E-cadherin status in breast cancer correlates with histologic type but does not correlate with established prognostic parameters

Our objective was to assess the loss of E-cadherin (EC) as a diagnostic marker or a predictor of prognosis. We stained 276 breast carcinomas with monoclonal antibodies to EC (invasive lobular carcinomas [ILC] and variants, 59; invasive ductal carcinoma and ductal special types [IDC], 204; tubulolobular carcinoma [TLC], 4; and invasive carcinoma [IC], uncertain whether lobular or ductal type, 9). The results were as follows: EC+IDCs, 99.5%; EC-ILCs, 90%; EC+ILCs, 10%; EC+pleomorphic ILCs, 20%; EC-ICs, 44%. All 4 TLCs showed positive tubules while cords were negative. Statistically a correlation of EC loss with a positive diagnosis of ILC was found but there was no correlation with any prognostic tumor variables. A negative EC stain confirms the diagnosis of ILC (specificity, 97.7%; negative predictive value, 96.8%; sensitivity, 88.1%; positive predictive value, 91.2%). EC is helpful in classifying cases with indeterminate histologic features. EC loss is uncommon in nonlobular carcinomas with no correlation to currently established prognostic variables.     

Invasive breast cancer: Current perspectives and emerging views

Invasive breast cancer constitutes a heterogeneous group of tumors. They comprise various histological types that differ in clinical presentation, imaging features, histopathological characteristics, biomarker profiles, prognostic and predictive parameters. The current classification of invasive breast cancer is based primarily on histopathological features. Invasive carcinoma of no special type accounts for the majority, with some rare entities also being described. With recent research and advances, there are emerging concepts, including new genetic insights of invasive breast cancer and the role of the stromal microenvironment. With greater understanding of the pathogenesis of invasive breast cancer, changes based on the correlation of histologic and genetic findings have been incorporated in the latest World Health Organization classification of breast tumors. Medullary carcinomas are subsumed as invasive carcinoma of no special type with basal‐like and medullary features, regarded as part of the spectrum of tumor infiltrating lymphocyte‐rich breast cancers. Tall cell carcinoma with reversed polarity is proposed as a distinct entity in recognition of unique IDH2 mutations. This article reviews conventional prognostic parameters, new histological entities, and updates on breast cancer classification, with inclusion of some genetic insights into breast cancer and the role of tumor infiltrating lymphocytes.     

Patterns of distribution of cytokeratins 20 and 7 in special types of invasive breast carcinoma: a study of 123 cases

Metastatic adenocarcinomas of unknown primary site are a common clinical problem. Invasive ductal carcinomas of the breast and some special types of invasive breast carcinoma are common sources of metastases. Immunohistochemical algorithms, such as a combination of cytokeratins 20 and 7, can be helpful in this situation. Detailed phenotyping of the different types and subtypes of primary invasive carcinomas and their metastases is an essential prerequisite for a successful search for an unknown primary tumor. A series of 123 primary invasive breast adenocarcinomas of special type and of 27 lymph node metastases was analyzed. Sections of selected blocks were stained with two monoclonal cytokeratin antibodies (CK20 and CK7) and evaluated as negative (no staining), focally positive or diffusely positive. Of the 123 carcinomas, 113 (92%) proved to be CK20 negative. Three of 82 (4%) invasive lobular carcinomas, three of 11 (27%) mucinous carcinomas, one of 10 (10%) tubular carcinomas, and one invasive papillary carcinoma stained diffusely with CK20. Additionally, a tubulolobular carcinoma and a medullary carcinoma showed focal CK20 positivity. One hundred twenty (98%) of the 123 tumors were CK7 positive, five of them only focally. One of the four solid invasive lobular carcinomas, one medually carcinoma, and one invasive papillary carcinoma were completely negative for CK7. Only two cases, one mucinous and one invasive papillary carcinoma, exhibited the CK20(+)/CK7(-) ("colorectal") pattern. One of the lymph node metastases was CK20(+); another was CK7(-). Like their ductal counterparts, invasive breast carcinomas of special type are usually CK20(-)/CK7(+); they generally retain this phenotype in their metastases. However, there are CK20-positive special-type breast carcinomas that can be confused with gastrointestinal or pancreaticobiliary carcinoma in metastases, especially if they are mucinous or invasive lobular.     

