Expression of c-kit protein in proliferative lesions of human breast: sexual difference and close association with phosphotyrosine status

PURPOSE: The c-kit gene which codes transmembrane tyrosine kinase receptor protein plays an important role in several types of normal and/or neoplastic human tissues. We examined the expression patterns of c-kit protein in proliferative lesions of human breast tissues in both sexes. METHODS: The localization of c-kit protein was examined immunohistochemically in human breast, consisting of 366 normal tissue, 156 benign lesions (fibroadenoma, fibrocystic change, intraductal papilloma, benign phyllodes tumor, and gynecomastia), 13 borderline diseases (atypical ductal hyperplasia, atypical lobular hyperplasia, and borderline malignant phyllodes tumor), and 197 malignant lesions (non-invasive and/or invasive ductal carcinoma and malignant phyllodes tumor). RESULTS: In normal tissues and benign proliferative lesions, c-kit product was consistently detected on epithelial cell membranes and/or cytoplasms regardless of gender difference. In contrast, we failed to find c-kit product in female borderline epithelial lesions, including atypical lobular hyperplasia, or in female malignant lesions, except for two carcinomas. In situ hybridization analysis of c-kit mRNA in female tissues gave results comparable to those obtained by immunohistochemistry. On the other hand, c-kit product was consistently detected in male benign and malignant proliferative lesions. Apart from the female breast carcinomas which lacked c-kit, c-kit expression was almost always accompanied by positivity for phosphotyrosine in the breast tissues examined, suggesting possible phosphorylation of tyrosine residues of the c-kit receptor protein. CONCLUSIONS: Loss of c-kit product was related to malignant transformation in female breast, but not in the case of male breast. We suggest that the oncogenesis pathway of breast epithelium is different between males and females in terms of c-kit expression.     

Histological and biological evolution of human premalignant breast disease

Most human invasive breast cancers (IBCs) appear to develop over long periods of time from certain pre-existing benign lesions. Of the many types of benign lesions in the human breast, only a few appear to have significant premalignant potential. The best characterized of these include atypical hyperplasias and in situ carcinomas and both categories are probably well on along the evolutionary pathway to IBC. Very little is known about earlier premalignant alterations. All types of premalignant breast lesions are relatively common but only a small proportion appear to progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect epidemiological evidence. Although lesions within specific categories look alike, they must possess underlying biological differences causing some to remain stable and others to progress. Recent studies suggest that they evolve by highly diverse genetic mechanisms and research into these altered pathways may identify specific early defects that can be targeted to prevent premalignant lesions from developing or becoming cancerous. It is far more rational to think that breast cancer can be prevented than cured once it has developed fully. This review discusses histological models of human premalignant breast disease that provide the framework for scientific investigations into the biological alterations behind them and examples of specific biological alterations that appear to be particularly important.     

Identification of genes expressed in premalignant breast disease by microscopy-directed cloning.

Histopathologic study of human breast biopsy samples has identified specific lesions which are associated with a high risk of development of invasive breast cancer. Presumably, these lesions (collectively termed premalignant breast disease) represent the earliest recognizable morphologic expression of fundamental molecular events that lead to the development of invasive breast cancer. To study molecular events underlying premalignant breast disease, we have developed a method for isolating RNA from histologically identified lesions from frozen human breast tissue. This method specifically obtains mRNA from breast epithelial cells and has identified three genes which are differentially expressed in premalignant breast epithelial lesions. One gene identified by this method is overexpressed in four of five noncomedo ductal carcinoma in situ lesions and appears to be the human homologue of the gene encoding the M2 subunit of ribonucleotide reductase, an enzyme involved in DNA synthesis.     

Retrospective multivariate analysis of radio-pathological correlations of nonpalpable breast lesions. Experience of the Hospital Saint-Louis

