Signet ring cells in breast carcinoma. An immunohistochemical and ultrastructural study.

Two cases of breast carcinoma composed predominantly of neoplastic cells with a signet ring appearance, one a case of invasive lobular carcinoma (ILC) and the other a case of invasive ductal carcinoma (IDC), were examined electron microscopically and immunohistochemically. In signet ring cells in the ILC, mucin was demonstrated ultrastructurally in the intracytoplasmic lumina and also to a small degree in the cytoplasmic mucous granules, whereas in signet ring cells in the IDC, mucin was found only in the cytoplasmic mucous granules. Immunohistochemically, signet ring cells in the ILC were intensely positive for gross cystic disease fluid protein (GCDFP-15), but those in the IDC showed no immunoreaction for GCDFP-15. Thus ultrastructural features and GCDFP-15 immunoreactivity appear to be useful for distinguishing between the two different types of signet ring cells.     

Gastric metastasis of mammary signet ring cell carcinoma--a differential diagnosis with primary gastric signet ring cell carcinoma.

Metastasis of breast carcinoma to the stomach is relatively uncommon, although metastasis to other organs such as lung, bone, and lymph nodes is not rare. It may cause difficulty in differentiating from primary gastric carcinoma. We report a case of signet ring cell carcinoma of the breast with metastasis to the stomach with illustrations of histologic findings of both lesions. The results of immunohistochemical stainining with GCDFP-15 (gross cystic disease fluid protein-15), that can be used to differentiate primary gastric signet ring cell carcinoma and metastatic mammary signet ring cell carcinoma, are described.     

上皮钙依赖粘附素相关分子在乳腺浸润性小叶癌和导管癌中的表达及意义

目的 探讨上皮钙依赖粘附素相关分子α-、β-、γ-catenin在乳腺浸润性小叶癌（ILC）和浸润性导管癌（IDC）中的表达及其意义。方法 采用免疫组织化学LSAB法检测了19例ILC和32例IDC组织中α-、β-、γ-catenin的表达,并根据阳性癌细胞占肿瘤细胞的比例进行半定量化分析和统计学x^2检验。结果 α-、β-、γ-catenin在19例ILC中表达缺失和明显减少的分别为15例（78.9%),10例（52.6%)和16例（84.2%),而在32例IDC癌组织中的表达缺失和明显减少为24例（75.0%),14例（43.8%)和26例(81.3%)例。另外,这3种蛋白在浸润性癌组织中表达强度弱于原位癌灶的表达强度。α-catenin和β-catenin在乳腺浸润性癌中的表达具有明显的正相关性,未发现α-、β-、γ-catenin在乳腺浸润性癌中的表达与有无伴有淋巴结转移病例之间的关系有统计学意义。结论 α-、β-、γ-catenin在乳腺ILC和IDC中表达均为明显缺失和减少,说明这些粘附分子在乳腺浸润性癌发生中确实丧失了其正常的细胞粘附功能。     

Primary mucin-producing adenosquamous carcinoma of the thyroid gland

A rare case of mucin-producing adenosquamous carcinoma of the thyroid gland is reported in a 57-year-old woman. Light microscopically, much of the tumor showed a feature of mucin-producing adenosquamous carcinoma; squamous cells and mucous signet ring cells. In the lower portion of the tumor, a calcified area containing small foci of follicular carcinoma and its squamous cell metaplasia was accompanied. Histochemically, neutral, non-sulphated and sulphated acid mucins were found in the mucous cells, and no thyroglobulin or calcitonin was detected in the tumor cells. Electron microscopically, some tonofibrils and mucin production were observed concomitantly in the tumor cells. These findings suggested the possibility that this mucin-producing adenosquamous carcinoma originated from squamous cell metaplasia of pre-existing follicular carcinoma.     

