Lobular carcinoma of the breast with extracellular mucin: New variant of mucin‐producing carcinomas?

The presence of mucin in infiltrating lobular carcinomas has been described as occurring exclusively in an intracytoplasmic location. To the best of the authors' knowledge, infiltrating lobular carcinoma displaying extracellular mucin has not been described in the literature. Herein is presented a case of lobular carcinoma with extracellular mucin in a 60-year-old female patient, who also had a contralateral ductal carcinoma of the cribriform type. Histologically the tumor had the classical appearance of infiltrating lobular carcinoma with signet ring cells and 'Indian file' infiltration of the stroma as well as pools of extracellular mucin. It is of great importance to appropriately classify breast carcinomas as ductal or lobular in origin due to the different treatment, prognosis, and clinical behavior of these lesions. The present finding opens the door for discussion of the current knowledge concerning histological variants of lobular carcinoma and should alert pathologists to the fact that the presence of extracellular mucin in an otherwise classical infiltrating lobular carcinoma does not preclude this diagnosis.     

Patterns of immunohistochemical staining for proliferating cell nuclear antigen and p53 in benign and neoplastic human endometrium

Signet ring cell differentiation in adenocarcinoma of the prostate is uncommon. In a review of 200 cases of prostatic carcinoma, we identified five cases with this change, all in moderately to poorly differentiated prostatic carcinomas. The signet ring cells in prostatic carcinoma contain an intracytoplasmic lumen, shown on electronmicroscopy to be lined by microvilli. Transition stages were seen from solid to acinar to signet ring cells to mucinous variants. We believe that this change is part of the spectrum of appearances of prostatic carcinoma and should not be regarded as a subtype of specific significance.     

Primary signet ring cell carcinoma of the breast

Three examples of primary signet ring cell carcinoma of the breast are described. This form of breast carcinoma deserves recognition as an entity because its prognosis may differ from colloid carcinoma of the breast and because of potential difficulty in distinguishing it from metastatic carcinoma.     

An ultrastructural study of mucoid carcinoma of the breast: variability of cytoplasmic features

The ultrastructural characteristics of 14 cases of mucoid carcinoma of the breast, with different histological appearances, have been examined. Thirteen of the tumours were observed to consist of two populations of tumour cells, one showing secretory changes while the other group showed no evidence of activity. In one tumour only synthetically active cells were observed. Ultrastructurally, six different types of cytoplasmic granules, comprising typical mucin plus glycoprotein or protein-containing granules, were identified within the synthetically active tumour cells. The number of types of granules and the relative proportion of the various granules varied between tumours with only mucin granules present in all tumours. It would appear that synthetic pathways are activated in certain tumours which result in protein/glycoprotein granules associated with the argyrophilia observed histologically. In addition, the tumours varied with respect to luminal differentiation, presence of intracytoplasmic lumina, intracytoplasmic mucin pools, lipid droplets, ciliated cells and areas of calcification. The marked heterogeneity of the ultrastructural features of the mucoid carcinoma of the breast prevents the tumours from being readily divided into distinct subgroups.     

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.     

Spindle cell squamous carcinoma: ultrastructural observations

Two spindle cell carcinomas of the skin and one of the breast have been studied by electron microscopy. In one tumour the spindle cells were of purely mesen-chymal type and in the other two the spindle cells exhibited both mesenchymal and epithelial features within the same cells. The significance of the findings in relation to the histogenesis of the spindle cells is discussed, with special reference to the possible alternative roles of mesenchymal metaplasia of the epithelial component and spontaneous cell fusion between carcinoma cells and stromal cells.     

Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas

Pleomorphic lobular carcinomas (PLC) of the breast display histological features associated with classic invasive lobular carcinoma (ILC), yet they also exhibit more conspicuous nuclear atypia and pleomorphism, and an aggressive clinical behaviour. From a breast cancer progression perspective, it is unclear whether PLC is a variant of ILC or is a high-grade invasive ductal carcinoma (IDC) that has lost E-cadherin. The molecular features of 26 PLC were studied using immunohistochemistry [oestrogen receptor (ER), progesterone receptor (PR), HER2, p53 and E-cadherin], 0.9 Mb resolution, microarray-based comparative genomic hybridization (aCGH), fluorescent (FISH) and chromogenic (CISH) in situ hybridization and loss of heterozygosity. Comparative analysis was performed with aCGH data from PLC with classic ILC (16 cases) and high grade IDC (35 cases). PLCs were frequently ER- and PR-positive, E-cadherin-negative and occasionally HER2- and p53-positive. Recurrent copy number changes identified by aCGH included gains on 1q, 8q, 11q, 12q, 16p and 17q and losses on 8p, 11q, 13q, 16q and Xq. Highly recurrent 1q+ (100% of cases), 16p+ (93%), 11q- (53%) and 16q- (93%) and evidence of the der(1;16)/der(16)t(1;16) rearrangement, as detected by FISH, suggested that PLC had a 'lobular genotype'. Focal amplifications were evident at 8p12-p11, 8q24, 11q13.1-q14.1, 12q14, 17q12 and 20q13. Loss of BRCA2 was detected in 40% of PLC by LOH. Comparative analysis of aCGH data suggested the molecular features of PLC (ER/PR-positive, E-cadherin-negative, 1q+, 11q(-), 16p+ and 16q(-)) were more closely related to those of ILC than IDC, implicating an overlapping developmental pathway for these lobular tumour types. Molecular alterations found in PLC that are more typical of high-grade IDC than ILC (p53 and HER2 positivity, 8q+, 17q24-q25+, 13q(-) and amplification of 8q24, 12q14, 17q12 and 20q13) are likely to drive the high-grade and more aggressive biology of PLC.     

Formation of intracellular lumina in human prostate carcinoma (DU145) cells,maturation into signet cells,and the cribriform morphology of tumors

The intracellular or intracytoplasmic lumen (IL) is an enigmatic histological structure that occurs in various tumor cells. A reassessment of diverse ILs fine-structure micrographs obtained out of previous studies encompassing the human prostate carcinoma (DU145) cell line and xenotransplanted carcinomas enabled us to propose aspects of ILs development in cancer cells: a combination of altered expressions in intercellular contacts and their cytoskeletal components would favor a disarray of self-apical polarity orientation; those defects, associated with a local, entwined enriched membranous structures growing as microvilli-like formations out of a disrupted endoplasm and trans-Golgi sorting, create ILs in cells’ perikarya. These misplaced intracytoplasmic domains can become enlarged through spaces made between the finger-like structures by accruing membranes of coalescent intracytoplasmic vesicles then adding microvilli and glycocalyx to constitute ILs. Cationic mucins added with or without a progressive or total loss of microvilli and content generate signet or ring cell, while ILs enlarge. Variable build-ups of these cells’ populations in carcinomas result in architectural mix-up of adjacent cells around these voids, misconstrued as new lumen, and establish a “cribriform” tumor pattern that often implies a poor cancer prognosis. Alternatively, cytotoxic changes caused by anticancer pro-oxidant treatment favor membrane alterations and exaggerate the ILs in xenotransplants into intracellular crypts that accompany other tumor degenerative changes.     

Stromal changes in invasive breast carcinoma: an ultrastructural study

The stroma in infiltrating breast carcinomas, with particular reference to stromal spindle cells, has been studied by electron microscopy. A mixture of cells including resting fibroblasts, active fibroblasts, early myofibroblasts, and mature myofibroblasts has been identified. In loose stroma, myofibroblasts possessed prominent organelles and showed secretory products along the cell surface, whereas in dense stroma, there was relative prominence of cytoplasmic filaments as well as other features consistent with a contractile state of myofibroblasts. The degree of myofibroblastic proliferation was related to the growth pattern of the tumour. It is suggested that the infiltrating process of cancer cells is analogous to wound production and healing with continuous granulation tissue and scar formation resulting in the characteristic desmoplastic reaction seen in certain breast carcinomas.     