PURPOSE: Several studies have demonstrated that systematic breast cancer screening increases overall survival. We report our experience regarding diagnosis of breast lesions detected using mammography. METHODS: Case reports of patients operated on in either 1992 or 1993 were retrospectively reviewed. A multivariate analysis of the clinico-pathological correlation was performed. RESULTS: Four hundred fifty seven patients representing on total 544 procedures, were included in the study. Mean age was 50.5 years (range 19-80 years). Most of the patients had no previous history of mammary lesion. Mammography was performed with prophylactic intent in more than 60% of the cases. Four hundred twelve (75.7%) benign lesions were diagnosed. Main lesions were: adenofibroma (15.7%), fibrocystic mastopathy (66.3%), adenosis (26.2%), ductal hyperplasia (23.9%), lobular hyperplasia (10.7%), and combined ductal and lobular hyperplasia (8.5%). Hyperplasia accompanied by cytonuclear atypia was observed in 49 (11%) cases. One hundred thirty two (24.3%) malignant lesions were reported, including 69 (52.3%) invasive carcinomas and 63 (47.7%) in situ carcinomas. Only nine axillary lymph node dissections were positive and 75 minimal breast cancers were diagnosed. The multivariate analysis showed that only radiological signs are a risk factor for cancer. The relative risk for cancer when focus of irregular and vermicular microcalcifications are diagnosed is 4.2 (2.0-8.5). It is 5.6 (2.5-12.5) in case of spiculated opacity. CONCLUSION: Exeresis following radiological prophylactic screening allows diagnosis of high-risk benign lesions and low-stage breast cancer. Radiological parameters are the most powerful predictive factors for malignancy.     

Nipple involvement and multicentricity in breast cancer

Summary Our study examined 166 patients with breast cancer with a mean age of 63 years. Each patient underwent mastectomy with the organ being investigated by histological giant sections and additional small sections from the nipple. Nipple involvement was found in 64 cases (38%). Multifocal carcinoma occurred in 76 patients. Further multicentric carcinomatous foci (36 cases) demonstrated a significant increase in affected nipples. Additional atypical ductal or lobular hyperplasia was observed in 53 cases and showed involvement in 34. Nine carcinomas of ductal origin were combined with lobular carcinoma in situ, all cases proved to have carcinomatous changes in the nipple. It is concluded that apart from the well-known influence of advanced tumor stages and tumor localization, nipple involvement correlates with multicentricity and multifocality of breast cancer as a disease of the whole organ.Supported by the Bundesministerium für Forschung und Technologie (TNM 009)     

Risk of subsequent invasive breast cancer after breast carcinoma in situ

The standardised incidence rates for invasive breast cancer were estimated in a cohort of 3455 women with a primary lobular or ductal carcinoma in situ of the breast.     

3.0T磁共振扩散加权成像在乳腺癌诊断及病理分型中的应用价值

目的探讨3.0T磁共振扩散加权成像（DWI）在乳腺癌诊断中的应用价值,并分析表观弥散系数（ADC）对乳腺癌病理分型的意义。 方法回顾性分析2017年9月至2018年9月牡丹江医学院附属红旗医院收治的经手术或穿刺活检病理证实的72例乳腺癌患者。比较MR平扫、DWI及两者联合诊断乳腺癌的准确性;比较b值为1000 s/mm²时不同病理类型乳腺癌ADC值的差异。 结果本组72例乳腺癌患者,病理证实非浸润性癌19例（导管内原位癌17例,小叶原位癌2例）;浸润性癌53例（浸润性导管癌42例,浸润性小叶癌11例）。MR平扫、DWI及两者联合诊断本组72例乳腺癌患者的准确率分别为88.9%（64/72）、65.3%（47/72）、95.8%（69/72）。b值为1000 s/mm²时,导管内原位癌与浸润性导管癌、小叶原位癌与浸润性小叶癌平均ADC值差异均有统计学意义（t=0.015,P<0.001;t=3.095,P<0.05）。 结论DWI对乳腺癌的诊断有一定的临床价值,MR平扫与DWI两者联合对乳腺癌诊断具有较高的准确性。ADC值对乳腺浸润性癌与非浸润性癌的区分有价值。     

Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas.

BACKGROUND/AIMS: Multiple genetic alterations are involved in the development of pancreatic neoplasm. Here we investigated the incidence of p53, ras, bcl-2 and c-erbB-2 gene alterations in intraductal papillary-mucinous tumors and invasive ductal adenocarcinoma of the pancreas by immunohistochemical method to identify and analyze their relationship in terms of these genetic alterations. METHODOLOGY: Fifty-four pancreatic lesions, including 18 benign (hyperplasia (3) and intraductal papillary adenoma (15)), and 16 malignant (carcinoma in situ (2) and intraductal papillary adenocarcinoma (14)) cases of intraductal papillary-mucinous tumor; and 20 cases of invasive ductal adenocarcinoma, were immunostained by avidin-biotin peroxidase conjugate method. RESULTS: p53 and rasp21 expressions were significantly greater in malignant intraductal (P < 0.01, P < 0.05) and invasive ductal (P < 0.01, P < 0.01) tumors than in benign intraductal papillary-mucinous tumors; while bcl-2 and c-erbB-2 expressions were significantly greater in invasive ductal adenocarcinoma than both benign (P < 0.01, P < 0.05) and malignant (P < 0.05, P < 0.05) intraductal papillary-mucinous tumors. CONCLUSIONS: Different groups of genetic alterations are involved in different phases of pancreatic tumorigenesis. p53 and ras gene alterations occur at an early stage during the development of intraductal papillary-mucinous tumor, while additional alterations of bcl-2 and c-erbB-2 occur during the development of invasive ductal adenocarcinoma of the pancreas.     

