invasive surgery is widely used in the treatment of early gastric cancer; however, no definite guidelines exist regarding indications for less invasive surgery to treat early gastric cancer with signet ring cell histology. The aim of this study was to identify risk factors for lymph node metastasis (LNM) in early signet ring cell carcinoma (SRC). An extensive search of PubMed, Embase and the Cochrane library was performed for pertinent articles involving early SRC and LNM. Eligible data (gender, depth of invasion, lymphovascular invasion, size, ulceration, macroscopic type and location) were extracted from the included studies and systematically reviewed via a meta-analysis. Review Manager version 5.3 was used to perform the data processing. The Newcastle-Ottawa Scale was utilized to evaluate the quality of the included articles. Fourteen studies were included in the final analysis. After meta-analysis, female gender, submucosal invasion, lymphovascular invasion and size >20 mm were associated with LNM in early SRC. Four variables were identified as risk factors for LNM in early SRC. The significance of the results of the present study should be further confirmed in more early SRC patients for future clinical use.

ERBB pathway alterations in advanced gastric signet-ring cell carcinoma (SRCC) and the implications for targeted therapy.

e15586 Background: Studies have shown that ERBB3 mutations are associated with poor clinical prognosis and ERBB3 targeted therapeutics can be effective against ERBB3 mutant-driven tumors. ERBB signal pathway plays a very important role in the initiation and progression of gastric cancer, however the ERBB2 expression and mutation rate is relative low especially in gastric SRCC. Thus, ERBB3 might be a promising target for the treatment in SRCC patients. The aim of this study is to speculate the prognostic and targeted therapy value in gastric SRCC by evaluating the mutation rate and type of ERBB3. Methods: 92 patients with histological diagnosis of advanced gastric SRCC were retrospectively selected. ERBB3 mutation was evaluated by next generation sequencing from formalin-fixed paraffin-embedded (FFPE) samples. ERBB2 expression was tested by immunohistochemistry. Correlations between ERBB2/3 status and clinical pathologic characteristics and overall survival (OS) were performed. Results: All of the 92 patients were diagnosed as local advanced or metastatic gastric SRCC (92.4% were stage III, 7.6% were stage IV). All the patients received 5-FU-based first-line chemotherapy. 14 out of all 92 patients were ERBB3 mutated SRCC, in which only 2 samples were ERBB2 positive. 12 of all the 14 mutations were in the extracellular domain, 2 were in the transmembrane region. There was no correlation between ERBB3 mutation and serosa invasion (P = 0.389) or lymph node metastasis (P = 1.000). The median OS was 20.5 months (95% CI = 10.05to 30.95 months) for patients with ERBB3 mutation, and 19.0 months (95% CI = 15.54 to 22.46 months) for patients without ERBB3 mutation (P = 0.567). There was no difference in OS according to HER2 positive or negative in ERBB3 mutated patients (14.8 months vs 20.5 month, P = 0.374). Conclusions: Our study demonstrated 15.2% of gastric SRCC patients harboring ERBB3 mutation, providing a potential subgroup of gastric SRCC for targeted treatment on ERBB pathway. No difference of OS was observed, probably due to the relative small sample size and low ERBB2 positive rate in SRCC patients. Further investigation on ERBB3 is warranted to clarify mechanisms of ERBB pathway in gastric SRCC.

The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy.

e15609 Background: Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in SRCC patients. Methods: SRCC samples from 89 patients were stained by immunohistochemistry to evaluate PD-L1, PD-1, CD3+ T cells, and MSI. EBV was detected by DNA in-situ hybridization. Results: All 89 patients had advanced gastric SRCC (89.9% were stage III, 10.1% were stage IV). All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r = 0.363, p &lt; 0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. However, there was no association between the expression of PD-L1, PD-1 or MSI status to overall survival (OS). Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r = 0.256, p = 0.012) and MSI status (r = 0.208, p = 0.05). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p = 0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR = 0.68, 95% CI: 0.42-1.10, p = 0.116). Conclusions: CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer characteristics and immunotherapy markers of the gastric SRCC immune microenvironment may highlight targets for immunotherapy.

Prognosis and value of preoperative radiotherapy in locally advanced rectal signet-ring cell carcinoma

As well known, signet-ring cell carcinoma (SRCC) is a rare histological subtype of colorectal adenocarcinoma, which has been associated with poor prognosis and resistant to non-surgery therapy compared with common adenocarcinoma. In this study, we assessed the effect of preoperative radiotherapy (PRT) for locally advanced rectal SRCC in a large patient group from the Surveillance, Epidemiology, and End Results program (SEER, 1988–2011) database. SRCC was found in 0.9% (n = 622) rectal cancer (RC) patients in our study. In the PRT setting, SRCC had significantly worse cancer-specific survival than mucinous adenocarcinoma and nonmucinous adenocarcinoma patients (log-rank, P < 0.001). In terms of SRCC, stage III RC patients benefited from PRT (log-rank, P < 0.001) while stage II did not (P = 0.095). The multivariate Cox proportional hazard model showed that PRT was an independent benefit factor in stage III rectal SRCC patients (HR, 0.611; 95% CI, 0.407–0.919; P = 0.018). In conclusion, SRCC was an independent predictor of poor prognosis in stage III RC patients, but not in stage II. In the PRT setting of locally advanced RC, SRCC patients had significantly worse prognosis. PRT was an independent prognostic factor associated with improved survival in stage III rectal SRCC.