HER2/neu amplification in breast cancer: stratification by tumor type and grade

The presence of HER2/neu gene amplification is prognostically and therapeutically significant for patients with breast cancer. We sought to determine whether a relationship exists between HER2/neu gene amplification and the histologic type and grade of tumor. The histologic features and corresponding HER2/neu amplification results of 401 cases of invasive breast carcinoma were reviewed. Lobular carcinomas were less likely than ductal carcinomas to have HER2/neu amplification. Amplification was less frequent in Scarff-Bloom-Richardson grade I ductal carcinomas than in grades 2 and 3. Metastatic carcinomas frequently displayed HER2/neu amplification (6/20 [30%]). Our results support a correlation between HER2/neu amplification and the histologic type and grade of breast cancer. We suggest reexamination of tumors diagnosed as Scarff-Bloom-Richardson grade I invasive ductal carcinomas or lobular carcinomas if the lesion displays HER2/neu amplification to assure the exclusion of a higher grade of lesion or of missed ductal components.     

Oncocytic carcinoma of the breast: frequency, morphology and follow-up

Oncocytic breast carcinomas are tumors composed of no fewer than 70% of oncocytic cells (World Health Organization). The purpose of this study was to determine the frequency, morphologic, immunohistochemical, and clinical features of invasive oncocytic carcinoma in a large series. Twenty-eight cases of putative oncocytic breast carcinoma (selected cases group) and 76 consecutive cases of invasive breast carcinoma (consecutive cases group) were analyzed. Immunohistochemistry for mitochondria, gross cystic disease fluid protein 15, chromogranin, estrogen receptor, progesterone receptor, androgen receptor, HER2/Neu, cytokeratin 7, cytokeratin 14, epithelial membrane antigen, and differentiation cluster 68 was performed. Score for mitochondria was based on intensity and percentage of immunopositive cells. Classes were as follows: (1) oncocytic carcinoma: at least 70%, 3+; (2) mitochondrion-rich carcinoma: 50% to 70%, 3+, or more than 50%, 2+; and (3) all the other cases were referred to as invasive breast carcinoma. Ultrastructural examination was available for 6 cases of oncocytic carcinoma. Morphologic and immunohistochemical features of the 3 groups were compared using Fisher exact test (P < .05). For overall survival analysis, Kaplan-Maier curves were compared using log-rank and Wilcoxon tests (P < .05). Our results suggest that oncocytic breast carcinoma is a morphologic entity with distinctive histologic and ultrastructural features. Mitochondrion-rich carcinomas are histologically similar to oncocytic carcinomas and constitute 19.7% of all invasive carcinomas, indicating that cytoplasmic eosinophilia in breast cancer cells is often due to accumulation of mitochondria. Oncocytic carcinomas and mitochondrion-rich carcinomas are more often grade III tumors and show human epidermal growth factor receptor 2 overexpression. Clinical features and overall survival of oncocytic carcinomas are not distinctive because they are similar to those of the other cases when matched for grade and stage.     

Tumor-infiltrating lymphocytes and PD-L1 in breast cancer (and,what happened to medullary carcinoma?)

Tumor-infiltrating lymphocytes (TILs) and PD-L1 have emerged as important immune biomarkers in breast cancer, particularly triple negative breast carcinomas (TNBC) and human epidermal growth factor-2 positive (HER-2⁺) breast carcinomas. These components of the tumor immune microenvironment can be harnessed or targeted with immunotherapy, which represents a significant advancement in the management of TNBC. TILs are a prognostic biomarker in breast cancer, and this recognition has led to reclassification of medullary carcinoma (which were TILs rich by definition) as a pattern of invasive ductal carcinoma (no special type) rather than a distinct histologic type. PD-L1 is a predictive biomarker in TNBC, and two different PD-L1 assays have been approved as companion diagnostics for immune checkpoint inhibition in TNBC. This review will cover the roles of TILs and PD-L1 testing in breast cancer, both of which provide important clinical information to guide patient prognosis and therapy. This is a rapidly evolving and exciting field with significant implications for patient care.     