Mucinous carcinoma of the rectum

We have studied and compared 316 mucinous and 45 signet ring cell carcinomas of the rectum with 413 non-mucinous carcinomas. Mucinous carcinomas were subdivided according to the amount of mucus which was gauged subjectively as either more or less than 75% of the tumour volume. Five year survivals for non-mucinous, mucinous (less than 75%), mucinous (greater than 75%) and signet ring cell carcinoma were 62%, 60%, 53% and 13%. Mucinous carcinomas (less than 75%) were relatively well differentiated and showed an age distribution identical to their non-mucinous counterparts, but differed in their strong association with villous adenoma. Mucinous carcinomas (greater than 75%) were less well differentiated and, like signet ring cell carcinomas, occurred in younger patients and showed no special association with villous adenoma. Clinically important and independent predictive variables were found by the method of multivariate regression analysis to be number of lymph node metastases, extent of spread in continuity, character of invasive margin and peritumoural lymphocytic infiltration. After adjustment for these factors, typing of rectal cancer as mucinous, non-mucinous and signet ring cell gave no additional, clinically useful prognostic information.     

Neuroendocrine (Merkel cell) carcinomas of the skin: an ultrastructural study of nine cases

Nine neuroendocrine tumors of the skin were examined by light and electron microscopy. The patients (7 males and 2 females) had an average age of 57 years. Seven tumors were located in the head and neck region. Light microscopic examination showed sheets of cells. In 4 cases, a tendency to form small groups of cells was observed. Contact with the epidermis was seen in only 2 cases. The dominant ultrastructural feature was the presence of cytoplasmic processes that contained membrane-bound granules 100-200 nm. Three tumors recurred locally, and in 7 patients, regional nodal metastases occurred. Three patients died of disseminated disease.     

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。     

Stromal changes in early invasive and non-invasive breast carcinoma: an ultrastructural study

Six examples of histologically diagnosed, non-invasive breast carcinomas were studied by electron microscopy to elucidate the ultrastructural features for an accurate diagnosis of in situ carcinoma. The results obtained revealed two patterns of basal lamina/stromal cells relationship. One pattern showed intact basal lamina with associated periductal stromal cells consisting entirely of fibroblasts, the other pattern showed disruption of basal lamina by gaps and malignant cell protrusions with associated stromal cells consisting of both fibroblasts and myofibroblasts. As myofibroblasts are not a component of normal breast stroma but are known to be a prominent feature in the stroma of infiltrating breast carcinoma, the present observations suggest that myofibroblastic proliferation around in situ carcinoma represents an early sign of carcinomatous infiltration. Hence the definitive diagnosis of non-invasive carcinoma of the breast requires an intact basal lamina and a complete absence of a myofibroblastic reaction.     

Cytoplasmic vacuolation,intracytoplasmic lumina,and DPAS staining in ductal carcinoma of the breast

A retrospective study was carried out on 30 cases of histologically proven invasive ductal carcinoma of the breast with a prior fine-needle aspiration (FNA) cytology. On evaluating the May-Grünwald-Giemsa (MGG) FNA smears, cytoplasmic vacuolation was observed in 70% cases. Positivity with periodic acid Schiff-positive, diastase-resistant (DPAS) staining was observed in 90% of cases. The chi(2) value on a McNemar test was 4.16. Thus, DPAS staining was significantly superior to MGG staining for picking up cytoplasmic vacuoles (P < 0.05). In 56.67% cases, DPAS staining showed an improvement in score as compared to MGG smears. This was highly significant (P < 0.001) on Wilcoxon matched-pairs signed-ranks test. Applying the strict criteria of thick-walled cytoplasmic vacuoles with a central darkly stained dot, none of our cases revealed true intracytoplasmic lumina. Larger studies are required to establish a role for DPAS staining in separating borderline, in situ, and invasive breast lesions, and to see if such positvity can be incorporated into the grading systems for breast carcinoma.     

