Cytokeratin profiles of male breast cancers

AIMS: The prognostic factors and expression of molecular markers in male breast carcinomas are similar to those in female breast cancers. The identification of distinct cytokeratin (CK) profiles (basal as opposed to luminal cells) helps to identify subsets of tumours with different clinical behaviour. The aim of this study was to investigate CK expression in male breast cancer. METHODS AND RESULTS: Thirty-two cases of male breast cancer were studied. The panel of CKs studied by immunohistochemistry included: 5/6, 14, 17, 18 and 19. Pathological findings and CK expression were analysed in all cases. Histological patterns included ductal carcinoma in situ, invasive ductal carcinoma and mixed patterns. Four cases were positive for CK5/6 and CK14, identifying a basal-like phenotype. CK17 was negative in all but two cases. All cases expressing either CK5/6 or CK14 were invasive carcinomas of high nuclear and histological grade and were also larger compared with the tumours not expressing CK5/6 and CK14. All tumours except three (also negative for CK5/6) expressed CK18 and CK19. The four basal-like tumours were negative for Her-2 expression. CONCLUSIONS: Male breast carcinomas have a basal-like phenotype that is similar in frequency to that of female breast carcinomas. The expression of CK5/6 and CK14 identifies a subset of pathologically aggressive male breast cancers.     

The cancer genetics and pathology of male breast cancer

Male breast cancer (MBC) is an uncommon and poorly understood disease. Recent molecular studies have shown important differences from female breast cancer which are likely to influence treatment strategies from the current female‐based management towards a more tailored approach. Significantly more MBCs than female breast cancers arise with an underlying germline cancer predisposition, and display a vastly different penetrance compared with females. Furthermore, the genophenotypical association of basal‐like cancer with BRCA1 present in female breast cancer is not observed in male breast cancer. Differences in somatic changes between male and female breast cancer have also been reported, with particular enrichment of PIK3CA mutations and a paucity of TP53 mutations. In general, chromosomal‐based changes, in particular regions of gains, are seen more frequently in male than female breast cancer and methylation is seen less frequently. Clinically, several molecular subtypes with prognostic relevance have been described, including chromosomal complex high and methylation high groups, and subgroups with profiling signatures pertaining to epithelial mesenchymal transition and hormonal therapy insensitivity. As with female breast cancer, attention to male specific multicentre trials based on the individual characteristics are needed, together with establishment of reliable preclinical models to understand more clearly the pathogenesis of male breast cancer and improve the general poor outcome of this disease.     

Pathology of the male breast

The male breast encompasses a number of benign and malignant breast conditions. The commonest cause of male breast enlargement is gynaecomastia. This can be physiological, idiopathic or pathological. Male breast cancer (MBC) is a rare disease comprising less than 1% of all breast cancers. The commonest histology is grade 2 ductal no special type carcinoma. Unlike the female breast, papillary in situ and invasive carcinomas are not uncommon in the male breast. MBC is often of the luminal A phenotype, similar to the post menopausal female breast cancer. Here we review a range of benign and malignant lesions of the male breast with a special emphasis on the two most common lesions: gynaecomastia and MBC. We describe the risk factors, pathogenesis, diagnostic criteria and management of those lesions.     

男性乳腺癌11例临床病理分析并文献复习

目的：分析男性乳腺癌临床病理特点、分子亚型特点。方法：收集本院2010年1月到2014年12月的男性乳腺癌病例,回顾并分析其临床病理特点和分子亚型,并复习相关文献。结果：男性乳腺癌患者11例,占同期乳腺癌患者0.92%,男性乳腺癌就诊年龄38~80岁,中位年龄61岁,左侧7例,右侧4例。其中9例为浸润性导管癌,2例为囊内乳头状癌,其中1例伴浸润癌成分。组织学分级Ⅱ级9例,Ⅲ级2例。确诊时伴淋巴结转移4例。免疫组织化学染色：ER均阳性;9例PR阳性;1例送检两次标本HER2检测分别为++,+++,FISH检测无扩增,余均为阴性(0/+);Ki-67高表达(≥20%)4例,低表达(<20%)7例。分子表型4例为Luminal A型,7例为Luminal B型。结论：男性乳腺癌少见,发病年龄较晚,临床分期较高,预后较差,加强对其认识,争取早期诊断和治疗是非常重要的。     

