Is neoadjuvant chemotherapy followed by surgery the appropriate treatment for esophagogastric signet ring cell carcinomas? A systematic review and meta-analysis.

Background: The impact of neoadjuvant chemotherapy (nCTX) on survival and tumor response in patients with esophagogastric signet ring cell carcinoma (SRCC) is still controversial. Methods: Two independent reviewers performed a systematic literature search in Medline, CENTRAL, and Web of Science including prospective and retrospective two-arm non-randomized and randomized controlled studies (RCTs). Data was extracted on overall survival (OS) and tumor regression in resected esophagogastric SRCC patients with or without nCTX. Survival data was analyzed using published hazard ratios (HR) if available or determined it from other survival data or survival curves. OS and histopathological response rates by type of tumor (SRCC vs. non-SRCC) were also investigated. Results: Out of 559 studies, ten (1 RCT, 9 non-RCTs) were included in this meta-analysis (PROSPERO CRD42022298743) investigating 3,653 patients in total. The four studies investigating survival in SRCC patients treated with nCTX + surgery vs. surgery alone showed no survival benefit for neither intervention, but heterogeneity was considerable (HR, 1.01; 95% CI, 0.61-1.67; p = 0.98; I2 = 89%). In patients treated by nCTX + surgery SRCC patients showed worse survival (HR, 1.45; 95% CI, 1.21-1.74; p < 0.01) and lower rate of major histopathological response than non-SRCC patients (OR, 2.47; 95% CI, 1.78-3.44; p < 0.01). Conclusion: The current meta-analysis could not demonstrate beneficial effects of nCTX for SRCC patients. Histopathological response to and survival benefits of non-taxane-based nCTX seem to be lower in comparison to non-SRC esophagogastric cancer. However, certainty of evidence is low due to the scarcity of high-quality trials. Further research is necessary to determine optimal treatment for SRCC patients. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022298743).

Survival impact of gastrectomy and chemotherapy on gastric signet ring-cell carcinoma with different metastatic lesions: A population-based study.

BACKGROUND: A comprehensive understanding of gastric signet ring cell carcinoma (SRCC) is limited. The aim of our study was to analyze metastatic patterns of gastric SRCC and evaluate impacts of gastrectomy and chemotherapy for metastatic gastric SRCC. METHODS: We obtained data of gastric cancer patients between 2010 and 2017 in the Surveillance, Epidemiology, and End Results database. Chi-square tests were used to compare data significance. Kaplan-Meier, Cox proportional hazards regression and Fine-Gray competing risk analysis were used to analyze the difference in the overall survival (OS) and cancer-specific survival (CSS). Propensity-score matching was used to adjust numerical difference. RESULTS: Among 36,459 eligible gastric cancer patients, 6264 (17.2 %) were SRCC patients. Bone metastasis was more common in SRCC patients than in non-SRCC patients. The multivariate analysis showed that chemotherapy (HR = 0.30, 95 %CI = 0.27-0.33, p < 0.01) and gastrectomy (HR = 0.51, 95 %CI = 0.45-0.59, p < 0.01) were protective prognostic factors in certain stage Ⅳ SRCC patients. For the effect of gastrectomy, survival benefits could be found in patients with liver metastasis. The gastrectomy was not associated with improved OS in patients with lung or multiple metastases. In subgroup analysis, SRCC patients with metastasis who received gastrectomy and chemotherapy (HR = 0.17, p < 0.01; HR = 0.03, p < 0.01) had a better OS and CSS than those who had chemotherapy only (HR = 0.30, p < 0.01; HR = 0.18, p < 0.01). CONCLUSION: Our study analyzed the unique metastatic patterns of gastric SRCC and recommended chemotherapy as the first choice in metastatic SRCC. For patients with liver metastasis, gastrectomy plus chemotherapy can be considered.

The percentages of signet-ring cells (SRCs) affects the prognosis after radical gastrectomy for advanced gastric cancer.

