Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer.

BACKGROUND: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer . METHODS: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction. RESULTS: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78). CONCLUSIONS: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention.

Microsatellite Instability-high Signet Ring Cell Carcinoma of the Colon Treated With Immunotherapy: Report of a Case.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are attracting increasing attention as a novel and potentially curative therapy for microsatellite instability-high (MSI-H) colorectal cancer (CRC). CASE REPORT: An 80-year-old female visited our hospital with complaints of lower abdominal pain due to bowel obstruction caused by descending colon cancer. After 1 month of metallic stent detention, she underwent radical surgery, although laparotomy showed broad peritoneal dissemination. Based on the genetic finding of MSI-H status, pembrolizumab therapy was administered in two cycles. Unfortunately, the therapy was ineffective, and the patient died after being discharged 5 months after surgery. CONCLUSION: The findings in this case of MSI-H CRC with a poor response to an ICI suggest the importance of confirming HLA status, including beta-2-microglobulin and HLA expression, before starting ICI therapy in cases of MSI-H CRC.

Clinicopathologic significance of Her-2 and P53 expressions in gastric cancer.

BACKGROUND: To detect the expression of HER-2 and P53 patients with gastric cancer and to analyze their correlation. METHODS: A total of 249 gastric cancer patients with complete clinical data who received surgical treatment from China-Japan Union Hospital of Jilin University were selected. The expression of Her-2 and P53 were detected by immunohistochemistry using the streptavidin-biotin-peroxidase method. The correlations between HER-2 and P53 in gastric cancer were analyzed. RESULTS: The positive rate of Her-2 and P53 expression was 37.3% (93/249) and 100% in all the specimens, respectively. The intensity of Her-2 expression was significantly different in patients with different degrees of gastric cancer cell differentiation (P = 0.012). Meanwhile, the expression of her-2 was closely related to whether the pathological type of gastric cancer was a signet-ring cell carcinoma (P = 0.022). Different percentage of positive P53 expression was closely related to the grade of tumor differentiation (P = 0.035) and positive Ki67 expression (P = 0.001). There was a significant positive correlation between HER-2 and P53 expression in gastric cancer (P = 0.003). These findings suggest that HER-2 and P53 have synergistic effects in gastric cancer. CONCLUSION: Her-2 and P53 are important markers for invasion and metastasis of gastric cancer. Combined detection of P53 and Her-2 expression in gastric cancer tissue can be used to assess prognosis and screen cancer patients at high risk of metastasis.

Novel Criteria for Intratumoral Budding with Prognostic Relevance for Colon Cancer and Its Histological Subtypes.

Peritumoral budding and intratumoral budding (ITB) are important prognostic factors for colorectal cancer patients. Scientists worldwide have investigated the role of budding in tumor progression and its prognosis, but guidelines for reliably identifying tumor buds based on morphology are lacking. In this study, next-generation tissue microarray (ngTMA®) construction was used for tumor bud evaluation, and highly detailed rule-out annotation was used for tumor definition in pancytokeratin-stained tissue sections. Initially, tissues of 245 colon cancer patients were evaluated with high interobserver reliability, and a concordance of 96% was achieved. It was shown that high ITB scores were associated with poor distant metastasis-free survival (p = 0.006 with a cut-off of ≥10 buds). This cut-off was defined as the best maximum value from one of two/three ngTMA® cores (0.6 mm diameter). ITB in 30 cases of mucinous, medullary, and signet ring cell carcinoma was analyzed for the subsequent determination of differences in tumor bud analyses between those subtypes. In conclusion, blinded randomized punched cores in the tumor center can be useful for ITB detection. It can be assumed that this method is suitable for its adoption in clinical routines.

Transcriptome Analysis and the Prognostic Role of NUDC in Diffuse and Intestinal Gastric Cancer.