TMPRSS3 is a novel poor prognostic factor for breast cancer

It has recently been reported that transmembrane protease, serine 3 (TMPRSS3) is overexpressed in cancer. However, TMPRSS3 expression and its biological roles in breast cancer (BC) have not been reported. This study aims to investigate the TMPRSS3 expression in BC and its relation with the outcome of the BC. This study involves a total of 149 BC tissues and adjacent non-cancerous tissues that were diagnosed between 2004 and 2007. Immunohistochemistry is used to compare the pattern of TMPRSS3 expression in BC and in adjacent non-cancerous tissues. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of TMPRSS3 expression among BC patients. The results are as follow: TMPRSS3 expression is significantly in BC compared to adjacent non-cancerous tissues. High TMPRSS3 expression was related to TNM stage, lymph node metastasis, and Ki-67 expression. Furthermore, the overall survival (OS) and disease-free survival (DFS) in BC patients with high TMPRSS3 expression were lower than those in patients with low TMPRSS3 expression. Based on multivariate analysis, lymph node metastasis, TNM stage and TMPRSS3 expression are independent prognostic factors for OS in BC, while lymph node metastasis and TMPRSS3 expression are independent prognostic factors for DFS in BC. This study proves that TMPRSS3 expression is an independent prognostic factor for BC patients. Bioinformatic analysis of potential TMPRSS3 binding proteins revealed that TMPRSS3 could be a key regulator of cancer pathways. This study helps us better understand the function of TMPRSS3 in cancer.     

Prognostication of invasive ductal breast cancer by quantification of E-cadherin immunostaining: the methodology and clinical relevance

AIMS: We tried to improve the evaluation of E-cadherin immunostaining in paraffin sections, to distinguish the less aggressive variants of ductal infiltrating breast cancer from other variants. METHODS AND RESULTS: The method graded the membrane staining and estimated the fraction of area of cancer tissue stained at the respective staining grade, resulting in an immunohistochemical staining index. At the cut-point 0.35 the index divided all 157 patients (P=0.0188), and 57 node-positive patients (P= 0.0006) into two groups of different survival. In multivariate analysis (all patients) E-cadherin immunoscore was inferior to mitotic index (SMI) (P=0.0002), but still significant (P=0.0031). Among node-positive patients E-cadherin was even more powerful and superior (P=0.0001) to the still significant SMI (P=0.0023), and E-cadherin immunostaining and the mitotic activity (SMI) combined did not need the support of other prognosticators in the Cox model. CONCLUSIONS: The study suggests that E-cadherin immunostaining can be used efficiently in finding patients with favourable outcome among node-positive patients.     

PTP1B在ER阳性乳腺癌中的表达及临床预后意义

目的探讨PTP1B在ER阳性乳腺癌中的表达及其临床与预后的意义。方法应用免疫组化SP两步法检测179例乳腺癌标本中PTP1B蛋白的表达,分析PTP1B表达与乳腺癌临床病理特征及预后的关系。结果在ER阳性乳腺癌中,PTP1B表达水平与T分期(P=0.038)、淋巴结转移(P=0.021)、肿瘤分期相关(P=0.008)。Kaplan-Meier检测结果显示,与PTP1B低表达组相比,PTP1B高表达组患者的总生存率更低(P=0.006)。多因素分析显示T分期、腋窝淋巴结转移和PTP1B表达是影响患者总生存的独立预后因素。结论 ER阳性乳腺癌中PTP1B的表达与肿瘤进展和患者不良预后密切相关,PTP1B可能是ER阳性乳腺癌预后不良评估的指标之一。     

Cytomorphology of male breast lesions: diagnostic pitfalls and clinical implications

