The pathology of familial breast cancer: Clinical and geneticcounselling implications of breast cancer pathology

Approximately 5% of all breast cancers are due to one of the high-risk breast cancer genes BRCA1 and BRCA2, or possibly to a third or fourth moderate- to high-risk gene(s). A further proportion of cases arise in the presence of a less striking family history, with later average age at onset and lower penetrance: familial breast cancer. Bilaterality is a recognized feature of hereditary breast cancer. Cancers often present at an early age, with the contralateral risk high within 10 years. Proof that bilateral malignancies are separate primaries can be difficult histologically, however, especially within 3 years. The recent finding of specific pathological features related to BRCA1 and, to a lesser extent, BRCA2 mutations means that, in addition to bilaterality and family history, a pathological element can be entered into the risk calculation for the presence of BRCA1/BRCA2 mutations. This will facilitate the targeting of mutation testing to families in which a positive result is most likely, and may subsequently influence the clinical management of these families.     

The pathology of familial breast cancer: Morphological aspects

A small proportion of breast cancers are due to a heritable predisposition. Recently, two predisposition genes, BRCA1 and BRCA2, have been identified and cloned. The morphological features of tumours from patients harbouring mutations in the BRCA1 and BRCA2 genes differ from each other and from sporadic breast cancers. Both are of higher grade than are sporadic cases. An excess of medullary/atypical medullary carcinoma has been reported in patients with BRCA1 mutations. Multifactorial analysis, however, shows that the only features independently associated with BRCA1 mutations are a high mitotic count, pushing tumour margins and a lymphocytic infiltrate. For BRCA2 mutation, an association with tubular/lobular carcinoma has been suggested, but not substantiated in a larger Breast Cancer Linkage Consortium study. In multifactorial analysis, the independent features were a lack of tubule formation and pushing tumour margins only. The morphological analysis has implications for clinical management of patients.     

The pathology of familial breast cancer: The pre-BRCA1/BRCA2 era - historical perspectives

A proportion of breast carcinomas develop as a result of a genetic predispostion to the disease. Prior to cloning of the BRCA1 and BRCA2 genes a limited number of studies were carried out to identify specific histopathological characteristics of hereditary breast cancer. These studies are the subject of this review. The main finding was the association of the (atypical) medullary type of breast cancer with a family history; the most important caveat being that medullary breast cancer is found more frequently in young patients. In view of the frequent bilateral occurrence of lobular cancer, this histologic type is also likely to be associated with a predisposing genetic defect. Future investigations will have to test this hypothesis. In addition to mutations in the BRCA1 and BRCA2 genes, there are as yet unidentified genetic defects predisposing to breast cancer development, and histopathology may well help in identifying these genes in the future.     

家族性和早发性乳腺癌BRCA1基因突变分析

目的 分析中国黑龙江省家族性和早发性乳腺癌中BRCA1基因的突变情况。方法 以黑龙江地区的92例家族性和早发性乳腺癌(发病年龄≤35岁)为研究对象。由静脉血提取基因组DNA,对BRCA1基因的全部编码序列(除外1,4号外显子)进行扩增。由聚丙烯酰胺凝胶电泳分析(SSCP)进行突变的初筛,之后进行DNA直接测序证实。结果 在92例乳腺癌患者中发现有5种致病性突变,其中3种为新发现的突变,发现的已报道的2种突变均为无义突变。结论 在中国黑龙江人群中,BRCA1基因的突变对于遗传性乳腺癌的发生可能具有较重要意义;新发现的3个突变位点可能是中国人群中的特有突变;黑龙江地区BRCA1在家族性乳腺癌中突变率明显低于国内外报道,但其中的移码突变3712insG分别在3个患者中检出,提示有可能成为该地区的基础突变。     

