Downregulation of Gelsolin Correlates with the Progression to Breast Carcinoma

The actin cytoskeleton underlies several normal cellular functions and is deranged during carcinogenesis. Gelsolin, a multifunctional actin-binding protein, is downregulated in several types of tumors and its abnormal expression is one of the most common defects noted in invasive breast carcinoma (ICA). This study utilizes immunohistochemistry to examine the expression of gelsolin in 95 ICA, 59 ductal carcinoma in situ (DCIS) and 36 benign lesions, including 17 atypical ductal hyperplasia (ADH). Cytoplasmic staining was scored as positive, reduced or negative. Gelsolin expression was then correlated with patients age, tumor size, histologic grade and lymph node status. All unremarkable breast biopsies, 88% of ADH, 44% of DCIS and 28% of ICA were positive for gelsolin. This represents a significant difference among the groups (p=<0.0001) and the trend towards reduced gelsolin with the progression to ICA is significantly linear (p=<0.0001). For invasive carcinoma, patients older than 44 years were significantly more likely to have decreased expression of gelsolin than patients 44 years old and younger (p=0.007). Bivariate analysis showed no correlation of gelsolin expression with lymph node status (p=0.62), tumor size (p=0.10), histologic grade (p=0.42), estrogen receptor status (p=1.0) or other clinicopathologic parameters. In clinical follow-up, there were 18 breast tumor related deaths within a median follow-up time of 4.2 years. Survival analysis indicated that the level of gelsolin expression may be associated with survival (p=0.06). In summary, the frequency of gelsolin deficiency increases significantly with progression from ADH to DCIS to ICA. Additionally, gelsolin expression may be an independent marker of prognosis.     

A Comparison of the Biological and Clinical Features of Invasive Lobular and Ductal Carcinomas of the Breast

Altogether 295 consecutive pure lobular invasive breast cancers diagnosed between 1990 and 1999 in the area of Tampere University Hospital were compared to 295 ductal invasive breast cancers. Biological factors, DFS, OS, recurrence types, survival after recurrence and other primary cancers were analyzed. ILC tumors were more often hormone receptor-positive, slowly proliferative and Erbb-2-negative. During the mean follow-up time of 5.1 years 76 recurrences in both groups were discovered. During the whole follow-up time there was more metastation to gynecological organs and GI tract in the ILC group. Bilateral breast cancers did not differ between the groups. DFS and OS were the same between the groups despite the fact that ILC patients received statistically significantly less adjuvant treatment. In conclusion, since ILC cancers are more often hormone receptor-positive, there is a good option to adjuvant endocrine therapy with present and future preparations, this possibly leading to improvement in OS.     

TIMP-2在乳腺癌中的表达及临床意义

目的:探讨组织金属蛋白酶抑制剂-2（tissue inhibitors of metalloproteinase-2,TIMP-2）在乳腺正常组织、不典型增生、原位癌、浸润性癌组织中的表达水平,分析其与浸润性乳腺癌临床病理指标及乳腺癌生存情况之间的关系。方法:收集20例正常乳腺组织、28例不典型增生、40例导管内癌、80例浸润性乳腺癌标本,用免疫组化SP法检测各组TIMP-2的表达,分析其在浸润性乳腺癌不同临床病理指标分组中的表达差异;并通过120例乳腺癌患者的随访,分析其对乳腺癌生存状况的影响。结果:TIMP-2在乳腺正常组织（25.0%）、不典型增生组织（28.6%）、原位癌组织（60.0%）、浸润性癌组织（66.3%）中表达阳性率依次增高,在乳腺原位癌与不典型增生之间比较有统计学差异（P＜0.05）。浸润性乳腺癌TIMP-2的表达在部分组织学分级分组中比较有统计学差异（P＜0.05）,在不同月经状态、年龄、肿块大小、临床分期、淋巴结转移数目、激素受体状态分组之间无统计学差异(均P＞0.05)。原位癌TIMP-2表达阳性组5年无病生存率高于表达阴性组,有统计学差异（P＜0.05）;浸润性乳腺癌TIMP-2表达阳性组5年无病生存率与表达阴性组无统计学差异（P＞0.05）。结论:TIMP-2参与了乳腺癌发生、发展的过程,在乳腺癌不同发展阶段具有不同预后价值。     

