Signet Ring Cell Change Research Articles

Diagnostic Pitfall of Gastric Signet-Ring Cells: How to Diagnose a Benign Signet-Ring Cell From a Malignant One.

Sometimes non-neoplastic changes of the gastric mucosa mimic diffuse-type gastric carcinoma, specifically signet-ring cell adenocarcinoma. In fact, gastric epithelial cells undergoing signet-ring cell change have a cellular morphology that is almost identical to signet-ring cell adenocarcinoma, often leading to misdiagnosis. Accurate recognition of signet-ring cell change is essential to avoid overdiagnosis and overtreatment of signet-ring cell adenocarcinoma. Research on this topic is limited and clinicians lack formal diagnostic tools when signet-ring cells are detected in biopsy specimens. The aims of this study are 3-fold. Firstly, to increase the awareness of both clinicians and pathologists of this rare but highly significant entity. Secondly, to report 4 additional examples of signet-ring cell change and analyze them alongside signet-ring cell adenocarcinoma to compare their morphological and phenotypic features and their evolution over time. Finally, to highlight the potential utility of endoscopic resection to confirm the diagnosis. Cells in signet-ring cell change strongly express E-cadherin, show a wild-type p53 expression, and have a low Ki67 index. In contrast, cells in signet-ring cell adenocarcinoma strongly express p53, have high proliferation rates, and show either no or weak E-cadherin staining. Genetic analysis may be useful in identifying patients at risk of hereditary early diffuse gastric adenocarcinoma, which can mimic signet-ring cell change.

Gastric biopsies that keep you up at night

The diagnosis of gastric carcinoma can be challenging in several situations. Diffuse-type carcinomas can be readily overlooked, especially when inconspicuous tumour cells infiltrate between benign gastric glands and elicit little, if any, stromal response. Metastases, particularly from the breast, bear striking similarities with gastric carcinomas and should always be considered in the differential diagnosis when poorly cohesive tumours develop in women. Benign mimics of diffuse-type adenocarcinoma can also result from artifactual or inflammation-induced disruption of non-neoplastic gastric epithelium. Benign foveolar epithelial cells assume a globoid appearance (i.e., signet ring cell change) when they are not confined to the basement membrane. Tubular adenocarcinomas show glandular crowding, branching, villiform or cribriform growth, and cystically dilated crypts that can simulate regenerative atypia. Rare tumours are extremely well-differentiated with minimal architectural abnormalities and only slight nuclear enlargement. Distinction between primary carcinomas and their potential mimics will be discussed during the presentation.

Degenerative Signet Ring Cell Change in a Bile Duct Brushing.

Degenerative Signet Ring Cell Change in a Bile Duct Brushing.

Invasive Lobular Carcinoma With Extracellular Mucin: Not All Mucinous Mammary Carcinomas Are Ductal!

Mucinous component in mammary carcinoma indicates ductal phenotype. Although intracytoplasmic mucin and signet ring cell change are frequently described with lobular carcinomas, extracellular mucin is not associated with lobular phenotype. We report 4 cases of invasive lobular carcinoma with extracellular mucin (ILCEM) and review findings of previously published cases of this rare ILC variant. Variable amount of extracellular mucin and pseudoglandular architectural pattern may lead to diagnosis of ILCEM as ductal mucinous carcinoma. Pathologists should be aware of this rare variant of ILC that will help identify more cases of this entity and clarify relevance of extracellular mucin production in ILC.

ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India.

