Colorectal Signet-ring Cell Carcinoma Research Articles

Clinical Significance of Signet-Ring-Cell Colorectal Cancer as a Prognostic Factor.

PurposeThe aim of this study is to evaluate the prognosis for patients with a signet-ring-cell carcinoma (SRCC) who undergo curative surgery by comparing them to patients with an adenocarcinoma (ADC), excluding a mucinous ADC.MethodsBetween September 1994 and December 2013, 14,110 patients with colorectal cancer underwent surgery and among them, 12,631 patients were enrolled in this study. 71 patients with a SRCC and 12,570 patients with a ADC were identified. We analyzed the disease-free survival and the overall survival rates before and after a 1:2 propensity score matching and evaluated those rates after stage stratification.ResultsThe median follow-up durations were 48.5 months for the SRC group and 48.6 months for the ADC group. The disease-free survival rates and the overall survival rates were significantly lower in the SRC group before and after propensity score matching (P < 0.001). After stratification by stage, no differences were observed between the SRC and the ADC groups for the disease-free survival (DFS) and the overall survival (OS) rates for patients with cancer in its early stages (P = 0.913 and P = 0.380 for the DFS and the OS, respectively, in stages 0 and I, and P = 0.223 and P = 0.991 for the DFS and the OS, respectively, in stage II), but those rates were significantly lower in the SRC group for cancer in its later stages (P < 0.001, respectively in stages III and IV).ConclusionFor cancer in advanced stages, patients with a resectable colorectal SRCC had a poorer prognosis after propensity score matching than those with an ADC did. Therefore, more intensive surveillance and closer observation should be offered to such patients.

Survival in signet ring cell carcinoma varies based on primary tumor location: a Surveillance, Epidemiology, and End Results database analysis

ABSTRACTBackground: The aim of this study was to investigate the survival of patients with signet ring cell carcinoma (SRCC) based on primary tumor location.Methods: Patient data were obtained from the Surveillance, Epidemiology, and End Results database (1988–2012) with ≥200 cases per tumor location. Cox regression analysis was used to investigate prognostic factors of cause-specific survival (CSS).Results: We identified 24,171 patients. Of the patients, 63.4% had gastric SRCC, followed by colon (18.2%), esophageal (5.0%), rectal (3.5%), lung (3.1%), pancreatic (1.8%), breast (1.5%), bladder (1.3%), small intestine (1.1%), and gallbladder SRCC (1.0%). The 5-year CSS was 22.1%, 69.0%, 33.2%, 28.1%, 24.8%, 16.1%, 13.6%, 12.6%, 11.0%, 6.4% in patients with gastric, breast, colon, rectum, bladder, small intestine, esophageal, gallbladder, lung, and pancreatic SRCC, respectively (P < 0.001). Multivariate analyses showed that the primary tumor location was an independent prognostic factor of survival. Patients with lung, small intestine, and bladder SRCC had a comparable CSS to gastric SRCC, while breast and colorectal SRCC had better survival than gastric SRCC. Esophageal, gallbladder, and pancreatic SRCC were significantly associated with poor CSS compared with gastric SRCC.Conclusion: Our study suggests a major difference in survival of SRCC based on the primary tumor locations.

Characteristics and prognostic factors of colorectal mucinous adenocarcinoma with signet ring cells.

