Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family

We have previously provided evidence showing an association between some precursor lesions with low nuclear grade breast carcinomas (LNGBCs). In this study, further immunophenotypic support to our proposed route of pathogenesis of LNGBC and their precursor lesions was provided. Precursor lesions including columnar cell lesions, atypical ductal hyperplasia, ductal carcinoma in situ, usual epithelial hyperplasia, and lobular neoplasia were compared with matching "morphologically normal" terminal lobular duct units and matching invasive carcinoma. The epithelial cells in the putative precursor flat epithelial atypia, atypical ductal hyperplasia, lobular neoplasia, ductal carcinoma in situ lesions, and their coexisting LNGBC were negative for basal and myoepithelial markers, but positive for CK19/18/8, estrogen receptor (ER)-alpha, Bcl-2, and cyclin D1. The ER-alpha/ER-beta expression ratio increased during carcinogenesis, as did expression of cyclin D1 and Bcl-2. p53 immunopositivity was found 3% in LNGBC versus 43% in high nuclear grade breast carcinoma (HNGBC), whereas ataxia telangiectasia mutated expression was absent or reduced in 22% of LNGBC versus 53% of HNGBC cases. In summary, our findings support the concept that flat epithelial atypia is the earliest morphologically identifiable nonobligate precursor lesion of LNGBC. These may represent a family of precursor, in situ and invasive neoplastic lesions belonging to the luminal "A" subclass of breast cancer. The balance between ER-alpha and ER-beta expression may be important in driving cyclin D-1 and Bcl-2 expression. Ataxia telangiectasia mutated may be one of the alternative regulatory mechanisms to TP53 mutation or dysfunction in low-grade and high-grade breast carcinoma. Our findings support the concept that progression of LNGBC to HNGBC (basal-like or HER2+) phenotype is an unlikely biologic phenomenon.     

人乳头状瘤病毒16、18型在乳腺浸润性导管癌和导管非典型增生中的表达及意义

目的:探讨乳腺浸润性导管癌、导管不典型增生和良性上皮增生中人乳头瘤病毒(HPV)16、18型感染的差异.方法:用原位杂交法检测乳腺病变组织中HPV 16、18型表达.结果:HPV 16、18型感染率、共同感染率和总感染率在乳腺浸润性导管癌和导管非典型增生中均高于良性上皮增生.结论:HPV 16、18型感染与乳腺癌前病变有关,是乳腺癌发病的高危因素.     

COX-2、VEGF和E-cad在乳腺癌组织中的表达及临床病理意义

目的：探讨环氧化酶-2（COX-2）、血管内皮生长因子（VEGF）和E-钙黏附蛋白（E-cad）在乳腺癌组织中的表达及与临床病理特征之间的关系。方法：应用免疫组化S-P法检测30例乳腺单纯性增生、30例乳腺导管内癌、70例乳腺浸润性导管癌组织中COX-2、VEGF和E-cad的表达情况。结果：COX-2在乳腺单纯性增生、乳腺导管内癌、乳腺浸润性导管癌组织中的表达率分别为10.0%、46.6%、72.8%,乳腺单纯性增生与乳腺导管内癌、乳腺浸润性导管癌差异均有统计学意义（P〈0.01）;乳腺导管内癌与乳腺浸润性导管癌差异有统计学意义（P〈0.05）。VEGF在乳腺单纯性增生、乳腺导管内癌、乳腺浸润性导管癌组织中的表达率分别为3.3%、50.0%、65.7%,乳腺单纯性增生与乳腺导管内癌、乳腺浸润性导管癌相比差异均有统计学意义（P〈0.01）;乳腺导管内癌与乳腺浸润性导管癌差异无统计学意义（P〉0.05）。E-cad在乳腺单纯性增生、乳腺导管内癌、乳腺浸润性导管癌组织中的表达率分别为93.3%、43.30%、32.8%,乳腺单纯性增生与乳腺导管内癌、乳腺浸润性导管癌差异均有统计学意义（P〈0.01）;乳腺导管内癌与乳腺浸润性导管癌差异无统计学意义（P〉0.05）。COX-2在乳腺浸润性导管癌的阳性表达与淋巴结转移有关（P〈0.05）,与年龄、肿瘤大小、组织学分级无关（P〉0.05）。VEGF、E-cad在乳腺浸润性导管癌的阳性表达与组织学分级、淋巴结转移密切相关,与年龄、肿瘤大小无关。COX-2、VEGF在乳腺浸润性导管癌中的表达呈正相关（R=0.44,P〈0.01）,COX-2在乳腺浸润性导管癌中的表达与E-cad的表达呈负相关（R=-0.26,P〈0.05）。结论：COX-2、VEGF的高表达及E-cad的低表达在乳腺癌的发生发展过程中起重要的作用,检测其表达异常对判断临床进展、推测预后以及制定针对性的治疗方案有一定的参考价值。     

Expression of estrogen receptor (ER-alpha and ER-beta) mRNA in human prostate cancer.

