Journal of Clinical Pathology current issue

Breast pathology today: morphology and molecules

Rakha, E. A., O'Toole, S. A., Ellis, I. O., Tan, P. H. — 2013-05-22T21:01:43-07:00

This theme issue on breast pathology is a blend of articles of relevance for today's diagnostic practice that focuses on morphological recognition and classification of breast tumours, integration with molecular features and contribution to management decisions. The molecular reviews open the window into a future where scientific investigations into pathogenesis and biology of breast disease can be potentially translated into effective therapeutics for women with breast cancer.

Classification of breast tumours remains a mainstay of pathological assessment. In light of the recent publication of the 4th edition of WHO Classification of Tumours of the Breast in 2012,1 an update is provided of specific entities of myoepithelial, epithelial–myoepithelial, mesenchymal and fibroepithelial lesions.2 Key changes concerning these conditions emanating from the prior edition, and the rationale behind some of the revisions are summarised. Apart from emergent data and information since the prior volume that drive...

Pitfalls in outcome prediction of breast cancer

Rakha, E. A. — 2013-05-22T21:01:43-07:00

Breast cancer represents a heterogeneous group of diseases with varied presentation, morphological and biological features, behaviour, and response to therapy. Management of breast cancer relies on availability of robust predictive and prognostic factors to support decision making. Identifying and validating the prognostic and predictive value of a given marker is based on studying its association with clinical outcome with or without consideration for therapy, respectively. In the field of cancer research, clinical outcome is determined by assessing certain time-dependent events: ‘endpoints’ such as tumour progression, recurrence and patient mortality. Guidelines for reporting tumour markers have been published and there is a perception that outcome determination in breast cancer is well documented. However, reviewing the literature has highlighted the varied use of definitions used in clinical outcome measures and there are pitfalls in outcome analysis. This may have contributed to the discrepancies in the literature and to the inconsistent conclusions seen in published studies assessing the same markers. Identification of these pitfalls is expected to improve prognostic and predictive marker assessment. Here issues related to outcome determination in breast cancer including definitions and pitfalls and some critical views are presented.

Myoepithelial and epithelial-myoepithelial, mesenchymal and fibroepithelial breast lesions: updates from the WHO Classification of Tumours of the Breast 2012

Tan, P. H., Ellis, I. O. — 2013-05-22T21:01:43-07:00

In the 4th edition of the WHO Classification of Tumours of the Breast, myoepithelial lesions are retitled myoepithelial and epithelial–myoepithelial lesions in order to better reflect the dual participation of luminal and myoepithelial compartments in some key entities. Malignant myoepithelioma, described as a section within the chapter on myoepithelial lesions in the 3rd edition, is recognised in the 4th edition as part of metaplastic carcinoma. Adenomyoepithelioma with malignancy is categorised in terms of the cellular component undergoing malignant transformation. The list of antibodies that can be used for identifying myoepithelial cells is updated. Among mesenchymal lesions, new additions are nodular fasciitis and atypical vascular lesions, while the haemangiopericytoma is removed. The 3rd edition stated that pathological prediction of behaviour of phyllodes tumours is difficult in the individual case. In the 4th edition, some progress has been made in prioritisation and weighting of histological parameters that can potentially estimate probability of recurrence. The WHO Working Group advocates leaning towards a diagnosis of fibroadenoma in cases where there is histological uncertainty in distinction from a benign phyllodes tumour, or adopting the neutral term ‘benign fibroepithelial neoplasm’, as the clinical behaviour of fibroadenoma overlaps with that of benign phyllodes tumour. The 3rd edition terminology of ‘periductal stromal sarcoma’ is revised to ‘periductal stromal tumour’, akin to the widespread consensus to avoid the use of the term ‘cystosarcoma’ in the context of phyllodes tumours.

Use of immunohistochemistry in the diagnosis of problematic breast lesions

Lee, A. H. S. — 2013-05-22T21:01:43-07:00

Most diagnoses in breast pathology can be made with H&E sections. Nevertheless immunohistochemistry plays a useful supplementary role. This article reviews the common uses of immunohistochemistry in diagnostic breast pathology. It is important to be aware of the limitations of individual antibodies. Such problems can often be overcome by using panels of antibodies. Quality control is also essential: internal and external controls should show appropriate staining. Immunohistochemistry must be interpreted in combination with the morphology seen on H&E sections. Myoepithelial markers, such as smooth muscle actin, smooth muscle myosin heavy chain and p63, are useful for distinguishing invasive carcinoma from sclerosing lesions and ductal carcinoma in situ (DCIS), and in the classification of papillary lesions. Basal cytokeratins can help distinguish epithelial hyperplasia of usual type (UEH) and clonal proliferations such as DCIS and lobular carcinoma in situ (LCIS). UEH usually shows patchy expression whereas DCIS and other clonal proliferations are typically negative. E-cadherin can usually separate DCIS and LCIS: DCIS typically shows membrane staining and most LCIS is negative. Cytokeratins can be used to detect small nodal metastases or subtle invasive carcinomas such as invasive lobular carcinomas. Immunohistochemistry plays a useful role in diagnosing spindle cell lesions such as a panel of cytokeratins to identify spindle cell carcinomas. Immunohistochemistry is helpful in recognising metastases to the breast. Different antibodies are useful for different tumours: WT1 for ovarian carcinoma; TTF1 for pulmonary adenocarcinoma; S100, melan-A and HMB45 for melanoma; and lymphoid markers for lymphoma.