The thyroid gland: recurring problems in histologic and cytologic evaluation

Nodules of the thyroid gland are frequently encountered, occurring in up to 7% of the population, and although most of these nodules are benign, carcinomas of the thyroid gland are the most common malignancy of the endocrine system. Although the different types of thyroid carcinoma are few, a wide variety of recurring problems exists in both their histologic and cytologic evaluation. Here, I will review a selected group of problematic areas, including unusual histologic variants of follicular adenoma, criteria for diagnosing minimally invasive follicular carcinoma, the use of fine-needle aspiration as a screening test for follicular neoplasia, challenging variants of papillary carcinoma, and features of poorly differentiated carcinoma.     

Merkel cell carcinoma,melanoma, metastatic mimics of breast cancer

Merkel cell carcinoma and melanoma can each occur primarily in breast skin, or metastasize to the breast. The breast is a rare site of metastasis of essentially any and every type of tumor, including carcinomas, sarcomas, and hematolymphoid neoplasms, and 10–30% of breast metastases may represent the initial presentation of disease. Although metastases generally recapitulate histologic features of the primary tumor, they are diagnostically challenging given their rarity and morphologic overlap with breast carcinoma, including special types of breast cancer. Histologic clues may include lack of carcinoma in situ, lack of central elastosis, pattern of infiltration around normal breast structures, yet none of these are specific. Careful correlation with clinical history and judicious use of immunostain panels is essential in approaching these cases.     

Expression of c-kit in adenoid cystic carcinoma of the breast

Breast adenoid cystic carcinoma (BACC) is a biologically distinct tumor with morphologic mimickers, which might make accurate classification problematic. Because c-kit expression has been reported in adenoid cystic carcinoma of various anatomic sites, we evaluated BACC for c-kit by immunohistochemical analysis, comparing the findings to similarly stained mimickers. Tested cases included 6 BACCs, 15 low-grade infiltrating ductal carcinomas (LGIDCs) chosen as potential mimickers, and 15 head-neck adenoid cystic carcinomas (HNACCs). All BACCs showed plasma membranous and cytoplasmic staining equal to or greater than that of adjacent benign epithelium. Five BACCs (83%) expressed c-kit in more than 50% of tumor cells. Only 2 of 15 LGIDCs expressed low-intensity, focal c-kit staining. Of the 15 HNACCs, 10 (67%) expressed c-kit. Hormone receptors were consistently negative in BACCs. All BACCs expressed c-kit, whereas LGIDCs infrequently expressed low-intensity c-kit. Immunohistochemical evaluation for c-kit might aid in accurately classifying carcinomas with histologic features overlapping adenoid cystic carcinoma and LGIDC.     

Pathological prognostic factors in breast cancer. IV: Should you be a typer or a grader? A comparative study of two histological prognostic features in operable breast carcinoma

In a study of 1529 patients with primary operable breast carcinoma we have assessed the effect of applying both histological grade and tumour type to determine their comparative value as prognostic factors in human breast cancer. The prognostic group the patient was placed in, based on histological type alone, was less accurate than using grade and type together for many tumours. The importance of performing histological grading of ductal/no special type carcinoma (50% of the women in this series) is confirmed in this series. The 10-year-survival varied from 76% for women with grade 1 carcinoma to 39% for those with grade 3 tumours. Some of the 'special types' of breast carcinoma including tubular, tubulo-lobular, invasive cribriform and grade 1 mucinous carcinomas behaved as would be predicted, with a greater than 80% 10-year-survival in this series. Others, including grade 2 mucinous carcinomas, however, behaved less well with a 60% to 80% 10-year-survival. Indeed, many of the histological tumour types including tubular mixed, ductal/no special type, mixed ductal with special type and lobular carcinomas of classical, solid or mixed types showed a variation in behaviour that could not be predicted by typing alone. Histological grade and tumour type, when used together, more accurately predicted prognosis. In multivariate analysis of a larger group of 2658 cases of primary breast carcinomas (including the 1529 study cases) when histological grade, lymph node status and tumour size were entered, grade was the most important factor in predicting for survival. When histological type of carcinoma was included it was also found to be independently significant, although comparatively of less importance than grade. We conclude that tumours should be typed and graded in order to predict prognosis most accurately and to enable the choice of optimum treatment for women with primary breast carcinoma.     

