Deep Learning Models for Gastric Signet Ring Cell Carcinoma Classification in Whole Slide Images.

Signet ring cell carcinoma (SRCC) of the stomach is a rare type of cancer with a slowly rising incidence. It tends to be more difficult to detect by pathologists, mainly due to its cellular morphology and diffuse invasion manner, and it has poor prognosis when detected at an advanced stage. Computational pathology tools that can assist pathologists in detecting SRCC would be of a massive benefit. In this paper, we trained deep learning models using transfer learning, fully-supervised learning, and weakly-supervised learning to predict SRCC in Whole Slide Images (WSIs) using a training set of 1,765 WSIs. We evaluated the models on two different test sets (n = 999, n = 455). The best model achieved a ROC-AUC of at least 0.99 on all two test sets, setting a top baseline performance for SRCC WSI classification.

Histotype influences emergency presentation and prognosis in colon cancer surgery.

AIM: To investigate whether differences in histotype in colon cancer correlate with clinical presentation and if they might influence oncological outcomes and survival. METHODS: Data regarding colon cancer patients operated both electively or in emergency between 2009 and 2014 were retrospectively collected from a prospectively maintained database and analyzed for the purpose of this study. Rectal cancer was excluded from this analysis. Statistical univariate and multivariate analyses were performed to investigate possible significant variables influencing clinical presentation, as well as oncological outcomes and survival. RESULTS: Data from 219 patients undergoing colorectal resection for cancer of the colon only were retrieved. One hundred seventy-four patients had an elective procedure and forty-five had an emergency colectomy. Emergency presentation was more likely to occur in mucinous (p < 0.05) and signet ring cell (p < 0.01) tumors. No definitive differences in 5-year overall (44.7% vs. 60.6%, p = 0.078) and disease-free (51.2% vs. 64.4%, p = 0.09) survival were found between the two groups as a whole, but the T3 emergency patients showed worse prognosis than the elective (p < 0.03). Lymph node invasion, laparoscopy, histology, and blood transfusions were independent variables found to influence survival. Distribution assessed for pTNM stage showed T3 cancers were more common in emergency (p < 0.01). CONCLUSIONS AND DISCUSSION: Mucinous and signet ring cell tumors are related to emergency presentation, pT3 stage, poorest outcomes, and survival. Disease-free survival in patients who had emergency surgery for T3 colon cancer seems related to the histotype.

Signet ring cell component predicts aggressive behaviour in colorectal mucinous adenocarcinoma.

Mucinous adenocarcinoma (MAC) is defined by the presence of extracellular mucin covering more than 50% of the tumour area; however, MAC is histologically heterogeneous and some cases exhibit signet ring cell components. The aim of this study was to determine the prognostic impact of such variable morphology. A total of 299 consecutive MAC patients who underwent curative surgery were included. MACs were classified into four categories according to the predominant pattern of floating tumour cells: strips (27.1%), clusters (51.8%), signet ring cells (6.7%), and mixed clusters and signet ring cells (14.4%). In addition, we categorised MACs according to the relative amount of mucin. MACs with signet ring cell component were clearly associated with poor overall and recurrence-free survivals. Moreover, MACs with more than 50% signet ring cell component showed particularly poor clinical outcome just like non-mucinous signet ring cell carcinoma. MACs with a greater amount of extracellular mucin were associated with poor recurrence-free survival, independent of the pathological stage. In addition, lymphovascular and perineural invasion, advanced pathological stage, and old age at diagnosis were also prognostic factors for poor overall survival. MACs with more than 50% signet ring cell component should be classified as signet ring cell carcinoma and the presence of signet ring cells should be included in the pathology report of MACs with 10-50% signet ring cell component.

Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma.