Neuroendocrine and mucinous differentiation in signet ring cell carcinoma of the stomach: evidence for a common cell of origin in composite tumors

Composite tumors are rare neoplasms containing a mixture of 2 different cellular components present in roughly equal proportions. It is hypothesized that composite tumors arise from a multipotential stem cell with subsequent bidirectional differentiation. We present an unusual composite tumor of the stomach composed equally of signet ring cell carcinoma and low-grade neuroendocrine carcinoma. Twenty-one additional patients with signet ring cell carcinomas of the stomach were studied to determine the prevalence of neuroendocrine differentiation by morphology and immunohistochemistry for synaptophysin and chromogranin A. Immunohistochemistry for mucins 5AC and 2 was performed to assess for divergent differentiation toward foveolar and intestinal mucin phenotypes, respectively, and to evaluate for any potential relationship with neuroendocrine differentiation. We found morphologic evidence of neuroendocrine carcinoma in 4 (19%) of 21 consecutive signet ring carcinomas. E-cadherin immunostaining was subsequently performed on these 4 tumors plus the index case. All 5 tumors demonstrated concordance between the signet ring and neuroendocrine components. There was no distinct relationship to mucin 5AC/mucin 2 profiles, with the exception that all 11 intramucosal signet ring cell carcinomas from 4 patients with germ line cadherin 1 gene mutations were composed exclusively of mucin 5AC+ signet ring cells that lacked intestinal mucin and neuroendocrine differentiation. The concordant E-cadherin status in the neuroendocrine and signet ring cell tumor components and the frequent admixture of mucin 5AC+ cells with foveolar differentiation and mucin 2+ cells with intestinal differentiation may support the hypothesis that composite tumors arise from a common stem cell with bilineage or multilineage differentiation.     

PRIMARY MUCIN-PRODUCING ADENOSQUAMOUS CARCINOMA OF THE THYROID GLAND

A rare case of mucin-producing adenosquamous carcinoma of the thyroid gland is reported in a 57-year-old woman. Light microscopically, much of the tumor showed a feature of mucin-producing adenosquamous carcinoma; squamous cells and mucous signet ring cells. In the lower portion of the tumor, a calcified area containing small foci of follicular carcinoma and its squamous cell metaplasia was accompanied. Histochemically, neutral, non-sulphated and sulphated acid mucins were found in the mucous cells, and no thyroglobulin or calcitonin was detected in the tumor cells. Electron microscopically, some tonofibrils and mucin production were observed concomitantly in the tumor cells. These findings suggested the possibility that this mucin-producing adenosquamous carcinoma originated from squamous cell metaplasia of pre-existing follicular carcinoma. ACTA PATHOL. JPN. 37: 1157 -1164, 1987.     

Mucin-producing carcinomas of the breast: ultrastructural observations

The ultrastructural characteristics of mucin production in mammary mucoid carcinoma, signet ring cell carcinoma (Harris, Wells & Vasudev 1978), papillary carcinoma and lobular carcinoma are compared. The mucin in lobular carcinoma is confined to intracytoplasmic lumina whereas it is present as membrane bound granules in the other three types, although intracytoplasmic lumina also occur in the latter. A possible origin of intracytoplasmic lumina from distended Golgi cisternae is proposed. Possibly, extracellular mucin acts as a mechanical barrier between tumour cells and lymphatics, thus explaining the good prognosis of typical mucoid carcinomas.     

前列腺原发性印戒细胞癌的病理诊断和形态发生机制

目的：探讨前列腺原发性印戒细胞癌的组织发生、病理特征和鉴别诊断。方法：在262例经穿刺活检证实的前列腺癌中选出10例印戒细胞癌,用SP法作前列腺特异性抗原（PSA）、前列腺酸性磷酸酶（PAP）、雄激素受体（AR）等9种免疫组织化学标记和AB／PAS,黏液卡红染色,3例作电镜观察,并与10例胃肠道印戒细胞癌作比较。结果：10例中仅1例为纯印戒细胞癌,9例与经典型前列腺癌混合,印戒细胞癌成分均大于癌总量的25％。按形态特征和形成机制,可将印戒细胞分为胞质内空泡或内腔形成和胞质内PSA、PAP分泌物积聚二种类型,二种类型印戒细胞均缺乏胞质内黏液,故不同于消化道印戒细胞癌。结论：原发性印戒细胞癌是来自前列腺腺泡上皮的低分化特殊组织学类型腺癌。在穿刺活检中可以与来自消化道,泌尿道的浸润性或转移性印戒细胞癌鉴别,也不同于放疗或内分泌治疗后经典型前列腺癌的空泡变性。     

"Signet Ring" sinus histiocytosis mimicking metastatic adenocarcinoma: report of two cases with immunohistochemical and ultrastructural study.

