Bench to bedside: research influencing clinical practice in breast cancer

Based on recent evidence derived from clinical trials and translational research, breast cancer pathology has witnessed a rapid increase in the utilization of predictive markers, companion diagnostics and molecular testing for tailored management of patients with breast cancer. New diagnostic entities with specific molecular phenotypes have also been included in the classification of breast cancer. Genomic assays including Oncotype DX®21-gene Recurrence Score (RS), Prosigna and EndoPredict are currently used in routine practice to guide adjuvant/neoadjuvant therapy. The analysis of established biomarkers such as ER and PR immunohistochemistry has been updated to recognize new categories with different clinical behaviour and significance, such as the ER low expressors and HER2 low carcinomas. PD-L1 testing and PIK3CA mutation have been introduced for advanced TNBC and recurrent ER positive breast cancer respectively. This review provides an update on the rapidly evolving field of predictive & prognostic markers, companion diagnostics, molecular and genomic testing of breast cancer.     

Bench to bedside: research influencing clinical practice in prostate pathology

Prostate cancer is biologically heterogeneous ranging from clinically indolent disease that “old men die with” to aggressive tumours that metastasise and cause death. Optimal management of this disease requires accurate prognostication to avoid over-treatment of the former and prompt appropriate treatment of the latter. Prognostication of prostate cancer is challenging as tumour is often not well visualized on radiological examination, is often detected in non-targeted systematic biopsies and cannot be subjected to a wide local excision for detailed histological examination. Several histopathological parameters that aid risk stratification of prostate cancer have been identified but some tumours lacking adverse pathology findings exhibit aggressive behaviour. Tissue biomarkers could improve the accuracy of prognostication of prostate cancer. This review outlines how histopathological research has impacted the diagnosis, prognostication, and treatment of prostate cancer. We also highlight limitations of the current evidence base and outline the role of the practicing histopathologist in optimizing the clinical utility of biomarker assays.     

AI-guided histopathology predicts brain metastasis in lung cancer patients

Brain metastases can occur in nearly half of patients with early and locally advanced (stage I–III) non-small cell lung cancer (NSCLC). There are no reliable histopathologic or molecular means to identify those who are likely to develop brain metastases. We sought to determine if deep learning (DL) could be applied to routine H&E-stained primary tumor tissue sections from stage I–III NSCLC patients to predict the development of brain metastasis. Diagnostic slides from 158 patients with stage I–III NSCLC followed for at least 5 years for the development of brain metastases (Met⁺, 65 patients) versus no progression (Met⁻, 93 patients) were subjected to whole-slide imaging. Three separate iterations were performed by first selecting 118 cases (45 Met⁺, 73 Met⁻) to train and validate the DL algorithm, while 40 separate cases (20 Met⁺, 20 Met⁻) were used as the test set. The DL algorithm results were compared to a blinded review by four expert pathologists. The DL-based algorithm was able to distinguish the eventual development of brain metastases with an accuracy of 87% (p < 0.0001) compared with an average of 57.3% by the four pathologists and appears to be particularly useful in predicting brain metastases in stage I patients. The DL algorithm appears to focus on a complex set of histologic features. DL-based algorithms using routine H&E-stained slides may identify patients who are likely to develop brain metastases from those who will remain disease free over extended (>5 year) follow-up and may thus be spared systemic therapy. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Recent advances in breast cancer research impacting clinical diagnostic practice

During the last decade, the genomics revolution has driven critical advances in molecular oncology and pathology, and a deeper appreciation of heterogeneity that is beginning to reshape our thinking around diagnostic classification. Recent developments have seen existing classification systems modified and improved where possible, gene-based diagnostics implemented and tumour–immune interactions modulated. We present a detailed discussion of this progress, including advances in the understanding of breast tumour classification, e.g. mixed ductal–lobular tumours and the spectrum of triple-negative breast cancer. The latest information on clinical trials and the implementation of gene-based diagnostics, including MammaPrint and Oncotype Dx and others, is synthesised, and emerging targeted therapies, as well as the burgeoning immuno-oncology field, and their relevance in breast cancer, are discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Expression of proliferating cell nuclear antigen in lung cancer: a systematic study and correlation with DNA ploidy

Heterogeneity of expression of the proliferating cell nuclear antigen (PCNA) was assessed immunohistochemically in 156 tissue samples from 33 surgically resected pulmonary carcinomas using the monoclonal antibody 19A2. The DNA content of each of these samples was measured by flow cytometry. Mean PCNA expression was higher in squamous carcinomas than in adenocarcinomas but there was marked intra-tumour variation in PCNA index in almost all cases. Intra-tumour heterogeneity of DNA content was noted in 11 cases. The PCNA index of these cases (34.1) was higher than that of DNA homogeneous cases (19.4). The wide variation in PCNA expression between different samples within a tumour would indicate that systematic sampling and counting will be necessary in future immunohistochemical studies of cell proliferation in tumour material.     