INTRODUCTION: There have been few studies about gene differences between patients with diffuse-type gastric cancer and those with intestinal-type gastric cancer. The aim of this study was to compare the transcriptomes of signet ring cell gastric cancer (worst prognosis in diffuse-type) and well-differentiated gastric cancer (best prognosis in intestinal-type); NUDC was identified, and its prognostic role was studied. MATERIALS AND METHODS: We performed next-generation sequencing with 5 well-differentiated gastric cancers and 3 of signet ring cell gastric cancer surgical samples. We performed gene enrichment and functional annotation analysis using the Database for Annotation, Visualization and Integrated Discovery bioinformatics resources. Immunohistochemistry was used to validate NUDC expression. RESULTS: Overall, 900 genes showed significantly higher expression, 644 genes showed lower expression in signet ring cell gastric cancer than in well-differentiated gastric cancers, and there was a large difference in adhesion, vascular development, and cell-to-cell junction components between the 2 subtypes. We performed variant analysis and found 52 variants and 30 cancer driver genes, including NUDC. We analyzed NUDC expression in gastric cancer tissue and its relationship with prognosis. Cox proportional hazard analysis identified T stage, N stage, and NUDC expression as independent risk factors for survival (P < 0.05). The overall survival of the NUDC-positive group was significantly higher (53.2 ± 0.92 months) than that of the NUDC-negative group (44.6 ± 3.7 months) (P = 0.001) in Kaplan-Meier survival analysis. CONCLUSION: We found 30 cancer driver gene candidates and found that the NUDC-positive group showed significantly better survival than the NUDC-negative group via variant analysis.

Proteomic Profiling of Gastric Signet Ring Cell Carcinoma Tissues Reveals Characteristic Changes of the Complement Cascade Pathway.

Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared with adenocarcinomas (ACs). The lack of a systematic molecular overview of this disease has led to slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumors and adjacent tissues, including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate the cellular heterogeneity of the tissues. The proteomes of tissues were profiled by data-independent acquisition (DIA) mass spectrometry (MS). Based on the over 6000 proteins quantified, univariate analysis and pathway enrichment revealed that some proteins and pathways demonstrated differences between SRCC and ACs. Importantly, the upregulation of a majority of complement-related proteins was notable for SRCC but not for ACs. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, and the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to establish appropriate cell models for gastric SRCC through proteomic comparison of the 15 gastric cell lines and gastric tumors. The predictions of a supervised classifier suggested that none of these gastric cell lines qualified to mimic SRCC. This study discovered that the complement cascade is activated at a higher level in gastric SRCC than in ACs.

Livedoid cutaneous metastasis of signet-ring cell gastric carcinoma.

Cutaneous metastasis of gastric cancer is extremely rare. Nodular forms are more common and inflammatory forms are exceptionally encountered. Herein, we report a case of inflammatory cutaneous metastasis of signet-ring cell gastric cancer (poorly cohesive gastric carcinoma with signet-ring cell component) masquerading as livedo reticularis. To our knowledge, such a clinical presentation of cutaneous metastasis has not been reported for gastric cancer. It is imperative to preserve a high index of clinical suspicion for diagnosing cutaneous metastases. Our case highlights the importance of obtaining a skin biopsy in patients with a known history of internal malignancy. Bizarre, newly erupting, evolving, persistent, or treatment-refractory dermatologic lesions (such as nodules, ulcers, erythematous, reticular, or livedoid patches) might be clues for an underlying internal malignancy and require prompt histopathological sampling. Personal medical history, histopathological examination, and immunohistochemical profiling are equally important in distinguishing primary cutaneous carcinomas from secondary metastatic deposits. Early recognition of a cutaneous metastasis might enable appropriate staging and timely intervention, thereby prolonging survival.

NAD(P)-dependent steroid dehydrogenase-like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics.

BACKGROUND: Gastric cancer (GC) is the third most common cause of cancer deaths worldwide. In the present study, we aimed to identify novel GC biomarkers by integrating isobaric tags of relative and absolute quantitation (iTRAQ) for aberrantly expressed proteins in GC patients. METHODS: Using stable isotope tags, we labeled an initial discovery group comprising four paired gastric cancer and adjacent gastric tissue samples, and subjected them to LC-ESI-MS/MS. We used a validation set comprising 129 paired gastric cancer and adjacent gastric tissues from patients and benign healthy controls to validate the candidate targets. RESULTS: We identified two proteins, NAD(P)-dependent steroid dehydrogenase-like (NSDHL) and neutral cholesterol ester hydrolase 1 (NCEH1), that were significantly overexpressed in GC tissues. The sensitivity and specificity of NSDHL were 80.6% and 74.4%, respectively, in GC compared with a sensitivity of 25.6% in adjacent tissues and 24% in benign healthy controls. The area under the ROC curve (AUC) for NSDHL was 0.810 for GC detection. Overexpression of NSDHL in GC was significantly correlated with local tumor invasion. The sensitivity and specificity of NCEH1 were 77.5% and 73.6%, respectively, in GC compared with a sensitivity of 26.4% in adjacent tissues and 20% in benign controls. The AUC for NSDHL was 0.792. Overexpression of NCEH1 was significantly associated with tumor histological classification and local invasion. Moreover, a combined analysis of NSDHL and NCEH1 achieved a sensitivity and specificity of 85.7% and 83%, respectively, and the AUC was 0.872. The combined analysis of NSDHL and NCEH1 was significantly correlated with histological grade and TNM Ⅱ-Ⅳ staging. CONCLUSIONS: iTRAQ-labeled quantitative proteomics represents a powerful method to identify novel cancer biomarkers. The present study identified NSDHL and NCEH1 as useful biomarkers for screening, diagnosis, and prognosis of patients with gastric cancer.