ALK gene rearrangement in the lung adenocarcinomas is the second most common (1.6-11.7% of NSCLC) targetable genomic change after EGFR mutations. However, the prevalence and clinicopathological features of ALK-rearranged lung adenocarcinomas from North India are lacking. A total of 240 cases of lung adenocarcinoma were screened for EGFR mutations and for ALK expression. Smoking status, TNM stage, and treatment response were recorded in all cases. Out of 240 cases screened, 37 cases were positive for EGFR mutations and 17 cases (7.08%) showed ALK positivity with immunohistochemistry and break-apart FISH. On excluding 37 EGFR mutation-positive cases, the incidence of ALK-positive adenocarcinoma appears to be higher (17/203 cases, 8.03%). Eight were men and nine were women with mean age of 51.7 years. Majority (62.5%) were non-smokers and had unresectable disease (70.6% stage IV, 17.6% IIIB). The morphological patterns noted were solid (12 cases), papillary (four cases), and micropapillary (one case). Signet ring (two cases) and clear cell change (one cases) were noted. Out of five patients who received crizotinib, three had partial response and two had stable disease. ALK-rearranged lung adenocarcinomas account for a minor proportion of NSCLC with prevalence similar to that reported in literature. However, as contrast to published data in our series, patients were in older age group and had solid and papillary pattern on morphology with an aggressive course.

Florid artefactual signet ring cell change in the bladder: A report of two cases

Artefactual signet ring cell change has been reported in the prostate following transurethral prostatic resection (TURP), biopsy and simple prostatectomy. A similar feature has not however, been reported in the bladder. Herein, two cases of artefactual signet ring cell change occurring in the bladder are presented.

Admixed foamy cell and signet ring cell change in a cutaneous angiosarcoma – A diagnostic pitfall

Cutaneous epithelioid angiosarcomas are known to exhibit various morphological variations. The present case is first of its own kind describing admixture of foamy cell and signet ring cell morphological patterns in a case of cutaneous angiosarcoma occurring in a 64-year-old female. The initial incisional biopsy revealed predominantly cytoplasmic vacuolations in the tumor cells with only focal presence of typical angiosarcomatous component, while in subsequent resection specimen, these variations were present only focally with predominant classical angiosarcomatous areas. This case highlights the importance of awareness of such morphological variations in angiosarcomas as these can be easily missed or misdiagnosed in small biopsies due to sample selection.

The spectrum of rare morphological variants of cutaneous epithelioid angiosarcoma.

Unusual cytoplasmic alterations have recently been reported in poorly differentiated cutaneous angiosarcoma, making an accurate diagnosis challenging. As these tumours remain poorly documented, we aimed to study their clinicopathological characteristics more comprehensively. Six cutaneous angiosarcomas with unusual cytoplasmic alterations were identified from referral files. All tumours arose as nodules or plaques (range: 05-195 mm) on sun-damaged skin of the head and neck of elderly males (median age: 76.5 years). Histologically, the tumours were composed of enlarged epithelioid cells showing prominent signet ring (n = 3), foam (n = 2) or granular cell (n = 1) change. Vasoformative elements were only focally noted. By immunohistochemistry, all tumours expressed CD31 and avian v-ets erythroblastosis virus E26 oncogene homologue (ERG). Foam cell change was associated with additional expression of CD68 and CD163. Follow-up (median: 8 months) showed death from disease (n = 1), death from a gastrointestinal bleed (n = 1), and a cutaneous metastasis (n = 1). Only two patients are alive with no evidence of disease. Our findings outline the morphological spectrum of cytoplasmic change in cutaneous angiosarcoma. Awareness and a high degree of suspicion in the context of tumours affecting sun-damaged skin of the elderly are necessary to direct appropriate immunohistochemical work-up with inclusion of the endothelial cell markers CD31 and ERG.