Stable 'portrait' of breast tumors during progression: data from biology, pathology and genetics

It is widely believed that ductal breast cancer dissemination involves a succession of clinical and pathological stages starting with carcinoma in situ, progressing into invasive lesion and culminating in metastatic disease. Such changes have frequently been attributed to the sequential acquisition of various alterations in a single cell followed by clonal selection and expansion, thus leading to intra-tumor diversity. According to this multi-step view, extensive genotype and phenotype (marker expression, grade) shift may occur in the same tumor during progression; this may lead to the co-existence of molecularly and/or pathologically different areas within the same lesion. An increasing amount of data of various natures now appear to challenge this concept: only a few distinct 'portraits', in relation to estrogen receptor (ER) status and grade, may be found among tumors. Moreover, although undergoing increasing genetic alteration, most individual lesions largely maintain their phenotype when they evolve from in situ to the metastatic state. While many of the data presented here are related to ductal tumors, lobular cancer is also discussed.     

Invasive lobular breast cancer and its variants: How special are they for systemic therapy decisions?

The WHO classification of breast tumors distinguishes, besides invasive breast cancer ‘of no special type’ (former invasive ductal carcinoma, representing 60–70% of all breast cancers), 30 special types, of which invasive lobular carcinoma (ILC) is the most common (5–15%). We review the literature on (i) the specificity and heterogeneity of ILC biology as documented by various analytical techniques, including the results of molecular testing for risk of recurrence; (ii) the impact of lobular histology on prediction of prognosis and effect of systemic therapies in patients. Though it is generally admitted that ILC has a better prognosis than IDC, is endocrine responsive, and responds poorly to chemotherapy, currently available data do not unanimously support these assumptions. This review demonstrates some lack of specific data and a need for improving clinical research design to allow oncologists to make informed systemic therapy decisions in patients with ILC. Importantly, future studies should compare various endpoints in ILC breast cancer patients among the group of hormonosensitive breast cancer.     

The influence of family history and histological stratification on breast cancer risk in women with benign breast disease: a meta-analysis

Purpose  

Benign breast disease (BBD) is an important risk factor for subsequent breast cancer. However, it is unclear whether breast cancer risk is higher in cases of atypical ductal hyperplasia (ADH) than atypical lobular hyperplasia (ALH). Furthermore, it is unclear whether family history increases risk in women with various subtypes of BBD.     

促凋亡蛋白BAD在乳腺导管增生及乳腺癌组织中表达的研究

目的检测促凋亡蛋白BAD在人乳腺导管增生及乳腺癌组织中表达,探讨其在乳腺癌癌变过程中的作用及意义.方法采用免疫组织化学S-P法,检测131例乳腺导管增生及乳腺癌组织中促凋亡蛋白BAD的表达.结果BAD蛋白在正常乳腺组织中的阳性率为33.3%（3/9）.从普通导管增生、轻中度不典型导管增生、重度不典型增生及导管原位癌到浸润性导管癌组织,BAD蛋白表达阳性率呈递增趋势,在乳腺普通导管增生和重度不典型增生及原位癌组间阳性表达率差异均具有统计学意义（P＜0.05）.结论促凋亡蛋白BAD蛋白表达在乳腺癌癌变过程中呈递增趋势;BAD蛋白表达水平与组织学分级有关,组织学分级越低,其蛋白表达阳性率越高.     

肺癌前病变的形态学和免疫组织化学标记物研究进展

世界范围内,肺癌已跃居成为癌症患者死亡原因的首位.早期诊断对降低肺癌病死率至关重要.世界卫生组织已确定了支气管上皮的3种癌前病变:鳞状上皮异常增生和原位癌、非典型腺瘤样增生和弥漫性特发性神经内分泌细胞增生.另外,细支气管炎和细支气管柱状细胞不典型增生也被认为是腺癌的癌前病变.对肺癌癌前病变形态学特征及其伴随的分子和基因学变化的深入了解可能为肺癌的早期诊断提供新的方向.     