家族性乳腺癌与散发性乳腺癌的临床生物学特性分析

目的比较家族性乳腺癌与散发性乳腺癌的临床和分子生物学特性，探讨家族性乳腺癌的临床特点和预后。方法回顾性分析河北医科大学第四医院外科2005年6月至2006年5月收治的681例乳腺癌患者的临床资料，其中家族性乳腺癌18例，散发性乳腺癌663例，比较两组间临床生物学行为特点。结果家族性乳腺癌的组织学分级Ⅲ级比例（44．4％）明显高于散发性乳腺癌（17．2％），两组间差异有统计学意义（Х^2=9．943，P=0．007）；家族性乳腺癌的ER阴性率（50．0％）高于散发性乳腺癌（27．0％），两组间差异有统计学意义（Х^2=6．203，P=0．045）；家族性乳腺癌的VEGF表达阳性率（44．4％）高于散发性乳腺癌（21．9％），两组间差异有统计学意义（Х^2=6．783，P=0．034）。但家族性乳腺癌和散发性乳腺癌患者在年龄分布（Х^2=0．505，P=0．918），绝经状况（Х^2=0．915，P=0．633），肿瘤大小（Х^2=1．595，P=0．660），临床分期（Х^2=1．882，P：0．597），病理类型（Х^2=2．430，P=0．876），腋淋巴结转移率（Х^2=0．999，P=0．607），PR（Х^2=3．088，P=0．214）及C—erbB-2表达（Х^2=3．094，P=0．213）等方面的差异均无统计学意义。结论家族性乳腺癌的组织学分级、ER阴性率、VEGF表达阳性率均明显高于散发性乳腺癌，提示预后较差。     

Mutation analysis of five candidate genes in familial breast cancer

Most of the known breast cancer susceptibility genes (BRCA1, BRCA2, CHEK2 and ATM) are involved in the damage response pathway. Other members of this pathway are therefore good candidates for additional breast cancer susceptibility genes. ATR, along with ATM, plays a central role in DNA damage recognition and Chk1 relays checkpoint signals from both ATR and ATM. PPP2R1B and PPP2R5B code for subunits of protein phosphatase 2A (PP2A), which regulates autophosphorylation of ATM. In addition, EIF2S6/Int-6, which was originally identified as a common integration site for the mouse mammary tumour virus in virally induced mouse mammary tumours, is a candidate breast cancer susceptibility gene because of its putative role in maintaining chromosome stability. To investigate the role of ATR, CHK1, PPP2R1B, PPP2R5B and EIF2S6/Int-6, we carried out mutation analysis of these genes in the index cases from non-BRCA1/BRCA2 breast cancer families. We also screened sporadic breast tumours for somatic mutations in PPP2R1B and PPP2R5B. Although we identified many novel variants, we found no evidence that highly penetrant germline mutations in these five genes contribute to familial breast cancer susceptibility.     

腋淋巴结阴性乳腺癌临床病理特征和预后的回顾性分析

目的:分析腋窝淋巴结阴性乳腺癌的临床病理特征及预后的影响因素。方法:收集215例腋窝淋巴结阴性及225例淋巴结阳性乳腺癌患者的临床病理及预后资料,应用χ2检验进行组间比较,以logistic回归进行多因素分析。结果:单因素分析显示,两组间月经状况(P=0.04)、肿瘤大小(P<0.001)、肿瘤分级(P=0.008)、肿瘤位置(P=0.001)差异均有统计学意义。多因素分析显示,肿瘤大小和肿瘤位置是影响淋巴结阴性和阳性乳腺癌患者独立的临床病理因素。两组预后指标分析显示,阴性组有较低的复发率(P<0.001)及远处转移率(P=0.002),有较高的术后生存率(P<0.001)。其中,肿瘤大小(P<0.001)、肿瘤分级(P=0.003)、肿瘤位置(P<0.001)是影响淋巴结阴性乳腺癌患者5年无病生存的因素;肿瘤大小(P=0.012)和肿瘤位置(P<0.001)是影响淋巴结阴性乳腺癌患者5年总生存的因素。结论:淋巴结阴性乳腺癌患者有较好的预后,肿块大小、肿瘤位置是淋巴结阴性乳腺癌患者的独立临床病理因素,也是影响淋巴结阴性乳腺癌患者5年无病生存率及总生存率的预后指标。     

A case of familial breast cancer

The occurrence of breast cancer in 5 members of a family is reported. No specificity of the location, staging or histological typing of the lesions was observed in these cancers. But the characteristics of "hereditary breast cancer", early onset and the occurrence of metachronous double cancers, were observed. As for heredity, it is suspected to be autosomal dominant trait; on the other hand it is more appropriate to assume a poly genic pattern. Recognizing the importance of familial cancer occurrence, it may be possible to detect early cancerous lesions in family members.     