Signet‐ring cell change in adenoid cystic carcinoma: a clinicopathological and immunohistochemical study of four cases

Signet-ring cell (SRC) change has not been reported in adenoid cystic carcinoma (ACC). The aim of this study was to describe the clinicopathological and immunohistochemical findings in four cases of ACC with SRCs (ACC-SRC), in which the relative proportion of the SRC component ranged from 25% to 50%. The median age was 58years (range: 48-81years), and all patients were women. The involved sites were sinonasal, lip, and submandibular. Two patients developed lung metastasis, and one died of disease 63months after tumour resection. Neither mucinous nor lipid substances were detected in the SRCs. These showed positive staining for AE1/AE3, cytokeratin 14, and epithelial membrane antigen, which highlighted the intracytoplasmic vacuole borders. The SRC nests were surrounded by myoepithelial cells positive for α-smooth muscle actin and p63. The SRCs showed similar p53 positivity but lower Ki67 and mitotic indices than the conventional component. SRCs were c-Myb-negative. Ultrastructural examination revealed that the intracytoplasmic vacuoles were lumina lined by microvilli. ACC-SRC is a non-mucin-producing and non-lipid-producing phenomenon, possibly related to disturbed differentiation of ductal/luminal cells. This cellular modification in ACC apparently does not change the biological behaviour of the tumour, but it may cause significant diagnostic problems, particularly in incisional biopsies.

Benign signet ring cells in pseudomembranous colitis: A diagnostic trap

A 71-year-old female patient was admitted with intractable diarrhea and abdominal distention following several courses of broad spectrum antibiotic therapy. Colonic biopsy revealed pseudomembranous colitis with foci of signet ring cell (SRC) change. The SRCs possessed bland nuclei and were confined to the basement membranes of the crypts with no infiltration into the lamina propria. Benign SRCs in pseudomembranous colitis is an uncommon phenomenon. Awareness of this rare, but potential pitfall is of utmost importance to avoid a misdiagnosis of SRC carcinoma.

Signet-ring cell change in adenoid cystic carcinoma: a clinicopathologic and immunohistochemical study of four cases.

Signet-ring cell (SRC) change has not been reported in adenoid cystic carcinomas (ACC). This study describes the clinicopathological and immunohistochemical findings in four cases of ACC with SRCs (ACC-SRC), in which the relative proportion of the SRC component ranged from 25% to 50%. The median age was 58 years (range: 48 to 81 y) and all patients were women. The involved sites were sinonasal, lip and submandibular. Two patients developed lung metastasis and one died of disease 63 months after tumor resection. Neither mucinous nor lipid substances were detected in the SRCs. These were positive for AE1/AE3, CK14 and EMA; which highlighted the intracytoplasmic vacuole borders. The SRC nests were surrounded by α-SMA and p63 positive myoepithelial cells. When compared to the conventional component, the SRCs exhibited similar p53 positivity but lower Ki-67 and mitotic indices. SRCs were C-Myb negative. Ultrastructural examination revealed that the intracytoplasmic vacuoles were lumens lined by microvilli. ACC-SRC is a nonmucin and nonlipid producing phenomenon, possibly related to disturbed differentiation of ductal/luminal cells. This cellular modification in ACC apparently does not change the biological behavior of the tumor but it may cause significant diagnostic problems, particularly in incisional biopsies. © 2012 Blackwell Publishing Ltd.

