Vincenzo Eusebi

Breast cancer prognostic classification in the molecular era: the role of histological grade

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for ‘basal-like cancer’, which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.

Pleomorphic lobular carcinoma of the breast: An aggressive tumor showing apocrine differentiation

Pleomorphic lobular carcinoma of the breast is a recently recognized subtype of invasive lobular carcinoma (ILC). Cytologic features are pleomorphic to a degree that contrasts with the cytologic uniformity of classic ILC. It is this feature that simultaneously gives its name to the tumor and highlights the difficulty of identifying it correctly and distinguishing it from ductal carcinoma. In our series of 10 cases, six tumors also contained lobular carcinoma in situ. Nodal metastases were typically sinusoidal. All tumors showed the dissociated, linear, and single file pattern of classic ILC, together with a targetoid distribution. Intracytoplasmic lumina were present in 50% of the tumors. An eosinophilic, slightly granular cytoplasm suggests the possibility of apocrine differentiation, a suggestion derived also from the frequent presence of foamy cells, a cell type previously identified in histiocytoid lobular carcinoma and shown to have apocrine features. The GCDFP-15 apocrine marker was positive in all 10 tumors, while all control ILCs were negative, confirming the presence of apocrine differentiation in pleomorphic lobular carcinoma. Six of 10 patients died within 42 months of diagnosis. Three other patients developed recurrence or distant metastases at short intervals. Pleomorphic lobular carcinoma is a very aggressive tumor. This behavior is perhaps predictable on the basis of tumor size at presentation and the frequency of nodal metastases. Since grading of lobular carcinoma is difficult, recognition of the pleomorphic subtype is useful in identifying a lethal variant.

Endocrine differentiation in mucoid carcinoma of the breast

Mucoid carcinoma of the breast is not a single homogeneous entity. It comprises two main variants separable on structural and cytological grounds and a smaller transitional type. The salient pathological differences are detailed. One variant is usually arygrophilic and contains dense core granules of the type seen in endocrine tumours. Both endocrine and amphicrine cells have been identified in this subtype. The relationship of this endocrine variant of mucoid carcinoma to other argyrophil carcinomas (so‐called ‘carcinoids’) of the breast is discussed.

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

Aims: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. Methods: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. Results: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. Conclusions: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

CGH analysis of ductal carcinoma of the breast with basaloid/myoepithelial cell differentiation

2–18% of ductal carcinoma-No Special Type (NST) are reported to express basal cell keratin 14 and such tumours may have a different metastatic pattern and prognosis. We performed immunohistochemistry for cytokeratins 19 (luminal) and 14 (basal) on 92 ductal carcinoma-NST. Those tumours showing CK14 expression were further characterized by immunohistochemistry for myoepithelial cell phenotype and analysed by comparative genomic hybridization. The 7 cases of ductal carcinoma-NST exhibiting a basal cell phenotype were all grade III tumours and showed a molecular cytogenetic profile similar to more conventional myoepithelial cell carcinomas. Therefore it appears that grade III invasive ductal carcinomas contain a subset of tumours with specific morphological and cytogenetic characteristics, and probably prognosis for the patient.

Salivary gland-like tumours of the breast: surgical and molecular pathology

Breast glands and salivary glands are tubulo-acinar exocrine glands that can manifest as tumours with similar morphological features, but that differ in incidence and clinical behaviour depending on whether they are primary in breast or salivary glands. Salivary gland-like tumours of the breast are of two types: tumours with myoepithelial differentiation and those devoid of myoepithelial differentiation. The first and more numerous group comprises a spectrum of lesions ranging from “bona fide” benign (such as benign myoepithelioma and pleomorphic adenoma), to low grade malignant (such as adenoid cystic carcinoma, low grade adenosquamous carcinoma, and adenomyoepithelioma), to high grade malignant lesions (malignant myoepithelioma). The second group comprises lesions that have only recently been recognised, such as acinic cell carcinoma, oncocytic carcinoma of the breast, and the rare mucoepidermoid carcinoma.

Keratin-positive epithelioid angiosarcoma of thyroid. A report of four cases

We present four cases of a malignant thyroid tumor showing morphologic, immunocytochemical, and ultrastructural features of endothelial cell differentiation. The tumor cells had epithelioid features and displayed strong immunoreactivity for keratin. There was no evidence of follicular or C-cell differentiation in any instance. We interpreted these cases as keratin-positive epithelioid angiosarcomas. The findings presented here support the existence of primary malignant vascular tumors in the thyroid even in the presence of keratin positivity, a marker traditionally regarded as indicative of epithelial differentiation.

Carcinomas of the breast showing myoepithelial cell differentiation

Abstract Myoepithelial cells are normally located between the epithelial cells and the basal lamina of secretory elements of exocrine glands. Their role in the histogenesis of breast tumours has been studied extensively, and a definite differentiation towards myoepithelial cells has been demonstrated in adenoid cystic carcinoma, adenomyoepithelioma, low-grade adenosquamous (syringomatous) carcinoma, pure malignant myoepithelioma and poorly differentiated myoepithelial-rich breast carcinoma. All these tumours are of low malignancy, with the exception of malignant myoepithelioma and poorly differentiated myoepithelial-rich carcinoma. When a low-grade tumour is associated with a spindle cell component, distant metastases must be expected. Pure malignant myoepithelioma shows morphological and clinical features similar to those of monophasic sarcomatoid carcinomas, and it is possible that this last tumour is linked histogenetically to sarcomatoid carcinomas.