Hormone receptor expression in breast cancer: postanalytical issues

Lee, M., Lee, C. S., Tan, P. H. — 2013-05-22T21:01:43-07:00

Hormone receptor expression is a critical part of the pathological evaluation of breast cancer. Underpinning not only therapeutic decisions and prognosis, oestrogen receptor (ER) and progesterone receptor (PR) have been a consistent thread in the expanding knowledge of breast cancer. Accurate laboratory testing requires care and precision in preanalytical, analytical and postanalytical processes. In this report, postanalytical issues of pathologist interpretation of ER and PR status in breast cancer are discussed. Apart from key elements of the actual pathological assessment, it is important to realise that there are additional factors that can impact on sensitivity, specificity and dynamic range of hormone receptor expression as rendered on pathology. These include tumour characteristics and heterogeneity, biological changes of tumour progression and interacting molecules, all of which can influence the degree of hormone responsiveness in a particular individual with hormone receptor-positive breast cancer. There is a need to ensure participation in quality assurance programmes and slide exchanges, as well as to constantly keep abreast of emerging data on clinical trials and outcomes of hormone receptor-positive breast cancer.

Breast cancer stem cells: an update

Iqbal, J., Chong, P. Y., Tan, P. H. — 2013-05-22T21:01:43-07:00

Breast cancer is a significant cause of morbidity and mortality in women with a high incidence of recurrence or treatment failure. Growing evidence suggests that cancer stem cells (CSCs) most likely contribute to tumour progression, spread and therapy failure. However, despite extensive research and the tremendous clinical potential of such cells in possible therapeutic management, the real nature of CSCs remains an enigma. In this review, we discuss the fundamental properties and molecular target of CSCs and focus on recent advances regarding the identification of CSC markers with emphasis on breast cancer and the underlying molecular mechanism of CSC phenotypes. We also discuss experimental evidence of targeting molecular pathways in order to modulate breast CSC behaviour in tumourigenesis and the controversies associated with it that potentially weaken the CSC model in breast cancer and other cancers as well.

The significance of the senescence pathway in breast cancer progression

Pare, R., Yang, T., Shin, J.-S., Lee, C. S. — 2013-05-22T21:01:43-07:00

Invasive breast cancer develops through prolonged accumulation of multiple genetic changes. The progression to a malignant phenotype requires overriding of growth inhibition. It is evident that some breast cancers have an inherited basis, and both hereditary and sporadic cancers appear to involve molecular mechanisms that are linked to the cell cycle. Frequently, changes in the molecular pathways with gene deletions, point mutations and/or overexpression of growth factors can be seen in these cancers. Recent evidence also implicates the senescence pathway in breast carcinogenesis. It has a barrier effect towards excessive cellular growth, acting as the regulator of tumour initiation and progression. Later in carcinogenesis, acquisition of the senescence associated secretory phenotype may instead promote tumour progression by stimulating growth and transformation in adjacent cells. This two-edge role of senescence in cancer directs more investigations into the effects of the senescence pathway in the development of malignancy. This review presents the current evidence on the roles of senescence molecular pathways in breast cancer and its progression.

Recent insights into the molecular pathogenesis of mammary phyllodes tumours

2013-05-22T21:01:44-07:00

Phyllodes tumours (PTs) of the breast are true biphasic neoplasms within which interactions between the epithelium and stroma are critical for tumour development and progression. Despite numerous studies reporting the results of ancillary marker investigations in PTs, the current histological grading systems remain unreliable at predicting clinical outcome even when supplemented by these markers. As a consequence, there has been much interest in the prospect of using molecular/genetic techniques to develop a more robust "grading" system. This review focuses on recent cytogenetic and molecular studies investigating the pathogenesis of PTs and those correlating molecular findings with clinicopathological features of the tumours. Recent data highlight that intratumoural genetic heterogeneity is common in PTs and may account for the reported lack of correlation between histological grading and clinical behaviour. The entire spectrum of molecular aberrations in PTs are yet to be fully defined, however recent array-based studies using comparative genomic hybridisation have reported that copy number changes increase with the progression from benign PT to malignancy. Tumour recurrence and progression is likely to reflect the presence of under-recognised subclones. p^16INK4a (CDKN2A) inactivation also appears to be important in PT pathogenesis. Further additional studies will be required to identify and validate new prognostic markers and therapeutic targets in order to improve the diagnosis, classification, prediction of outcome and management of patients with this rare neoplasm. Data generated from modern sequencing technologies are likely to provide new insights into the disease and assist in this endeavour.