BackgroundColorectal signet ring cell (SRC) carcinoma occurs rarely with a poor prognosis. The present study assessed the prognostic factors and predictive value of SRC ratio in colorectal mucinous adenocarcinoma (MAC) with SRCs (MAC-SRC).Patients and methodsA total of 95 consecutive colorectal MAC-SRC patients, confirmed pathologically from February 1987 to December 2015, were analyzed retrospectively in our institute. Clinical characteristics, pathological grade, TNM staging, and SRC ratio were assessed to identify the prognostic factors related to progression-free survival (PFS) and overall survival (OS). SPSS 22.0 was used for statistical analyses.ResultsThe median follow-up time was 29.7 months (range 0.8–165). Meanwhile, 5-year PFS and OS rates were 25.6% (95% confidence interval [CI] 16.192–35.008%) and 40.5% (95% CI 29.524–51.476%), respectively. Among the 81 patients who underwent surgery, 78 (96.3%) were diagnosed as stage T3 or T4; 74 (91.4%) showed lymph node involvement, and 27 (29.3%) presented distant metastasis. Metastases of the peritoneal cavity and ovaries were observed commonly in colorectal MAC-SRC. In the multivariate Cox regression model, SRC ratio ≥35%, absence of preoperative radiotherapy, and distant metastasis were independent predictors of PFS. Furthermore, SRC ratio ≥35%, absence of preoperative chemotherapy (pre-CT), and distant metastasis were independent risk factors for poor prognosis.ConclusionA long-term follow-up of colorectal MAC-SRC reveals that it is a rare subtype of colorectal MAC with a dismal prognosis. Furthermore, SRC ratio, pre-CT, and M stage seem to affect OS independently.

Colorectal signet ring cell carcinoma: Influence of EGFR, E-cadherin and MMP-13 expression on clinicopathological features and prognosis.

Signet ring cell carcinoma (SRCC) is unique rare subtype of mucin-producing colorectal adenocarcinoma characterized by presence of signet ring cells, in >50% of the tumor tissue. This study aims to investigate expression of EGFR, E-cadherin and MMP-13 expression on clinicopathological features of signet ring cell type and its prognostic effect using manual tissue microarray technique. In this work, we studied tumor tissue specimens from 150 patients with colorectal cancer cases among which 19 cases of SRCC. High density manual tissue microarrays were constructed using modified mechanical pencil tips technique and immunohistochemistry for EGFR, E-cadherin and MMP-13 expression was done. We found that SRCC was significantly associated with younger age and more frequency of LN metastasis than all other groups. SRCC was also significantly associated with annular gross picture, more depth of invasion, advanced stage, more lymphovascular emboli, more perineural invasion and less arousal from an overlying adenoma. In conclusion, colorectal SRCC has distinctive clinicopathological and histological features with different unique mechanisms of carcinogenesis and more aggressive biologic behavior than other colorectal carcinoma subtypes. Negative/low expressions of EGFR and E-cadherin and MMP-13 were found in SRCC with no effect on the prognosis.

Environmental Risk Factors for Signet Ring Cell Colorectal Carcinoma in Low Risk Populations

Colorectal cancer (CRC) is the second leading cause of death in western countries. Historically, 20-25% of individuals with CRC have significant risk factors such as age, lifestyle, associated medical conditions or polygenic inheritance, placing them as high-risk. Screening guidelines exist for high-risk populations however there is limited data for young, low risk patients.?? Overall, only 2-3% of CRCs occur in young adults and are mainly associated with aggressive, sporadic malignancies such as mucinous and signet ring cell colon cancer (SRCC). The latter, representing an independent, poor prognostic factor and a 42-57% higher risk of death. We present the case of a 24-year-old Hispanic male from El Salvador with no previous medical history who noticed 6 months of persistent, progressive constipation with accompanying change in caliber to a “pencil sized” diameter. Our patient was self medicating with lactulose however following an inability to void for five days, he presented to the Emergency Department. He has a family history significant for a brain tumor in his brother and lymphoma in his maternal aunt. The patient was an agricultural worker until immigrating to the United States. ??His physical exam was significant for diffuse abdominal tenderness and distension. Abdominal CT scan revealed a partial obstruction in the mid sigmoid colon and a subsequent colonoscopy showed an obstructing mass 15cm from the anal verge. Surgical biopsy of the mass revealed it to be an invasive, poorly differentiated SRCC.?? A palliative colostomy was created due to the presence of carcinomatosis and the unresectable nature of the malignancy. He unfortunately has a poor prognosis and only palliative measures will be pursued for his care. It is our hypothesis that either a germ line mutation or exposure to agricultural carcinogens will ultimately be implicated in our patient's SRCC. Agricultural exposure has been linked to various cancers however the impact of environmental factors in the pathogenesis of SRCC is still unexplored. Insecticides and agricultural compounds may constitute the necessary milieu for the development of genetic mutations as evidenced by our patient's development of SRCC. This case depicts a young patient who presented with an advanced stage of a rare malignancy. His classic symptomatology and presentation of chronic, progressive constipation may have prompted earlier detection and improved prognosis if pursued promptly.