CD147和MMP9在乳腺浸润性导管癌中的表达及意义

[目的]探讨CD147和MMP9在乳腺浸润性导管癌中的表达及意义。[方法]应用免疫组织化学方法SP法检测60例乳腺浸润性导管癌及60例乳腺纤维腺瘤组织中CD147和MMP9的表达情况。[结果]CD147及MMP9在60例乳腺纤维腺瘤中均阴性表达,CD147、MMP9在乳腺浸润性导管癌中的阳性表达率分别为91.7%（55/60）和86.7%（52/60）（P均=0.000）。CD147和MMP9的表达均与乳腺浸润性导管癌患者的组织学分级及淋巴结转移相关,与年龄、肿瘤大小、家族史及临床分期无关。CD147和MMP9在乳腺浸润性导管癌中表达呈显著性相关（r=0.830）。[结论]CD147和MMP9在乳腺浸润性导管癌中高表达,两者在乳腺癌的发生发展中发挥着重要作用。     

mTOR和4EBPS在乳腺浸润性导管癌中的表达及意义

[目的]探讨mTOR和4EBPS在乳腺浸润性导管癌中的表达及意义。[方法]采用免疫组化SP法检测45例乳腺癌及癌旁正常组织中mTOR和4EBPS的表达。[结果]mTOR在乳腺癌中的阳性率为75.56%（34/45）,在正常乳腺组织中的阳性率为20.00%（9/45）,差异有显著性（P〈0.05）。mTOR表达与乳腺癌淋巴结转移明显相关（P〈0.05）。4EBPS在乳腺癌中的阳性率为31.11%（14/45）,在正常乳腺组织中的阳性率为95.56%（43/45）,差异有显著性（P〈0.05）。4EBPS表达与乳腺癌淋巴结转移无关（P〉0.05）。mTOR与4EBPS表达呈负相关（r=-0.614,P〈0.05）。[结论]mTOR和4EBPS在乳腺癌组织中的异常表达可能与乳腺癌的发生有关,且mTOR的异常表达可能与乳腺癌的转移有关。     

Cyclooxygenase-2 Expression in Invasive Breast Carcinomas of No Special Type and Correlation with Pathological Profiles Suggest a Role in Tumorigenesis Rather than Cancer Progression

Background: COX-2 has been shown to play an important role in the development of breast cancer andincreased expression has been mooted as a poor prognostic factor. The purpose of this study was to investigatethe relationship between COX-2 immunohistochemical expression and known predictive and prognostic factorsin breast cancer in a routine diagnostic histopathology setting. Materials and Methods: Formalin-fixed paraffinembeddedtumour tissue of 144 no special type (NST) invasive breast carcinomas histologically diagnosed betweenJanuary 2009 and December 2012 in Hospital Sultanah Bahiyah, Alor Setar, Kedah were immunostained withCOX-2 antibody. COX-2 overexpression was analysed against demographic data, hormone receptor status, HER2-neu overexpression, histological grade, tumour size and lymph node status. Results: COX-2 was overexpressedin 108/144 (75%) tumours and was significantly more prevalent (87%) in hormone receptor-positive tumours.There was no correlation between COX-2 overexpression and HER2/neu status. Triple negative cancers had thelowest prevalence (46%) (p<0.05). A rising trend of COX-2 overexpression with increasing age was observed.There was a significant inverse relationship with tumour grade (p<0.05), prevalences being 94%, 83% and66% in grades 1, 2 and 3 tumours, respectively. A higher prevalence of COX-2 overexpression in smaller sizetumours was observed but this did not reach statistical significance. There was no relationship between COX-2expression and lymph node status. Conclusions: This study did not support the generally held notion that COX-2overexpression is linked to poor prognosis, rather supporting a role in tumorigenesis. Larger scale studies withoutcome data and basic studies on cancer pathogenetic pathways will be required to cast further light on whetherCOX-2 inhibitors would have clinical utility in cancer prevention or blockage of cancer progression. In eithersetting, the pathological assessment for COX-2 overexpression in breast cancers would have an important rolein the selection of cancer patients for personalized therapy with COX-2 inhibitors.     

