Time for change: a new training programme for morpho-molecular pathologists?

The evolution of cellular pathology as a specialty has always been driven by technological developments and the clinical relevance of incorporating novel investigations into diagnostic practice. In recent years, the molecular characterisation of cancer has become of crucial relevance in patient treatment both for predictive testing and subclassification of certain tumours. Much of this has become possible due to the availability of next-generation sequencing technologies and the whole-genome sequencing of tumours is now being rolled out into clinical practice in England via the 100 000 Genome Project. The effective integration of cellular pathology reporting and genomic characterisation is crucial to ensure the morphological and genomic data are interpreted in the relevant context, though despite this, in many UK centres molecular testing is entirely detached from cellular pathology departments. The CM-Path initiative recognises there is a genomics knowledge and skills gap within cellular pathology that needs to be bridged through an upskilling of the current workforce and a redesign of pathology training. Bridging this gap will allow the development of an integrated 'morphomolecular pathology' specialty, which can maintain the relevance of cellular pathology at the centre of cancer patient management and allow the pathology community to continue to be a major influence in cancer discovery as well as playing a driving role in the delivery of precision medicine approaches. Here, several alternative models of pathology training, designed to address this challenge, are presented and appraised

Breast cancer receptor status assessment and clinicopathological association in Nigerian women: A retrospective analysis

Background: Breast cancer markers are becoming increasingly important in breast cancer research due to their impact on prognosis, treatment and survival. The present retrospective study was carried out to quantify the proportion of estrogen (ER), progesterone (PR), and human epithelial receptor 2 (HER2) expressions and their association with tumour grade, age, and tumour size in breast cancer patients in Nigeria. Materials and methods: The paraffin embedded tissue sections were analysed for breast cancer markers using monoclonal antibody SP1 for ER and SP2 for PR and polyclonal antibody ErbB2 for HER2. Results: A total of 286 breast cancer paraffin wax tissue sections were analysed for ER, PR and HER2 expression. Of all the tissue samples examined, 20 (7%) were ER-positive, 6 (2.1%) were PR-positive, 11 (3.8%) were HER2-positive whereas 248 (87%) were triple-negative breast carcinoma. ER- and PR-positivity was associated with early grade I and II tumours (P 50mm (P < 0.0001). Conclusion: A small proportion of Nigerian women with breast cancer are ER/PR-positive which are associated with less aggressive, better prognosis and benefit from endocrine therapy. An even smaller proportion of patients with aggressive tumors were HER2-posivite but responsive to Herceptin treatment. Unfortunately, a very high proportion of cases were triple-negative which is associated with very aggressive tumours and no targeted treatment, which may explain the high mortality rates from breast cancer in Nigeri

Characterising the tumour morphological response to therapeutic intervention:an ex vivo model

In cancer, morphological assessment of histological tissue samples is a fundamental part of both diagnosis and prognosis. Image analysis offers opportunities to support that assessment through quantitative metrics of morphology. Generally, morphometric analysis is carried out on two dimensional tissue section data and so only represents a small fraction of any tumour. We present a novel application of three-dimensional (3D) morphometrics for 3D imaging data obtained from tumours grown in a culture model. Minkowski functionals, a set of measures that characterise geometry and topology in n-dimensional space, are used to quantify tumour topology in the absence of and in response to therapeutic intervention. These measures are used to stratify the morphological response of tumours to therapeutic intervention. Breast tumours are characterised by estrogen receptor (ER) status, human epidermal growth factor receptor (HER)2 status and tumour grade. Previously, we have shown that ER status is associated with tumour volume in response to tamoxifen treatment ex vivo. Here, HER2 status is found to predict the changes in morphology other than volume as a result of tamoxifen treatment ex vivo. Finally, we show the extent to which Minkowski functionals might be used to predict tumour grade.Minkowski functionals are generalisable to any 3D data set, including in vivo and cellular systems. This quantitative topological analysis can provide a valuable link among biomarkers, drug intervention and tumour morphology that is complementary to existing, non-morphological measures of tumour response to intervention and could ultimately inform patient treatment

The expression pattern of MUC1 (EMA) is related to tumour characteristics and clinical outcome of invasive ductal breast carcinoma