BACKGROUND AND AIMS: Clinicopathological characteristics of gastric cancer (GC) are changing, especially in the West with a decreasing incidence of distal, intestinal-type tumours and the corresponding increasing proportion of tumours with Laurén diffuse or WHO poorly cohesive (PC) including signet ring cell (SRC) histology. To accurately assess the behaviour and the prognosis of these GC subtypes, the standardization of pathological definitions is needed. METHODS: A multidisciplinary expert team belonging to the European Chapter of International Gastric Cancer Association (IGCA) identified 11 topics on pathological classifications used for PC and SRC GC. The topics were debated during a dedicated Workshop held in Verona in March 2017. Then, through a Delphi method, consensus statements for each topic were elaborated. RESULTS: A consensus was reached on the need to classify gastric carcinoma according to the most recent edition of the WHO classification which is currently WHO 2010. Moreover, to standardize the definition of SRC carcinomas, the proposal that only WHO PC carcinomas with more than 90% poorly cohesive cells having signet ring cell morphology have to be classified as SRC carcinomas was made. All other PC non-SRC types have to be further subdivided into PC carcinomas with SRC component (< 90% but > 10% SRCs) and PC carcinomas not otherwise specified (< 10% SRCs). CONCLUSION: The reported statements clarify some debated topics on pathological classifications used for PC and SRC GC. As such, this consensus classification would allow the generation of evidence on biological and prognostic differences between these GC subtypes.

Phenotypic classification of gastric signet ring cell carcinoma and its relationship with K-ras mutation.

We aimed to analyze gastric signet ring cell (SRC) carcinoma subtypes by investigating gastric and intestinal phenotypic marker expression, and explore the relationship between phenotype and K-ras mutation. Immunohistochemistry was performed on 163 SRC carcinoma patient specimens to detect gastric (MUC1, MUC5AC, and MUC6) and intestinal (MUC2 and CDX2) phenotypic markers, and tumors were classified into gastric (G), intestinal (I), and gastrointestinal (GI) phenotypes. DNA was extracted from the formalin-fixed, paraffin-embedded tumor samples, and K-ras mutations in codons 12, 13, and 61 were identified using polymerase chain reaction-based direct DNA sequencing. G, GI, and I phenotypes were observed in 63 (38.6%), 71 (43.5%), and 29 cases (17.8%), respectively. Expression of MUC2 was significantly associated with invasion depth and lymph node metastasis (P = 0.001 and 0.002, respectively), whereas that of CDX2 significantly corresponded to tumor size and submucosal invasion (P = 0.004 and 0.001, respectively). MUC5AC expression was inversely associated with gastric wall invasion (P = 0.001). Intestinal phenotypic marker expression was positively associated with gastric wall invasion and lymph node metastasis. K-ras mutations, all of which were in codon 12, were detected in 20 (12.27%) tumors, were significantly associated with the I phenotype, and exhibited an inverse relationship with MUC5AC and MUC6 expression. I-phenotype SRC carcinomas should be distinguished from those of the G phenotype because of their increased malignancy regarding invasion and metastasis, and higher K-ras aberration rate. The different K-ras mutation frequencies observed imply distinct genetic mechanisms in the carcinogenesis of I- and G-phenotype gastric SRC carcinomas.

Is the recent WHO histological classification for gastric cancer helpful for application to endoscopic resection?

BACKGROUND: Endoscopic resection is performed in undifferentiated-type early gastric cancer (UD-EGC), including poorly differentiated (PD) adenocarcinoma and signet ring cell (SRC) carcinoma. We previously found that different approaches are needed for PD adenocarcinoma and SRC carcinoma for curative resection. However, according to the 2010 WHO classification, diffuse-type PD adenocarcinoma and SRC carcinoma are categorized in the "poorly cohesive carcinomas." Thus, we assessed whether the WHO classification is helpful when endoscopic resection is performed for treatment of UD-EGC. METHODS: We analyzed clinicopathological features of 1295 lesions with SRC carcinoma and PD adenocarcinoma treated by open surgery. We recategorized them into intestinal-type PD adenocarcinomas and poorly cohesive carcinomas (SRC carcinoma, diffuse-type PD adenocarcinoma). We also recategorized 176 lesions treated by endoscopic resection into intestinal-type PD adenocarcinomas and poorly cohesive carcinomas. RESULTS: According to the open surgery data, the rates of lymph node metastasis (LNM) and lymphovascular invasion were significantly lower in SRC carcinoma than in diffuse-type and intestinal-type PD adenocarcinomas. The rates of LNM and lymphovascular invasion were significantly higher in diffuse-type PD adenocarcinoma than in SRC carcinoma. Endoscopic resection data showed no recurrence if the carcinoma was curatively resected. However, the commonest cause of noncurative resection was different in SRC carcinoma and PD adenocarcinoma. A positive lateral margin was the commonest cause in SRC carcinoma versus a positive vertical margin in both intestinal-type and diffuse-type PD adenocarcinoma. CONCLUSIONS: The clinical behavior differs in diffuse-type PD adenocarcinoma and SRC carcinoma. On the basis of LNM and outcomes of endoscopic resection, the recent WHO classification may not be helpful when endoscopic resection is performed for treatment of UD-EGC.

