Presence Of Signet Ring Cells Research Articles

Glioblastoma with signet-ring morphology: a case report and review of the literature

Primary central nervous system tumors with signet-ring morphology are exceedingly rare. We report an unusual case of glioblastoma with signet-ring cell features in an 81-year-old woman. Microscopic examination revealed a highly anaplastic tumor, with a prominent proportion of tumor cells exhibiting signet-ring appearance characterized by classic round cytoplasmic inclusions and eccentrically positioned nuclei. The tumor cells were immunoreactive for glial fibrillary acidic protein and S100, and negative for cytokeratins, confirming their glial origin. Ultrastructurally, the tumor cells were noted to contain intermediate filaments, and by fluorescence in-situ hybridization analysis, they demonstrated intact 1p/19q. The presence of signet-ring cells in the central nervous system should immediately raise the suspicion of metastatic carcinoma, particularly from the upper gastrointestinal tract. In the present case, however, the morphological and immunohistochemical features were diagnostic of a malignant primary glial neoplasm (glioblastoma). This case highlights the diagnostic difficulties that can arise in such instances, given the rarity of signet-ring morphology in primary central nervous system tumors.

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

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. 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. 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. 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.

Primary Ovarian Mucinous Tumors With Signet Ring Cells

The distinction between a primary ovarian mucinous carcinoma or even a borderline mucinous tumor and a metastatic mucinous carcinoma may be difficult. A constellation of clinical, gross pathologic and morphologic features is used in this distinction. One of the most important morphologic features suggesting a metastatic mucinous carcinoma in the ovary is the presence of signet ring cells; these are considered rare in primary ovarian mucinous tumors. In this study, we report 3 primary ovarian mucinous tumors with a component of signet ring cells. The tumors arose in patients aged 27, 55, and 60, were unilateral, confined to the ovary and stage IA. They ranged from 9 to 27 cm; 1 was grossly a multiloculated cystic lesion and 2 were cystic and solid. In one case, the neoplasm had the architecture of a mucinous adenofibroma but had frankly malignant cells lining glands and forming solid aggregates of cells. A second tumor also had the background of an adenofibroma. The third was mostly a mucinous cystadenoma. In one case, endometriosis was present in the same ovary; teratomatous elements were not identified in any case. Immunohistochemistry, performed in 2 cases, showed both to be diffusely positive with CK7 and CA19.9, including the signet ring cells. CK20 was positive in both cases (1 focal; 1 diffuse). Estrogen receptor and CA125 were diffusely positive and carcinoembryonic antigen and CDX2 focally positive in 1 case. Chromogranin and synaptophysin were negative. Investigations to exclude a gastrointestinal neoplasm in 2 cases were negative. Features favoring a primary rather than a metastatic neoplasm are unilateral tumor, low stage, background of adenofibroma or cystadenoma, associated endometriosis in 1 case and an absence of features which are characteristic of secondary mucinous carcinomas in the ovary, such as surface tumor deposits, a nodular growth pattern, and lymphovascular permeation. Immunohistochemistry is of limited value because of overlapping immunophenotype between a primary ovarian mucinous tumor and a metastasis from the stomach, pancreas, biliary tree, appendix, or colorectum, the most likely primary sites for a secondary exhibiting similar features. Our study illustrates that signet ring cells occur rarely in a primary ovarian mucinous tumor; even when conspicuous the features differ from those of the usual Krukenberg tumor. At least some cases of so-called primary Krukenberg tumor may be similar to our cases. However, the designation primary Krukenberg tumor should not be used as, apart from the signet ring cells, a resemblance to a "true" Krukenberg tumor of the secondary type is limited. The tumors should be classified according to the underlying background neoplasm with a notation concerning the signet ring cell component.