Urachal Carcinomas of the Nonglandular type

The vast majority of malignant urachal epithelial tumors have a glandular morphology (ie, adenocarcinoma), to which our principal understanding of urachal carcinoma and its prevailing set of diagnostic criteria are largely ascribed. The 2004 World Health Organization classification of genitourinary tumors recognizes other rarer histologic types of urachal carcinomas such as urothelial, squamous cell, and other carcinomas. However, the clinicopathologic data for these nonglandular groups of urachal carcinomas are very limited, being detailed only in sporadic case reports. Some of the criteria recommended for pathologic confirmation of urachal carcinomas were formulated almost exclusively for urachal adenocarcinoma and may not be relevant or applicable for nonglandular tumors. Here, we present 7 examples of pure (5) and mixed predominant (2) nonglandular urachal carcinomas. Patients were 45 to 85 years of age (mean, 64.1) with a male predominance (male-to-female ratio=6:1). Six tumors were related to the bladder [dome (3) or dome/supravesical (3)] and 1 was entirely supravesical. Histologically, 5 were urothelial carcinomas, of pure or mixed histology, all were high grade and invasive, and 2 were small cell carcinomas. Two urothelial carcinomas had focal (<5%) glandular differentiation and signet ring cell change, and 1 had admixed focal malignant squamous cells and high-grade dedifferentiated components. Four of 5 urachal urothelial carcinomas exhibited solid and partly cavitary or luminal growth with papillary structures and a variable amount of necrosis within the cavity. The 2 small cell carcinomas were pure, had classic undifferentiated neuroendocrine histology, were situated at the bladder dome, and were partly cavitary filled with necrotic debris. Urachal remnant was identified in 6 tumors mainly with dysplastic transitional cells in the urachal canal or rudimentary nests and tubules. All 6 bladder-related urachal tumors exhibited reverse invasive front from the surface, including 2 tumors that ulcerated the bladder mucosa. One tumor had concomitant in situ and noninvasive high-grade papillary urothelial carcinomas in the main bladder lumen. Sheldon stages at presentation were IIIA (2), IVA (3), and IVB (2). Follow-up in all 7 cases (<1 to 60 mo; median, 12.5 mo) showed that 6 patients had died of disease, including the 2 patients with small cell carcinoma. In conclusion, nonglandular urachal carcinoma may occur with pure histology or admixed with high-grade dedifferentiated morphologies and a minor adenocarcinoma component. These tumors may arise as deep-seated bladder-related or completely supravesical tumors along the urachal tract and may exhibit reverse invasive spread toward the bladder surface. Cavitary or luminal growth may occur that could be attributed to the intraurachal neoplastic proliferation. Urachal urothelial carcinomas in particular may contain papillary structures within the tumor and urachal cavity. Concomitant primary urothelial carcinoma outside of the urachus and tumor extension to bladder mucosa may occur, which should not negate diagnosis of an urachal primary. Behavior appears poor, as most tumors present with higher stage.

Nonneoplastic signet-ring cell change in gastrointestinal and biliary tracts: a pitfall for overdiagnosis

Nonneoplastic signet-ring cell change (SRCC) is a rare but known phenomenon in gastrointestinal and biliary tracts and is always associated with underlying mucosal ulceration/erosion secondary to infection, ischemia, or other etiology. Because nonneoplastic SRCC closely mimics signet-ring cell adenocarcinoma (SRCA), differentiation of these 2 entities is critical because misdiagnosis of nonneoplastic SRCC as SRCA can lead to intense therapeutic interventions such as surgery and/or chemoradiation therapy. In this review, a brief overview on nonneoplastic SRCC in gastrointestinal and biliary tracts, including the spectrum of clinical presentation, important histologic features, and immunohistochemical markers that are useful in differentiating nonneoplastic SRCC from SRCA, is provided. The pathogenesis of nonneoplastic SRCC in gastrointestinal and biliary tracts is discussed.

Gastric pseudo-signet ring cells: a potential diagnostic pitfall

Signet ring cells are characterised by a cytoplasmic inclusion or vacuole that pushes and displaces the crescent-shaped nucleus to the periphery of the cell. When the nuclei of the cells are hyperchromatic, pleomorphic and manifest mitoses, and when the cells infiltrate the lamina propria, this represents the histologic hallmark of signet ring cell carcinoma. The review of the medical literature reveals that the occurrence of mucus-negative pseudo-signet ring cells was first described in gastrectomy specimens of Japanese patients 25 years ago [1]. The authors of this paper Rubio et al. continued to publish extensively on this topic and postulated that these “pseudo-signet cells” or “glassy cells” may be due to environmental exposures [2]. Benign epithelial signet ring cells in the stomach have also been reported previously in association with ischaemia and ulceration [3–5]. We report two cases of benign signet ring cell change in gastric biopsy specimens which we believe to be a degenerative non-neoplastic change.