Perspectives on signet ring stromal cell tumor and related signet ring cell lesions of the gonads.

In this article, we discuss advances in our knowledge of the pathology of signet ring stromal cell tumor and related signet ring cell lesions of the ovary and a single case of signet ring stromal cell tumor of the testis. We divide ovarian signet ring cell lesions into 3 categories that reflect differences in their pathogenesis and histologic appearance. With 1 exception, all authentic cases of signet ring stromal cell tumor have been unilateral. Cases of ovarian signet ring stromal cell tumor from the literature can arise in 2 ways. The majority of cases arise multifocally from fibroma, whereas the remainder likely arise directly from the ovarian stroma. In difficult cases, immunocytochemistry provides improved diagnostic accuracy in distinguishing signet ring stromal cell tumor and its mimics from Krukenberg tumor. The most useful antibodies in this regard are epithelial membrane antigen and vimentin.

Clinicopathologic characteristics and prognostic value of various histological types in advanced gastric cancer.

The prognostic value of histological types in gastric cancer is not well defined. This study aims to clarify the clinicopathologic features of various WHO histological types and their prognostic significance in advanced gastric cancer (AGC). We retrospectively reviewed 741 patients with gastric cancer in our hospital from 1997 to 2007. The AGC (741 cases) were divided into five histological types: well-differentiated carcinoma (WD), moderately differentiated carcinoma (MD), poorly differentiated carcinoma (PD), mucinous carcinoma (MC), and signet ring cell carcinoma (SRC). The various AGC histological types presented significant differences in their clinical and tumor features. The five-year survival rates of patients with WD, MD, PD, MC, and SRC were 87.1%, 57.1%, 50.6%, 62.7%, and 43.4%, respectively (P=0.012). Multivariate analysis showed that cell differentiation, age, depth of invasion, and lymph node metastasis were independent prognostic factors in AGC, whereas MC and SRC were not. Cell differentiation is related to tumor aggression or patient stage. Advanced stage SRC carcinoma had more aggressive features and worse prognosis than the other types. MC carcinoma survival is correlated with the stage at diagnosis. The degree of cell differentiation is an important predictor of survival in AGC.

Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade.

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

Secretory myoepithelial carcinoma: a histologic and molecular survey and a proposed nomenclature for mucin producing signet ring tumors.