Non-small cell lung cancer in never smokers: a clinical entity to be identified

OBJECTIVES:

It has been recognized that patients with non-small cell lung cancer who are lifelong never-smokers constitute a distinct clinical entity. The aim of this study was to assess clinical risk factors for survival among never-smokers with non-small cell lung cancer.

METHODS:

All consecutive non-small cell lung cancer patients diagnosed (n = 285) between May 2005 and May 2009 were included. The clinical characteristics of never-smokers and ever-smokers (former and current) were compared using chi-squared or Student''s t tests. Survival curves were calculated using the Kaplan-Meier method, and log-rank tests were used for survival comparisons. A Cox proportional hazards regression analysis was evaluated by adjusting for age (continuous variable), gender (female vs. male), smoking status (never- vs. ever-smoker), the Karnofsky Performance Status Scale (continuous variable), histological type (adenocarcinoma vs. non-adenocarcinoma), AJCC staging (early vs. advanced staging), and treatment (chemotherapy and/or radiotherapy vs. the best treatment support).

RESULTS:

Of the 285 non-small cell lung cancer patients, 56 patients were never-smokers. Univariate analyses indicated that the never-smoker patients were more likely to be female (68% vs. 32%) and have adenocarcinoma (70% vs. 51%). Overall median survival was 15.7 months (95% CI: 13.2 to 18.2). The never-smoker patients had a better survival rate than their counterpart, the ever-smokers. Never-smoker status, higher Karnofsky Performance Status, early staging, and treatment were independent and favorable prognostic factors for survival after adjusting for age, gender, and adenocarcinoma in multivariate analysis.

CONCLUSIONS:

Epidemiological differences exist between never- and ever-smokers with lung cancer. Overall survival among never-smokers was found to be higher and independent of gender and histological type.     

The changing landscape of gynaecological cancer diagnosis: implications for histopathological practice in the 21st century

The era of molecular medicine has led to dramatically improved understanding of the genetic events that give rise to different types of cancers. In the case of gynaecological malignancies, this has resulted in distinct shifts in how these tumours are diagnosed in routine surgical pathology practice, with an increased emphasis on accurate subtype diagnosis. This has happened across all sites in the gynaecological tract and for most cell types, but in ways that are site‐specific and may appear to be subtle, as in most instances the diagnostic terminology has not changed. For example, the diagnosis of clear cell carcinoma of the ovary is still in use, but the diagnostic criteria and clinical implications are different in 2017 from what they were in 2000. As a result, there can be a failure to appreciate how important these changes are and the resulting necessity of incorporating them into our daily practice. In this review we will describe changes in diagnostic surgical pathology occasioned by improved understanding of molecular events during pathogenesis, for cancers of ovary/tube, endometrium, cervix and vulva, and highlight how current practice differs from that of only a few years ago.     

Beclin 1 and p62 expression in non-small cell lung cancer: relation with malignant behaviors and clinical outcome

Autophagy plays a complicated role in tumorigenesis in a variety of cancers. Recently, many studies report that some autophagy-related markers could be detected in several types of human tumors. However, fewer studies have been conducted to evaluate the relationship between autophagy and lung cancer, especially in non-small cell lung cancer (NSCLC). In this study, the expression levels of autophagy-related markers Beclin 1 and p62 were detected by Western blot analysis and cell immunofluorescence staining in three human NSCLC cell lines A549, H1299 and HCC827. Then, tissue microarray and immunohistochemical staining were used to determine Beclin 1 and p62 expression in 104 NSCLC specimens collected from patients. Beclin 1 and p62 were observed to primarily distribute in the cytoplasm of the cells. Beclin 1 was expressed more predominantly in male and heavy-smoker and its expression was significantly correlated with the differentiation and lymph node metastasis. p62 expression was negatively correlated with TNM stage and lymph node metastasis. Univariate Cox regression analysis revealed that low expression of Beclin 1 and high expression of p62 were significantly associated with shorter survival. Meanwhile, multivariate Cox regression analysis indicated that Beclin 1 and p62 were independent risk factors related to overall survival for patients with NSCLC. Collectively, our study suggests that Beclin 1 and p62 could serve as potential indicators for the prognosis of patients with NSCLC.     