Aims: To clarify MUC1 patterns in invasive ductal breast carcinoma and to relate them to clinicopathological parameters, coexpression of other biological markers and prognosis. Methods and results: Samples from 243 consecutive patients with primary ductal carcinoma were incorporated into tissue microarrays (TMAs). Slides were stained for MUC1, oestrogen receptor (ER), progesterone receptor (PR), Her2/neu, p53 and cyclin D1. Apical membrane MUC1 expression was associated with smaller tumours (P = 0.001), lower tumour grades (P < 0.001), PR positivity (P = 0.003) and increased overall survival (OS; P = 0.030). Diffuse cytoplasmic MUC1 expression was associated with cyclin D1 positivity (P = 0.009) and increased relapse-free survival (RFS; P = 0.034). Negativity for MUC1 was associated with ER negativity (P = 0.004), PR negativity (P = 0.001) and cyclin D1 negativity (P = 0.009). In stepwise multivariate analysis MUC1 negativity was an independent predictor of both RFS [hazard ratio (HR) 3.5, 95% confidence interval (CI) 1.5, 8.5; P = 0.005] and OS (HR 14.7, 9 5% Cl 4.9, 44. 1; P < 0.001). Conclusions: The expression pattern of MUC1 in invasive ductal breast carcinoma is related to tumour characteristics and clinical outcome. In addition, negative MUC1 expression is an independent risk factor for poor RFS and OS, besides 'classical' prognostic indicators

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGEþ) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGEþexpression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+ did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+ and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+ residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC

PHYLLOIDES TUMOUR: REVIEW OF AN UNCOMMON BREAST PATHOLOGY AT A SPECIALIZED CANCER CENTRE

Purpose: Phyllodes tumours are rare breast tumours that comprise almost 1% of breast tumours. The outcome for these tumours is generally considered better than breast cancers. We review the cases of phyllodes tumour presenting to a specialised cancer centre over a 14 year period. Materials and Methods: All case records with the diagnosis of phyllodes tumour between 1999 and 2012 were retrieved from the cancer registry. Patient demographics, tumour site, size, axillary lymph node status, whether primary or recurrent, metastatic status, histological type, type of surgery, any complication, margin positivity, post-operative radiation therapy, local or distant recurrence, morality and follow-up duration were recorded. Data were analysed using SPSS. Results: A total of 77 cases of phyllodes tumour were seen between 1999 and 2012. All patients were female with a mean age of 39.9 years. All patients presented with a breast lump with median duration of 8 months. Almost two-thirds (65%) of the patients presented with primary tumour compared to 10% recurrent tumours and the rest were referred after surgery outside. Median size on histopathology was 5 cm (IQR 3.5–8.5 cm). Over a median follow-up duration of 31 months (IQR 9–48 months), 69 patients (89.6%) were alive, while 3 patients (3.9%) did not survive and 5 patients (6.4%) were lost to follow-up. Recurrence was seen in 10 (13%) patients with median time to recurrence of 12 months (IQR 7–24). Involved axillary lymph nodes and borderline or malignant histopathology were found to be signi cantly associated with recurrence (P = 0.04), while margin positivity, post operative radiation therapy and histopathology were not signi cantly associated with recurrence. Conclusion: Phyllodes tumour is an uncommon breast tumour that is predominantly treated with surgical excision. Although survival with these tumours is better compared to breast cancers, involvement of axillary nodes and borderline or malignant histopathology confer an increased risk of recurrence in these patients. Key words: Breast cancer, phyllodes tumours, survival

Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Background: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Results: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Conclusion: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer

A Preliminary Investigation into Search and Matching for Tumour Discrimination in WHO Breast Taxonomy Using Deep Networks

Breast cancer is one of the most common cancers affecting women worldwide. They include a group of malignant neoplasms with a variety of biological, clinical, and histopathological characteristics. There are more than 35 different histological forms of breast lesions that can be classified and diagnosed histologically according to cell morphology, growth, and architecture patterns. Recently, deep learning, in the field of artificial intelligence, has drawn a lot of attention for the computerized representation of medical images. Searchable digital atlases can provide pathologists with patch matching tools allowing them to search among evidently diagnosed and treated archival cases, a technology that may be regarded as computational second opinion. In this study, we indexed and analyzed the WHO breast taxonomy (Classification of Tumours 5th Ed.) spanning 35 tumour types. We visualized all tumour types using deep features extracted from a state-of-the-art deep learning model, pre-trained on millions of diagnostic histopathology images from the TCGA repository. Furthermore, we test the concept of a digital "atlas" as a reference for search and matching with rare test cases. The patch similarity search within the WHO breast taxonomy data reached over 88% accuracy when validating through "majority vote" and more than 91% accuracy when validating using top-n tumour types. These results show for the first time that complex relationships among common and rare breast lesions can be investigated using an indexed digital archive

Metastases to the kidney: a clinicopathological study of 43 cases with an emphasis on deceptive features

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110732/1/his12524.pd