OBJECTIVE: The distribution of the two estrogen receptors (ER-alpha, ER-beta) in human prostate tissue have not been fully clarified, so the present study investigated the mRNA expression of the receptors to explain the broad spectrum of estrogen activity in prostate cancer. MATERIALS AND METHODS: Four human prostate cancer cell lines (LNCap, JCA-1, DU-145 and PC-3) and 24 pairs of untreated prostate cancer tissue and noncancerous tissue from resected prostate glands were subjected to RT-PCR testing. RESULTS: Both LNCap and JCA-1 expressed the mRNA of both receptors, but DU-145 and PC-3 only expressed ER-beta mRNA. In the human prostate tissue samples, 20 of the 24 prostate cancer tissues expressed ER-alpha, and 23 of the 24 expressed ER-beta. Of the 24 noncancer tissues, 14 expressed ER-alpha mRNA and 17 expressed ER-beta mRNA. The incidence of ER-beta mRNA expression between the paired cancer and noncancer tissues was statistically significantly different (p<0.05). CONCLUSIONS: A higher incidence of ER-beta mRNA expression in untreated prostate cancer tissues was observed. Furthermore, the absence of ER-alpha mRNA and the presence of ER-beta mRNA expression in hormone-independent and/or untreated prostate cancer cells leads to a tentative speculation of the mechanism of the hormone refractory feature of prostate cancer.     

Expression of estrogen receptor alpha and beta mRNAs in prostate cancers treated with leuprorelin acetate

OBJECTIVE: The discovery of a novel estrogen receptor (ER), ER-beta, has given rise to new possibilities regarding estrogen's roles in the prostate. Although ER-beta is reported to be expressed preferentially in the rat prostate, its expression in the human prostate and relationship to cancer development has not been investigated. Thus the purpose of the study was to examine mRNA levels of ER-alpha and ER-beta in benign prostatic hyperplasia and prostate carcinoma. METHODS: Samples of 15 prostate cancers obtained at radical prostatectomy were examined. All the patients had been maintained on androgen withdrawal therapy for at least 3 months. ER-alpha and ER-beta mRNAs were measured with a competitive PCR technique. RESULTS: Both ER-alpha and ER-beta mRNAs were detected in all of the prostate cancer tissues examined, as well as in PC3 and LNCap cells, although the levels varied among specimens. Interestingly, both types were significantly decreased in cases with lymph node metastasis. However, there was no correlation between ER mRNA levels and any other clinicopathological parameters. CONCLUSIONS: (1) Both ER-alpha and ER-beta mRNAs are expressed in prostate cancer and (2) expression of ER mRNA may not be related to cancer progression but may be negatively correlated with metastasis.     

Encor真空负压旋切系统在乳腺良性肿物切除术中的应用

目的探讨超声引导下Encor真空负压旋切系统对乳腺良性肿物切除术中的应用价值。方法 2010年7月～2011年7月采用超声定位引导,利用Encor真空负压旋切系统（美国强生公司Model CART01型）对119例391个乳腺良性肿物进行切除,术后加压包扎48 h。切除标本常规行快速石蜡病理检查。结果 117例389个乳腺良性肿物被完全切除,1例肿物少量残留,1例手术失败改传统开放性手术。术后病理诊断：乳腺纤维腺瘤276个,纤维腺瘤伴导管内乳头状瘤25个,乳腺导管扩张性症68个,导管内乳头状瘤14个,上皮非典型增生6个,乳腺腺病2个。术中大量出血（10～30 ml）6例,术后血肿3例,皮下瘀斑11例。119例术后随访3～15个月,平均8个月,血肿、瘀斑消失,乳房外形正常,1例残余肿瘤无明显变化,余118例未发现病灶残留、复发。结论应用超声引导Encor真空负压旋切系统切除乳腺良性肿物效果好,微创优势明显,操作简单、安全,对乳腺良性肿物可完全切除,值得推广。     

Expression of estrogen receptor-alpha and -beta in anterior vaginal walls of genuine stress incontinent women.