Because lesions of the male breast have been exceeded in number by those of the female breast, marginal attention was given to these lesions in the past. Fortunately, this has changed over the years leading to an increased awareness about male breast cancer. Although male breast cancer constitutes only about 1% of all diagnosed breast cancer cases, an increased mortality is seen in this patient population. This is probably caused by late diagnosis as a consequence of low level of concern about breast cancer among male patients. However, the vast majority of lesions of the male breast are benign, gynecomastia being the number one cause of unilateral or bilateral breast mass. Since it is important to avoid unnecessary surgical treatment without missing malignancy, accurate diagnostic tools are necessary in order to triage these patients. Fine-needle aspiration biopsy has demonstrated excellent accuracy in the diagnosis and management of breast lesions in female patients. In addition, several authors have proven the value of this technique in the evaluation of lesions of the male breast. Fine-needle aspiration biopsy permits accurate diagnosis in many lesions arising in the male breast. It also allows gathering cytological material that can be used for ancillary studies which enhances the diagnostic value of this technique.     

Oestrogen receptor and epidermal growth factor receptor expression in male breast carcinoma.

Male breast carcinomas are probably hormone-dependent, but receptor studies are few because this is a relatively rare tumour. We have studied 21 cases of male breast carcinoma immunohistochemically for oestrogen receptor (ER) and epidermal growth factor receptor (EGFR) expression employing the antibodies ER-ICA and 12E on formalin-fixed, paraffin-embedded material. In our series, 86 per cent of male breast cancers were ER-positive and 76 per cent were EGFR-positive. Male breast carcinomas do not exhibit the inverse correlation between ER and EGFR expression that characterizes female breast carcinomas. Owing to the limitations of a small series, we were unable to comment on the relationship between ER and EGFR expression and patient survival. However, the relatively high incidence of ER expression may provide a growth advantage for this tumour in a male environment characterized by low levels of oestrogen. In addition, high EGFR expression may also contribute to a poor prognosis independent of ER status.     

Secretory carcinoma of the breast in a 51-year-old male

Approximately 100 female secretory Carcinoma cases have been reported. Although thls tumor was Initially termed juvenile carcinoma as the patients were all children and adolescent females, subsequent reports demonstrated that it occurs in females of all ages. Moreover, to date, only five males with this tumor have been reported. As with the initial female secretory carcinoma cases, all five were children or young adutts. A very rare case of non-invasive secretory carcinoma of the breast arising in a 51-year-old Japanese male Is described. He presented with a lump in his left breast. The surgically resected tumor was a typical secretory carcinoma histologically, except that there was no Infiltration of the surrounding stroma, and was composed of tumor cells with vacuolated cytoplasm that contained secretory materials. This case, the first recorded secretory carcinoma of the breast in a middle-aged male, demonstrates that this tumor may also arise in mature males, as is the case in females. Physicians should not rule out the possibility of a secretory carcinoma of the breast regardless of patient age and gender.     

A rare case of secretory breast carcinoma in a male adult with axillary lymph node metastasis

Secretory breast carcinoma is a rare tumor originally described in children but occurring equally in adult population, especially in women. This unusual subtype has a generally favorable prognosis, although several cases have been described in adults with increased aggressiveness and a risk of metastases even death. So far, merely ten cases of secretory breast carcinoma with metastatic axillary lymph node in male were reported. Here, we describe the eleventh case, a 24-years-old male who presented with a painless mass in the right breast was diagnosed to be “secretary breast carcinoma”, and subsequently underwent modified radical mastectomy and adjuvant chemotherapy.     