Clinicopathological and Corresponding Genetic Features of Colorectal Signet Ring Cell Carcinoma.

Europe and the United States have high morbidity rates of colorectal cancer, it being the third most common new cancer among both men and women each year. Colorectal cancer morbidity is also high in Japan. Advances in surgery, chemotherapy, and molecular targeted drugs have extended the prognosis of colorectal cancer, although the effects of these treatments remain poor in some patients. Colorectal cancer almost always presents as differentiated adenocarcinoma, although one tissue type, signet-ring cell carcinoma, occurs rarely. Overall, colorectal signet-ring cell carcinoma is very infrequent among cases of colorectal cancer, however, its prognosis is reported as being extremely poor. Several reports have addressed its clinicopathological and typical genetic characteristics, such as mutation of viral oncogene Kirsten rat sarcoma (KRAS) gene, but there have been few comprehensive investigations of its characteristics and genetic background. In this review, we examine features of colorectal signet-ring cell carcinoma by summarizing its clinical and genetic characteristics.

Comparison of CT manifestations of primary colorectal mucinous adenocarcinoma and signet ring cell carcinoma

To compare the difference in CT manifestations between primary colorectal mucinous adenocarcinoma and signet ring cell carcinoma in order to improve radiologic diagnosis. Clinicopathological data and CT findings of 109 patients with colorectal mucinous adenocarcinoma and 46 patients with primary colorectal signet-ring cell carcinoma confirmed by surgery and pathology from March 2008 to February 2015 in the Tumor Hospital of Yunnan Province were retrospectively collected. Differences in age, gender, tumor location, length and thickness of the involved intestinal wall, thickening pattern of the intestinal wall, lesion density, calcification, contrast-enhanced form, peri-intestinal invasion, occurrence of intestinal obstruction and metastasis of other organs were compared between the two groups. Among 109 patients with colorectal mucinous adenocarcinoma, 68 were men and 41 were women with a mean age of (56.8±15.4) years. Among 46 patients with primary colorectal signet-ring cell carcinoma, 26 were men and 20 were women with a mean age of (42.9±15.6) years. Compared with mucinous adenocarcinoma group, signet-ring cell carcinoma group showed more concentric bowel-wall thickening[93.5%(43/46) vs. 81.6%(89/109), χ2=9.19, P=0.030], higher lesion density [(42.0±3.0) Hu vs. (28.5±1.5) Hu, t=37.30, P=0.000], more marked enhancement [54.3%(25/46) vs. 12.8%(14/109), χ2=35.21, P=0.000], less vast-low-density region in enhanced CT imaging[2.2%(1/46) vs. 45.0%(49/109), χ2=73.31, P=0.000] and more severe peri-intestinal invasion [41.3% (19/46) vs. 17.4%(19/109), χ2=10.25, P=0.006]. Calcification was found in 18.3%(20/109) of mucinous adenocarcinoma cases, but was not found in signet-ring cell carcinoma cases (χ2=9.69, P=0.002). Target ring sign in contrast-enhanced scan was observed in 15.2%(7/46) of signet-ring cell carcinoma cases, while in none of mucinous adenocarcinoma cases (χ2=17.37, P=0.000). There were no statistically significant differences in lesion location, length and thickness of the involved intestinal wall, occurrence of intestinal obstruction, lymph node metastasis, liver or peritoneum metastasis between two groups(all P>0.05). Signet-ring cell carcinoma is often found in younger patients, whose CT manifestation is characterized by the target ring sign in contrast-enhanced scan, while primary colorectal mucinous adenocarcinoma is often in older patients, whose CT manifestation is characterized by calcification in unenhanced scan and low density region in enhanced CT show.

