pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up

Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedure, mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features--the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables: three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P less than 0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.     

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.     

An update on the pathological classification of breast cancer

Breast cancer (BC) is a heterogeneous disease, encompassing a diverse spectrum of tumours with varying morphological, biological, and clinical phenotypes. Although tumours may show phenotypic overlap, they often display different biological behaviour and response to therapy. Advances in high-throughput molecular techniques and bioinformatics have contributed to improved understanding of BC biology and refinement of molecular taxonomy with the identification of specific molecular subclasses. Although the traditional pathological morphological classification of BC is of paramount importance and provides diagnostic and prognostic information, current interest focusses on the use of a single gene and multigene assays to stratify BC into distinct groups to guide decisions on systemic therapy. This review considers approaches to the classification of BC, including their limitations, and with particular emphasis on the fundamental role of morphology in establishing an accurate diagnosis of primary invasive carcinoma of breast origin. This forms the basis for further morphological characterization and for all other approaches to BC classification that are used to provide prognostic and therapeutic predictive information.     

Association of maspin expression with the high histological grade and lymphocyte-rich stroma in early-stage breast cancer

AIMS: Maspin is a recently described member of the serpin family or protease inhibitors that is known to be a tumour suppressor gene product. Loss of maspin expression has been found in most breast cancer cases and is correlated with cell motility and tumour invasiveness. However, its precise role in human breast cancer remains to be discovered. We aimed to evaluate the role of maspin in early-stage breast cancer. METHODS AND RESULTS: We analysed the expression of maspin in 192 stage I and II primary breast cancers by immunohistochemistry. Of these cases, 34.4% showed maspin expression. Maspin expression was more frequently found in invasive ductal carcinoma (36.4%) than in invasive lobular carcinoma (7.1%). High maspin expression was demonstrated in breast cancers showing high histological grade or lymphocyte-rich stroma (P < 0.05). Maspin expression was not associated with overall and disease-free survival rate of breast cancer. CONCLUSIONS: The results indicate that different biological mechanisms may be responsible for maspin expression in histologically distinct types of breast cancer. Our survey suggests that maspin expression in breast cancer might have a compensatory role rather than prognostic one.     

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology – the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for ‘mixed’ MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

不同分子亚型乳腺癌细胞系中RUNX3蛋白表达及定位研究

目的:检测人类Runt相关转录因子3(RUNX3)在不同分子亚型乳腺癌细胞系中的表达及其亚细胞定位情况,为进一步揭示RUNX3的失活机制和发现新的治疗靶点提供理论依据。方法:在5种乳腺癌细胞(MCF-7、T47D、SKBR-3、MDA-MB-231和BT-549)及正常乳腺上皮细胞(MCF-10A)中,通过Western blot和免疫荧光实验检测RUNX3的蛋白表达和亚细胞定位情况;采用来普霉素B(Leptomycin B)抑制RUNX3的出核,利用CCK-8法检测细胞活力的改变,EdU染色检测细胞增殖情况,Western blot和免疫荧光实验检测RUNX3的蛋白表达和亚细胞定位的改变。结果:与MCF-10A细胞相比,5种乳腺癌细胞系中RUNX3的核定位减少、胞浆定位增多。经Leptomycin B处理后,CCK-8实验结果显示5种乳腺癌细胞的活力明显减弱,EdU染色显示5种乳腺癌细胞增殖能力明显降低,Western blot和免疫荧光实验显示5种乳腺癌细胞胞浆中的RUNX3蛋白表达量明显降低、胞核中的RUNX3蛋白表达量明显增多(P0.05)。结论:不同分子亚型乳腺癌细胞中均存在RUNX3的胞浆转位失活现象,针对性地逆转RUNX3的出核过程可以明显降低肿瘤细胞的活力和增殖能力,可能成为乳腺癌潜在的治疗靶点。     

The molecular basis of cancer immunotherapy by cytotoxic T lymphocytes

 The disappointing clinical results of cancer immunotherapy of the past few decades have not diminished the optimism about the potential of the new generation of immunotherapeutic strategies towards treatment of malignant disease. Tremendous progress has been made over recent years in unveiling the molecular basis of antigen presentation and recognition by cytotoxic T lymphocytes (CTL). The molecular concepts that have emerged from these studies have led to the design of novel anticancer vaccines and CTL-based immunotherapeutics. This review is to highlight the current molecular insights of antigen presentation and CTL recognition/activation, and their impact on the rational design of therapeutic interventions that may result in protective, CTL-based antitumor immunity. Received: 21 February 1997 / Accepted: 7 May 1997     

不同分子分型及临床病理特征与乳腺癌术后患者预后的关系

目的探讨不同分子分型和临床病理特征与乳腺癌术后患者预后的关系。方法收集283例乳腺癌患者的临床病理资料,根据ER、PR和HER-2的免疫组化结果,将其分成Luminal A型、Luminal B型、HER-2过表达型和三阴型4组,并进行随访。结果不同分子分型的乳腺癌患者术后5年总生存期和无病生存期,差异有统计学意义(P0.05)。两两比较结果显示,与Luminal A型相比,HER-2过表达型和三阴型乳腺癌患者术后5年无病生存期和总生存期短(P0.05)。应用Cox风险回归模型分析,肿瘤大小和淋巴结转移数目是影响乳腺癌患者术后5年总生存期和无病生存期的预后因素(P0.05);但实验未能揭示分子分型是影响乳腺癌患者术后5年总生存期和无病生存期的预后因素(P0.05)。结论肿瘤大小和淋巴结转移数目是影响乳腺癌患者术后5年总生存期和无病生存期的预后因素。     