The axillary lymph nodes from two patients with invasive breast carcinoma showed "signet ring" histiocytosis with sinusoidal distribution of cells having prominent cytoplasmic vacuolization which simulated metastatic adenocarcinoma. Immunohistochemical studies confirmed the histiocytic nature of the signet ring cells and eliminated the possibility of metastatic adenocarcinoma. Electron microscopy in one case revealed lipid within the cytoplasmic vacuoles. The etiology of this reactive change is unknown; however, a history of previous surgery involving the chest wall may be causally related with disruption of adipose tissue. Prior to ipsilateral mastectomy both patients had undergone a contralateral mastectomy for mammary carcinoma. Signet ring sinus histiocytosis is a reactive sinusoidal proliferation that can mimic metastatic carcinoma, but close inspection will usually reveal the histiocytic nature of the cells.     

胃印戒细胞癌癌旁粘膜球样异型增生的病理学观察

本文使用粘液组织化学和ＡｇＮＯＲ银染色方法，观察了胃印戒细胞癌癌旁粘膜的球样异型增生。从１１０例（３４例印戒细胞癌，７６例含印戒细胞的其他类型癌）中检出２８例存在球样异型增生（２５．５％），其中４例可见球样异型增生与癌移行。认为球样异型增生是胃印戒细胞癌发生的途径之一。     

Immunohistochemical characterization of a B-cell signet ring cell lymphoma. Report of a case

Signet ring cell lymphoma is a non-Hodgkin's lymphoma, characterized by neoplastic lymphoid signet ring cells very similar to epithelial mucin producing cells. We describe here a case of signet ring cell lymphoma in which the immunophenotypic markers of signet ring cells parallel those of plasma cells, being intensively T10+ (CD 38), weakly HLA-DR+, and To15 (CD 22) and T200 (CD 45) negative. The morphologic and immunohistochemical features of the case and the main differential diagnosis are preceded by a review of the literature.     

Clinicopathologic features and incidence of invasive lobular carcinoma in Japanese women

Intending to clarify the true Incidence of Invasive lobular carcinoma of the breast In Japanese women as well as the frequency of unilateral multlcentriclty, 362 cases of clinically defined monocentrlc breast cancer without pre-operative biopsy (previously fine needle aspiration or needle biopsy were routinely carried out for every case) were examined by whole mammary gland serial sectioning. On the basis of pathology and the World Health Organization classification of breast tumors, each case was assigned to one of two main histologlc types: Invasive lobular carcinoma (ILC) or Invasive ductal carcinoma (IDC). Invasive lobular carcinoma was further separated into classic and variant types by employing previously published criteria. Twenty-one cases of ILC (5.8%) were diagnosed, which Is more than In most previous Japanese studies. Unilateral multicentric breast carcinoma was detected In 9.5% of ILC and 16.1% of IDC (the difference was found not significant). Microscopically, ILC tumors were found to be, on average, larger than IDC. Patients with classic type ILC tended to be younger than those with variant type or IDC. Estrogen receptor expression was found more frequently In variant type ILC than in classic type. These results suggest that the incidence of invasive lobular carcinoma of the breast In Japanese women is low and that unilateral multicentricity Is not significantly higher in ILC than in IDC.     

乳腺原发性印戒细胞癌

目的：观察乳腺原发性印戒细胞癌的形态特征。方法：通过HE及AB/PAS染色,对4例乳腺原发性印戒细胞癌进行观察。结果：4例癌细胞内印戒细胞均超过205。HE染色呈典型印戒样细胞,AB/PAS染色胞质内阳性。导管内型及小叶型各1例,浸润性导管型及小叶型各1例。结论：乳腺原发性印戒细胞癌是一种特殊型癌,诊断时应排除转移性印戒细胞癌。     

Infiltrating lobular carcinoma of the breast with histiocytoid features: three cases