Signet ring cell colorectal cancer: Genomic insights into a rare subpopulation of colorectal adenocarcinoma.

606 Background: Colorectal signet ring cell carcinoma (SRCC) has been shown to be associated with advanced tumor stage at presentation and worse outcomes. Due to the rarity of this subtype, 1% of all colorectal adenocarcinoma (CRC), little is known about its molecular characteristics. We aimed to characterize the molecular alterations of this subgroup. Methods: Metastatic CRC (mCRC) patients (pts) with signet ring cell (SC) histology who had tumors evaluated with next generation sequencing between February 2009 and November 2015 were reviewed. SC mCRC were classified into 2 groups; SRCC (&gt;50% of signet cells) and adenocarcinoma (AC) with SC component. Genomic alterations, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) status noted in SC mCRC were compared to non-SC mCRC pts from the Assessment of Targeted Therapies Against Colorectal Cancer program at MD Anderson Cancer Center using Pearson’s χ 2 test. Results: A total of 665 mCRC pts were included in this study. 93 pts (14%) had SC histology of which 30 (32.3%) pts were SRCC. The Table below shows key cancer genes mutation frequencies. Conclusions: Colorectal SRCC has distinct molecular features compared with non-SC and AC with SC component CRC. The frequencies of KRAS, PIK3CA and APC mutations were lower than the frequencies reported in non-SC CRC. SRCC was not associated with MSI-H or CIMP-H tumor in this study. Further studies on identification of activated pathways underlying this worse prognosis and potential therapeutic targets are required. [Table: see text]

The Characteristics and Prognostic Effect of E-Cadherin Expression in Colorectal Signet Ring Cell Carcinoma.

PurposeSignet ring cell carcinoma (SRCC) is rare. The aim of this study is to understand the clinicopathological features and identify the possible prognostic factors in colorectal SRCC.MethodsPatients with SRCC who underwent primary lesion resection at Fudan University Shanghai Cancer Center from September 2008 to July 2014 were retrospectively analyzed. Patient’s gender, age, tumor location, depth of invasion, lymph node metastasis, synchronous distant metastasis, perineural invasion, lymphovascular invasion, and E-cadherin expression were studied with prognosis, and the correlation between E-cadherin expression and clinicopathological features were analyzed. All clinicopathological and molecular factors were put into multivariate analysis using Cox proportional hazards model for detecting independent prognostic factors.Results59 patients accounting for 0.89% of total colorectal cancer patients met the criteria and were enrolled in the study. The median survival time is 28.9 months, and the 3-year survival rate is 62.7%. SRCC were seen more common in young male patients. Advanced stage was more common in SRCC, 58 (98.3%) patients had T3/T4 lesions, 52 (88.1%) patients had lymph node metastasis, and 14 (23.7%) patients had distant metastasis. Distant metastases were seen more common in peritoneal cavity. Distant metastasis (HR = 4.194, 95% CI: 1.297–13.567), lymphovascular invasion (HR = 2.888, 95% CI: 1.115–7.483), and E-cadherin expression (HR = 0.272, 95% CI: 0.096–0.768) were independent predictors for survival.ConclusionsSRCC is a rare subtype of colorectal cancer with poor prognosis. Distant metastasis, lymphovascular invasion, and E-cadherin expression can predict prognosis of colorectal SRCCs independently. More precise therapy and more close surveillance are needed for these patients.

Prognostic relevance of histopathological features in signet ring cell carcinoma of the colorectum.