Signet ring cell (mucin producing) adenocarcinoma is a rare low grade salivary gland malignancy. While currently designated as an adenocarcinoma, myoepithelial differentiation has been implied in previously reported cases. We herein perform a survey of our cases of signet ring cell adenocarcinoma and review the literature in order to refine categorization of this rare tumor. Five cases were retrieved. One was reclassified as a mammary analogue secretory carcinoma, leaving four that fulfilled the criteria for signet ring cell adenocarcinoma: the presence of prominent signet ring or vacuolated cells arranged in islands, interconnecting strands, cords or sheets in a myxoid or hyaline stroma, or pools of mucin. An extensive panel of histochemical and immunohistochemical stains and fluorescence in situ hybridization (FISH) (modeled after common phenotypes and molecular alterations seen in signet ring and myoepithelial tumors at other sites) was performed. The male-to-female ratio was 3:1. The mean age was 56 years (range 18-81). Sites involved included buccal mucosa (2), soft palate (1) and deep parotid (1). Perineural and angiolymphatic invasion were present in three and two cases respectively. One patient was lost to follow up and the remainder were alive and without disease at time of last follow up (mean 38 months). All cases showed mucicarmine positive vacuolated/signet ring cells embedded in a myxoid stroma. Three cases showed at least focal p63 staining and two cases showed positivity for calponin. Membranous E-cadherin was retained in all cases. FISH was negative for ETV6, EWSR1, and ALK1 rearrangements in all four cases. Based on the current series and the previously reported cases, it is evident that signet ring adenocarcinomas have a dual secretory and myoepithelial phenotype and thus as a whole more appropriately designated as 'secretory myoepithelial carcinoma.' They behave in a fairly indolent fashion and do not share the major molecular alterations seen in other signet ring and myoepithelial tumor types.

[Clinicopathologic and immunohistochemical study on early gastric signet-ring cell carcinoma].

OBJECTIVE: To study the expression of gastric and intestinal phenotypic markers in gastric signet-ring cell (SRC) carcinoma and the relationship with the clinicopathologic parameters and prognosis. METHODS: Immunohistochemical study was carried out in 91 cases of early-stage SRC carcinoma using MUC1, MUC5AC and MUC6 antibodies as the gastric phenotypic markers and MUC2 and CDX2 antibodies as the intestinal phenotypic markers. According to the expression of phenotypic markers, the tumors were classified into three different subgroups: gastric, intestinal and mixed. The findings were analyzed together with various clinical parameters and follow-up data. RESULTS: Amongst the 91 cases studied, 53 cases (58.2%) belonged to gastric type, 22 cases (24.2%) mixed type and 16 cases (17.6%) intestinal type. The positive rates of MUC2 and CDX2 in early submucosal carcinoma were significantly higher than those in mucosal carcinoma (P < 0.01). On the other hand, the rates of MUC5AC and MUC6 expression in early submucosal carcinoma were significantly lower than those in mucosal carcinoma (P < 0.01 and P < 0.05). The rates of MUC2 and CDX2 expression in cases with lymph node metastasis and vascular invasion were significantly higher than those in cases without nodal or vascular involvement (P < 0.05). The expression of CDX2 was also significantly higher in cases with larger tumor size (P < 0.05). Cases with intestinal phenotype more likely had invasion deeper than mucosal layer and carried higher chance of lymph node metastasis (P = 0.000 and P = 0.003). Intestinal and mixed types correlated with shortened five-year survival. CONCLUSIONS: The intestinal type of SRC carcinoma is associated with poorer biologic behavior and prognosis, as compared with that of the gastric type. Classification on the basis of immunophenotypic markers may be useful in predicting prognosis and guiding treatment for patients with gastric SRC carcinoma.

Prognosis of 980 patients with gastric cancer after surgical resection.

BACKGROUND AND OBJECTIVE: Although surgery is the only possible means to cure gastric cancer, the prognosis is often discrepant. The American Joint Committee on Cancer / International Union against Cancer (AJCC/UICC) published the TNM classification of Malignant Tumors (seventh edition) for gastric cancer recently. This study aimed to use this new edition staging system to investigate the prognostic factors for gastric cancer. METHODS: The clinicopathologic data of 980 patients with gastric cancer treated by surgical resection in our hospital between January 2000 and December 2006 were analyzed retrospectively. The overall survival rate was determined by using Kaplan-Meier method and log-rank test was used to determine significance. The prognosis was analyzed using univariate analysis and multivariate analysis with the Cox proportional hazards model. The 6th and 7th edition AJCC/UICC TNM staging systems were used to compare the survival outcomes for the cohort of patients. RESULTS: The overall 1-, 3-, 5-year survival rates for the whole group were 82.5%, 58.7%, and 52.6%. The 5-year survival rates for patients with pTNM stage I, II, III, and IV disease classified by the 7th edition staging system were 93.2%, 72.4%, 39.1%, and 5.2%, respectively. In both univariate analysis and Cox multivariate analysis, age, tumor site, tumor size, histological type, resection type, radical resection, lymphatic/venous invasion, depth of invasion, nodal status, metastasis, retrieved lymph nodes, metastatic lymph node ratio, and adjuvant chemotherapy were prognostic factors with these patients. CONCLUSION: Compared with the 6th edition system, the new edition of TNM staging system for gastric cancer can accurately predict the survival after operation.