Reticulin Staining Clarifies Florid Benign Signet Ring Cell Change With Mitotic Activity in a Penetrating Gastric Ulcer

Signet ring cell change is a benign process that can be mistaken for signet ring cell adenocarcinoma. Signet ring cell change remains confined within the basement membrane and lacks an infiltrative growth pattern. It typically lacks cellular atypia, nuclear hyperchromasia, prominent nucleoli, or mitotic activity. This study illustrates a case of signet ring cell change with mitotic activity in a background of Helicobacter pylori gastritis with a penetrating ulcer. The signet ring cell change shows normal E-cadherin expression, absence of p53 expression, and confinement within glands on reticulin staining. The intact gastric mucosa adjacent to the signet ring cells shows significant mitotic activity, which likely explains the mitoses within the signet ring cell change. Mitotic activity in signet ring cells should be interpreted in the context of adjacent mucosa and should not preclude the diagnosis of benign signet ring cell change. Reticulin staining of the involved glands is helpful for excluding the invasion of the lamina propria in signet ring cell change.

Non-neoplastic endometrial signet-ring cell change

Background Non-neoplastic signet-ring cell change in the endometrium appears to be a degenerative phenomenon associated with abnormal bleeding and exogenous hormone use. It more often occurs from the fourth decade onwards. Understanding this change can aid in distinguishing this condition from potential malignant mimicks. Case report We report four cases of endometrial curettings displaying florid non-neoplastic endometrial signet-ring cell change from women in their fourth and fifth decades with menorrhagia and/or post-menopausal bleeding. All women were on exogenous hormone therapy. All biopsies showed inactive endometrium, with prominent stromal pseudo-decidualisation. The decidual cells showed prominent cytoplasmic vacuolation and were negative for mucin (PAS-D, Alcian blue, mucicarmine), pancytokeratins (AE1/AE3) and histiocytic markers (CD68, MAC387). Electron microscopy showed the vacuoles devoid of organelles. Follow-up curettings showed no neoplastic change. Discussion Non-neoplastic signet-ring change should be recognised and reported where present. The change was first described as an idiopathic postmenopausal decidual reaction. It was recognised as a potential mimick of metastatic carcinoma. The incidence of non-neoplastic endometrial signet-ring cell change is not known. Further study is required to understand this change, and may provide insight to an individual’s response to a specific exogenous hormone regime. A panel of histochemical and immunohistochemical methods should be applied to differentiate this change from various signet-ring cell neoplasms. Conclusions Non-neoplastic endometrial signet-ring cell change is a benign condition. It is important to differentiate this change from a primary or secondary signet-ring cell neoplasm.

Nonneoplastic signet-ring cells in the gallbladder and uterine cervix. A potential source of overdiagnosis

We describe 3 cases of nonneoplastic signet-ring cell change in ulcerated mucosa, 2 of them in the gallbladder and 1 in an endocervical polyp. In the gallbladder cases, there were focal collections of signet-ring cells both on the mucosal surface and within the lumen of tubules, whereas in the endocervical polyp, the signet-ring cell aggregates were entirely confined to the mucosal surface. In all 3 cases, the signet-ring cells were positive for Mayer's mucicarmine and immunoreactive for keratin AE1/AE3. The lack of nuclear atypicality, the arrangement in superficial and intraluminal nests, and the admixture with histiocytes and other inflammatory cells are in keeping with the interpretation that the signet-ring cells are disrupted mucosal goblet cells exhibiting hyperplastic and degenerative changes. A review of the literature disclosed only other 2 previously reported cases of benign signet-ring cell changes in the gallbladder and none--to the best of our knowledge--in an endocervical polyp. Awareness of this phenomenon is of importance to avoid a potential overdiagnosis of signet-ring cell adenocarcinoma.