Invasive carcinomas of the male breast: a morphologic study of the distribution of histologic subtypes and metastatic patterns in 778 cases

The current investigation was conducted to evaluate the proportional distribution of the various histologic subtypes (including newly recognized variants) of male breast carcinomas, to determine whether any histologic subtypes occur with a frequency that is markedly discordant with the expected frequencies from published data on parallel female breast tumors. We also aimed to document the distribution of malignancies metastatic to the breast. Seven hundred fifty-nine archived cases of primary invasive carcinoma involving the male breast were retrieved and subcategorized into histologic subtypes according to contemporary criteria. Six hundred forty-three (84.7%) tumors were pure infiltrating ductal carcinoma (IDC) not otherwise specified. The most common of the remainder included papillary carcinoma with invasion in the form of IDC (n = 34), mixed IDC and mucinous carcinoma (n = 26), and pure mucinous carcinoma (n = 21). In 19 cases, metastases from other sites involved the breast, most commonly (58%) cutaneous melanoma. Invasive carcinoma of the male breast appears to display a morphologic spectrum and distribution of histologic subtypes that is comparable to those of the female breast, with some expected variation. Compared with published experience on their female counterparts, there is a two-fold increase in the frequency of invasive papillary carcinoma in the male breast. Finally, the most common tumor metastatic to the male breast in this series was cutaneous melanoma. The opinions and assertions contained herein are the private views of the authors and are not to be considered official or as necessarily reflecting the opinion of the United States Government or any of its subsidiaries.     

Breast carcinoma with micropapillary features: clinicopathologic study and long-term follow-up of 100 cases

To study the clinicopathologic characteristics and prognosis of invasive micropapillary carcinoma of breast (IMPC), 100 cases of invasive breast carcinoma with an IMPC component were reviewed. Compared with invasive ductal carcinoma, not otherwise specified, with similar histologic grades, carcinomas with IMPC were larger sized, had a higher lymph node metastasis rate with more nodes involved per case, and exhibited increased lymphovascular invasion. The presence of IMPC strongly correlated with the more aggressive behavior. No significant association was established between the proportion of the IMPC component and overall tumor size, histologic grade, lymph node metastasis rate, and distant metastasis, but a trend was noted. Long-term follow-up demonstrated a poorer 5-year and 10-year survival rate for patients with breast carcinoma containing an IMPC component. Breast carcinomas with micropapillary features are more aggressive tumors with a poorer prognosis. This specific structure should be carefully evaluated in the surgical pathology examination of breast carcinoma specimens.     