Characteristics of Invasive Breast Ductal Carcinoma,NOS, Diagnosed in a Tertiary Institution in the East Coast of Malaysia with a Focus on Tumor Angiogenesis

Background: Prognosis of breast cancer depends on classic pathological factors and also tumor angiogenesis.This study aimed to evaluate the clinicopathological factors of breast cancer in a tertiary centre with a focus onthe relationship between tumor angiogenesis and clinicopathological factors. Methods: Clinicopathological datawere retrieved from the archived formal pathology reports for surgical specimens diagnosed as invasive ductalcarcinoma, NOS. Microvessels were immunohistochemically stained with anti-CD34 antibody and quantifiedas microvessel density. Results: At least 50% of 94 cases of invasive breast ductal carcinoma in the study wereadvanced stage. The majority had poor prognosis factors such as tumor size larger than 50mm (48.9%), positivelymph node metastasis (60.6%), and tumor grade III (52.1%). Higher percentages of estrogen and progesteronereceptor negative cases were recorded (46.8% and 46.8% respectively). Her-2 overexpression cases and triplenegative breast cancers constituted 24.5% and 22.3% respectively. Significantly higher microvessel density wasobserved in the younger patient age group (p=0.012). There were no significant associations between microvesseldensity and other clinicopathological factors (p>0.05). Conclusions: Majority of the breast cancer patients of thisinstitution had advanced stage disease with poorer prognostic factors as compared to other local and westernstudies. Breast cancer in younger patients might be more proangiogenic.     

bcl-2蛋白在良性乳腺病变及乳腺癌组织中的表达

目的　观察bcl-2蛋白在乳腺癌及良性乳腺病变中的表达。方法　采用免疫组化方法检测 15例正常乳腺组织、18例导管增生、10例不典型导管增生 ,10例小叶增生 ,6 9例浸润型乳腺癌和 45例乳腺导管原位癌中bcl -2蛋白表达。结果　bcl -2在 15例正常乳腺组织、18例导管增生、10例不典型导管增生及 10例小叶增生中均呈阳性 (10 0 % ) ,且均为高表达 ;bcl -2蛋白在 6 9例浸润型乳腺癌和 45例导管原位癌的表达阳性率分别为 6 5 2 % (45例 )和 75 6 % (3 4例 )。结论　bcl -2蛋白在正常乳腺组织良性乳腺病变的表达明显高于乳腺癌的表达。可能是在肿瘤的发展过程中bcl -2失去表达的结果 ,其原因和机理还有待进一步研究     

乳腺不同级别导管癌和不典型增生病变基因组DNA拷贝数变化及其意义初探

  目的   研究乳腺不同级别导管内癌、浸润性导管癌和不典型增生病变基因组DNA拷贝数的变化,探索从分子遗传学角度解释乳腺癌的发生发展机制。   方法  采用比较基因组杂交技术检测导管上皮不典型增生、高低级别导管内癌和浸润性导管癌45例,以分析其遗传物质的增益和缺失情况,并分析比较共同的染色体异常区段。   结果  低级别癌的染色体平均增益数、缺失数及总的变化数均明显低于高级别癌,但是与浸润性癌之间无显著性差异。不典型增生样本中染色体异常水平明显高于癌组织样本,与低级别癌样本有共同的变化位点。高级别原位癌和浸润性癌具有相同的染色体及其位点的遗传学异常,有多个共同的缺失位点。   结论  不典型增生的细胞遗传学变化先于形态学上的改变,可能与低级别癌发生存在密切的遗传学联系;同级别导管内癌和浸润性导管癌可能有共同的遗传学变化和演变途径。      