Low-grade adenosquamous carcinoma of the breast

Soo, K., Tan, P. H. — 2013-05-22T21:01:44-07:00

Low-grade adenosquamous carcinoma is a rare and unique form of invasive mammary carcinoma. Though it is categorised as a variant of metaplastic carcinoma, it differs from its counterparts in this heterogeneous category by its relative clinical indolence, also reflected histologically in its low-grade cytomorphology. Descriptions of such a tumour were reported as early as 1912. However, low-grade adenosquamous carcinoma was only formally recognised in 1987 with the publication of Rosen and Ernsberger's landmark paper. Since then, several case reports and larger series have reaffirmed the clinicopathological characteristics of this unusual and uncommon tumour. Due to its rarity, however, many aspects of low-grade adenosquamous carcinoma, including its immunohistochemical and genetic profiles, remain unclear. This paper reviews the literature on this entity from 1987 to date, summarising its clinical and pathological features, and highlighting the diagnostic challenges it poses.

Ki67 and proliferation in breast cancer

Pathmanathan, N., Balleine, R. L. — 2013-05-22T21:01:44-07:00

New approaches to the prognostic assessment of breast cancer have come from molecular profiling studies. A major feature of this work has been to emphasise the importance of cancer cell proliferation as a key discriminative indicator of recurrence risk for oestrogen receptor positive breast cancer in particular. Mitotic count scoring, as a component of histopathological grade, has long formed part of a routine evaluation of breast cancer biology. However, there is an increasingly compelling case to include a specific proliferation score in breast cancer pathology reports based on expression of the cell cycle regulated protein Ki67. Immunohistochemical staining for Ki67 is a widely available and economical test with good tolerance of pre-analytical variations and staining conditions. However, there is currently no evidence based protocol established to derive a reliable and informative Ki67 score for routine clinical use. In this circumstance, pathologists must establish a standardised framework for scoring Ki67 and communicating results to a multidisciplinary team.

Occurrence and significance of epithelial-mesenchymal transition in breast cancer

Roxanis, I. — 2013-05-22T21:01:44-07:00

By contrast with developmental epithelial-mesenchymal transition (EMT), where epithelial characteristics undergo transformation to a mesenchymal-like phenotype in a coordinated fashion, oncogenic EMT occurs in the context of unpredictable genetic changes present in the tumour cells, as well as an abnormal tumour microenvironment. Therefore, a partial form of EMT has been proposed as variably participating in the establishment of invasive phenotype in different types of breast carcinoma, in keeping with their morphological and phenotypical diversity. A complex network of signalling pathways and transcription factors appears responding to various growth factors and cytokines released by stromal and neoplastic elements, endowing the system with abundant regulatory opportunities. The process of EMT is largely elusive in histopathological preparations, prompting doubts regarding its significance in tumour progression. This might be related to the presumed focal occurrence of EMT in the majority of tumours. Detailed topological studies might facilitate understanding of the orchestration of events taking place in vivo. Even more importantly, clinical correlations can be endeavoured and, in parallel with advancement in molecular pathology, a contribution to taxonomy refinement can be envisaged.

Molecular alterations in metaplastic breast carcinoma

2013-05-22T21:01:44-07:00

Metaplastic carcinoma of the breast is a rare and heterogeneous subtype of breast carcinoma with a generally poor outcome, and few therapeutic options once disease recurs or progresses. Metaplastic carcinomas of the breast are usually of a larger size at diagnosis, with less frequent nodal metastasis compared with invasive ductal carcinoma no special type, and lack hormone and HER2 receptor expression. Recent research has revealed some potentially actionable genetic changes in a subset of these rare tumours. However, ongoing efforts to further characterise the genetic basis and the molecular alterations underlying the distinctive morphological and clinical characteristics of these tumours are needed in order to identify new targets for treatment. This review will describe the theories of pathogenesis of metaplastic breast carcinoma, and highlight genetic changes and potential therapeutic targets in this generally poor prognosis malignancy.

Therapeutic targets in triple negative breast cancer

2013-05-22T21:01:44-07:00

Outcomes have improved significantly for many women diagnosed with breast cancer. For the heterogeneous group of tumours lacking expression of the oestrogen, progesterone and HER2 receptors, ‘triple negative’ breast cancers (TNBC), the prognosis overall has remained quite poor. When TNBC recurs, there is often little response to chemotherapy, and there are a few treatment options in this setting. Thus, there is an urgent clinical need to identify new therapeutic targets in order to improve the outlook for these patients. This review highlights the most promising therapeutic targets identified through new sequencing technologies, as well as through studies of apoptosis. We also present mounting evidence that the developmental signalling pathways Wnt/β-catenin, NOTCH and Hedgehog play an important role in the pathogenesis and progression of TNBC with new therapeutic approaches inhibiting these pathways in advanced preclinical studies or early clinical trials.