Signet ring cell carcinoma (SRCC) is a rare variant of colorectal cancer (CRC), by definition composed of at least 50% of neoplastic cells showing signet ring cell morphology. Colorectal SRCC is mainly characterized by aggressive clinical behavior, high pTNM stage and microsatellite instability (MSI). We assessed the prognostic value of several histopathological parameters (histological grade, venous invasion, lymphovascular invasion, MSI, mucin content, tumour budding, pTNM stage) in terms of disease free survival (DFS) and cancer specific survival (CSS) in a series of 32 SRCCs. We confirm that pTNM stage at diagnosis is relevant for predicting DFS and CSS in SRCC. In addition, we show on haematoxylin and eosin or immunohistochemically stained (CD34, podoplanin) sections that venous invasion and lymphovascular invasion are significantly associated with shorter DFS and CSS in SRCC. Notably, venous invasion assed by immunohistochemistry had the highest risk ratio and proved to be the only independent prognostic variable. Finally, we show that histological grade, as assessed on the percentage of formed glands, has prognostic relevance in SRCC as high-grade tumours (<50% of glands) had significantly shorter CSS compared to low-grade tumours. This remained an independent variable at multivariate analysis. If our findings are confirmed in further studies, venous invasion as assessed by immunohistochemistry and histological Tgrade might be added to guidelines for SRCC reporting as significant prognostic factors.

Clinical Features and Prognosis of Resectable Primary Colorectal Signet-Ring Cell Carcinoma.

Background/AimsWe attempted to investigate the prognosis of signet-ring cell carcinoma (SRC) patients who underwent curative surgery by comparing them with age-, sex-, and stage-matched non-mucinous adenocarcinoma (NMAC) patients.MethodsBetween January 2003 and December 2011, 19 patients with primary SRC of the colorectum underwent curative surgery. Four SRC patients under the age of 40 were excluded, and the clinicopathological data of 15 patients (7 men; median age, 56 years) were reviewed and compared with the data of 75 NMAC patients matched by age, sex, and pathologic stage.ResultsThe median follow-up duration was 30.1 months for the SRC group and 43.7 months for the NMAC group (P=0.141). Involvement of the left side of the colon (73.3% vs. 26.7%, P=0.003) and infiltrative lesions such as Borrmann types 3 and 4 (85.7% vs. 24.0%, P=0.001) were more common in the SRC group than in the NMAC group. The five-year overall survival rate was significantly lower for patients with SRC than for those with NMAC (46.0% vs. 88.7%, hazard ratio, 6.99; 95% confidence interval, 2.33-20.95, P=0.001).ConclusionsPatients with even resectable primary colorectal SRC had a poorer prognosis than age-, sex-, and stage-matched colorectal NMAC patients.

Colorectal signet-ring cell carcinoma: Responsive to adjuvant chemotherapy but still a poor prognosis.

529 Background: Colorectal signet-ring cell carcinoma (SRCC) has been associated with a poor survival compared to mucinous adenocarcinoma (MC) and the common adenocarcinoma (AC). Prognostic impact of tumor localization is unknown and efficacy of adjuvant chemotherapy in SRCC has never been assessed. This study analyses prognostic impact of SRCC and determines whether SRCC patients benefit from adjuvant chemotherapy for colon cancer equally compared with AC. Methods: Data on 196,757 patients with CRC in the Netherlands in the period 1989 and 2010 was included in this nationwide population-based study. Five-year relative survival estimates were calculated and multivariate relative survival analyses using a multiple regression model of relative excess risk (RER) were performed. Results: SRCC was found in 1.0% of CRC patients. SRCC patients presented more frequently with stage III or IV disease than AC (75.2% versus 43.6%, P&lt;0.0001) and SRCC was more frequently found in the proximal colon (57.7% versus 32.0%, P&lt;0.0001). SRCC patients had a poor 5-year relative survival of 31% in colon and 20% in the rectum compared to 57% and 59% in AC (P&lt;0.0001). This poorer survival for SRCC was found in stage II, III and IV. In comparison with AC, there was no significant interaction between SRCC and adjuvant chemotherapy (RER 1.10, 95% CI 0.81-1.51), suggesting a comparable benefit from adjuvant chemotherapy in AC and SRCC. Conclusions: Prognostic impact of SRCC is dismal in both colon and rectal cancer patients, but colonic SRCC patients seem to benefit from adjuvant chemotherapy equally compared with AC. Reduced efficacy of adjuvant chemotherapy therefore does not seem to explain the poor outcome in SRCC patients. We recommend to adhere to adjuvant treatment guidelines for all histological subtypes, but encourage clinical trials to take histological subtype into account for stratification.