50例中国男性乳腺癌临床特征和遗传学病因

目的拟通过男性乳腺癌(MBC)病例报道,为中国MBC的精准诊疗提供了依据。方法回顾了2015年至2019年北京市两家肿瘤专科医院收治的50例MBC患者的人口学特征、临床和病理特征、治疗及随访情况。进一步对于其中25例MBC患者进行了乳腺癌易感基因1号和2号(BRCA1/2)等基因的二代测序。结果入组MBC患者平均发病年龄为(58±11.5)岁,超重和肥胖患者占60.00%,绝大部分MBC患者为雄激素受体阳性(95.24%)和雌激素受体阳性(89.36%),而三阴性乳腺癌比例(10.64%)较国外更高。在治疗方面,保乳术(6.12%)和前哨淋巴结活检(26.53%)比例相对较低,内分泌治疗(84.00%)在术后辅助治疗中占重要地位,但术后辅助放疗(20.00%)和化疗(52.00%)相对不足。此外,在接受基因检测患者中有2例(8.00%)患者存在BRCA1/2致病性突变。结论 MBC患者的临床特征和遗传学病因具有一定特殊性。在治疗方面,手术方式可以进一步做"减法",而术后辅助放疗和化疗则应作"加法"。     

Profiling the expression of cytochrome P450 in breast cancer

Murray G I, Patimalla S, Stewart K N, Miller I D & Heys S D
(2010) Histopathology 57 , 202–211 Profiling the expression of cytochrome P450 in breast cancer Aims: The cytochrome P450s (P450) are key oxidative enzymes that metabolize many carcinogens and anticancer drugs. Thus, these enzymes influence tumour development, tumour response to therapy and are putative tumour biomarkers. The aim was to define the P450 expression profile in breast cancer and establish the significance of P450 expression in this tumour type. Methods and results: A tissue microarray containing 170 breast cancers of no special type was immunostained for a panel of 21 P450s. The highest percentage of strong immunopositivity in breast cancers was seen for CYP4X1 (50.8%), CYP2S1 (37.5%) and CYP2U1 (32.2%), while CYP2J (98.6%) and CYP3A43 (70.7%) were the P450s that most frequently displayed no immunoreactivity. CYP4V2 (P = 0.01), CYP4X1 (P = 0.01) and CYP4Z1 (P = 0.01) showed correlations with tumour grade. CYP1B1 (P = 0.001), CYP3A5 (P = 0.001) and CYP51 (P = 0.005) showed the most significant correlations with oestrogen receptor status. Correlations with survival were identified for CYP2S1 (P = 0.03), CYP3A4 (P = 0.025), CYP4V2 (P = 0.026) and CYP26A1 (P = 0.03), although none of these P450s was an independent marker of prognosis. Conclusions: This study has defined the expression profile of cytochrome P450s in breast cancer and may offer their potential application as biomarkers to aid decisions regarding optimal adjuvant hormonal therapy.     

E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance

BACKGROUND: E-cadherin is a cell adhesion molecule that is expressed in normal breast tissue and is often considered useful as a phenotypic marker in breast cancer diagnosis, with absence of its expression frequently observed in tumours of lobular subtype. However, the clinicopathological and prognostic value of E-cadherin in the more frequent non-lobular types of breast carcinoma is unclear. METHODS AND RESULTS: E-cadherin expression was assessed immunohistochemically in a large and well-characterized series of invasive non-lobular breast carcinoma types (n=1665) with long-term clinical follow-up (median 56 months) using tissue microarray technology, to determine the relationship between its expression and primary tumour characteristics and disease outcome. Only membranous expression of E-cadherin was considered in this study and its expression was categorized as normal (H-score>100) or reduced [absent or below the median (score相似文献   