Histiocytoid carcinoma of the breast, a cellular variant of invasive breast cancer, is mainly found among infiltrating lobular carcinomas (ILC). It can be easily confused with benign conditions or other mammary tumors also composed of cells with a pink granular to foamy cytoplasm and an eccentric nucleus. We report 3 cases of histiocytoid ILC. Our aim is to discuss recent immunocytochemical data that could suggest a special type of apocrine differentiation of tumor cells, including a diffuse immunoreactivity for GCDFP-15 (Gross Cystic Disease Fluid Protein 15) and a predominant expression of androgen receptor, and to describe the features useful for the differential diagnosis.     

Clonal profiling of mixed lobular and ductal carcinoma revealed by multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization

A needle biopsy of a mass in the right breast of a 36‐year‐old woman revealed invasive ductal carcinoma (IDC), and approximately 20% of cancer cells showed unequivocal membranous staining with the HercepTest. After systemic therapy with trastuzumab and paclitaxel followed by FEC (fluorouracil + epirubicin + cyclophosphamide), a right mastectomy was performed. By histological and immunohistochemical examinations, the resected tumor consisted mainly of E‐cadherin‐negative invasive lobular carcinoma (ILC), and the rest was ERBB2‐positive IDC; thus, the diagnosis was mixed ductal and lobular carcinoma. Multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization (FISH) analyses revealed that ILC and IDC shared high‐level amplification of CCND1 in homogeneously staining regions (HSR) and that IDC had an additional HSR‐type amplicon of ERBB2. These findings strongly indicate that IDC and ILC had a common precursor cell with CCND1 amplification. Review of the biopsy specimen with FISH showed IDC with gene amplifications of CCND1 and ERBB2 as a minor component, IDC without amplification of CCND1 or ERBB2 as a major component, and a minute portion of ILC with CCND1 amplification. We speculate that chemotherapy and trastuzumab caused a marked reduction in IDC; however, ILC with CCND1 amplification was resistant to chemotherapy and grew.     

Pleomorphic lobular carcinoma in situ of the breast composed almost entirely of signet ring cells

Some examples of lobular carcinoma in situ (LCIS) may be composed in part of signet ring cells. Such proliferations have been considered examples of pleomorphic LCIS based on pathological features of the more conventional component. However, the occurrence of LCIS composed entirely of signet ring cells is extraordinarily rare. This report describes an example of an in situ proliferation that was composed almost entirely (>95%) of signet ring cells, which was unassociated with an invasive carcinoma and which showed comedo-type necrosis. There was only focal lobulocentric distention by lesional cells, as is typical of classic LCIS. However, discrete, ductal-type cross-sectional profiles showed a purely intraepithelial proliferation of remarkably discohesive signet ring cells. The signet ring cells had intermediate-grade nuclear atypia, no significant mitotic activity and were positive for mucicarmine and PAS stains (the latter with and without diastase predigestion). The cells displayed marked immunoreactivity for high-molecular-weight keratin (stained by 34beta E12 antibody), MUC1, gross cystic disease fluid protein-15, cytokeratin 7 and were negative for cytokeratin 20, E-cadherin, progesterone receptor and HER2/neu. It is concluded that this is an example of a purely signet ring variant of pleomorphic LCIS.     

Collecting-duct carcinoma of the kidney with prominent signet ring cell features.

We report a case in a 74-year-old woman of collecting-duct carcinoma of the kidney with prominent signet ring cell features. Grossly, the tumor measured 5.5 cm in greatest dimension, occupied the entire upper pole of the kidney, and was well circumscribed. Microscopically, it displayed a predominant tubulopapillary pattern of growth with a hyalinizing stroma. The tumor tubules were lined by a single layer of cells with large, pleomorphic nuclei, some of which had a hobnail appearance. Large intracytoplasmic vacuoles with compression of nuclei (signet ring cells) were present throughout the tumor. Alcian blue, mucicarmine, and periodic acid-Schiff stains failed to identify intracellular mucin or glycogen in the signet ring cells. Enlarged cells with intracytoplasmic vacuoles were also noted in the adjacent collecting ducts. The tumor cells were immunohistochemically positive for cytokeratin including cytokeratin 7, CAM 5.2, AE1/3, and 34 beta E12, vimentin, peanut lectin agglutinin, and Ulex europaeus agglutinin. Electron microscopy revealed that the intracytoplasmic vacuoles were due to intracellular edema. To the best of our knowledge, this is the first reported case of renal collecting-duct carcinoma with prominent signet ring cell features.     