Pathological features of primary breast cancer in the elderly based on needle core biopsies--a large series from a single centre

Most breast cancer patients are diagnosed at>65 years but research efforts are mainly focussed on younger patients. Knowledge related to elderly breast cancer is urgently needed. Patients>70 years presenting with early operable primary breast cancer were studied. Pathological features of diagnostic needle core biopsies taken from 2078 tumours from 2061 consecutive patients managed under a dedicated elderly breast cancer service, in 1987-2006, were reviewed. There were 1996 invasive carcinoma of mammary type (96%) with (N=200) or without associated ductal carcinoma in situ (DCIS); 81 were DCIS only (3.9%). One malignant adenomyoepithelioma was seen. Among the invasive carcinomas, ductal carcinoma of no special type was seen in 87.1% while lobular and mucinous features were noted in 6.9% and 3.1%, respectively. Histological grades and oestrogen receptor (ER) status were assessed respectively in 826 and 1557 invasive carcinomas. Majority were grade 2 (62.7%), followed by grade 1. Around 82% were ER-positive. Their pattern was compared with that in 2674 tumours from younger (70 years this distribution was more marked, with a great preponderance of highly ER-positive tumours, and a substantial minority being ER-negative, with very few in intermediate groups. We believe that this is the largest dataset of pathological features of elderly primary breast cancer from one institution. We have clearly confirmed the high frequency of ER-positive tumours in elderly patients. Further work is underway to assess long-term outcome and clinical relevance.     

The gene associated with trichorhinophalangeal syndrome in humans is overexpressed in breast cancer

A comprehensive differential gene expression screen on a panel of 54 breast tumors and >200 normal tissue samples using DNA microarrays revealed 15 genes specifically overexpressed in breast cancer. One of the most prevalent genes found was trichorhinophalangeal syndrome type 1 (TRPS-1), a gene previously shown to be associated with three rare autosomal dominant genetic disorders known as the trichorhinophalangeal syndromes. A number of corroborating methodologies, including in situ hybridization, e-Northern analysis using ORF EST (ORESTES) and Unigene EST abundance analysis, immunoblot and immunofluorescence analysis of breast tumor cell lines, and immunohistochemistry, confirmed the microarray findings. Immunohistochemistry analysis found TRPS-1 protein expressed in >90% of early- and late-stage breast cancer, including ductal carcinoma in situ and invasive ductal, lobular, and papillary carcinomas. The TRPS-1 gene is also immunogenic with processed and presented peptides activating T cells found after vaccination of HLA-A2.1 transgenic mouse. Human T cell lines from HLA-A*0201+ female donors exhibiting TRPS-1-specific cytotoxic T lymphocyte activity could also be generated.     

Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA

The transition from ductal carcinoma in situ to invasive ductal carcinoma is a key event in breast cancer progression that is still not well understood. To discover the microRNAs regulating this critical transition, we used 80 biopsies from invasive ductal carcinoma, 8 from ductal carcinoma in situ, and 6 from normal breast. We selected them from a recently published deep-sequencing dataset [Farazi TA, et al. (2011) Cancer Res 71:4443-4453]. The microRNA profile established for the normal breast to ductal carcinoma in situ transition was largely maintained in the in situ to invasive ductal carcinoma transition. Nevertheless, a nine-microRNA signature was identified that differentiated invasive from in situ carcinoma. Specifically, let-7d, miR-210, and -221 were down-regulated in the in situ and up-regulated in the invasive transition, thus featuring an expression reversal along the cancer progression path. Additionally, we identified microRNAs for overall survival and time to metastasis. Five noncoding genes were associated with both prognostic signatures--miR-210, -21, -106b*, -197, and let-7i, with miR-210 the only one also involved in the invasive transition. To pinpoint critical cellular functions affected in the invasive transition, we identified the protein coding genes with inversely related profiles to miR-210: BRCA1, FANCD, FANCF, PARP1, E-cadherin, and Rb1 were all activated in the in situ and down-regulated in the invasive carcinoma. Additionally, we detected differential splicing isoforms with special features, including a truncated EGFR lacking the kinase domain and overexpressed only in ductal carcinoma in situ.     

Risk of mortality by histologic type of breast cancer among women aged 50 to 79 years