Our objective was to study the expression of estrogen receptor (ER) isoforms, ER-alpha and ER-beta, in the anterior vaginal wall of menopausal and fertile women with genuine stress incontinence (SI) by immunohistochemistry and Western blot analysis. Eighteen menopausal women with SI who either were or were not taking estrogen/progestin replacement therapy and 14 fertile women with SI who either were or were not taking contraceptives were enrolled in the study. Biopsies from the suburethral anterior vaginal wall were obtained at tension-free vaginal tape (TVT) operation. Monoclonal antibody to ER-alpha and polyclonal antibody to ER-beta were used to stain frozen sections of vaginal tissue. The receptor expressions were scored based on percentage of positive cells. ER-alpha was detected in vaginal epithelial, stromal and smooth muscle cells. In menopausal SI women ER-alpha was detected significantly more frequently in the vaginal walls of estrogen/progestin-treated patients than in those who were untreated. Fertile SI women had significantly higher expression of ER-alpha than menopausal SI women. ER-alpha was not observed in vaginal blood vessels. ER-beta was detected in epithelial and vascular smooth muscle cells of the vagina. No significant difference in ER-beta expression was observed between different groups of patients. The expression of ER-alpha was not correlated with that of ER-beta. Both ER-alpha and -beta were detected, indicating a potential role for both types of estrogen receptor in the human vaginal wall. The expression of ER-alpha, but not of ER-beta, in menopausal SI women was regulated by estrogen/progestin replacement therapy. The presence of ER-beta in vaginal vascular smooth muscle cells raises the possibility of vascular effects of estrogen on the human vaginal wall.     

Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management

AimsThe risk of finding carcinoma in excisions following a core needle biopsy diagnosis of radial scar is not well defined and clinical management is variable.The aim of this study is to determine the frequency of high-risk lesions, ductal carcinoma in situ, and invasive carcinoma in excisions following a core biopsy diagnosis of radial scar.Methods and resultsDedicated breast pathologists and radiologists correlated the histologic and radiologic findings and categorized radial scars as the target lesion or an incidental finding. High-risk lesions were defined as atypical hyperplasia or classical lobular carcinoma in situ.Of the 79 radial scars identified over a 14-year period, 22 were associated with atypia or carcinoma in the core biopsy. Thirty-seven (37) of the 57 benign radial scars underwent excision with benign findings in 30 (81%), high-risk lesions in six (16%), and flat epithelial atypia in one (3%). There were no upgrades to carcinoma. One patient with a benign radial scar developed a 3-mm focus of intermediate-grade estrogen receptor-positive ductal carcinoma in situ in the same quadrant of the ipsilateral breast 72 months after excision. One patient with an incidental un-excised benign radial scar was diagnosed with ductal carcinoma in situ at a separate site of suspicious calcifications.ConclusionsIn this series, none of the benign radial scars was upgraded to carcinoma. Radial scar was the targeted lesion in all cases with high-risk lesions on excision. Surgical excision may not be mandatory for patients with benign incidental radial scars on core biopsy.     

�������������Բ��估��Σ���䲡��ѧ����ʶ

??New sight of pathology for breast benign proliferative and high-risk lesions LI Ting. Department of Pathology, Peking University First Hospital, Beijing 100034, China
Abstract So called “breast benign proliferative lesions” are a large group of extremely heterogeneous diseases, and the principle consensus for their clinic-pathological features had been reached since the end of the last century. In which, the high-risk lesions of the breast represent a group of clinically, pathologically, and biologically heterogeneous lesions associated with an elevated risk of breast cancer development, although with varying degree of risk levels and different management strategies. Atypical ductal hyperplasia and atypical lobular hyperplasia are associated with relative risk of breast cancer development. Lobular carcinoma in situ is both an indicator of an increased risk of breast cancer development and a non-obligated precursor lesion, while ductal carcinoma in situ represents a true precursor of invasive breast cancer. Up to date, clinicopathological features or molecular alterations identifying the individuals with high-risk breast lesions that will progress to invasive breast carcinoma remain to be identified, and the further study is needed.     

