Signet-ring Cell Carcinoma Histology Research Articles

Comparative analysis of tumor biology and prognosis in mucinous and signet-ring cell colon cancers versus classical adenocarcinoma.

Background: Limited information is currently available on the natural history and prognosis of two distinct histological subtypes of adenocarcinoma (AC) in the colon: mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC). Therefore, the aim of this study is to examine the clinicopathological characteristics of colon MAC and SRCC, comparing them to classical AC, using a large cohort of cases from the United States. Methods: Patients diagnosed with colon AC, MAC, or SRCC from the SEER database between 2000 and 2018 were included in our study. Incidence trends, patient demographics, tumor characteristics, treatment, and survival were analyzed. Results: In our study, we analyzed a total of 310,813 patients with colon cancers, including 271,382 cases of classical AC, 34,750 cases of MAC, and 4,681 cases of SRCC. Over the study period, we observed a decline in the age-adjusted incidence rates of colon AC, MAC, and SRCC. Notably, the MAC and SRCC cohorts differed significantly from AC in terms of patient characteristics, tumor locations, and treatment patterns. Patients with MAC and SRCC had poorer survival outcomes compared to those with AC. Factors associated with worse survival included older age, male sex, poorly differentiated tumors, advanced stage, and the presence of MAC or SRCC histology. On the other hand, surgical intervention was associated with improved survival. Conclusion: Our study underscores the significance of recognizing the distinct features and outcomes associated with different histological subtypes of colon cancer. Further research is warranted to delve into the underlying biological traits that contribute to these differences and to develop more tailored treatment strategies.

Overexpression of AKR1B10 Predicts Poor Prognosis in Gastric Cancer Patients Undergoing Surgical Resection.

Aldo-keto reductase family 1 member B10 (AKR1B10) is associated with several cancers, but the prognostic role in gastric cancer (GC) remains unclear. We enrolled 359 GC patients who underwent a gastrectomy with D2 lymph node dissection. AKR1B10 expression was scored using an immunoreactive scoring system based on immunohistochemistry. Adjuvant chemotherapy with S-1 or oxaliplatin plus capecitabine was administered to pathological stage II or III disease patients. There were 117 (32.6%) and 242 (67.4%) patients with AKR1B10 overexpression and low expression, respectively. Patients overexpressing AKR1B10 had worse 5-year disease-free survival (DFS) and overall survival (OS) rates than those with low expression of AKR1B10. Pathological T3-T4 stage, pathological stage III, lymph node ratio ≥25%, and AKR1B10 overexpression were independent prognostic factors for worse DFS and OS in univariate and multivariate analyses. For 162 stage II or III patients who received adjuvant chemotherapy after surgical resection and 59 patients with signet ring cell carcinoma histology, AKR1B10 overexpression was also associated with inferior DFS and OS. AKR1B10 was not associated with clinical survival in stage I GC patients. In conclusion, AKR1B10 overexpression may be an independent prognostic factor for worse survival in GC patients who underwent gastrectomy with D2 lymph node dissection.

Outcomes of IBD-associated colorectal cancer and implications in early-onset colorectal cancer.