PURPOSE: Only recently has the percentage of signet-ring cells (SRCs) been shown to affect the prognosis following gastric cancer surgery. It is uncertain whether the SRC percentage has a role in tumour biology or prognosis of gastric signet-ring cell carcinoma (GSRCC). For this research, we assessed the effect of the SRC percentage on the clinicopathological and prognostic characteristics of gastric cancer (GC) tumours and created and verified a prognostic nomogram to assess the overall survival (OS) of GSRCC patients. METHODS: In our study, 1100 GC patients with signet-ring cell carcinoma (SRCC) at Zhejiang Cancer Hospital from December 2013 to December 2018 who underwent curative gastric cancer resection were retrospectively analysed. The patients were separated into two groups: those with SRCC (SRC percentage >50%; n = 157) and those with partial signet-ring cell carcinoma (PSRCC) (SRC percentage ≤50%; n = 943). We compared the clinicopathological characteristics of both groups. To estimate OS and determine correlations with the SRC percentage, the Kaplan-Meier method and log-rank test were used. To develop the prognostic nomogram, independent prognostic indicators for OS were identified using Cox regression analyses. Predictions were assessed using the calibration curve and C-index. RESULTS: Our research showed that there was no discernible difference in OS between the two groups. The preoperative CA242 level, pT stage, pN stage, age, nerve invasion, neoadjuvant chemotherapy, postoperative chemotherapy, and maximum tumour diameter were independent prognostic risk factors for OS for GC (all p < 0.05). However, for advanced GC, the SRC percentage (HR = 1.571, 95% CI 1.072-2.302, p = 0.020) was an independent prognostic factor of OS. Other independent prognostic risk factors were age, pT stage, pN stage, nerve invasion, tumour location, neoadjuvant chemotherapy, postoperative chemotherapy, preoperative CA50 level, and preoperative CEA level (all p < 0.05). On these bases, nomograms were constructed for GC and advanced GC, with C-indexes of 0.806 (95%CI 0.782-0.830) and 0.728 (95%CI 0.697-0.759), respectively. CONCLUSIONS: In cases of advanced gastric cancer, the SRC percentage served as a standalone prognostic indicator for OS. An effective tool for assessing the prognosis of GSRCC was offered by the nomogram.

Grayscale ultrasound feature typing of metastatic ovarian tumors, particularly signet-ring cell carcinoma.

Background: To describe grayscale ultrasound (US) features of metastatic ovarian tumors (MOTs) based on origin of the primary tumor in a large sample size study. Methods: This retrospective cross-sectional single-center study included 112 patients with 190 histopathologically confirmed MOTs. Among the patients, 102 collectively had 144 masses, which were detected via US. The clinical data and static US images of MOTs were collected. Results: The MOTs were mostly bilateral (78.9%) but had a lower rate of bilaterality when detected by US (55.6%). Breast cancer metastasis had the highest nondetection rate (69.6%), because its focal metastasis could only be recognized using histology or immunohistochemistry. The stomach was the most common origin of metastasis (45.3% and 50.7% detected via pathology and US, respectively). The US images were classified into three subtypes: multilocular solid (Type A), purely solid (Type B), and solid with several round or oval cysts (Type C). The MOTs that originated from the colon mostly belonged to Type A (65.1%) and closely mimicked primary epithelial ovarian tumor morphologically. The MOTs that originated from the stomach predominantly belonged to Types B (31.5%) and C (57.5%). Signet-ring cell carcinoma (SRCC) corresponded to Types B and C regardless of origin. Conclusions: The developed novel typing method provides more vivid images for classifying MOTs compared with existing typing methods. Given that no specific sonographic parameters have been established to distinguish MOTs from primary invasive ovarian tumors, these images may be helpful in diagnosing these masses.

Gastrointestinal metastatic signet ring cell breast cancer in young females: a case report.

Background: Signet ring cell carcinoma (SRCC) is characterized by strong invasiveness and rapid progression. It occurs mostly in young and middle-aged patients, and early patients may have no clinical symptoms. Gastric SRCC with breast cancer metastasis is relatively rare. It often presents challenges for clinicians and pathologists and may lead to an absolutely different therapeutic strategy. Case Description: In this paper, we report on a 37-year-old woman who was admitted to the hospital with a left breast mass discovered 5 days earlier, the mass was occasionally painful, and there was no skin swelling, skin depression, or other abnormalities. The initial diagnosis considered her to have a left breast tumor. The patient was previously healthy with no family history of tumor. Considering the possibility of malignant lesions, she underwent resection of the left breast tumor and surrounding tissue. Postoperative pathological findings suggested SRCC (left breast mass). Although the patient had no history of gastrointestinal tumors, considering that SRCC can also appear in the gastrointestinal tract and other organs. We performed gastroscopy on the patient, showed an ulcerative mass in the greater curvature of the gastric body, with irregular nodular uplift of the surrounding mucosa. The excised breast lesions were analyzed by immunohistochemistry, and the pathological result showed SRCC (left breast tumor). Combined with the results of immunohistochemistry, it was consistent with gastrointestinal metastasis. Through our multi-faceted differential diagnosis, the final diagnosis of the patient was clear, which not only bought time for the patient's subsequent treatment, but also avoided misdiagnosis and blind treatment due to the particularity and rarity of the case. Conclusions: Gastric cancer should be considered when breast tumors show SRCC without in situ lesion. Signet ring cell gastric cancer (occult) should be excluded even if the patient has no family history of gastric cancer. It is important to distinguish metastatic cancer from primary breast cancer to avoid misdiagnosis and blind treatment due to the particularity of the case, at which point an early recognition can be made and an optimal treatment plan can be chosen.