iNOS在不同乳腺病理组织中的表达水平及其与肿瘤临床预后的相关性

目的:检测诱导型一氧化氮合酶（iNOS）在正常乳腺组织、不典型增生、原位癌以及浸润性乳腺癌组织中的表达水平,探讨其与浸润性乳腺癌临床相关病理指标及临床预后相关性。方法:收集148例不同乳腺病理组织（28例不典型增生、40例导管内癌及80例浸润性乳腺癌）以及20例正常乳腺组织,使用免疫组化SP法检测各组中iNOS的表达水平。分析浸润性乳腺癌中iNOS表达水平与肿瘤大小、腋窝淋巴结受累情况、TNM分期等临床病理指标,以及与临床预后的相关性。结果:iNOS在乳腺正常组织中未见阳性表达;而在乳腺不典型增生组织、原位癌组织及浸润性乳腺癌组织中阳性率分别为25.0%、52.5%及78.8%,各组间差异有统计学意义（均P<0.05）。在浸润性乳腺癌中,随着临床分期越晚及肿瘤直径越大,iNOS染色阳性率逐渐升高。在原位癌中iNOS染色阳性组5年无病生存率（61.9%）低于阴性组（84.2%）,差异有统计学意义（P<0.05）;而在浸润性乳腺癌中,iNOS染色阳性组5年无病生存率（63.5%）与阴性组（70.6%）无统计学差异（P>0.05）。结论:iNOS在乳腺癌发生的早期阶段（不典型增生）即已出现表达升高,其表达水平与临床分期与肿瘤直径相关,并影响原位癌患者预后。因此,iNOS可作为乳腺癌早期诊断及预后评估的潜在指标。     

Histologic associations and long-term cancer risk in columnar cell lesions of the breast: a retrospective cohort and a nested case-control study

BACKGROUND: Mammary columnar cell lesions with atypia have been receiving increased scrutiny in view of their association with atypical hyperplasia (AH) and carcinoma. However, the few retrospective outcome studies performed have failed to establish an increased risk for recurrence or carcinoma on long-term follow-up. METHODS: The authors evaluated the overall cancer risk for 1261 biopsies with columnar cell lesions (CCL) in 4569 women from the Nashville Breast Cohort who were biopsied between 1969 and 1988. On the basis of Schnitt and Vincent-Salomon's classification, they also classified 229 biopsies with CCL into 3 categories: without hyperplasia or atypia, with hyperplasia lacking atypia, and with atypia. By using a nested case-control design, they compared the risks of invasive cancer associated with these 3 categories. RESULTS: A 2- to 3-fold increase in the occurrence of AH in the presence of CCL versus in their absence (P< .005) was observed. Relative risk of invasive breast cancer for women with both AH and CCL compared with those with AH alone did not differ significantly (risk ratio [RR]=1.55; P= .29). The presence of CCL alone was associated with a mild increase in the overall cancer risk (RR=1.47; P= .05). In the nested case-control study, no significant risk difference was observed among the 3 categories of CCL. CONCLUSIONS: The authors observed a positive association between CCL and AH. The possibility that CCL by themselves significantly elevate breast cancer risk is not well supported. However, a finding of CCL on benign breast biopsy may indicate the presence of AH, a more worrisome lesion.     

Ductal carcinoma in situ (DCIS) of the breast: perspectives on biology and controversies in current management

The incidence of ductal carcinoma in situ (DCIS) has increased because of increasing use of sensitive imaging modalities. MRI is commonly used for the detection of breast cancer but has not yet been validated in randomized trials. There have not been randomized trials addressing optimal margins of excision or axillary sampling. Whole breast radiation after lumpectomy decreases the risk of recurrence but may be omitted in selected patients. Adjuvant Tamoxifen reduces the risk of recurrence but has no impact on overall survival rates.     