Relationship between clinicopathological features and mucin phenotypes of advanced gastric adenocarcinoma.

AIM: To investigate a relationship between the clinicopathological features and mucin phenotypes in advanced gastric adenocarcinoma (AGA). METHODS: Immunohistochemical staining was performed to determine the mucin phenotypes in 38 patients with differentiated adenocarcinomas (DACs), 9 with signet-ring cell carcinomas (SIGs), and 48 with other diffuse-type adenocarcinomas (non-SIGs) of AGA. The mucin phenotypes were classified into 4 types: gastric (G), gastrointestinal (GI), intestinal, and unclassified. RESULTS: The G-related mucin phenotypes were highly expressed in all the histological subtypes of AGA. The expression of the GI phenotype in SIG patients was lower than that in DAC patients (P = 0.02), and this phenotype was observed in 56% of the non-SIG patients in the intramucosal layer. Among non-SIG cases, the expression of the GI phenotype was significantly higher in patients with extended adenocarcinomas and those with positive rates of lymph node metastasis. There was no difference between the expressions of the G and other GI phenotypes factors. Among DAC and non-SIG patients, there were no differences between the survival rates of the corresponding patient groups. CONCLUSION: The GI phenotype might possess more invasive characteristics than the G phenotype in non-SIG. Neither of the phenotypes indicated a poor prognosis of DAC and non-SIG.

The pathobiological behaviors and prognosis associated with Japanese gastric adenocarcinomas of pure WHO histological subtypes.

Japan is a high-risk region for gastric carcinoma with a comparatively early stage and favorable prognosis. To clarify the pathobiological behaviors and prognosis of Japanese gastric adenocarcinoma, we analyzed the clinicopathological characteristics of different WHO subtypes of carcinomas. The expression of ki-67, CPP32, p53, FHIT, maspin, parafibromin, GRP78, GRP94, EMMPRIN, VEGF, P-GSK3beta-ser9, fascin, cortactin, Arp2, Arp3 MUC-2, MUC-5AC and MUC-6 was examined using immunohistochemistry and tissue microarrays. The majority of cases were well-, poorly-, or moderately-differentiated subtype, whereas the minority were papillary or signet ring cell carcinoma (SRC). Patients with poorly-differentiated or SRC carcinoma were predominantly young and female. Poorly-differentiated and mucinous carcinomas were larger, with deeper invasion, more venous or lymphatic invasion, frequent lymph node involvement and peritoneal dissemination, or higher staging. The SRC group exhibited weaker expression of ki-67, CPP32, p53, parafibromin, GRP78, GRP94, P-GSK3beta-ser9, VEGF or cortactin. The moderately-differentiated subtype exhibited lower expression of FHIT and Arp3 positivity. The poorly-differentiated group showed weaker expression of CPP32, EMMPRIN, MUC-2, MUC-5AC, and MUC-6. Survival analysis indicated that the patients with poorly-differentiated or mucinous subtypes had a lower cumulative survival rate than those with papillary, well-, moderately-differentiated, or SRC carcinomas (P<0.05). The age, invasive depth, lymphatic invasion, peritoneal dissemination, and WHO classification were independent prognostic factors for carcinoma patients (P<0.05). It was suggested that poorly-differentiated and mucinous subtypes are more aggressive and of unfavorable prognosis among Japanese gastric carcinomas. Lower levels of proliferation and apoptosis, as well as alterations in tumor suppressor genes, mucin production and ER stress protein played important roles in the pathogenesis of poorly-differentiated and SRC carcinomas.