原发性皮肤黏液癌3例临床病理观察及文献复习

目的：探讨原发性皮肤黏液癌的临床病理学特点及预后。方法：通过临床资料总结、病理形态学观察、免疫表型分析,并复习文献资料。结果：皮肤原发性黏液癌直径0.3~15 cm不等,生长缓慢,病程常为数月至数十年。组织学上,表皮完整,肿瘤主要位于真皮层,并常累及皮下脂肪组织,大量黏液形成黏液湖,纤细的纤维将黏液湖分隔成多房性、蜂窝状。黏液湖中可见散在岛状、簇状、小腺样肿瘤上皮团。肿瘤细胞小,呈立方形,胞浆丰富,细胞核小,未见核分裂。免疫组化：癌细胞例1：CEA、EMA、ER、PR、P53、CK7、GCDFP-15(+),TTF-1、S-100、CK20(?)。例2：CEA、EMA、P53、CK7、GCDFP-15(+),ER、PR、TTF-1、S-100、CK20(?),Ki-67低表达(1%~3%)。例3：CEA、EMA、CK7、GCDFP-15(+),P53、ER、PR、TTF-1、S-100、CK20(?), Ki67(+<10%)。结论：原发于皮肤的黏液癌少见,好发于老年男性的头面部,组织学上与转移性黏液癌鉴别困难,须结合临床及免疫组化标记排除转移癌后方可诊断。免疫组织化学多表达CK7、GCDFP-15、EMA、CEA,Ki67阳性率低<10%。治疗主要采用手术局部扩大切除肿瘤,预后较好。     

Expression of autophagy related proteins in invasive lobular carcinoma: comparison to invasive ductal carcinoma

The aim of this study is to compare the expression of autophagy related proteins in invasive lobular carcinoma (ILC) with that of autophagy related proteins in invasive ductal carcinoma (IDC), and to determinate its implication. Tissue microarray containing 114 ILC and 692 IDC was constructed, and immunohistochemistry was performed for autophagy related protein (beclin-1, LC3A, LC3B, p62) and Ki-67. No significant difference in expression of autophagy-related proteins between pleomorphic type (n = 12) and classic type (n = 102) of ILC was observed, whereas ILC and IDC showed distinguished features that tumoral beclin-1, stromal LC3A, tumoral LC3B, tumoral p62 were highly expressed in IDC and tumoral BNIP3 was highly expressed in ILC (P < 0.001). Beclin-1 expression was correlated with ER negativity (P = 0.016) and TNBC type (P = 0.024). BNIP3 expression was correlated with ER positivity (p = 0.040). Using multivariate Cox analysis, shorter overall survival was associated with tumoral beclin-1 positivity (hazard ratio: 21.19, 95% CI: 1.098-409.1, P = 0.043). In conclusion, ILC and IDC showed different expression pattern of autophagy-related proteins in tumor and stroma that demonstrated by higher expression of tumoral beclin-1, stromal LC3A, tumoral LC3B, tumoral p62 in IDC, and higher expression of tumoral BNIP3 in ILC.     

SIGNET RING CELL CARCINOMA IN A POLYP OF THE COLON

Undifferentiated adenocarcinoma of the colon occurring in a 6-year-old boy was presented. The tumor characterized by the signet ring cell appearance developed in a polyp of the descending colon. The signet ring cell carcinoma is in general a rare morphologic form of colonic carcinoma. According to our review of the literature there have been described 16 patients under 10 years of age with colonic or rectal carcinoma, disclosing 2 cases of undifferentiated or signet ring cell carcinoma including the present case. In children, mucin producing adenocarcinoma is the most predominant type of colonic carcinoma, and 48% of the colonic carcinomas are of signet ring cell carcinoma in children under 17 years of age.