Heterogeneity of expression of cytokeratin subtypes in squamous cell carcinoma of the lung: with special reference to CK14 overexpression in cancer of high-proliferative and lymphogenous metastatic potential

In surgically resected specimens of squamous cell carcinoma (SCC) of the lung from 45 patients, we immunohistochemically examined the expression of 13 subtypes of cytokeratin (CK), the intermediate filament in cytoplasm of epithelial cells. To investigate heterogeneity of CK, its expression was compared among tumor cell nests with or without keratinization and stratification. Furthermore, the relationship between CK expression and Ki-67 labeling index or p53 expression was investigated.The tumor cell nests with keratinization showed the expression of CK1 and CK10 as a central pattern and the expression of CK14 as a peripheral pattern. The nests with stratification showed CK14 expression as a peripheral pattern, whereas those without stratification showed the expression as a diffuse pattern. The tumor cell nests showing stromal invasion with fibrosis in the marginal zone were diffusely positive for CK14. Ki-67 antigen labeling index was significantly higher in the nests where CK14 expression was diffuse or peripheral than in the nests where the expression was focal or negative. In lymph node metastases, the tumor cells often showed CK14 expression, like trabecular nests in the primary carcinoma. These results suggest that CK14 is a parameter of proliferative activity and metastatic potential of SCC of the lung.     

Smoking‐related changes in the background lung of specimens resected for lung cancer: a semiquantitative study with correlation to postoperative course

Aims: To assess the pathological findings in lobectomy specimens, to correlate them with smoking history and postoperative course and to compare the findings with those in smoking‐related interstitial lung disease. Methods and results: Patients who had undergone lobectomy for lung cancer were reviewed. Subjects included 230 non‐smokers and 587 smokers, of whom 572 had a known smoking index (SI). They were classified into mild, moderate and heavy smokers. Centrilobular emphysema (CLE), respiratory bronchiolitis, airspace enlargement with fibrosis (AEF), the presence of foci resembling usual interstitial pneumonia pattern (UIP/P) and the rate of postoperative respiratory failure were assessed. The incidence of AEF was 6.5% in mild smokers, and 17.7% in moderate smokers (P < 0.01) with lower lobe predominance. There were significant correlations (P < 0.01) between AEF and CLE and AEF and UIP/P. The rate of respiratory failure after lobectomy was 6%, and 10% in patients having UIP/P with or without AEF, but was not seen in patients with AEF alone (P < 0.01). Conclusions: AEF is an important smoking‐related change in the lung that appears to correlate with the smoking history, and its distinction from UIP/P may be important.     

Aldehyde dehydrogenase 1 expression in cancer cells could have prognostic value for patients with non‐small cell lung cancer who are treated with neoadjuvant therapy: Identification of prognostic microenvironmental factors after chemoradiation

Prognostic factors for patients with non‐small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. The purpose of this study was to analyze prognostic biomarkers in NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and stromal cells. A total of 52 patients with NSCLC who were treated with neoadjuvant therapy followed by complete resection were included. We examined the expressions of nine markers in the cancer cells and stromal cells. The 5‐year disease‐free survival rate of patients with high aldehyde dehydrogenase 1 (ALDH1) expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P = 0.023). The other molecules expressed in cancer cells did not exhibit any prognostic value. In NSCLC without neoadjuvant therapy (case control, n = 104), expression of ALDH1 in cancer cells was not correlated with prognosis (P = 0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease‐free survival (P = 0.045). The current study indicated that the immunophenotypes of ALDH1 in cancer cells could have prognostic value for patients with NSCLC who are treated with neoadjuvant therapy.     

Dynamic contrast‐enhanced MRI texture analysis for pretreatment prediction of clinical and pathological response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

The aim of this study was to investigate the potential of texture analysis, applied to dynamic contrast‐enhanced MRI (DCE‐MRI), to predict the clinical and pathological response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) before NAC is started. Fifty‐eight patients with LABC were classified on the basis of their clinical response according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines after four cycles of NAC, and according to their pathological response after surgery. T₁‐weighted DCE‐MRI with a temporal resolution of 1 min was acquired on a 3‐T Siemens Trio scanner using a dedicated four‐channel breast coil before the onset of treatment. Each lesion was segmented semi‐automatically using the 2‐min post‐contrast subtracted image. Sixteen texture features were obtained at each non‐subtracted post‐contrast time point using a gray level co‐occurrence matrix. Appropriate statistical analyses were performed and false discovery rate‐based q values were reported to correct for multiple comparisons. Statistically significant results were found at 1–3 min post‐contrast for various texture features for the prediction of both the clinical and pathological response. In particular, eight texture features were found to be statistically significant at 2 min post‐contrast, the most significant feature yielding an area under the curve (AUC) of 0.77 for response prediction for stable disease versus complete responders after four cycles of NAC. In addition, four texture features were found to be significant at the same time point, with an AUC of 0.69 for response prediction using the most significant feature for classification based on the pathological response. Our results suggest that texture analysis could provide clinicians with additional information to increase the accuracy of prediction of an individual response before NAC is started. Copyright © 2014 John Wiley & Sons, Ltd.