Correlation of PRL3 expression with colorectal cancer progression.

OBJECTIVES: To evaluate the relationship between phosphatase of regenerating liver 3 (PRL3) expression and clinical outcome in colorectal cancer (CRC). BACKGROUND: PRL3, a protein tyrosine phosphatase functions as one of the key regulatory enzymes of various signal transduction pathways. PRL3 is highly expressed in a majority of cancers and is a novel potential therapeutic target. METHODS: PRL3 expression was evaluated by immunohistochemistry in 167 patients with CRC, 37 patients with no disease, and 26 patients with metastatic CRC (mCRC). Phosphorylated Akt at serine 473 (p-Akt S473) expression was also evaluated by immunohistochemistry in mCRC patients. RESULTS: High expression of PRL3 was correlated with CRC progression, and every one unit increase in PRL3 level contributed to an increase in the rate of death by 1%-1.7%. PRL3 expression was significantly higher in liver metastases compared with primary tumors and showed a significant positive correlation with the expression level of p-Akt S473. CONCLUSION: PRL3 expression levels associated with CRC progression and metastasis, and positively correlated with activated Akt level in mCRC. Together, these findings indicated that PRL3 might be a potential marker for increased risk of CRC-specific tumor burden and identify PRL3 as an attractive therapeutic target for mCRC treatment.

Is there any relationship between Helicobacter pylori infection and human epidermal growth factor receptor 2 expression in gastric cancer?

PURPOSE: Helicobacter pylori(HP) is a significant causative agent of gastric cancer (GC). However, the underlying mechanisms involved in its pathogenesis and association with oncoproteins are unclear. The aim of the present study was to evaluate the relationship between HP infection and human epidermal growth factor receptor 2 (HER2) expression in GC patients. MATERIALS AND METHODS: Surgery (173) or endoscopic biopsy (35) specimen of 208 patients diagnosed with GC was evaluated for the presence of HER2 and HP. HER2 expression was assessed by fluorescence in situ hybridization (FISH) method, whereas HP status was evaluated histologically. Giemsa stain was used to identify HP status, in case HP could not be recognized in routine H and E-stained sections despite careful examination. RESULTS: The median age was 63 years (27-91), and most patients were male (male/female: 149/59). Of all the 208 patients, HP was positive in 87 (41.8%) and negative in 121 (58.2%) patients. FISH positivity for HER2 was observed in 41 (19.7%) patients, whereas FISH negativity was observed in 167 (80.3%) patients. According to the Chi-square test, patient distribution was 21 in HER2-positive HP-negative group, 20 in HER2-positive HP-positive group, 100 in HER2-negative HP-negative group, and 67 in HER2-negative HP-positive group. No correlation was found between HP and HER2 status (P = 0.314). HP positivity had significant effect on median overall survival (27.4 vs. 12.9 months, P = 0.046). CONCLUSIONS: Our results suggest that there is no relationship between HP infection and HER2 status in patients with GC.

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

Low metabolic activity in primary gastric adenocarcinoma is associated with resistance to chemoradiation and the presence of signet ring cells.