CD10|p63及calponin在乳腺良恶性病变鉴别诊断中的意义

目的探讨乳腺肌上皮细胞标志物CD10,p63及calponin在乳腺良、恶性上皮性病变鉴别诊断中的意义。方法应用免疫组织化学染色法检测CD10,p63及calponin在乳腺普通型增生(UDH),非典型导管上皮增生(ADH),导管原位癌(DCIS)和浸润性导管癌(IDC)中的表达,分析其在乳腺良、恶性上皮病变诊断中的意义。结果 3种标志物在UDH,ADH和DCIS组中均有不同程度的表达,且主要表达于导管周围的肌上皮。该3组间calponin的表达量无明显差异(P>0.05);p63的表达量依次为UDH组>ADH组>DCIS组(均P<0.05);CD10的表达量在UDH组与ADH组间无明显差异,但两组均明显高于DCIS组(均P<0.05)。IDC组几乎无CD10和p63的表达,肿瘤间质有少量calponin的表达,与前3组比较,差异均有统计学意义(均P<0.0 5)。结论联合应用CD1 0,p6 3及calponin标志物的检测可鉴别诊断乳腺良恶性病变,CD1 0和p6 3特异性较好,而calponin的敏感性较好,但特异性较差。     

Mucocele‐like lesions diagnosed on breast core biopsy: Low risk of upgrade and subsequent carcinoma

Mucocele‐like lesions of the breast diagnosed on core biopsy are usually excised to exclude the possibility of partial sampling of an invasive mucinous carcinoma. The goal of this study was to correlate the pathologic and radiologic features of mucocele‐like lesions to determine if excision is mandatory. Over a 16 year period we identified 32 patients with mucocele‐like lesions diagnosed on 27 (84%) stereotactic and 5 (16%) ultrasound‐guided core biopsies. The indications for core biopsy were: calcifications in 24 (75%), a mass in 7 (22%), and a mass with calcifications in 1 (3%). There were 22 (69%) mucocele‐like lesions without atypia and 10 (31%) with atypical ductal hyperplasia or detached groups of atypical cells. Of the 22 mucocele‐like lesions without atypia, 19 (86%) were excised: 15/19 (79%) were benign, 3/19 (16%) had atypical ductal hyperplasia and 1/19 (5%) had ductal carcinoma in situ. None of the patients with mucocele‐like lesions without atypia were upgraded to invasive carcinoma. The single patient who was upgraded to low‐grade ductal carcinoma in situ had a history of ductal carcinoma in situ in the same breast. Of the 10 patients with mucocele‐like lesions with atypia, 9 (90%) were excised: 5/9 (56%) were benign, 1/9 (11%) had atypical ductal hyperplasia and 3/9 (33%) had invasive carcinoma. Of the patients with mucocele‐like lesions with atypia who were upgraded to invasive carcinoma, one had a BIRADS 5 mass and discordant pathology and one had a history of Hodgkin lymphoma and mantle radiation. There were 24 patients with mucocele‐like lesions with or without atypia who were not upgraded on excision, and none developed breast cancer after a median of 51 months (range 7‐192). These findings indicate that mucocele‐like lesions without atypia are unlikely to be upgraded on excision and are associated with a low risk for the subsequent development of carcinoma.     

乳腺良性增生性病变及高危病变病理学新认识

所谓“乳腺良性增生性病变”包含乳腺一大组非常异质性的病变,对其基本认识在20世纪末已达成基本共识。乳腺高危病变是其中一组临床、病理学和生物学上的异质性疾病,这些疾病诊断之后长期持续性乳腺浸润性癌发生的危险性增加,但危险程度和水平各异,有些预示乳腺癌的发生风险,而有些则是乳腺癌的直接前驱病变,因此,临床意义与干预策略也不同。该组病变中非典型导管增生、非典型小叶增生和小叶原位癌双侧乳腺发生浸润性癌的相对危险性增加,小叶原位癌危险性更高并为非责任性前驱病变;导管原位癌被认为是真正的前驱病变,同侧最终发展为乳腺癌的风险较大。平坦上皮不典型性危险水平尚不明确。目前尚缺乏临床病理学和分子方面个体化危险性预测指标,这是未来个体化危险性处理战略的关键所在。     

Correlation of nipple aspiration and ductal lavage cytology with histopathologic findings for patients before scheduled breast biopsy examination