22 Background: Inflammatory bowel disease (IBD) increases the risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) mortality is on the rise. It has been postulated that CA-CRC may be contributing to the increasing prevalence of early-onset CRC (EOCRC) but supportive studies are currently lacking. Molecular and clinical differences between CA-CRC and sporadic-CRC (S-CRC) have been reported, however outcomes for CA-CRC remains unclear. Signet ring cell carcinoma (SRC) is a rare subtype of CRC which is seen at higher frequencies, along with mucinous histology, in both CA-CRC and EOCRC. In this study, we validate the association of SRC and mucinous (SRC/M) histology with CA-CRC and EOCRC, and utilize it to estimate the amount of EOCRC attributable to undiagnosed or subclinical IBD. Methods: A retrospective study was conducted using three independent mCRC patient datasets from MDACC. The mATTACC discovery cohort consisted of 32 IBD- and 425 S-mCRC patients enrolled in a prospective biomarker trial. Validation of tumor histology was completed with a tumor registry (n=1696), excluding the MSI-High samples, and a real-world evidence (RWE) cohort from MDACC containing 269 CA-mCRC and 29,596 S-mCRC patients, was used as our validation cohort. Results: In the mATTACC cohort SRC/M histology was found in 37.5% of CA-mCRC and 11.7% of S-mCRC, showing a strong association between SRC/M and CA-mCRC (OR = 4.54, 95% CI: 2.19-9.43). The RWE cohort confirmed the correlation of SRC/M with CA-mCRC (28.6%) relative to S-mCRC (11.4%) patients (OR = 3.13, 95%CI: 2.39-4.09). An association was found between SRC/M and EOCRC (OR = 1.35; 95% CI: 1.24-1.47). By comparing the prevalence of SRC/M in EOCRC and late-onset CRC and correcting by the proportion of CA-CRC cases with SRC/M histology, we estimate that between 8.28% to 10.15% of EOCRC may attributable to undiagnosed/subclinical IBD. Using the RWE cohort, median overall survival was determined to be lower for CA-mCRC (31m) relative to S-mCRC (39m; p=0.007), yielding a HR of 1.26 (95% CI: 1.06-1.48). CA-mCRC patients with EOCRC (25m) were also found to have significantly worse outcomes than S-mCRC patients (40m) with EOCRC (p=0.0005; HR = 1.61, 95%CI: 1.23-2.11). Within CA-mCRC, patients with SRC or SRC/M histology (21m) had decreased OS compared to mucinous histology (51m), indicating the poor prognosis of SRC in CA-mCRC (p=0.028; HR=0.53, 95% CI: 0.3-0.94). Conclusions: Tumor biology consistent with CA-CRC, including SRC/M histology, may be present in 8.3% – 10.2% of patients with EOCRC without a clinical diagnosis of IBD, and harbors worse outcomes. Although other confounding biology may be underlying this association, recognition of undiagnosed IBD in CRC patients, especially those with metastatic disease, is important as it may impact prognosis and treatment strategies for this high-risk patient population.

Wnt Signaling Shapes the Histologic Variation in Diffuse Gastric Cancer

Diffuse-type gastric cancer (GC) is currently subdivided into signet-ring cell carcinoma (SRCC) and non-SRCC, referred to as poorly cohesive carcinoma not otherwise specified (PCC-NOS). Although these subtypes are considered to be independent, they often coexist in the same tumors, raising a question of whether they clonally differ or not. To tackle this question, we established an experimental platform for human diffuse GC that enables accurate modeling of histologic subtypes. Seven patient-derived diffuse GC organoid lines were established, characterized by histopathologic analysis, in situ hybridization, and gene expression analysis. For genetic modeling of diffuse GC, we knocked out CDH1 and/or TP53 in human normal gastric organoids. Green fluorescent protein-labeled GC organoids were xenotransplanted into immune-deficient mice for invivo assessment. PCC-NOS organoids transformed into SRCC-like structures on removal of Wnt and R-spondin from the culture medium. This morphologic change paralleled downregulation of Wnt-target and gastric stem cell genes, including LGR5, and elevation of differentiation markers, such as KRT20 and MUCs. The association between Wnt target gene expression and histologic subtypes was confirmed in 3 patient-derived GC tissues. Invivo, single clone-derived organoids formed tumors that comprised 2 distinct histologic compartments, each corresponding to SRCC and PCC-NOS. The transition from PCC-NOS to SRCC histology reflected the abundance of surrounding R-spondin-expressing fibroblasts. SRCC and PCC-NOS were clonally identical, and their morphology was regulated by extracellular Wnt and R-spondin expression. Our results decoded how genetic mutations and the tumor environment shape pathohistologic and biologic phenotypes in human diffuse GCs.