PURPOSES: Preoperative chemoradiation is a potential treatment option for localized gastric adenocarcinoma (GAC). Currently, the response to chemoradiation cannot be predicted. We analyzed the pretreatment maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) on positron emission tomography/computed tomography as potential predictors of the response to chemoradiation. METHODS: We analyzed the SUVmax and TLG data from 59 GAC patients who received preoperative chemoradiation. We used logistic regression models to predict a pathologic complete response (pCR) and Kaplan-Meier curves to determine overall survival among patients with high and low SUVmax or TLG. RESULTS: Twenty-nine patients (49%) had Siewert type III adenocarcinoma and 30 (51%) had tumors located in the lower stomach. Forty-one patients had poorly differentiated GAC, and 26 had signet ring cells. The median SUVmax was 7.3 (0-28.2) and the median TLG was 56.6 (0-1881.5). Patients with signet ring cells had a low pCR rate, as well as a low SUVmax and TLG. In the multivariable logistic regression model, high SUVmax was a predictor of pCR (odds ratio = 11.1, 95% confidence interval = 2.12-50.0, p = 0.004). Overall survival was not associated with the SUVmax (log-rank p = 0.69) or TLG (log-rank p = 0.85) CONCLUSION: A high SUVmax was associated with sensitivity to chemoradiation and pCR in GAC, and signet ring cells seemed to confer resistance.

ACTH-Cell Pituitary Adenoma With Signet Ring Cells: A Rare Case Report and Review of The Literature.

Here, we present a case of pituitary adenoma producing adrenocorticotropic hormone (ACTH) in a 19-year-old woman. The patient was admitted to neurosurgery clinic because of a headache and decreased visual acuity. Transsphenoidal resection was performed. Microscopic examination of the tumor revealed signet-ring-like cell areas intermixed with conventional pituitary adenoma cells. Both populations of tumor cells showed immunoreactivity for chromogranin, synaptophysin, and ACTH. To date, there have been 3 reports of pituitary adenoma with signet-ring-like changes. To our knowledge, this is the first case of ACTH-secreting pituitary adenoma with signet-ring-like cell changes. The clinical reflection of signet cells in pituitary adenoma is unclear. Accumulation of the similar cases and investigation of molecular background of them may lighten the importance of this morphologic variance.

Association of the tumour stroma percentage in the preoperative biopsies with lymph node metastasis in colorectal cancer.

BACKGROUND: Preoperative prediction of lymph node (LN) status is integral to determining the most appropriate treatment strategy for colorectal cancer (CRC). This study aimed to develop and validate a nomogram to predict LN metastasis in CRC preoperatively. METHODS: A total of 530 patients were enrolled and divided into training and validation cohorts. The tumour stroma percentage (TSP) of the preoperative biopsies was assessed. The risk factors for LN metastasis were selected, and a nomogram was constructed subsequently. The performance of the nomogram was assessed by using the AUROC and the calibration curve, and then validated in the validation cohort. RESULTS: High TSP was significantly associated with LN metastasis in both the training and validation cohorts. Computed tomography (CT)-reported T stage, CT-reported LN status, preoperative tumour differentiation, carcinoembryonic antigen, carbohydrate antigen 19-9 and TSP were independent predictors of LN metastasis in CRC. A nomogram incorporating the six predictors was constructed. The nomogram yielded good discrimination and calibration, with an AUROC of 0.846 (95% CI: 0.807-0.886) and 0.809 (95% CI: 0.745-0.872) in the training and validation cohorts, respectively. CONCLUSIONS: Assessment of TSP in the preoperative biopsies provided additional information about the LN status. The nomogram was useful for tailored therapy in CRC preoperatively.

High SLC17A9 expression correlates with poor survival in gastric carcinoma.

Aim: To elucidate the clinicopathological significance and prognostic value of SLC17A9 expression in gastric carcinoma (GC). Methods: SLC17A9 mRNA level and its relationship with TP53 mutation was analyzed. SLC17A9 protein expression was examined by immunohistochemistry in 161 patients. Results: SLC17A9 mRNA and protein expression were higher in GC tissues than in adjacent normal tissues (p < 0.01). SLC17A9 mRNA expression was higher in GC tissues having mutated TP53 than in tissues with wild-type TP53 (p < 0.001). High SLC17A9 expression was also significantly associated with poor overall survival and recurrence-free survival and was also found to be an independent prognostic factor for long-term survival in GC patients.Conclusion: Our results show that SLC17A9 may serve as a potential prognostic biomarker in GC patients.

Tissue Expression of Melanoma-associated Antigen A6 and Clinical Characteristics of Gastric Cancer.