Signet ring cell differentiation in mucinous colorectal carcinoma

Approximately 10% of all colorectal carcinomas are mucinous carcinomas, characterized by extracellular mucin. Occasionally, mucin accumulates intracellularly in these tumours, causing signet ring cell differentiation. We hypothesized that signet ring cells arise from a separate genetic pathway. In this study the molecular background of signet ring cell differentiation was investigated by analysing genetic changes, changes in the expression of adhesion molecules, and mucin content. Furthermore, its clinical relevance was addressed. Cell lines of colorectal tumours with non-mucinous (AC), mucinous (MC), and signet ring cell phenotype (MCSRC) were used for Multiplex Ligation-dependent Probe Amplification to detect deletions and amplifications in specific oncogenes and tumour suppressor genes. Furthermore, the expression of E-cadherin, beta-catenin, ITF (intestinal trefoil factor), and MUC2 in signet ring cells was studied by immunohistochemistry, immunofluorescence, and mRNA in situ hybridization. Results were validated using a large cohort of rectal carcinomas from which clinicopathological data were available. Specific amplifications and deletions in cell lines of AC, MC, and MCSRC were detected. Bcl-2 was amplified in MCSRC and MC cell lines, but not in AC cell lines. Bcl-2 FISH analysis confirmed this in patient material. Signet ring cells had decreased expression of adhesion molecules (E-cadherin, beta-catenin) and were strongly positive for ITF and MUC2, two peptides which are normally only produced by goblet cells. RNA in situ hybridization confirmed the production of ITF. Mucinous carcinomas with signet ring cell differentiation presented at a higher T stage than adenocarcinomas and mucinous carcinomas (16% pT4 versus 3-5%, p<0.001) and were more frequently node positive (77% vs 39-44%; p<0.001). Prognosis was significantly worse. In conclusion, the presence of signet ring cells in carcinomas with mucinous differentiation correlates with increased T-stage and poor prognosis. These cells, characterized by ITF and MUC2 production, show disruption of the E-cadherin/beta-catenin complex, as well as amplification of Bcl-2.

Carcinoma urotelial de alto grado vesical con patrón de células "en anillo de sello": A propósito de un caso

The presence of signet ring cells within a transitional cell carcinoma is a factor of poor prognosis. We report the case of a 69-year-old male patient with the diagnosis of high grade transitional cell carcinoma with signet ring cell pattern, the presence of which could have been foreseen in serial cytological tests performed after the clinical debut. To achieve such a diagnosis, it is necessary to rule out the possibility of metastasis or infiltration of a neoplasia from other organ. Both the presence of an in situ neoplasia or the coexistence of infiltrative transitional cell tumor can help to determine primary origin of these neoplasias.

Cancer gastrique héréditaire diffus

Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.

Signet-Ring Cell or Mucinous Histology after Preoperative Chemoradiation and Survival in Patients with Esophageal or Esophagogastric Junction Adenocarcinoma

The survival of patients with local-regional adenocarcinoma of the esophagus or esophagogastric junction (EGJ) treated with preoperative chemoradiation is much better in patients with pathologic complete response than those with residual tumor. Some adenocarcinomas have mixed patterns, including signet-ring cell and mucinous histology, but the clinical significance of these subtypes is unknown. We studied 412 consecutive patients with esophageal or EGJ adenocarcinoma treated with chemoradiation followed by esophagectomy (193 patients) or surgery alone (219 patients). We evaluated signet-ring cell and mucinous histology in the resection and pretherapy biopsy specimens and compared clinicopathologic features with overall survival. The fraction of signet-ring cell and mucinous histology was similar in evaluated specimens of patients treated with preoperative chemoradiation or surgery alone (17% and 18%, respectively). The overall survival rate at 5 years of patients treated with preoperative chemoradiation was significantly better if residual signet-ring cell or mucinous histology was present in the esophagectomy specimen (63% versus 28%; P = 0.02). All 13 patients with acellular mucin pools and no residual carcinoma are still alive after an average follow-up time of 36 months. By contrast, in patients treated with surgery alone, overall survival rate was significantly worse if signet-ring cell or mucinous histology was present (14% versus 30%; P = 0.05). In multivariate analysis, overall survival was independently predicted by presence of signet-ring cell or mucinous histology (P = 0.04). Our study showed that patients with esophageal or EGJ adenocarcinoma who have signet-ring cell or mucinous histology benefited substantially from preoperative chemoradiation and esophagectomy.