Influence of histologic subtype on metastatic pattern in colorectal cancer.

395 Background: In colorectal cancer (CRC) mucinous adenocarcinoma (MC) and signet-ring cell carcinoma (SRCC) have been associated with differences in metastatic patterns compared to the more common adenocarcinoma (AC). This study systematically evaluates metastatic patterns of different histological subtypes and analyses metastatic disease based upon primary tumor localization. Methods: A nationwide retrospective review of pathological records of 5,813 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch Pathology Registry (PALGA). To validate metastatic patterns in rectal cancer patients, data was compared to the prospective randomized multicentre TME-trial that investigated efficacy of preoperative radiotherapy. Results: In the autopsy study 1,675 patients with CRC had metastatic disease. Metastatic disease was more frequently found in MC and SRCC than in AC (33.9%, 61.2% and 27.5%; P&lt; 0.0001) and more often had metastases at multiple sites (58.6% and 70.7% versus 49.9%; P=0.001). AC more commonly metastasized to the liver compared with MC and SRCC, 73.0% versus 52.2% and 31.7% (P&lt;0.0001). The occurrence of metastases exclusively to the liver was less common in MC and SRCC patients. In SRCC patients, liver metastases were almost always observed in combination with other metastases. MC and SRCC metastasized to the peritoneal surface frequently, 48.2% and 51.2%, compared with 20.1% in AC (P&lt;0.0001). Colon cancer patients presented more frequently with intra-abdominal metastases, than rectal cancer patients. Rectal cancer patients presented more often with extra-abdominal metastases. Results from the TME-trial confirmed findings in rectal cancer patients from the autopsy study. Conclusions: There are profound differences in metastatic patterns between different histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take histological subtype into account during pre-operative examination for metastases and during follow-up. Results also indicate that these factors should be considered a stratification factor in future research initiatives focusing on advanced disease.