ki67在三阴性乳腺癌中的临床病理意义

目的 通过检测三阴性乳腺癌中细胞增殖抗原ki67的表达情况,分析其与临床病理特征及预后的关系,明确ki67是否可以作为判断三阴性乳腺癌的预后指标.方法 应用免疫组织化学方法检测ki67在三阴性乳腺癌组织中的表达,分析ki67表达与三阴性乳腺癌患者临床病理特征的相关性及与预后的关系.结果 ki67在三阴性乳腺癌组织中的表达与肿瘤大小、TNM分期、组织学分级和淋巴结转移有关(x2=10.536、16.824、11.020、7.180、P＜0.05).单因素生存分析结果显示:肿瘤大小、临床分期、组织学分级、淋巴结转移和ki67与患者总生存均相关(OR=4.211、3.800、0.288、3.502、2.612,P＜0.05).Cox多因素生存分析显示,淋巴结转移与总生存有一定的相关性(OR=2.768,P＜0.05).结论 ki67表达与三阴性乳腺癌中肿瘤大小、TNM分期、组织学分级和淋巴结转移有关,对于三阴性乳腺癌的预后评估具有一定的价值,可作为评价三阴性乳腺癌预后的候选指标.通过Cox多因素生存分析,淋巴结转移可作为与总生存相关的独立预后因素.     

PTPN12在不同分子分型乳腺癌组织中的表达及其与预后的关系

目的观察乳腺癌组织中PTPN12的表达情况,初步探讨其可能作用的蛋白,并分析其与临床病理参数及预后的关系。方法收集2005-2009年南方医院收治的84例乳腺癌患者的病理及临床资料,其中＂三阴＂乳腺癌患者50例,＂非三阴＂乳腺癌患者34例。采用免疫组化染色方法检测组织中PTPN12、EGFR的表达,并分析PTPN12表达与临床病理参数以及患者预后的关系。结果 ＂三阴＂乳腺癌患者中PTPN12的缺失表达率、EGFR的阳性表达率显著高于＂非三阴＂乳腺癌患者（42.0%vs 20.6%,P=0.041;76.0%vs 47.1%,P=0.007）。PTPN12的表达与EGFR（rs=-0.208,P=0.058）、Her-2（rs=-0.250,P=0.022）存在负相关关系。PTPN12表达阴性的患者,其生存期更短。多因素分析表明PTPN12是乳腺癌独立的预后因子。结论PTPN12在＂三阴＂乳腺癌中具有更高的缺失突变,它的表达与EGFR和Her-2负相关。PTPN12是乳腺癌独立的预后因子。     

乳腺癌细胞核形态与预后关系的定量研究

应用图象分析技术测定５７例乳腺癌细胞核形态参数，观察它们在不同临床病理状况下与预后的关系。结果显示，雌激素受体阴性、淋巴结有转移的、低分化单纯癌及５０岁以下患者，细胞核大则生存期较短；而无淋巴结转移、高分化导管浸润癌及５０岁以上患者，大核乳腺癌术后５年生存率较高。生存组细胞核形状因子较大，且与各临床病理因素无明显相关。     

Generative adversarial network‐based super‐resolution of diffusion‐weighted imaging: Application to tumour radiomics in breast cancer

Diffusion‐weighted imaging (DWI) is increasingly used to guide the clinical management of patients with breast tumours. However, accurate tumour characterization with DWI and the corresponding apparent diffusion coefficient (ADC) maps are challenging due to their limited resolution. This study aimed to produce super‐resolution (SR) ADC images and to assess the clinical utility of these SR images by performing a radiomic analysis for predicting the histologic grade and Ki‐67 expression status of breast cancer. To this end, 322 samples of dynamic enhanced magnetic resonance imaging (DCE‐MRI) and the corresponding DWI data were collected. A SR generative adversarial (SRGAN) and an enhanced deep SR (EDSR) network along with the bicubic interpolation were utilized to generate SR‐ADC images from which radiomic features were extracted. The dataset was randomly separated into a development dataset (n = 222) to establish a deep SR model using DCE‐MRI and a validation dataset (n = 100) to improve the resolution of ADC images. This random separation of datasets was performed 10 times, and the results were averaged. The EDSR method was significantly better than the SRGAN and bicubic methods in terms of objective quality criteria. Univariate and multivariate predictive models of radiomic features were established to determine the area under the receiver operating characteristic curve (AUC). Individual features from the tumour SR‐ADC images showed a higher performance with the EDSR and SRGAN methods than with the bicubic method and the original images. Multivariate analysis of the collective radiomics showed that the EDSR‐ and SRGAN‐based SR‐ADC images performed better than the bicubic method and original images in predicting either Ki‐67 expression levels (AUCs of 0.818 and 0.801, respectively) or the tumour grade (AUCs of 0.826 and 0.828, respectively). This work demonstrates that in addition to improving the resolution of ADC images, deep SR networks can also improve tumour image‐based diagnosis in breast cancer.     

The current understanding of the molecular determinants of inflammatory breast cancer metastasis

Inflammatory breast cancer is a highly aggressive and metastatic form of locally advanced breast cancer that carries a significantly worse prognosis than non-inflammatory breast cancers. Unfortunately, the molecular basis of this deadly form of breast cancer has been understudied. Over the past 10 years new studies have begun to reveal a unique molecular profile of IBC shedding light on its unique ability to rapidly invade and metastasize via the dermal lymphatic system of the skin overlying the breast. The goal of this review is to introduce IBC to the reader and provide a brief overview of what is known about the metastatic mechanisms of the disease.