FAK在乳腺癌组织和癌前病变组织中的表达

目的探讨黏着斑激酶（FAK）的表达与乳腺癌浸润和转移的关系。方法采用免疫组织化学和原位杂交方法检测42例乳腺癌组织、32例乳腺增生组织及20例正常乳腺组织中FAK的表达，并分析其与临床病理特征之间的关系。结果1）乳腺癌组织中FAK蛋白及mRNA阳性表达率分别为83．33％（35／42），78．57％（33／42），在不典型增生中阳性表达率分别为52．38％（11／21）和42．86％（9／21），在一般增生和正常乳腺组织中均未见表达。乳腺癌组显著高于正常组、一般增生组和不典型增生组（P〈0．01），不典型增生组也显著高于正常组和一般增生组（P〈0．05）；2）与无淋巴结转移的乳腺癌比较，有淋巴结转移的乳腺癌中FAK蛋白及mRNA阳性率较高，差异具有统计学意义（P〈0．05）；3）FAK蛋白及mRNA阳性表达率与乳腺癌的组织学类型无关，随着乳腺癌的临床分期的升高，FAK蛋白及mRNA的表达有着增高的趋势，但两组间进行比较，差异无统计学意义（P〉0．05）。结论FAK表达的高低可能作为乳腺癌发生、发展过程中较有价值的病理指标，可导致乳腺癌发生并加速恶性细胞的增殖、浸润和转移。     

Pathologic and technical considerations in the treatment of ductal carcinoma in situ of the breast with lumpectomy and radiation therapy

Background: Lumpectomy and radiation therapy is considered a standard treatment option for ductal carcinoma in situ (DCIS) of the breast. The incidence of locally recurrent carcinoma using this therapeutic approach ranges from 6%–19%. Multiple studies have attempted to identify factors associated with the development of local recurrences in these patients. Despite extensive reports examining this issue, no factor(s) has consistently been correlated with outcome.Methods: This review examines the criteria that various authors have proposed as being associated with recurrence, including DCIS grade, size, histologic subtype, status of surgical margins, and technical factors to help clarify their roles in optimizing treatment outcome. The issue of the definition of the type of recurrence is also addressed.Results: Though multiple studies have examined the impact of grade, histologic subtype, necrosis, and DCIS size on outcome, no consistent results have been observed to suggest that these factors can be routinely used to guide therapy. The adequacy of excision appears to correlate with local control but is imprecisely defined by margin status alone. Based upon recent data, it appears that atypical ductal hyperplasia and cancerization of lobules in the context of coexistent DCIS, may need to be considered as part of the DCIS lesion that should be excised. This issue may account for someof the disparate results of different studies of DCIS. For statistical purposes, recent studies also suggest that only recurrences developing within or adjacent to the bed of the initial DCIS lesion should be considered when analyzing factors associated with outcome. Recurrences developing elsewhere in the breast may include new DCIS and invasive lesions that bear no biologic relationship with the initial DCIS lesion. Finally, since it is impossible to insure that all DCIS has been removed, it may be more appropriate to consider DCIS lesions as adequately or inadequately excised instead of completely or incompletely excised. Since DCIS is essentially a microscopic disease, pathologists should have a primary role in helping to define the adequacy of excision.Conclusions: Additional studies with complete pathology review and longer follow-up are needed to reach a consensus on which prognostic factors are consistently associated with recurrence for patients with DCIS treated with lumpectomy and radiation therapy. At the present time, adequacy of excision appears to correlate with outcome. However, more precise and consistent methods need to be developed to assist in the determination of adequate DCIS extirpation.     

FAK在乳腺癌组织和癌前病变组织中的表达

目的探讨黏着斑激酶(FAK)的表达与乳腺癌浸润和转移的关系。方法采用免疫组织化学和原位杂交方法检测42例乳腺癌组织3、2例乳腺增生组织及20例正常乳腺组织中FAK的表达,并分析其与临床病理特征之间的关系。结果1)乳腺癌组织中FAK蛋白及mRNA阳性表达率分别为83.33%(35/42),78.57%(33/42),在不典型增生中阳性表达率分别为52.38%(11/21)和42.86%(9/21),在一般增生和正常乳腺组织中均未见表达。乳腺癌组显著高于正常组、一般增生组和不典型增生组(P<0.01),不典型增生组也显著高于正常组和一般增生组(P<0.05);2)与无淋巴结转移的乳腺癌比较,有淋巴结转移的乳腺癌中FAK蛋白及mRNA阳性率较高,差异具有统计学意义(P<0.05);3)FAK蛋白及mRNA阳性表达率与乳腺癌的组织学类型无关,随着乳腺癌的临床分期的升高,FAK蛋白及mRNA的表达有着增高的趋势,但两组间进行比较,差异无统计学意义(P>0.05)。结论FAK表达的高低可能作为乳腺癌发生、发展过程中较有价值的病理指标,可导致乳腺癌发生并加速恶性细胞的增殖、浸润和转移。     