E-cadherin immunohistochemical analysis of histiocytoid carcinoma of the breast

Histiocytoid carcinoma is a rare type of invasive breast carcinoma. It has been considered to be a variant of lobular carcinoma, a variant of apocrine ductal carcinoma, and an apocrine variant of lobular carcinoma and to resemble lipid-rich carcinoma. In attempts to elucidate its histogenesis, investigators have used mucin and oil red O histochemical analysis and GCDFP-15 immunostaining. E-cadherin is a relatively recent addition to the armamentarium of immunohistochemical markers used for cell differentiation and is a member of a family of transmembrane glycoproteins that has been shown to have a strong correlation with the histologic phenotypes of breast carcinoma. Most ductal carcinomas show diffuse membrane expression of E-cadherin, and lobular carcinomas are characterized by complete lack of membrane staining of E-cadherin. The object of this study was to use E-cadherin immunohistochemical analysis to help clarify the histogenesis of histiocytoid carcinoma. Fourteen cases containing the diagnosis of histiocytoid carcinoma of the breast were identified at M. D. Anderson Cancer Center (Houston, TX) from 1988 to 2001. All cases were rereviewed, histologic features were evaluated, and immunohistochemical staining with E-cadherin and GCDFP-15 was performed. Clinical information was extracted from the patients' medical records. Eleven cases met published histologic criteria for histiocytoid carcinoma. The remaining three cases were apocrine carcinoma. The pattern of tumor infiltration was solid, without secondary lumen formation in all cases of histiocytoid carcinoma. Lobular carcinoma in situ was identified in eight cases, but was absent in three. There was no E-cadherin immunohistochemical staining in eight of the 11 cases of histiocytoid carcinoma (72.7%). GCDFP-15 was immunoreactive in all 10 cases of histiocytoid carcinoma where it was performed. Follow-up data was available for nine of the 11 cases of histiocytoid carcinoma: six patients were alive with disease at 1.5 to 48 months, one patient had died of disease at 60 months, and two patients had no evidence of disease at 32 and 45 months. We conclude that histiocytoid carcinoma has an immunophenotypical profile consistent with both ductal and lobular differentiation. Moreover, the lack of consistent morphologic features, a specific clinical profile, and a distinct immunohistochemical pattern lead us to hypothesize that histiocytoid carcinoma is not a special type of breast cancer.     

Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up

The histological tumour type determined by current criteria has been investigated in a consecutive series of 1621 women with primary operable breast carcinoma, presenting between 1973 and 1987. All women underwent definitive surgery with node biopsy and none received adjuvant systemic therapy. Special types, tubular, invasive cribriform and mucinous, with a very favourable prognosis can be identified. A common type of tumour recognized by our group and designated tubular mixed carcinoma is shown to be prognostically distinct from carcinomas of no special type; it has a characteristic histological appearance and is the third most common type in this series. Analysis of subtypes of lobular carcinoma confirms differing prognoses. The classical, tubulo-lobular and lobular mixed types are associated with a better prognosis than carcinomas of no special type; this is not so for the solid variant. Tubulo-lobular carcinoma in particular has an extremely good prognosis similar to tumours included in the 'special type' category above. Neither medullary carcinoma nor atypical medullary carcinoma are found to carry a survival advantage over carcinomas of no special type. The results confirm that histological typing of human breast carcinoma can provide useful prognostic information.     

Mucinous breast carcinomas lack PIK3CA and AKT1 mutations

Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are among the most common molecular defects in invasive breast cancer. Point mutations in the downstream kinase AKT1 are seen in a minority of carcinomas. These mutations are found preferentially in estrogen receptor-positive and Her2-positive breast carcinomas; however, special morphologic types of breast cancer have not been well studied. Twenty-nine cases of pure invasive mucinous carcinoma and 9 cases of ductal carcinoma with mucinous differentiation were screened for a panel of point mutations (>321 mutations in 30 genes) using a multiplex polymerase chain reaction panel with mass spectroscopy readout. In addition, associated ductal carcinoma in situ, hyperplasia, or columnar cell lesions were separately tested where available (25 lesions). In 3 invasive cases and 15 ductal carcinoma in situ/proliferative lesions, PIK3CA hotspot mutations were, instead, tested by direct sequencing. No point mutations were identified in invasive mucinous breast carcinoma. This contrasts with the 35% frequency of PIK3CA mutations in a comparative group of invasive ductal carcinomas of no special type. Interestingly, PIK3CA hotspot point mutations were identified in associated ductal carcinoma in situ (3/14) and hyperplasia (atypical ductal hyperplasia [2/3], usual ductal hyperplasia [2/3], columnar cell change [1/5]), suggesting that PIK3CA mutations may play a role in breast epithelial proliferation. This series represents the largest study, to date, of PIK3CA genotyping in mucinous carcinoma and supports the unique pathogenetics of invasive mucinous breast carcinoma.     