Signet Ring Cell Colorectal Carcinoma

We evaluated a consecutive series of signet ring cell colorectal carcinomas in an attempt to correlate the histopathologic pattern of infiltration with molecular alterations and prognosis. Of the 4760 primary colorectal carcinomas surgically resected between the years 2002 and 2012, 53 (1%) were composed of >50% signet ring cells. Of the 53 signet ring cell carcinomas, 40 (75%) were composed of >50% extracellular mucin with signet ring cells floating within pools of mucin and were subclassified as mucin-rich signet ring cell carcinomas. Thirteen (25%) carcinomas were characterized by diffusely infiltrating carcinomas with minimal to no extracellular mucin and were subclassified as mucin-poor signet ring cell carcinomas. All 13 mucin-poor signet ring cell carcinomas were either stage III or IV, whereas many cases of mucin-rich signet ring cell carcinoma were stage I or II (17 cases) (P=0.005). Compared with mucin-rich tumors, mucin-poor signet ring cell carcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (13/13, 100% vs. 22/40, 55%; P=0.002), venous invasion (6/13, 46% vs. 3/40, 8%; P=0.004), and perineural invasion (11/13, 85% vs. 9/40, 23%; P=0.0001). Twenty-three of 53 (43%) signet ring cell carcinomas demonstrated high levels of microsatellite instability (MSI-H). Twenty-two of 23 (96%) MSI-H signet ring cell carcinomas were mucin rich; only 1 MSI-H signet ring carcinoma was mucin poor (P=0.0033). Mucin-poor signet ring cell carcinoma had significantly reduced overall and recurrence-free survival compared with mucin-rich signet ring cell carcinomas (P=0.0035 and 0.0001, respectively), even when adjusting for tumor stage. Mucin-poor signet ring cell carcinoma had a higher propensity for peritoneal dissemination (5/13, 38%) compared with mucin-rich signet ring cell carcinoma (5/40, 12.5%), although this was not statistically significant (P=0.052). Finally, MSI-H and microsatellite-stable signet ring cell carcinomas had similar overall and recurrence-free survival (P=0.2266 and 0.1055, respectively), even when adjusting for tumor stage. In conclusion, we identified a unique subset of signet ring cell colorectal carcinoma with diffuse infiltration and minimal to no extracellular mucin (mucin-poor signet ring cell carcinoma), which lacks MSI-H and has a dismal prognosis with an aggressive clinical course often with peritoneal dissemination. Further, our results confirm that MSI does not affect survival in colorectal signet ring cell carcinomas.

Colorectal signet ring cell carcinoma coexisting with tuberculosis

Background: Though tuberculosis and carcinoma of the bowel are fairly common conditions, the sites of predilection for the two differ, tuberculosis being common in the ileum while carcinoma in the large bowel. Both occurring at the same site is a very rare entity and very few cases have been reported in the literature and none has been recorded in the eastern part of Nepal. Case description: A 35 years old female presented with the complaint of constipation and passage of blood mixed stool since one month. Proctoscopy revealed constricting lesion in the rectum. Provisional diagnosis of carcinoma rectum was made. Histopathological examination showed ulceroinfiltrative lesion in the rectum measuring 11cm in length and extending upto the distal end of sigmoid colon. After microscopic examination a diagnosis of Signet ring cell carcinoma of rectum and sigmoid colon coexisting with tuberculosis was made. Seven lymph nodes dissected from the specimen showed metastatic tumor deposits along with coexisting tuberculous lymphadenitis. Special stain for AFB (TB) and IHC for mucicarmine was positive. Health Renaissance, January-April 2013; Vol. 11 No.1; 162-165 DOI: http://dx.doi.org/10.3126/hren.v11i2.8226

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

AbstractThe relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with high-level microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotype-positive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.

Colorectal Signet Ring Cell Carcinoma: Incidence and Epidemiological Distribution at a Tertiary Care Center from 2002 to 2012

Background: Primary colorectal signet ring cell carcinoma (SRCC) is a rare finding with an incidence of 0.9% to 4%. This entity is characterized by an aggressive tumor biological behavior and is associated with a worse outcome compared to mucinous or adenocarcinoma. SRCC are defined as carcinoma cells with ≥50% intracellular mucin of the tumor mass displacing the nuclei to the side. Tumor cells comprising ≥50% extracellular mucin of the tumor mass are classified as mucinous carcinomas. The aim of this study was to analyze the incidence and epidemiological distribution of SRCC in colorectal cancer patients at our tertiary care unit.

Site-Dependent E-Cadherin Cleavage and Nuclear Translocation in a Metastatic Colorectal Cancer Model