A case report of primary signet ring cell carcinoma of the lung: imaging study and literature review.

Signet ring cell carcinoma (SRCC) is a subtype of adenocarcinoma with characteristics of strong invasion and a poor prognosis. While it can occur in various organs, including the stomach, colon, esophagus, bladder, prostate, pancreas, and breast, primary lung SRCC is rare, and most SRCC found there are from gastrointestinal metastasis. Reports on primary lung SRCC are few and the aim of this study is to describe the imaging, histopathological, and immunohistochemical characteristics of a case of primary lung SRCC in our hospital. A 68-year-old female with no smoking history was admitted with recurrent cough, chest pain, and dyspnea of 2 months duration. Computed tomographic (CT) chest showed multiple solids nodules of different sizes and mass in the left upper lobe, lower lobe, and subpleural region. Multiple enlarged lymph nodes were seen in the mediastinum and left hilum. The aim of this paper is to improve the understanding of this tumor. A literature review identified 15 cases of primary lung SRCC with available CT imaging. Except for two patients with multiple ground glass nodules and multiple small nodules, the rest were solid, and ranged in size from 1.0 to 8 cm. Only one patient had a cavity in the solid lesion. Immunohistochemical stains for thyroid transcription factor-1 (TTF-1) (13/13) and CK7 (12/12) showed positive reaction in all cases evaluated, and napsin A (3/4) were also positive, while all cases including CK20 (12/12) and CDX2 (6/6) were negative.

Prognostic Value of Tumor Regression Grading in Patients Treated With Neoadjuvant Chemotherapy Plus Surgery for Gastric Cancer.

OBJECTIVE: To validate the prognostic value of tumor regression grading (TRG) and to explore the associated factors of TRG for advanced gastric cancer (AGC) with neoadjuvant chemotherapy (NACT) plus surgery. METHODS: Two hundred forty-nine AGC patients treated with NACT followed by gastrectomy at the Mayo Clinic, USA and the Fujian Medical University Union Hospital, China between January 2000 and December 2016 were enrolled in this study. Cox regression was used to identify covariates associated with overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to reveal factors predicting tumor regression grading. RESULTS: For patients with TRG 0-1, the 3- and 5-year OS rates were 85.2% and 74.5%, respectively, when compared to 56.1% and 44.1% in patients with TRG 2 and 28.2% and 23.0% in patients with TRG 3, respectively (p<0.001). TRGs were independent risk factors for OS. Similar findings were observed in RFS. Multivariable analysis revealed that an oxaliplatin-based regimen (p=0.017) was an independent predictor of TRG. The oxaliplatin-based regimen was superior to the nonoxaliplatin-based regimen for OS (38.4 months vs 19.5 months, respectively; p=0.01). Subgroup analyses by histological subtype indicated that the oxaliplatin-based regimen improved the OS in nonsignet ring cell carcinoma compared to the nonoxaliplatin-based regimen (53.7 months vs 19.5 months, respectively; p=0.011). However, similar findings were not observed in RFS. CONCLUSION: TRG was an independent factor of AGC treated with neoadjuvant chemotherapy plus surgery. Oxaliplatin-based neoadjuvant chemotherapy regimens improve tumor response and may have an overall survival benefit for patients with nonsignet ring cell carcinoma.

KRAS gene status in gastric signet-ring cell carcinoma patients and acts as biomarker of MEK inhibitor.

BACKGROUND: Signet-ring cell carcinoma (SRCC) is a specific subtype of stomach cancer with unique epidemiology. Here, we sought to explore the role of KRAS in SRCC. METHODS: KRAS status was studied both in The Cancer Genome Atlas (TCGA) and internal cohorts. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were performed in formalin-fixed and paraffin-embedded (FFPE) samples. We explored patients' survival and clinicopathological characteristics in terms of KRAS mutation and expression. We also explored KRAS status and drug response curve of MEK/mTOR inhibitors in SRCC cell lines. RESULTS: Patients with KRAS mutations and copy number variation (CNV) showed higher mRNA level compared to non-mutant cases (P=0.003 and P<0.001). In internal cohort, 15 samples harbored KRAS mutations. Survival analysis showed that these patients had significantly lower overall survival (OS) (P=0.048). We further analyzed 75 patients with sufficient FFPE samples. Eight patients showed KRAS mutations and one patient showed KRAS amplification. The median OS was 12.5 months for patients with KRAS mutation, and 19.5 months for patients without KRAS mutation (P=0.005). Positive expression of KRAS as shown by IHC was detected in majority of SRCC samples, which was higher than our intestinal cohort (28% vs. 12.6%, P=0.033). We further explored the correlation between KRAS status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored KRAS mutation, were hypersensitive to MEK and mTOR inhibitors than KRAS wide type cell lines KATO-III and NUGC-4. CONCLUSIONS: Our findings demonstrate that KRAS gene plays an important role in SRCC and reveals therapeutic potential of targeting tumors by inhibiting MEK and mTOR pathways.