The low nuclear grade breast neoplasia family

Breast cancer is a heterogeneous disease with varied morphological and molecular features and clinical behaviour. Recently a group of invasive tumours and precursor lesions was reported to exhibit strikingly similar low-grade nuclear features, immunophenotypic and molecular profiles and coexist at frequencies that could not be justified by chance alone. These lesions are grouped together into a single class termed low-grade breast neoplasia family (LGBNF) to differentiate them from high-grade neoplasms, which are thought to develop through different evolutionary pathways. Precursor lesions in this family include columnar cell lesions (CCLs), flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in-situ (LCIS) and low-grade DCIS. Invasive LGBNF tumours include invasive tubular and cribriform carcinomas, invasive lobular carcinoma, low-grade invasive mucinous and low-grade ductal no special type (NST) carcinomas. These lesions are characterized by strong uniform expression of hormone receptors, lack of HER2 expression and HER2 gene amplification, and exhibit a unique pattern of genetic aberrations mainly deletions of 16q and gains of 1q. In this review, we present the concept of LGBNF with emphasis on their characteristic phenotypic, genotypic and molecular profiles and their impact on BC management strategies and discuss a hypothetical model of breast cancer evolution and progression.     

Expression of the neuroendocrine phenotype in carcinomas of the breast

Neuroendocrine (NE) features are detectable in carcinomas of the breast either as scattered cells immunoreactive for NE markers in carcinoma of the usual type (NOS), or as special type of tumors where the vast majority of the cells display NE characteristics. The former type of lesions, whose biological and diagnostic significance is not clear yet, might reproduce the same phenomenon known to occur in carcinomas of the gastrointestinal tract and pancreas. In the present review we focus on the latter type of lesions, a spectrum of breast tumors largely composed of NE cells. These carcinomas, that we consider the "NE differentiated carcinomas of the breast," are here distinguished from "breast carcinomas NOS with NE differentiation." The diagnostic and histogenetic features of the various types of "NE differentiated carcinomas of the breast," their histological and cytological features and the role and value of ancillary diagnostic techniques, are reviewed. Data of the literature are discussed and related to a relatively large personal series. In addition, divergent differentiation in NE carcinomas of the breast, which is a relatively frequent phenomenon of diagnostic interest but of unknown significance (mainly involving mucinous intra- and extracellular production) is discussed.     

The hormone receptor, human epidermal growth factor receptor 2, and molecular subtype status of individual tumor foci in multifocal/multicentric invasive ductal carcinoma of breast

Multifocal/multicentric breast cancers are common. However, investigations of biomarkers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 in individual tumor foci of such cancers are rare. This study was designed to evaluate the status of the hormone receptors, human epidermal growth factor receptor 2, and its molecular subtypes in individual foci of multifocal/multicentric invasive ductal carcinoma of the breast and to identify the factors associated with the different phenotypes of individual foci. We performed immunohistochemical analyses of the estrogen receptor, progesterone receptor, cytokeratin 5/6, epidermal growth factor receptor, and p53 and fluorescence in situ hybridization of human epidermal growth factor receptor 2 in individual foci of 65 cases of multifocal/multicentric invasive ductal carcinoma and the associated ductal carcinoma in situ components using tissue microarrays. The estrogen receptor status differed in 2 (3%) of the 65 invasive ductal carcinomas, progesterone receptor status in 7 (11%), human epidermal growth factor receptor 2 status in 4 (6%), and molecular subtypes in 5 (8%). The presence of different molecular subtypes in the invasive tumor foci was associated with differences in histologic features (P = .005), high histologic and nuclear grade (P = .012 and P = .021, respectively), p53 overexpression (P = .006), and mixed molecular subtypes in the ductal carcinoma in situ components (P = .011). Multifocal/multicentric invasive ductal carcinomas usually have a single phenotype in terms of hormone receptors, human epidermal growth factor receptor 2, and molecular subtypes; and thus, immunohistochemical analyses of the index tumor may be sufficient in routine practice. However, if multifocal/multicentric invasive ductal carcinomas are of high grade, of different histologic features, or of heterogeneous ductal carcinoma in situ component, biomarkers of the various foci need to be evaluated separately.