Metastases are frequently found during colorectal cancer diagnoses and are the main determinants of clinical outcome. The lack of reliable models of metastases has precluded their mechanistic understanding and our capacity to improve outcome. We studied the effect of E-cadherin and Snail1 expression on metastagenesis in a colorectal cancer model. We microinjected SW480-ADH human colorectal cancer cells, transfected with an empty vector (Mock) or overexpressing Snail1 (Snail1(OE)) or E-cadherin (E-cadherin(OE)), in the ceca of nude mice (eight per group) and analyzed tumor growth, dissemination, and Snail1, E-cadherin, β-catenin, and Presenilin1 (PS1) expression in local tumors and/or metastatic foci. Snail1(OE) cells disseminated only to lymph nodes, whereas Mock or E-cadherin(OE) cells spread to lymph nodes and peritoneums. Peritoneal tumor foci developed by E-cadherin(OE) cells presented an increase in E-cadherin proteolysis and nuclear translocation, and enhanced expression of proteolytically active PS1, which was linked to increased tumor growth and shortened mouse survival. Interestingly, local and lymph node tumors in mice bearing E-cadherin(OE) cells overexpressed E-cadherin, but they did not show E-cadherin proteolysis or nuclear translocation. Remarkably, E-cadherin nuclear translocation and enhanced expression of active PS1 were found in a patient with colorectal signet-ring cell carcinoma. In conclusion, we have established a colorectal cancer metastasis model in which E-cadherin proteolyis and nuclear translocation associates with aggressive foci growth only in the peritoneal microenvironment.

Signet-ring cell carcinoma of colorectum—current perspectives and molecular biology

Colorectal signet-ring cell carcinoma (SRCC) is rare, and very little detailed information on the molecular biology of the disease is available. The literature on the clinical, pathological and, in particular, the molecular biology of this rare entity was critically reviewed. The reviewed articles take into account a total of 1,817 cases of SRCC, but only 143 cases have molecular data available. The characteristics of two patients with colorectal SRCC were also discussed. Colorectal SRCC mostly occurs in younger patients, is larger and has different site predilection compared with conventional colorectal adenocarcinoma. It can occur as one of the synchronous cancers in the colorectum. The cancer is usually diagnosed at advanced stages because of the late manifestation of symptoms, and aggressive treatment strategy is required. Limited reports in the literature have shown that the variant of colorectal cancer demonstrated a different pattern of genetic alterations of common growth kinase-related oncogenes (K-ras, BRAF), tumour suppressor genes (p53, p16), gene methylation and cell adhesion-related genes related to the Wingless signalling pathway (E-cadherin and beta-catenin) from conventional colorectal adenocarcinoma. Colorectal SRCC also showed high expression of mucin-related genes and genes related to the gastrointestinal system. There was also a higher prevalence of microsatellite instability-high tumours and low Cox-2 expression in colorectal SRCC as opposed to conventional adenocarcinoma. Colorectal SRCC has unique molecular pathological features. The unique molecular profiles in SRCC may provide molecular-based improvements to patient management in colorectal SRCC.

Primary colorectal signet-ring cell carcinoma: Clinicopathological features and postoperative survival

The objective of this study was to investigate the clinicopathological features and postoperative survival of primary colorectal signet-ring cell carcinoma. Nineteen patients with primary colorectal signet-ring cell carcinoma were identified from a database of 5884 surgical patients with colorectal cancers treated surgically at Osaka University Hospital and affiliated hospitals between 1993 and 2007. The clinicopathological data of those patients were compared with those of 5792 patients with non-signet-ring cell colorectal carcinoma (5417 with well or moderately differentiated adenocarcinoma and 375 with poorly differentiated adenocarcinoma or mucinous carcinoma). All patients showed a tumor depth of over T3. Lymph node involvement occurred in 14 patients. Seven of 19 patients presented with distant metastasis at the time of diagnosis. The overall 5-year survival rate in primary signet-ring cell carcinoma was significantly lower at 24.1%, in comparison to 77.5% in well or moderately differentiated adenocarcinoma and 57.7% in poorly differentiated adenocarcinoma or mucinous carcinoma. Likewise, the postoperative survival in Stage III was also significantly worse. On the other hand, no significant difference was observed in Stage II or IV. The most important feature of primary colorectal signet-ring cell carcinoma is the advanced stage at the time of diagnosis. In addition, the postoperative survival is worse than for other types of colorectal cancer.