The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy.

Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1(PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in 89 advanced SRCC patients. All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r=0.363, p<0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r=0.256, p=0.012) and MSI status (r=0.208, p=0.049). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p=0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR=0.68, 95% CI: 0.42-1.10, p=0.116). CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer immunotherapy markers of SRCC immune microenvironment may highlight targets for immunotherapy.

A potential pitfall in evaluating HER2 immunohistochemistry for gastric signet ring cell carcinomas

Signet ring cell carcinoma (SRC) more commonly presents as metastatic disease and renders patients to be considered for chemotherapy. While treatment options are limited overall, trastuzumab has been shown to be effective for HER2 positive SRC cases. The current algorithm for HER2 evaluation heavily relies on positive membrane-specific staining by immunohistochemistry (IHC), but several anecdotal reports have suggested that SRCs may be susceptible to misinterpretation due to non-specific staining in the marginated cytoplasm with/without nucleus. Results of two FDA-approved IHC methods of HER2 evaluation, Pathway and HercepTest, along with silver in situ hybridisation were interpreted retrospectively and compared in 155 primary SRC cases. IHC results were discrepant between the two assays in SRC even at the strongest IHC scores. Discordance indeed occurred due to dark, non-specific staining obscured by the unique SRC morphology. True HER2 positive SRC was identified in three cases (3/155, 1.9%). In this study, we demonstrate the importance of recognising potential discrepancy in interpreting HER2 status depending on the assay used. Understanding this possible pitfall may prevent unnecessary trastuzumab in SRC patients.

Signet ring cell carcinoma of resectable metastatic colorectal cancer has rare surgical value.

Signet ring cell carcinoma (SRCC) is a uniquely separated subgroup in metastatic colorectal cancer (mCRC). The aims are to investigate the value of resection in patients with resectable metastatic signet ring cell colorectal cancer. Patients with mCRC who underwent resection in Surveillance, Epidemiology, and End Results database during 1998-2010 were retrospectively analyzed. Kaplan-Meier and COX models were used to analyze the differences in the survival. Logistic regression models were used to evaluate the relationship between SRCC and other clinicopathological factors. Among the 3,568 patients, 94 (2.63%) patients had SRCC. The median survival time of patients with SRCC and non-SRCC were 17 and 29 months, respectively (P < 0.001). Multivariate analysis indicated that SRCC was an independent prognostic factor for poor overall survival. Logistic regression model based on variables identified by univariate analysis indicated that younger age (≤50 years old) (P = 0.005), female (P < 0.001), location in colon (P = 0.012), and N positive status (P = 0.003) were independent variables correlated with the SRCC subgroup. SRCC had a dramatically higher invalid surgical outcome rate than non-SRCC (P = 0.001). SRCC patients might benefit little from the resection of primary and metastatic lesions with a high rate of undergoing invalid operations. J. Surg. Oncol. 2016;114:1004-1008. © 2016 Wiley Periodicals, Inc.

Distribution of Lgr5-positive cancer cells in intramucosal gastric signet-ring cell carcinoma.

Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a putative intestinal stem cell marker that is also expressed in various tumors. To analyze its pathological characteristics in mucosal gastric signet-ring cell carcinoma (SRCC), we investigated Lgr5 expression in 35 intramucosal gastric SRCC patients using RNAscope, a newly developed RNA in situ hybridization technique. Lgr5 expression in individual tumor cells was scored semi-quantitatively from 0 to 400. Ki67 was also examined by immunohistochemistry, with a linear arrangement of Ki67-expressing cells present in 20 of 35 cases. This area of Ki67-expressing cells was topographically divided into upper, middle, and lower regions. All cases with linear Ki67 expression patterns also had Lgr5-positive cells arranged in a linear fashion in the lower area-which was distinct from the area of high Ki67 expression. The rate of Ki67 positivity in Lgr5-positive cells was significantly lower than that of Lgr5-negative cells in areas of high Ki67 expression. In intramucosal SRCC, the low mitotic activity of Lgr5-positive cells suggests that they may represent cancer stem cells as seen in other types of stomach carcinomas. Intramucosal SRCC may therefore contain stem cells expressing Lgr5 in the lower area of the lamina propria, akin to normal gastric pyloric mucosa.

Anaplastic lymphoma kinase (ALK) gene alteration in gastric signet ring cell carcinoma.

This study was aimed to investigating the frequency of Anaplastic lymphoma kinase (ALK) alterations in patients with gastric signet ring cell carcinoma (SRC) and the correlations between ALK alterations and the clinical-pathological features. The expression of ALK protein was first determined in paraffin-embedded tissue specimens (FFPE) from 177 pathologically confirmed SRC patients by Ventana Immunohistochemistry (IHC). Then patients with ALK positive detected by IHC were assayed in ALK rearrangement by Fluorescence in Situ Hybridization (FISH). We assessed 4 of 177 cases (2.3%) as positive by IHC. 3 of the 4 patients had T4 tumors and positive nodal status, and 1 of them had metastasis. All of them were HER2 negative. All of the 4 patients were positive for ALK rearrangement using the standard criteria of FISH. Our analysis showed that about 2.3% of Chineses SRC patients treated in our hospital were ALK positive. Ventana IHC and FISH were both of the reliable approaches in SRC patients. Patients with ALK positive seemed to have deep infiltrated and positive lymph nodes and HER2 negative.