827P - The molecular profiling and prognostic value of Chinese gastric signet ring cell carcinoma patients

BackgroundGastric cancer (GC) is one of the most common lethal malignancies worldwide. Signet ring cell carcinoma (SRCC) is a poorly differentiated gastric cancer. The molecular characteristics and prognostic of SRCC are not well studied. MethodsFormalin fixed paraffin embedded (FFPE) samples of 64 Chinese solid tumor patients were collected for next‐generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite stable (MSS) status and TMB (tumor mutational burden) were also acquired by an NGS algorithm. ResultsA total of 64 patients were identified as GC-SRCC through SRCC histology. The most frequently mutated genes were TP53(48%), CDH1(31%), ARID1A(14%), CDKN2A(9%), LRP1B(9%), KMT2D(6%), NF1(6%), ERBB2(9%) and GLI3(8%). Meanwhile, the copy numbers of FGFR2(14%), FGF3(8%), FGF19(8%), FGF4(8%), MYC(8%), CCND1(6%) and CDKN2A(9%) were frequently altered in SRCC.FGFR2 and 11q13 amplification is the first time reported in Chinese SRCC. Moreover, FGFR2 rearrangement (FGFR2/VTI1A and FGFR2/TACC2) was detected in 4% tumor samples. 34 cases had received chemotherapy, 4 cases had confirmed partial responses (PR); 14 cases had reached the stability of disease (SD). Noticeably, patients harboring gene rearrangement (N=9) were observed a much shorter overall survival time (OS) in comparison with patients without any gene rearrangement (N=14) (13.2 months vs 24.2 months, P<0.05). Additionally, patients with CDH1 mutation (N=9) showed a shorter OS than CDH1 wide type (N=25) (14.2 months vs 25.3 months, P=0.11), although the difference was not statistically significant. ConclusionsOur observation reveals the molecular characteristics of SRCC. Gene rearrangements might associate to shorter OS. FGFR2 and 11q13 region amplification were newly observed in SRCC. It might provide new possibilities for the treatment of SRCC. Due to the limitations of the number of samples, the results may require further research and validation. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Comprehensive molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon.

63 Background: Signet ring cell carcinoma (SRCC) is a rare variant of adenocarcinoma, accounting for about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however little is known about the underlying molecular characteristics. Herein, we aimed to characterize the molecular features of SRCCs, and to compare the molecular profile of SRCC to adenocarcinoma; further, we assessed the impact of tumor location on the molecular profile of SRCC. Methods: SRCCs were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry, and in-situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Chi-square and t-tests were used for comparative analyses. Results: A total of 8,500 CRC and 1,100 GC were screened for SRCC histology. Seventy-six SRCC were identified from the CRC cohort (&lt;1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%), KRAS (22%), RFN43 (16%), KMT2D (12%), KMT2C (11%), SMAD4 (10%) and BRAF (10%), while in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%), BAP1 (7%), PIK3CA (7%), ERBB2 (5%). When compared to non-SRCC histology (N=3522), CRC-SRCC (N=37) showed more frequently mutation in BRCA1 (11% vs 1%, P &lt; .001) and less mutation in APC (19% vs 78%, P &lt; .001), KRAS (22% vs 51%, P = .001) and TP53 (47% vs 73%, P = .001). Among GC cohort, SRCC (N=54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, and higher rate of amplification MYB compared to non-SRCC (N=540), although none of these differences were statistically significance. When we compared GC-SRCC vs. CRC-SRCC, only the mutation rate in APC (0% vs 25%) and KRAS (2% vs 22%) genes were significantly different (P &lt; .001). Conclusions: Our research is the first to comprehensively characterize the molecular features of SRCC. Our data suggest that SRCCs harbor similar molecular profile, regardless the tumor location. On the other hand, significant differences were observed between SRCCs and non-SRCC tumors, therefore tailored therapy should be provided to these patients.

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.

Sex Disparity in Gastric Cancer: Female Sex is a Poor Prognostic Factor for Advanced Gastric Cancer.

The overall incidence of gastric cancer (GC) is higher in males than females. Specifically, signet ring cell carcinoma (SRC) is more frequently observed in younger female patients. However, limited information focused on sex-specific differences in GC has been reported. The aim of our study was to analyze clinicopathological differences between sex groups to reveal sex disparities in GC. We retrospectively analyzed 4722 patients with GC who underwent gastrectomy (females: 1586 (33.6%); males: 3136 (66.4%), and analyzed clinicopathological features between these sex groups. The overall survival (OS) rate was investigated between the two sex groups, with special reference to the pathologic World Health Organization GC classifications. Immunohistochemistry staining of sex hormone receptors, including the estrogen receptor (ER)-α, ER-β, progesterone receptor, and androgen receptor, was performed according to sex and pathological classification. Female patients were significantly associated with a younger age, poorly differentiated adenocarcinoma, and SRC compared with males. Female patients showed a significantly poorer OS than male patients, especially among those with advanced GC (AGC) aged ≤45years. In females with AGC, those with SRC had a significantly poorer OS than those with other histologies. Moreover, the expression of ER-β was different between females and males with SRC. Females with GC were significantly younger and had a different SRC histology compared with males. Furthermore, females had significantly poorer prognostic factors among young patients with SRC. Thus, young female GC patients with SRC are a main target group in which to improve prognosis.