BACKGROUND: Gastric cancer (GC) exhibits heterogeneous clinical and molecular features, requiring the development of new biomarkers to further understand this disease. Our transcriptomic analysis detected overexpression of melanoma-associated antigen A6 (MAGEA6) in metastatic GC, leading us to determine the clinical significance of MAGEA6 in GC. MATERIALS AND METHODS: Fourteen GC cell lines and 230 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. Polymerase chain reaction array analysis was performed to identify coordinately expressed cancer-related genes, and immunohistochemistry (IHC) was used to detected MAGEA6 expression in situ. RESULTS: MAGEA6 mRNA levels were positively correlated with the expression of matrix metallopeptidase 9 mRNA. MAGEA6 mRNA levels were higher in GC tissues compared with those in normal adjacent tissues. Patients with high MAGEA6 expression had significantly worse prognosis. MAGEA6 protein levels in primary lesions predicted the likelihood of recurrence. CONCLUSION: Overexpression of MAGEA6 in GC tissues represents a promising biomarker for assessing the malignant phenotype of GC.

Genomic alterations in signet ring and mucinous patterned colorectal carcinoma.

BACKGROUND: The genetic alterations (GAs) in two specific histological subtypes of colorectal cancer (CRC), signet ring cell colorectal carcinoma (SRC) and mucinous colorectal carcinoma (MC), are not well known. In the present study, we employed next-generation sequencing to perform genetic profiling of SRC and MC, and compared the spectrum of GAs with the alterations found in conventional type colorectal cancer (CON). MATERIALS AND METHODS: We selected 46 CRCs comprising 17 SRCs and mucinous carcinoma with signet ring cell component (SRCCs), 17 MCs, and 12 CONs with microsatellite stability or microsatellite instability-low. Deep sequencing was performed using a targeted cancer panel composed of 171 cancer-related genes. SMAD4 protein expression was evaluated by immunohistochemical staining. RESULTS: We detected 108 mutations in 18 different genes. Overall, 2.34 GAs were detected per tumor (range, 0-14). The overall frequency of GA and alteration in targetable genes was less prevalent in SRC/SRCC compared to the frequency of alteration in MC/CON (p = 0.040 and p < 0.001, respectively). The GA profile of SRC/SRCC included TP53 (8/17, 47.1%), SMAD4 (5/17, 29.4%), KRAS (4/17.23.5%), APC (4/17.23.5%), PIK3CA, ATM, BRAF, and PIK3R1 (1/17, 5.9%, each). KRAS mutation was significantly less prevalent in SRC/SRCC compared to the number of KRAS mutations in MC (12/17, 70.6%) and CON (9/12, 75.0%) (p = 0.015 and 0.01, respectively). Compared to the 152 non-hypermutated CONs from TCGA database, SMAD4 alteration was predominant in SRC/SRCC (p = 0.045) with aberrant loss of SMAD4 expression (13/17, 76.5%) compared to the SMAD4 alterations in CON (5/15, 33.3%) (p = 0.031). Accordingly, KRAS (12/17, 70.6%), APC (6/17, 35.3%), SMAD4, TP53 (4/17, 23.5%, each), PIK3CA (3/17, 17.6%), AKT1, ATM, BRAF, EGFR, and EZH2 (1/17, 5.9%, each) were altered in MC. APC and TP53 mutations were less frequent in MC compared to those in TCGA-CON (p < 0.001 and 0.003, respectively) whereas KRAS mutation was prevalent (p = 0.041). CONCLUSION: Alterations of known cancer associated genes and targetable genes in SRC/SRCC are infrequent. The profile of GAs in SRC/SRCC and MC differs from the GA profile of CON. Specifically, SMAD4 mutation and loss of SMAD4 expression is frequently found in SRC/SRCC. The genetic profiles revealed in the present study may aid in developing precision medicine for CRC treatment based on histological subtype.

Signet ring cell mesothelioma; A diagnostic challenge.

Signet ring cell mesothelioma is a rare variant of epithelioid mesothelioma with limited cases published. It has a male predilection and most commonly occurs on pleura; it can also arise in the peritoneal cavity. The signet ring cell morphology can pose a challenge leading to a potential diagnostic error. A variety of benign and malignant diseases, including reactive histiocytic hyperplasia, adenocarcinoma, melanoma, and lymphoma with signet ring cell morphology should be considered in the differential diagnosis. In signet ring cell mesothelioma work up, mucin stains are of limited value. Even though immunohistochemistry is routinely used in mesothelioma diagnosis, there is no sole specific mesothelial marker. Hence, a panel of mesothelial and epithelial markers are used; these should be interpreted with caution especially in this variant. Electron microscopy and genetic testing can be very helpful in distinguishing signet ring cell mesothelioma from its mimickers.