Magnitude and laterality of breast cancer risk according to histologic type of atypical hyperplasia: results from the Nurses' Health Study

BACKGROUND: Atypical hyperplasia (AH) in a benign breast biopsy is associated with an increased breast cancer risk. However, the influence of the histologic type of AH on the magnitude and laterality of breast cancer risk is poorly defined. METHODS: The authors conducted a case-control study of benign breast disease and breast cancer risk nested within the Nurses' Health Study (395 cases, 1610 controls). Benign breast biopsy slides were reviewed and categorized as showing nonproliferative lesions, proliferative lesions without atypia, or AH. Slides that showed AH were categorized further as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH). RESULTS: The odds ratio (OR) for breast cancer among all women with AH was 4.1 (95% confidence interval [95% CI], 2.9-5.8). However, among premenopausal women, breast cancer risk was higher for women with ALH (OR, 7.3; 95% CI, 3.8-14.2) than for women with ADH (OR, 3.1; 95% CI, 2.0-4.8). Overall, 58.9% of invasive breast cancers that developed in women with AH were in the ipsilateral breast, and the frequency of ipsilateral breast cancer was similar for women with ALH (61.3%) and women with ADH (55.9%; P = .66). CONCLUSIONS: Women with AH in a benign breast biopsy were at a substantially increased risk for the development of breast cancer. Among premenopausal women, the risk appeared to be greater for those with ALH than those with ADH. Because only approximately 60% of cancers that develop in women with AH occur in the ipsilateral breast, for the purposes of clinical management, these lesions are viewed best as markers of a generalized (bilateral) increase in breast cancer risk.     

Invasive breast cancer following ductal and lobular carcinoma in situ of the breast

We considered the risk of subsequent invasive breast cancer in a population-based series of 579 carcinomas in situ (CIS) of the breast (482 ductal, 88 lobular) registered between 1977 and 2002 in the Swiss Canton of Vaud. A total of 55 cases of invasive breast cancer were observed vs. 12.3 expected, corresponding to a standardized incidence ratio (SIR) of 4.5 (95% confidence interval [CI], 3.4-5.8). The SIR was 4.6 after ductal and 4.2 after lobular CIS, was similar with passing time since CIS diagnosis, but was higher (SIR = 5.5) for women aged <55 years. At 20 years following CIS, the cumulative risk of invasive breast cancer was 26%, similar for lobular and for ductal CIS. The incidence of invasive breast cancer following CIS showed no consistent pattern of trends with age, all rates in subsequent age groups ranging between 10 and 18 in 1,000. This is compatible with the occurrence of a single mutational event in a population of susceptible women.     

Atypical epithelial hyperplasia of the breast: state of the art

Introduction: Atypical epithelial hyperplasia (AEH) of the breast is considered benign histological lesions with breast cancer risk. This review focuses on clinical signification and management of AEH that remains controversial.

Areas covered: A review of published studies was performed using medline database. In this review, we fully describe the current evidence available. In particular, we describe 1) data from immunohistochemistry and molecular studies that suggest AEH is a precursor of breast cancer; 2) epidemiological studies demonstrate low rate of breast cancer in women with AEH; 3) surgical excision is necessary after diagnosis of AEH, such as lobular carcinoma in situ or atypical ductal hyperplasia, on core needle biopsy; 4) although current recommendations are evolving to fewer (if not no) excisions for flat epithelial with atypia and classic lobular neoplasia found on percutaneous biopsy (without radiologic indications for excision).

Expert commentary: HEA management steel need prospective evidences, but recent retrospective data give some clue for less invasive management for some of HEA.