Gallbladder metastasis secondary to gastric cancer as a first site of recurrence presented with acute cholecystitis: Case report and literature review

Metastasis to the gallbladder from other malignancies is extremely rare and is related with a very poor prognosis. Malignant melanoma has been reported to be the most common origin of gallbladder metastasis. Although only eight cases of gallbladder metastasis originating from gastric cancer have been documented in the literature based on small series, of these cases, only one case with signet ring cell carcinoma histology has been reported previously. We report the case of a 58-year-old male with early-stage signet ring cell carcinoma of the stomach who presented with acute cholecystitis previously treated with curative gastrectomy. After laparoscopic cholecystectomy, the diagnosis of gallbladder metastasis with signet ring cell histology secondary to gastric cancer was made. To our knowledge, this is only the second case of signet ring cell carcinoma of the stomach metastasized to the gallbladder as a first site of recurrence. We suggest that for patients with gastric cancer who complain of the findings of acute cholecystitis or cholecystolithiasis, gallbladder metastasis from gastric cancer should be considered in the differential diagnosis.

Establishment and characterization of novel gastric signet-ring cell and non signet-ring cell poorly differentiated adenocarcinoma cell lines with low and high malignant potential

Poorly differentiated signet-ring cell carcinoma (SRCC) and non signet-ring cell carcinoma (NSRCC) are prevalent histological subtypes of gastric cancers with distinct morphological features. To date, however, the molecular basis of their growth, differentiation, and metastasis still remains unclear, because of the limitation of available cell lines. In the present study, we established novel SRCC and NSRCC cell lines (designated GPM-2 and GPM-1) derived from the ascites of two individual gastric cancer patients with peritoneal metastasis. Immunohistochemical and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that GPM-2 cells showed both gastric and intestinal differentiation phenotypes (E-cadherin+/MUC5AC+/MUC6+/Villin+), and formed xenografted tumors with typical SRCC histology in nude mice. In contrast, GPM-1 cells only weakly expressed differentiation markers, showing a phenotype of E-cadherin(low)+/MUC2-/MUC5AC-/Villin(low)+. Characteristically, GPM-2 cells were found to highly express both membrane-bound mucin (MUC1/MUC4) and secreted mucin glycoproteins (MUC5AC/MUC6), whose expression is regulated by an epigenetic mechanism such as histone acetylation. GPM-2 cells also secreted a large amount of sTn antigen into the culture medium. These mucin profiles of GPM-2 cells are distinct from those of conventional SRCC cell lines (KATO III and HSC-39), which preferentially express intestinal MUC2/MUC4 as well as sLe(x) and sLe(A) antigens. In addition, GPM-2 cells showed a slow growth rate, and a lower metastatic potential than GPM-1 cells. These results indicate that the cells of the new SRCC line, GPM-2 cells, are more differentiated and less aggressive than NSRCC-type GPM-1 cells, and would thus offer an excellent model for understanding the molecular mechanism underlying the growth, differentiation, and mucin production of an SRCC gastric cancer cell line.

Effect of signet-ring cell carcinoma histology on bladder cancer outcome.