BACKGROUND: Recent studies suggest that the use of combined estrogen and progestin hormone replacement therapy is associated with an increased risk of invasive lobular carcinoma (ILC), but that it has little association with risk of invasive ductal carcinoma (IDC). Also, the incidence rates of ILC have risen over the past 10 years while those of IDC have remained constant. Differences in survival rates by histologic types of tumor have been reported, but few of the published studies were population based or had adequate power to address this issue. METHODS: We conducted a retrospective cohort study spanning the years 1974 through 1998 using data from the 9 cancer registries that have participated in the Surveillance, Epidemiology, and End Results Program since 1974. The cohort consisted of 164 958 women aged 50 to 79 years who had been diagnosed as having 1 of 7 histologic types of invasive breast cancer. Risks of mortality due to any cause were estimated using the Cox proportional hazards model. RESULTS: Women with ILC had a risk of mortality 11% lower than women with IDC. The magnitude of this difference has increased over the past 10 years and, from 1994 through 1998, the risk of mortality was 26% lower for women with ILC. Also, the risk of mortality was between 8% and 34% lower in women with mucinous carcinoma, comedocarcinoma, or medullary, tubular, and papillary carcinomas compared with women with IDC. CONCLUSIONS: Differences in prognosis by histologic type of breast cancer were identified. The survival rate of women 50 to 79 years old who have ILC, the cancer whose histologic type is the most closely linked with the use of combined estrogen and progestin hormone replacement therapy, is more favorable than that of women with IDC and appears to be improving over time.     

Methylation of estrogen receptor beta promoter correlates with loss of ER-beta expression in mammary carcinoma and is an early indication marker in premalignant lesions

The function of estrogen receptor beta (ER-beta) in mammary tissue is not completely understood. While early observations were often conflicting, more recent data suggest an important role as a tumor-suppressor gene. A decrease of ER-beta expression has been observed in ductal carcinoma in situ and invasive carcinoma as compared with benign mammary epithelial cells. The loss of ER-beta resulted in abnormal growth of mammary epithelial cells. We have previously shown that the mRNA expression of the ER-beta gene is almost totally suppressed in breast carcinomas from patients with a poor prognosis. Here we analyzed whether methylation changes in the different promoters of ER-beta are responsible for the loss of expression of the gene. A methylation assay with high specificity and sensitivity was developed, and a panel of breast tissue samples (n = 175) was characterized for methylation status. In contrast to benign breast, more than two-thirds of invasive breast cancers showed a high degree of methylation. Importantly, increased methylation was also detectable in numerous premalignant lesions. By analysis of breast tumors, previously characterized by gene-expression profiling, methylation was predominantly detected in a subgroup of patients with an unfavorable prognosis, suggesting a possible prognostic value of the ER-beta methylation status. We also investigated the structural characteristics of the two ER-beta promoters, which were both found to be closely associated with a second, downstream, localized and opposite-oriented promoter. However, we could not detect endogenous antisense RNA transcribed from these promoters, which may be involved in epigenetic gene silencing. We also failed to induce ER-beta promoter methylation by expressing siRNAs in cell lines. Interestingly, by comparing the promoter sequences of ER-beta with other genes known to be epigenetically inactivated in breast cancers, we identified a sequence motif possibly involved in promoter methylation.     

Telomere fusions in early human breast carcinoma

Several lines of evidence suggest that defects in telomere maintenance play a significant role in the initiation of genomic instability during carcinogenesis. Although the general concept of defective telomere maintenance initiating genomic instability has been acknowledged, there remains a critical gap in the direct evidence of telomere dysfunction in human solid tumors. To address this topic, we devised a multiplex PCR-based assay, termed TAR (telomere-associated repeat) fusion PCR, to detect and analyze chromosome end-to-end associations (telomere fusions) within human breast tumor tissue. Using TAR fusion PCR, we found that human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. Telomere fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage. Our results provide direct evidence that telomere fusions are present in human breast tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in this cancer. Development of this robust method that allows identification of these genetic aberrations (telomere fusions) is anticipated to be a valuable tool for dissecting mechanisms of telomere dysfunction.     

Ductal adenocarcinoma of the head of the pancreas: incidence of tumor involvement beyond the Whipple resection line. Histological and immunocytochemical analysis of 37 total pancreatectomy specimens

Intrapancreatic tumor spread of ductal adenocarcinoma of head of pancreas was examined histologically in 37 total pancreatectomy specimens. Five to 10 tissue blocks were prepared from grossly tumor-free tissue of each pancreas and coded by anatomic location. Step sections from each block were analyzed for carcinoma in situ lesions, invasive carcinoma, and benign ductal lesions. Immunocytochemical staining with monoclonal antibodies (MAb) against carcinoembryonic antigen (CEA) and nonspecific cross-reacting antigen 95 (NCA 95) were used to help in discriminating carcinoma in situ from papillary duct hyperplasia. In 3 of 37 pancreatectomy specimens (8%) tumor was found to spread in continuity from the primary carcinoma into the body and tail. In two of these three cases with tumor beyond the usual Whipple resection line, the tumor was present as a "carcinoma in situ" lesion along the main pancreatic duct. Since discontinuous tumor growth was not observed, multicentricity of duct type adenocarcinoma seems to occur less frequently than was previously reported.