Management of familial breast cancer risk

Women who are members of breast cancer families are at increased risk for breast cancer. The cloning of BRCA1 and BRCA2 has made it possible to identify mutation carriers within some of these families. Management of breast cancer risk in these families, which presents enormous challenges to patients and clinicians, is addressed. Management should begin with a full evaluation of the patient, including construction of a three-generation pedigree, ascertainment of non-genetic factors that may impact on risk, information on previous and current breast health, practice of and attitudes toward screening, and the psychosocial impact of family history on the individual. Patient priorities in risk management should be explicitly reviewed; these may include survival, cancer prevention, breast preservation, optimization of quality of life or minimization of disruption of day-to-day activities. Approaches to risk management involve screening (usually considered the mainstay), anti-estrogens, prophylactic surgery and/or lifestyle modifications. Specific gene therapy may become available in the future. Management decisions should be individualized to reflect risk levels and patient priorities and goals, within bounds that are medically and scientifically reasonable. An explicit examination of different time-frames (1, 5, 10 years) is recommended given the rapid evolution of knowledge in this area.     

Optimal breast cancer pathology manifesto

This manifesto was prepared by a European Breast Cancer (EBC) Council working group and launched at the European Breast Cancer Conference in Glasgow on 20 March 2014.It sets out optimal technical and organisational requirements for a breast cancer pathology service, in the light of concerns about variability and lack of patient-centred focus.It is not a guideline about how pathology services should be performed. It is a call for all in the cancer community – pathologists, oncologists, patient advocates, health administrators and policymakers – to check that services are available that serve the needs of patients in a high quality, timely way.     

家族性乳腺癌的研究现状

乳腺癌是女性最常见的恶性肿瘤之一,家族史是目前流行病学最为肯定的乳腺癌高危因素之一。顾名思义,家族性乳腺癌是指具有家族聚集性的乳腺癌。在一个家族中出现多个乳腺癌患者,这提示我们有两种可能。第一,就是该家族成员携带着某一乳腺癌易感基因;第二种可能是他们共同暴露于     

Blood type A and familial breast cancer

The association between blood type A and breast cancer was evaluated in 648 patients with family histories of the disease, 1897 unselected patients, 4577 institutional blood donor controls, and 14,508 extramural blood donor controls. The familial patients were classified into three pedigree groups in which the lifetime breast cancer risks to first-degree relatives ranged from 11% to 32%. In the pedigree group associated with a relatively low risk to relatives, the authors saw a significant excess of blood type A individuals when compared with either control group. The unselected patient population, which was considered to refer to a general series of patients, also showed an excess of blood type A individuals with either control but a significant excess only in comparison with institutional controls. Patients from high-risk pedigrees with inherited forms of breast cancer showed no association when compared with either control group. The effect of blood type A on breast cancer risk was considered too small to be of use in identifying women at high risk. The results further suggested that the effect of blood type A on breast cancer development was capable of being masked by the effect of breast cancer susceptibility genes and/or that the inherited and noninherited types involve different etiologic mechanisms.     

Correlative Study on MRI Morphologic Features,Pathology, and Molecular Biology of Breast Cancer

OBJECTIVE To investigate the correlation among MRI morphologic features,pathology, and molecular biology of breast cancer.METHORDS MRI was used to analyze the morphologic features of breast cancers of 78 patients before operation. The mastectomy specimens of the breast neoplasms were immunohistochemically stained, and the expression of the estrogen (ER), progesterone receptor (PR), C-erbB-2, P53, and the distribution of microvessel density (MVD) measured. The pathologic results were compared with the MRI features.RESULTS Among the 80 breast cancers, ER positive expression was positively correlated with the spicular contour of breast cancers (P＜0.01),while showing a significant inverse correlation with the T-stage (P＜0.05). CerbB-2 and P53 positive expression were positively correlated with the necrotic center of the cancers (P＜0.05). The expression of PR was not significantly correlated with the spicular contour, obscure margin, necrotic center, and T-stage of these cancers (P＞0.05). Among 41 breast cancers examined with dynamic contrast enhanced MR, there was a positive correlation between the spatial distribution of the contrast agent and MVD(P＜0.01).CONCLUSION To a certain extent there is some correlation among the MRI morphologic features, pathology, and molecular biological factors in breast cancer. The biological behavior and prognosis of breast cancer can be assessed based on MRI features.     

Bilaterality in familial breast cancer patients

The authors conducted this study to determine the probability of a second primary developing in the contralateral breast of a patient, based on her present age, age at her first breast primary, and family history of breast cancer in her mother, sister, or second-degree relative. The study involved 556 patients. With premenopausal diagnosis of the first primary, the probabilities to the 19th year for the three types of family histories ranged from 35% to 38%; with postmenopausal diagnosis, they ranged from 11% to 26%. The probability for all familial patients was 28%. This contrasts with a probability of 13% reported for a general series of patients. An early age at diagnosis and family history of the disease thus have important enhancing effects on the development of second primaries. This information could be useful to physicians in deciding how best to manage the treatment of their patients.