275 Background: Signet-ring cell carcinoma (SRCC) of the urinary bladder is a rare entity. Recent case series of the condition showed inconsistent results. We used a population-based data set to compare the cancer specific survival of patients with signet-ring cell carcinoma vs. transitional cell carcinoma (TCC) of the urinary bladder. Methods: Signet-ring cell carcinoma of the urinary bladder and transitional carcinoma of the urinary bladder were identified in the Surveillance, Epidemiology and End Results program (2001 to 2004). Demographic and pathological characteristics at diagnosis were compared. Differences in cancer specific survival were compared with univariate and multivariate Cox regression analysis. Results: A total of 103 SRCC cases were present in the database from 2001 to 2004. In that time 14,648 cases TCC cases were diagnosed. SRCC was more common in younger than in older patients (p &lt;0.001); more commonly presented with high grade histology (p &lt;0.001) and advanced stage disease (p &lt;0.001). The 3-year cancer specific survival rate was 67.0% and 33.2% for TCC and SRCC, respectively. On multivariate analysis there was an increased mortality risk in patients with SRCC vs TCC (HR 1.42, 95% CI 1.03–1.97, p &lt;0.001). When only high grade cases of SRCC and TCC were compared, the risk was still worse in SRCC (HR 1.430, 95% CI 1.035–1.976, 0.03). When only local stage of SRCC and TCC were compared, the risk was worse in SRCC (HR 4.294, 95% CI 1.035–17.825, 0.045). Limited to patient who underwent cystectomy only, the difference in cancer specific survival disappeared (HR 1.289, 95% CI 0.771–2.155, 0.33). Conclusions: Even after adjusting for demographic, pathological and treatment factors, cancer specific survival is significantly worse in patients with SRCC than TCC. Further research into the biology of this rare tumor is required to explain these results. No significant financial relationships to disclose.

Advanced Gastric Carcinoma with Signet Ring Cell Histology

Background: Gastric signet ring cell carcinoma (SRC) is a histological type based on microscopic characteristics and not on biological behavior. This study compared the clinicopathological features and prognosis of advanced SRC with non-signet ring cell adenocarcinoma (NSRC) of the stomach. Methods: We reviewed the records of 4,759 consecutive patients diagnosed with advanced gastric adenocarcinoma who were resected surgically from 1987 to 2003. Of these, 662 patients (13.9%) had SRC and were compared with 4,097 patients with NSRC. Results: Significant differences were noted in tumor size, Borrmann type, depth of invasion, lymph node metastasis, peritoneal dissemination and TNM stage. The cumulative 5-year survival rate for advanced SRC was 42.4%, compared with 50.1% in NSRC (p = 0.009). Multivariate analysis showed that tumor size ≧5 cm, Borrmann III and IV, T3–4 invasion and SRC histology were independent risk factors for lymph node metastasis. Depth of invasion, lymph node metastasis, hepatic and peritoneal metastasis and surgical curability were significant factors affecting survival. SRC histology alone was not an independent prognostic factor. Conclusions: Advanced gastric SRC tends toward deeper tumor invasion and more lymph node and peritoneal metastasis than NSRC. Advanced gastric SRC had a worse prognosis than NSRC. Therefore, curative surgical operation with extended lymph node dissection is recommended.

Early gastric carcinoma with signet ring cell histology.

There has been much controversy surrounding the biologic behavior and prognosis of early stage gastric signet ring cell carcinoma (SRC). To clarify the biologic behavior of early stage gastric SRC (early SRC), we compared the clinicopathologic features and prognosis of early SRC with other histologic types. A total of 933 patients with early gastric carcinoma who had undergone gastrectomy from 1987 to 1995 were retrospectively analyzed. Among them, 263 patients with SRC were compared to 670 patients with other histologic types. Younger patients more often had SRC than non-SRC. Additionally, the proportion of females was greater in SRC than in non-SRC. Signet ring cell carcinoma had a larger proportion of mucosa-confined lesions and a lower rate of lymph node metastasis than non-SRC. Even after stratifying the clinicopathologic characteristics, SRC showed a lower rate of lymph node metastasis than non-SRC. When the lymph node metastasis rate was compared between SRC and undifferentiated histology other than SRC, SRC demonstrated a lower lymph node metastasis rate. Multivariate analysis showed that SRC histology was a negative independent risk factor for lymph node metastasis in early gastric carcinoma. The prognosis of SRC was significantly better than that of non-SRC (P = 0.0104). Early gastric carcinoma with SRC is a distinct type of gastric carcinoma in terms of clinicopathologic features and prognosis. The favorable prognosis and lower rate of lymph node metastasis in early SRC suggest that the patients with early gastric carcinoma with SRC could be candidates for less invasive surgeries for an improved quality of life.