Urothelial Signet-Ring Cell Carcinoma of the Renal Pelvis with Collagenous Spherulosis: A Case Report

We present a unique case of urothelial carcinoma of the right renal pelvis. It occurred in a 58-year-old woman. The tumor was located in the renal pelvis with extension into the adjacent renal medulla and cortex. Two years after surgical excision the patient is free of recurrence and metastasis. The tumor was well demarcated, without capsule, firm, solid, and whitish on the cut surface. It was 3x4 cm in largest diameter and without signs of necroses and hemorrhages. The tumor did not infiltrate the ureter. Histologically the predominant pattern of the tumor was adenocarcinomatous differentiation, and only very rare foci of urothelial carcinoma composed of typical transitional cells were found. No signs of intestinal type of metaplasia and adenocarcinoma, changes similar to the cystitis cystica or cystitis glandularis, were found in the tumor or in its vicinity. Most of the tumor looked like solid nests composed of cells with intracytoplasmic lumens. The resulting appearance was that of typical signet-ring cell change. These solid nests were usually surrounded by columnar epithelium, which in many areas formed papillary structures. A very striking feature was formation of collagen spherules. Small collagen spherules were often surrounded by a layer of the neoplastic cells so that collagenous rosettes were formed. In some areas these collagenous spherules clustered together so that they formed areas of collagenous spherulosis. The collagen in the spherules reacted positively with collagen IV. Ultrastructurally these spherules were formed by basal membrane-like material. Intracytoplasmic lumens of the signet-ring cell change were endowed by slender microvilli at ultrastructural level.

Primary signet-ring stromal tumor of the testis

We present, in a 47-year-old man, the first case of the signet-ring stromal tumor of the testis. The tumor was located beneath the tunica albuginea surrounded by the testicular tubules and rete testis. It was sharply circumscribed by a thin and irregular fibrous capsule. Histologically, it was composed of cells with a widespread signet-ring cell change separated by fibrous stroma. In some places, the signet-ring cells formed vague Indian files, thus resembling metastatic carcinomas with signet-ring cell morphology. Under high magnification, most of the cytoplasm of the tumor cells was seen to be replaced by an empty clear vacuole which pushed the nuclei to the periphery of the cells. Some of the nuclei were indented by the cytoplasmic vacuoles, others were without indentation. Only in a small area did the tumor show cells without a signet-ring cell change. They looked like epithelioid fibroblasts forming abortive and vaguely tubular structures. Mitoses and necroses were absent. Mucicarmine and PAS stains were negative. Immunohistochemically, the tumor was vimentin positive and it was negative with antibodies to cytokeratins, inhibin, prostatic acid phosphatase, prostate-specific antigen, smooth muscle actin, S-100 protein, EMA and calretinin. The signet-ring stromal tumor of the testis is thus similar morphologically and immunohistochemically to the signet-ring stromal tumor of the ovary. The patient was free of recurrence and metastasis 3 years after the excision.

Benign Signet Ring Cell Change with Multilayering in the Gallbladder MucosaA Case Report

We describe a case of benign signet ring cell change in the gallbladder mucosa. On histopathological examination of H & E-stained sections, the gallbladder epithelium showed multilayering. The epithelial cells were large, columnar to polygonal with a small round basal or eccentric nucleus and vacuolated cytoplasm, giving them a signet ring appearance. There was no nuclear atypia, hyperchromatism or mitotic activity. The cells showed uniform positivity with mucicarmine, PAS and Alcian blue stains. The cytoplasmic vacuolations were negative for fat stains (Oil red O and Sudan IV). On immunohistochemistry, the cells showed positivity with antibodies for pancytokeratin (PCK) and epithelial membrane antigen (EMA). A diagnosis of benign signet ring cell change with multilayering in the gall bladder mucosa was made. Thoroughly reviewing the literature, we found only one case of benign signet ring cell aggregates in the gallbladder mucosa documented earlier. The lesion is hereby reported because of the unique histomorphology and the diagnostic dilemma which can occur as a malignant change in situ has to be excluded.