Goblet or signet ring cells: that is the question.

Goblet cell carcinoid tumor is a rare mixed endocrine-exocrine neoplasm of the appendix. It carries an intermediate biologic behavior between a classic carcinoid tumor and a conventional adenocarcinoma. There has been a general lack of clinicopathologic parameters that can be reliably used to predict the clinical course and patient outcome. A recent retrospective study of a large number of appendiceal goblet cell carcinoids has shown that these tumors can be stratified into 3 subgroups based on careful histologic analysis: typical goblet cell carcinoid (group A); adenocarcinoma ex goblet cell carcinoid, signet ring cell type (group B); and adenocarcinoma ex goblet cell carcinoid, poorly differentiated carcinoma type (group C). Clinical follow-up data show that the histologic classification correlates with patient survival. Thus, meticulous histologic evaluation is of critical importance in determining the prognosis and guiding the management of patients with goblet cell carcinoids. This brief review summarizes these recent findings and raises a few issues that may need to be further addressed to better apply this classification to our practice.

Signet ring cells in fine needle aspiration cytology of breast carcinomas: review of the cytological findings in ten cases identified by histology.

OBJECTIVE: To establish whether the presence of signet ring cells (SRCs) in histology sections of breast carcinoma cases was reflected by their presence in fine needle aspiration cytology (FNAC) smears, correlating to the histological type of breast carcinoma. METHODS: We reviewed the FNAC findings of ten cases that had been diagnosed as primary breast carcinoma with SRCs on histological sections between 1998 and 2007. Slides and histological sections were obtained from the archives of Ege University Hospital. RESULTS: FNA smears were reviewed for the following cytomorphological features: background, cellularity, architecture, nuclear pleomorphism and the presence of SRCs. The background was bloody in eight cases, necrotic in one, and clean in one. There was no mucinous material in any of the cases. Cellularity was prominent in five cases (hypercellular), moderate in three (cellular) and low in two (hypocellular). Loosely cohesive groups of tumour cells of varying size were observed in all cases. A plasmacytoid appearance to some of the tumour cells was seen in all cases and discohesive tumour cells were present in eight. Nuclear pleomorphism was high in six cases and moderate in four. SRCs were observed in seven of the ten cases. Two of these seven cases also had a tubular pattern and one had tumour giant cells. CONCLUSIONS: FNAC should be evaluated carefully regarding the presence of SRCs when cells with a plasmacytoid appearance are observed in either hyper- or hypocellular smears. The presence of single SRCs in FNACs with hypercellularity, high nuclear grade and tubular formation or tumour giant cells may be a clue in favour of ductal carcinoma. The presence of single SRCs in FNACs with hypocellularity and mild to moderate nuclear grade may be suggestive of lobular carcinoma. However, larger studies would be needed to establish the predictive value of the presence of SRCs on FNAC.

Two distinct groups of colorectal cancer in inflammatory bowel disease.

BACKGROUND: The histological variability in colitis-associated colorectal cancer (CRC in inflammatory bowel disease [IBD]) and the association to clinical factors is unknown. METHODS: In population-based material including 67 patients with CRC in IBD, histopathology of the cancers and tissue samples from different colorectal localizations were reevaluated, and relationships to clinical factors analyzed. RESULTS: Forty-three of 60 patients (75%) showed dysplasia in the colorectum apart from the cancer, while 17 (25%) had no dysplasia at cancer diagnosis. Mean age at onset of IBD was 22 years in patients with and 34 years in patients without dysplasia (P = 0.01). The mean duration of colitis-CRC interval was 21 years in patients with and 16 years in patients without dysplasia (P = 0.02). The latter group included all patients with a colitis-CRC interval <10 years. Active inflammation was more likely to occur in patients with dysplasia (odds ratio [OR] 4.2). The 2 groups were not discriminated by gender, family history of CRC or IBD, diagnosis of PSC, medical treatment, active symptoms, or histological features like type of cancer and differentiation. In multiple logistic regression analysis the age at onset of IBD was the strongest predictive variable for dysplasia at cancer diagnosis (P = 0.025). CONCLUSIONS: Widespread neoplasia occurs in the majority of cases with CRC in IBD and is associated with early onset of IBD. Localized neoplasia occurs in about a quarter of the patients and shows an association with late-onset IBD. The 2 groups probably represent different pathogenetic entities of neoplasia in IBD. This might have consequences for surveillance strategies.

Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.

Appendiceal tumors exhibiting both neuroendocrine and glandular differentiation are uncommon and have caused difficulty in pathologic classification, prediction of prognosis, and clinical management. Previously, such lesions have been variously designated as adenocarcinoid, goblet cell carcinoid (GCC), and mixed adenocarcinoma carcinoid. In this study, we undertook a retrospective investigation of 63 such cases and classified them as typical GCC (group A) and adenocarcinoma ex GCC on the basis of the histologic features of the tumor at the primary site. The adenocarcinoma ex GCC group was further divided into signet ring cell type (group B) and poorly differentiated adenocarcinoma type (group C). The clinical characteristics and prognosis were compared within these groups and with conventional de novo appendiceal adenocarcinomas. Both groups A and B tumors shared a similar immunoprofile, which included generally focal immunoreactivity for neuroendocrine markers, and a normal intestinal type mucin glycoprotein profile (negative MUC1 expression and preserved MUC2 immunoreactivity). The proliferative index was relatively low in these tumors and slightly increased from groups A to B tumors (11% to 16%). Both beta-catenin and E-cadherin exhibited a normal membranous staining pattern in groups A and B tumors. The poorly differentiated adenocarcinomas ex GCC (group C) demonstrated abnormal p53 and beta-catenin immunoreactivity. The mean follow-up time was 49+/-5 (SE) months. The overall disease-specific survival for all subtypes was 77%, with 46% of patients without evidence of disease and 31% alive with disease. The mean survival was 43+/-7 months. All the patients with clinical stage of I or IIA disease had a favorable outcome after appropriate surgery with or without chemotherapy. Although most patients (63%) with GCC presented at an advanced clinical stage, their clinical outcome could be differentiated by subclassification of tumors. The stage IV-matched 5-year survival was 100%, 38%, and 0% for groups A, B, and C, respectively. In conclusion, GCC is a distinctive appendiceal neoplasm that exhibits unique pathologic features and clinical behavior. They display a spectrum of histologic features and possess the potential to transform to an adenocarcinoma phenotype of either signet ring cell or poorly differentiated adenocarcinoma types. Careful evaluation of the morphologic features of GCCs and appropriate pathologic classification are crucial for clinical management and prediction of outcome. Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C).

Phenotypic classification of gastric signet ring cell carcinoma and its relationship with clinicopathologic parameters and prognosis.

AIM: To distinguish subtypes of gastric signet ring cell (SRC) carcinoma by investigating the expression of gastric and intestinal phenotypic markers, and to study the significance of phenotypic classification in predicting tumor progression and outcome. METHODS: Immunohistochemistry was performed in 66 cases of SRC carcinoma with MUC2, VILLIN, CDX2, Li-cadherin antibodies as intestinal phenotype markers and MUC5AC, HGM, MUC6 antibodies as gastric phenotype markers, and the relationship was analyzed between the phenotypic expression pattern and clinicopathologic parameters, as well as the 3-year survival rate. RESULTS: Expression of intestinal phenotypic markers was positively associated with tumor size, wall invasion, vascular invasion, lymph node metastasis and tumor-node-metastasis (TNM) stage. Cases expressing one or more intestinal markers had a significant lower survival rate than cases expressing none of the intestinal markers. CONCLUSION: The SRC carcinomas expressing intestinal phenotype markers exhibited a high proliferative potential, bad biological behaviors and poor prognosis. Examination of phenotype expression may be useful in distinguishing histological type and in predicting the prognosis of gastric SRC carcinoma.