DEK overexpression is correlated with the clinical features of breast cancer

To investigate the clinicopathological significance of DEK overexpression in breast cancers, a total of 196 cases, including 20 of normal tissues, 12 of intraductal hyperplasia, 31 of ductal carcinoma in situ (DCIS) and 133 of invasive ductal carcinoma of the breast, were selected from the Department of Pathology, Yanbian Tumor Hospital for immunohistochemical staining of DEK, estrogen (ER), progesterone (PR) and Ki-67 proteins. In results, DEK protein had higher positivity in DCIS, compared with the adjacent normal breast tissues. Also, DEK protein was strongly positive in invasive ductal carcinoma of the breast on immunohistochemistry, which was significantly higher than normal breast tissues. However, only two (2/12) cases of intraductal hyperplasia of the breast showed positive staining for DEK protein. Additionally, DEK overexpression was significantly correlated with the increased proliferating index of Ki-67. For the histological grade, DEK positive rate was only 39.6% in G1 breast cancers, but significantly higher in G2 (92.3%) and G3 (97.0%) cases (P<0.05). Also, a strongly positive rate of DEK was lower in Stage-0 (21.4%) and Stage-I (40.9%) compared with Stage-IIa (87.5%), Stage-IIb (89.7%) and Stage-IIIa (92.3%) (P<0.05). And DEK protein showed higher expression level in < 3 years disease free survival breast cancers than it did in ≥ 3 years disease free survival cases (P<0.05). However, no statistically difference was found among DEK expression, lymph node metastasis, and ER and PR expressions. In conclusion, DEK overexpression appears to be associated with breast cancer progression and DEK may potentially be used as a breast cancer biomarker for the early diagnosis, prognostic evaluation and therapeutic target for breast cancer.     

The BRCAPRO 5.0 model is a useful tool in genetic counseling and clinical management of male breast cancer cases

No study has evaluated the performance of BRCA1/2 mutations prediction models in male breast cancer (MBC) series. Although rare, MBC deserves attention because male and female breast cancers share many characteristics, including the involvement of genetic predisposition factors such as BRCA1/BRCA2 mutations. Indeed, the occurrence of MBC is a commonly used criterion to select families for BRCA mutation testing. We evaluated the performance and clinical effectiveness of four different predictive models in a population-based series of 102 Italian MBC patients characterized for BRCA1/2 mutations. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each risk model at the 10% threshold. The area under the ROC (AUC) curves and its corresponding asymptotic 95% CIs were calculated as a measure of the accuracy. In our study, the BRCAPRO version 5.0 had the highest combination of sensitivity, specificity, NPV and PPV for the combined probability and for the discrimination of BRCA2 mutations. In individuals with negative breast–ovarian cancer family history, BRCAPRO 5.0 reached a high discriminatory capacity (AUC=0.92) in predicting BRCA2 mutations and showed values of sensitivity, specificity, NPV and PPV of 0.5, 0.98, 0.97 and 0.67, respectively, for the combined probability. BRCAPRO version 5.0 can be particularly useful in dealing with non-familial MBC, a circumstance that often represents a challenging situation in genetic counseling.     

Hierarchical clustering of PI3K and MAPK pathway proteins in breast cancer intrinsic subtypes

The phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer. We recently demonstrated the importance of analyzing multiple proteins as read-out for pathway activation in ER+/HER2− breast cancer, since single proteins are known to provide insufficient information. Here, we determined pathway activation in other primary breast cancer intrinsic subtypes derived from postmenopausal patients. Tumor blocks were recollected, and immunohistochemistry was performed using antibodies against PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-S6RP(Ser235/236) and p-ERK1/2, followed by unsupervised hierarchical clustering. In 32 ER+/HER2+, 37 ER−/HER2+ and 74 triple-negative breast cancer patients, subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. These subgroups likely reflect tumors with differences in biological behavior as well as treatment outcome.     

三阴性乳腺癌整合素连接激酶表达的预后意义

目的：探讨三阴性乳腺癌中整合素连接激酶（integrin-linked-kinase,ILK）的表达与患者预后的关系。方法：应用免疫组织化学SP法检测ILK在60例三阴性乳腺癌、36例非三阴性乳腺癌中的表达情况,并结合随访资料评价ILK表达水平对预测三阴性乳腺癌患者预后的价值。结果：三阴性乳腺癌中ILK的表达显著高于非三阴性乳腺癌（P〈0.01）;其ILK阳性表达与肿瘤大小、腋窝淋巴结转移、临床分期有关,而与患者年龄、月经状态无关;Kaplan-Meier生存曲线显示,ILK高表达组复发率高,病死率高,预后差。结论：ILK表达水平可作为判断三阴性乳腺癌患者预后的指标之一。