Clinical Relevance of Sialyltransferases ST6GAL-I and ST3GAL-III in Gastric Cancer

Aberrant glycosylation of membrane components due to specific alterations of glycosyltransferase activity is a common feature of carcinoma cells and is usually associated with invasion and metastasis. In a prospective study, the enzyme activity of the sialyltransferases ST6GAL-I and ST3GAL-III was studied in gastric cancer and normal mucosa in 55 patients by a radiometric assay. Cellular localization of sialyltransferase ST6GAL-I mRNA expression was studied by in situ hybridization. Sialyltransferase ST6GAL-I mRNA expression was mainly localized to epithelial cells. ST6GAL-I enzyme activity was enhanced within the tumor tissue. Significant correlations were found between the presence of signet ring cells and enhanced ST6GAL-I activity in the tumor tissue (p = 0.047) or in the mucosa (p = 0.024), and between signet ring cells and ST3GAL-III activity in the mucosa (p < 0.001). Multivariate Cox analysis demonstrated that only lymph node metastases (p = 0.044) had a significant influence on tumor-related survival. ST3GAL-III and ST6GAL-I activity showed no independent prognostic relevance in multivariate analysis, but high levels of ST3GAL-III and ST6GAL-I in the tumor tissue correlated with secondary local tumor recurrence (p = 0.005; p = 0.012). Interestingly, also the nonmalignant and uninvolved mucosa of tumor patients was altered on the molecular level and in some cases showed enhanced sialyltransferase levels indicative of the alteration of glycosylation very early during tumorigenesis.

Histopathological Identification of Colon Cancer with Microsatellite Instability

Cancer with high levels of microsatellite instability (MSI-H) is the hallmark of hereditary nonpolyposis colorectal cancer syndrome, and MSI-H occurs in approximately 15% of sporadic colorectal carcinomas that have improved prognosis. We examined the utility of histopathology for the identification of MSI-H cancers by evaluating the features of 323 sporadic carcinomas using specified criteria and comparing the results to MSI-H status. Coded hematoxylin and eosin sections were evaluated for tumor features (signet ring cells; mucinous histology; cribriforming, poor differentiation, and medullary-type pattern; sponge-like mucinous growth; pushing invasive margin) and features of host immune response (Crohn's-like lymphoid reaction, intratumoral lymphocytic infiltrate, and intraepithelial T cells by immunohistochemistry for CD3 with morphometry). Interobserver variation among five pathologists was determined. Subjective interpretation of histopathology as an indication for MSI testing was recorded. We found that medullary carcinoma, intraepithelial lymphocytosis, and poor differentiation were the best discriminators between MSI-H and microsatellite-stable cancers (odds ratio: 37.8, 9.8, and 4.0, respectively; P = 0.000003 to < 0.000001) with high specificity (99 to 87%). The sensitivities, however, were very low (14 to 38%), and interobserver agreement was good only for evaluation of poor differentiation (kappa, 0.69). Mucinous histopathological type and presence of signet ring cells had low odds ratios of 3.3 and 2.7 (P = 0.005 and P = 0.02) with specificities of 95% but sensitivities of only 15 and 13%. Subjective interpretation of the overall histopathology as suggesting MSI-H performed better than any individual feature; the odds ratio was 7.5 (P < 0.000001) with sensitivity of 49%, specificity of 89%, and moderate interobserver agreement (kappa, 0.52). Forty intraepithelial CD3-positive lymphocytes/0.94 mm2, as established by receiver operating characteristic curve analysis, resulted in an odds ratio of 6.0 (P < 0.000001) with sensitivity of 75% and specificity of 67%. Our findings indicate that histopathological evaluation can be used to prioritize sporadic colon cancers for MSI studies, but morphological prediction of MSI-H has low sensitivity, requiring molecular analysis for therapeutic decisions.

The influence of infiltrating lobular carcinoma on the outcome of patients treated with breast-conserving surgery and radiation therapy.