Cytological markers for predicting ALK-positive pulmonary adenocarcinoma.

BACKGROUND: ALK gene rearrangement is an important class of gene mutations in pulmonary adenocarcinoma. ALK-positive pulmonary adenocarcinoma exhibits characteristic histological features, such as signet ring cell carcinoma (SRCC) and a mucinous cribriform structure. However, when insufficient histological specimens are obtained, ALK-positivity must be predicted based on cytological features. The purpose of this study was to clarify the cytological characteristics of ALK-positive pulmonary adenocarcinoma. METHODS: We compared the cytological findings of 16 ALK-positive cases with 40 ALK-negative cases. We examined various cytoplasmic features of SRCC, including the presence of pink, yellow, or orange mucin; green, vacuolar, or vesicular cytoplasm; and green globular cytoplasmic secretions. We also examined whether the SRCC cells exhibited a pattern of individually scattered cells, the formation of cell clusters, and formation of a mucinous cribriform pattern. RESULTS: A univariate analysis showed that significantly frequent cytological findings included pink mucin, green cytoplasm, vacuolar cytoplasm, vesicular cytoplasm, green globular cytoplasmic secretions, an individually scattered pattern, cluster formation, and a mucinous cribriform structure (all, P < .05). A stepwise multivariate logistic regression analysis identified three significant contributing factors: pink mucin (P = .03), vesicular cytoplasm (P = .06), and an individually scattered pattern (P = .01) of SRCC. If the specimens showed two or three of these features, the sensitivity and specificity were both 88% for the prediction of ALK-positive cancers. CONCLUSION: Three cytological features of SRCC (pink mucin, vesicular cytoplasm, and an individually scattered pattern) could be useful cytological markers for the prediction of ALK-positive pulmonary adenocarcinoma.

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

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Metastatic signet ring cell carcinoma of unknown primary origin: a case report and review of the literature.

In spite of the increasingly sophisticated diagnostic workup, detailed investigations fail to reveal a primary site of origin for about 3-5% of metastatic tumors. The most commonly reported subtype in cancer of unknown primary origin is adenocarcinoma. Signet ring cell carcinoma (SRCC) is a rare poorly differentiated aggressive subtype of adenocarcinoma that most commonly arise from the gastrointestinal tract. It usually presents late and is associated with poor prognosis. Treatment options remain limited to anecdotal reports. However, immunohistochemical studies can be useful in suggesting an origin and therefore may help guide investigations and treatment options. Here we present an unusual case of metastatic SRCC of unknown primary origin presenting as peritoneal carcinomatosis in a 73-year-old man. We also review the literature on metastatic SRCC of unknown primary origin and discuss the relevant findings. This work highlights the importance of collaboration between clinicians and pathologists as well as detailed histopathological, immunohistochemical, and molecular analyses which can help guide investigations and management options.

Exploring signet-ring cells in pregnant female.

INTRODUCTION: Primary signet-ring cell carcinoma (SRCC) of the colon and rectum are rare form, which present at an advanced stage and have poor prognosis. Different treatment policies of SRCC during different gestational age of pregnancy are explored from the literature. CASE STUDY: A 26-year-old young pregnant female with 10-week gestation presented with constipation and blood in stools and on per rectal examination a tender circumferential stricture was present 2 cm above the anal verge. Magnetic resonant imaging (MRI) pelvis of the patient revealed rectal thickening, the biopsy of which revealed characteristic appearance of "linitis plastica" and diagnosed as poorly differentiated adenocarcinoma with signet ring morphology with wide spread positivity for cytokeratin & p53. With this diagnosis, patient underwent medical termination of pregnancy (MTP). DISCUSSION: SRCC of the colon comprises about only 1% of all cases of colon cancer. When compared with other types of adenocarcinoma, patients with SRCC in the colon are younger and more likely to experience lymph node metastasis. Its incidence in pregnancy is estimated to be less than 0.1%. Certainly, any pregnant patient who reports rectal bleeding or has hemoccult positive stool on examination deserves careful evaluation to rule out cancer. The complex treatment of colorectal cancer in pregnancy is based on the gestational age of the fetus, tumor stage and need for emergent vs. elective management.