Intracellular storage of IgA and secretory component in carcinomas of the female breast

Summary This study reports ten cases of mammary carcinoma with intracytoplasmic lumina and inclusion bodies visible by light microscopy; five tumors were classified as lobular in type and four as different forms of infiltrating ductular carcinomas. One tumor showed a lobular growth in combination with ductular structures. For the identification of the inclusion bodies, indirect immunofluorescence on paraffin embedded material was performed, which revealed IgA as well as secretory component within the intracytoplasmic lumina. It was concluded that the production of secretory component and the uptake of IgA is possible even in carcinomas without glandular structures, and that immunomorphology should supplement histological and histochemical evaluation in order to define the contents of intracytoplasmic lumina.     

Mucoid carcinomas of the breast: a study using mucin histochemistry and peanut lectin

The mucin secreted by mucoid carcinomas of the breast has been studied in a series of 20 tumours by histochemical methods and peroxidase labelled peanut lectin. The histochemical techniques showed that the carcinomas could be divided into two groups depending on whether the mucin was composed predominantly of acid or neutral mucopolysaccharides. The specific binding of peanut lectin to β -galactosyl groups, in combination with neuraminidase treatment, enabled further divisions to be made and so demonstrated the heterogenous nature of the mucin secreted by mucoid carcinomas and also the value of using lectins as specific probes in histological methods.     

Infiltrating lobular carcinoma of the breast

On review of the histology of 1050 primary breast carcinomas, 103 cases of infiltrating lobular carcinoma were identified and clinical and survival data collected in each case. The tumours were then separated into four groups on the basis of histological pattern and these groups shown to have significantly different survival times. Assessment of the presence of in situ carcinoma, elastosis and intracyto-plasmic lumina was performed in each case and the effect of these features on survival investigated. In addition to stage of disease at presentation, the major significant factor in predicting survival of patients with this type of invasive carcinoma is histological type.     

Chromogranin A expression correlates with tumour cell type and prognosis in signet ring cell carcinoma of the stomach

Aims:  To investigate neuroendocrine (NE) differentiation in gastric signet ring cell carcinoma (SRCC) using chromogranin A (CgA) as an indicator of a well-differentiated NE phenotype and to determine its relationship to cell type, stage and prognosis.
Methods and results:  102 SRCCs were categorized into five subtypes according to the predominant cell type in the World Health Organization classification. 38 cases (37.3%) showed focal or diffuse CgA positivity. The positive cells were mostly histiocytoid and eosinophilic SRCC cells and some were classical SRCC cells. Small cell and anaplastic-type SRCC cells were only rarely immunopositive. There was no significant relationship between CgA expression and the extent of invasion or presence of metastasis. However, a significant positive correlation existed between CgA positivity and favourable prognosis, with a tendency for greater positivity to be associated with better overall survival. Multivariate analysis showed expression of CgA to be an independent prognostic factor.
Conclusion:  CgA expression is restricted to certain tumour cell types and may help to predict prognosis in gastric SRCCs.     

Primary signet ring cell carcinoma of the pancreas: Cytopathology review of a rare entity

Primary signet ring cell carcinoma of the pancreas (PSRCCP) is an extremely rare diagnosis that has not been extensively studied in literature. Primary and metastatic neoplasms to the pancreas may exhibit cytomorphological similarities to signet ring cells, posing diagnostic challenges. In this article, we review PSRCCP and provide a study of several primary pancreatic neoplasms that may mimic the appearance of PSRCCP upon cytopathology evaluation, shedding light on the existence of this dilemma, and helping cytopathologists in navigating similar scenarios in their practice.