The role of conservative surgery and radiation therapy (CS and RT) in the treatment of patients with infiltrating ductal carcinoma is well established. However, the efficacy of CS and RT for patients with infiltrating lobular carcinoma is less well documented. The goal of this study was to examine treatment outcome after CS and RT for patients with infiltrating lobular carcinoma and to compare the results to those of patients with infiltrating ductal carcinoma and patients with mixed ductal-lobular histology. Between 1970 and 1986, 1624 patients with Stage I or II invasive breast cancer were treated with CS and RT consisting of a complete gross excision of the tumor and > or = 6000 cGy to the primary site. Slides were available for review for 1337 of these patients (82%). Of these, 93 had infiltrating lobular carcinoma, 1089 had infiltrating ductal carcinoma, and 59 had tumors with mixed ductal and lobular features; these patients constitute the study population. The median follow-up time for surviving patients was 133 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. Additional histologic features assessed for patients with infiltrating lobular carcinoma included histologic subtype, multifocal invasion, stromal desmoplasia, and the presence of signet ring cells. Five and 10-year crude results by site of first failure were similar for patients with infiltrating lobular, infiltrating ductal, and mixed histology. In particular, the 10-year crude local recurrence rates were 15%, 13%, and 13% for patients with infiltrating lobular, infiltrating ductal, and mixed histology, respectively. Ten-year distant/regional recurrence rates were 22%, 23%, and 20% for the three groups, respectively. In addition, the 10-year crude contralateral breast cancer rates were 4%, 13% and 6% for patients with infiltrating lobular, infiltrating ductal and mixed histology, respectively. In a multiple regression analysis which included established prognostic factors, histologic type was not significantly associated with either survival or time to recurrence. Patients with infiltrating lobular carcinoma have a similar outcome following CS and RT to patients with infiltrating ductal carcinoma and to patients with tumors that have mixed ductal and lobular features. We conclude that the presence of infiltrating lobular histology should not influence decisions regarding local therapy in patients with Stage I and II breast cancer.

Diagnostic significance of 'benign pairs' and signet ring cells in fine needle aspirates (FNAs) of the breast.

Most breast mass lesions are readily characterized by FNA with cytodiagnosis. Occasionally, benign but markedly proliferative lesions are diagnostically difficult to separate from well differentiated malignancies. We present information pertaining to the diagnostic significance of two cytologic findings observed in breast aspiration specimens, namely pairs of stripped bipolar nuclei and signet ring cells (SRC). We have evaluated aspirate smears from 219 cases of histologically proven benign (n = 114) and malignant (n = 105) breast lesions. Both singlets and pairs of bipolar nuclei and SRC were enumerated, and their numbers were correlated to histological diagnosis. Closely associated pairs of stripped bipolar nuclei were found in 68% of benign lesions compared with only 3.8% of carcinomas, establishing their presence as a highly specific indicator of a benign process. Large numbers of such 'benign pairs' also favoured the diagnosis of fibroadenoma. SRC were identified in 66% of histologically proven carcinomas (67% of ductal and 70% of lobular). SRC were also present in 10% of histologically benign cases. In the malignant cases, SRC were most frequently noted in a single cell distribution or within small, loosely cohesive tissue fragments. In the benign instances, SRC were most commonly noted within large fragments, and many of these cells were proved by immunohistochemical reactions to be vacuolated myoepithelial cells. We conclude that the presence of bipolar nuclei in closely associated pairs suggests benignity and aids in the subclassification of benign breast masses. In addition, the presence of SRC does not aid in the classification of tumour subtype (ductal vs lobular), and the occurrence of such cells in the proper context should prompt surgical biopsy.

Diagnostic significance of signet ring cells in fine-needle aspirates of the breast.

Fine-needle aspiration (FNA) is a reliable and cost-effective procedure in the evaluation and management of breast lesions. One diagnostic dilemma that may sometimes arise is the finding of signet ring cells. The isolated finding of such cells in aspirate smears may be particularly problematic in cases of low cellularity or those with otherwise benign features. Although it is generally held that such cells are almost exclusively associated with carcinoma (particularly the lobular subtype), their significance in FNA smears has never been systematically evaluated. To establish their diagnostic utility, we evaluated aspirate smears from 150 cases of histologically proven benign (77) and malignant (73) breast lesions for the presence of signet ring cells, defined as those containing a prominent intracytoplasmic vacuole with nuclear displacement. Signet ring cells were identified in 71% of malignant cases (75% of ductal carcinomas and 71% of lobular carcinomas), mostly as single cells or within small, loosely cohesive tissue fragments. Such cells also present in 6% of histologically proven benign lesions, most commonly within large tissue fragments. Many of these cells were proven to be vacuolated myoepithelial cells, based on histologic correlation and immunostaining results using anti-muscle-specific actin. On the basis of these findings, we conclude that (1) the presence of signet ring cells within small loose tissue fragments or as single cells in FNA smears should prompt close clinical follow-up (including repeat FNA and perhaps surgical biopsy), regardless of smear cellularity, (2) the presence of signet ring cells in cases of adenocarcinoma does not predict a particular tumor subtype, and (3) rare benign breast lesions may contain signet ring cells, particularly within large tissue fragments, and do not, in isolation, warrant surgical biopsy to exclude malignancy.

Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.

The following methodologies may be strictly applied to quantitatively evaluate patients with peritoneal carcinomatosis or sarcomatosis in regard to disease progression or regression: (1) Preoperative CT scan and the intraoperative assessment of cancer extent is analyzed region by region (AR-0-12) and an estimation of tumor volume (V0-V3) is evaluated according to the standardized scoring system previously described. At laparotomy, the volume of tumor nodules to adjacent organs, the viscosity (mucinous vs. solid) of tumor mass, and the pattern of distribution is assessed. (2) Radiologic abdominopelvic CT parameters that predict an incomplete cytoreduction are focal obstructions of bowel by CT assessment and tumor involvement of proximal ileum (AR-11). (3) The extent of prior surgical interventions (PS-1 through PS-3) must be recorded because aggressive deep dissections without perioperative chemotherapy severely jeopardize the possibility for complete cytoreduction. (4) Many tumor samples should be sent for histopathologic analysis. A proportion of mucin > 80% confirms a mucinous cancer. The malignant differentiation of cells, stroma morphology, the presence of signet ring cells, and evidence of invasion are used to grade cancers as mucinous tumor grade 0-3 (MTG-0 through MTG-3). (5) Once the cytoreductive procedure is accomplished, the surgeon estimates the residual volume of disease. (6) Objective response criteria from CT scan, tumor marker, and radiolabeled monoclonal antibody studies are necessary in a regular follow-up schedule.

Colorectal carcinoma associated with ulcerative colitis: A study of prognostic indicators

Fifty-two patients with ulcerative colitis and colorectal cancer undergoing colectomy at the Mount Sinai Hospital between 1973 and 1988 were studied retrospectively to determine the correlation of age, sex, duration of colitis, tumor location, number of cancers, tumor differentiation, colloid content, presence of signet ring cells, Dukes' classification, and DNA ploidy with survival. The mean age was 45 years, with a mean duration of colitis of 21 years. Five patients (10%) had Dukes' A lesions, 17 (33%) had Dukes' B lesions, 17 (33%) had Dukes' C lesions, and 13 (25%) had distant metastases. Thirty patients (58%) had well- or moderately differentiated tumors, whereas tumors were poorly differentiated in 22 (42%). Twenty-eight patients (54%) had colloid tumors, and, in 14 (27%), signet ring cells were present. Thirty-one patients (60%) had nondiploid tumors. Actuarial analysis revealed that the 5-year survival rate was significantly worse for patients with nondiploid tumors (76% versus 32%). When stratified by stage, only patients with Dukes' C lesions showed a significant difference in survival for diploid versus nondiploid tumors. Multivariate analysis showed that the Dukes' classification was the best prognostic indicator, followed by tumor differentiation and DNA ploidy. Tumor location, colloid content, number of cancers, duration of disease, age, and sex did not correlate with the prognosis.

Signet-ring cells in advanced gastric cancer. A clinical, pathological and histochemical study.

A pathological and histochemical study on the presence of signet-ring cells (SRC) in 108 advanced gastric cancer (AGC) has been evaluated. According to Laurén's classification, 59 were of intestinal (I) and 49 of diffuse (D) type. The amount of SRC seems to be a prognostic parameter in D-carcinoma: the 5-year survival rate was 49% and 22% in cases with 1-24% and 75-100% SRC, respectively. Histochemically, in our series of SRC D-carcinoma the quality of mucin secretion of SRC closely resembled the goblet cells of intestinal metaplasia. The histogenetic origin of D-gastric carcinoma was discussed.