BACKGROUND: The use of ductal lavage to obtain cells from within the breast ducts has been described for patients at high risk for breast cancer. The purpose of this study was to correlate ductal lavage cytologic findings with the corresponding histology. METHODS: Twenty-two patients were evaluated and 20 patients underwent ductal lavage followed by breast biopsy examination as a result of positive nipple aspiration fluid. Ductal lavage samples were classified by a cytopathologist as negative, mild atypia, marked atypia, or malignant. A different pathologist interpreted the histologic findings of the biopsy examination. RESULTS: Adequate specimens for cellularity were obtained in 12 of 22 (53%) patients: 6 of the 12 (50%) had both benign cytology and histology, 2 (16.7%) had benign cytology with atypical ductal hyperplasia or atypical lobular hyperplasia on histology, 2 (16.7%) had marked atypia on cytology and benign histology, and 2 (16.7%) had malignant cytology and benign histology. The specificity of the procedure was 83.4%. CONCLUSIONS: Ductal lavage yielding an adequate sample for analysis was successful in only 52% of patients. Of those, the cytologic-histologic correlation was discordant in 50%. The role of ductal lavage in accurately predicting lesions present on subsequent breast histologic evaluation of planned biopsy examinations requires further investigation.     

Histopathologic types of benign breast lesions and the risk of breast cancer: case-control study

The hypothetical multistep model of carcinogenesis indicates that breast cancer develops via a series of intermediate hyperplastic lesions through in situ to invasive carcinoma. To identify the risk inherent within the different morphologic lesions, we have analyzed the data from 674 benign biopsy specimens comprising 120 cases who subsequently developed breast cancer and 382 controls (matched for age and date of biopsy) spanning a period up to 20 years of follow-up (mean 66.95 months). In this series we have confirmed an increased risk associated with certain types of benign breast lesions. Atypical lobular hyperplasia was the most significant risk factor for breast cancer with more unfavorable outcome in patients <50 years of age (p = 0.003) and a relative risk (RR) of 4.55 (confidence interval [CI] 1.77-11.69). Hyperplasia of usual type showed an RR of 1.53 (CL 1.10-2.13) with a statistically worse probability of survival (cancer-free time) for patients >50 years. For atypical ductal hyperplasia the RR was 2.03 (CI 0.80-1.39). Blunt duct adenosis was significantly more common in cases progressing to breast cancer compared with controls, showing an RR of 2.08 (CI 1.12-2.85). We describe in detail the criteria of morphologic changes observed in blunt duct adenosis and define, for the first time, the level of risk associated with each of its six subtypes. Improved knowledge of breast carcinogenesis will provide insight for defining high-risk groups thus resulting in improved screening and management regimens.     

Cancer of the male breast with atypical ductal hyperplasia and contralateral gynecomastia

A case of right mammary invasive ductal carcinoma in young man with atypical ductal hyperplasia and gynecomastia of the second breast is described. The review of the existing literature stress the rarity of this observation. Nevertheless, in all cases of male mammary carcinoma the accurate examination must always include the contralateral breast to search the possible precancerous lesions or etiologic factors.     

Mucinous carcinoma of the skin, primary, and secondary: a clinicopathologic study of 63 cases with emphasis on the morphologic spectrum of primary cutaneous forms: homologies with mucinous lesions in the breast

We present the largest series of mucinous carcinoma involving the skin, describing the histopathologic, immunohistochemical, electron microscopic, and cytogenetic findings. Our aim was fully to characterize the clinicopathologic spectrum and compare it with that seen in the breast. In addition, we wished to reevaluate the differential diagnostic criteria for distinguishing primary mucinous carcinomas from histologically similar neoplasms involving the skin secondarily, and study some aspects of their pathogenesis. We demonstrate that primary cutaneous mucinous carcinomas span a morphologic spectrum compatible to their mammary counterparts. Both pure and mixed types can be delineated morphologically, and some lesions have mucocele-like configurations. Most lesions seem to originate from in situ lesions that may represent, using mammary pathology terminology, ductal hyperplasia, atypical ductal hyperplasia, or ductal carcinoma in situ or a combination of the three. Inverse cell polarity appears to facilitate the progression of the changes similar to lesions in the breast. The presence of an in situ component defines the neoplasm as primary cutaneous, but its absence does not exclude the diagnosis; although for such neoplasms, full clinical assessment is essential. Mammary mucinous carcinoma involving the skin: all patients presented with lesions on chest wall, breast, axilla, and these locations can serve as clue to the breast origin. Microscopically, cutaneous lesions were of both pure and mixed type, and this correlated with the primary in the breast. Dirty necrosis was a constant histologic finding in intestine mucinous carcinomas involving the skin, and this feature may serve as a clue to an intestinal origin.     

Invasive mammary carcinoma after immediate and short-term follow-up for lobular neoplasia on core biopsy

Lobular neoplasia (LN), including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ, may be encountered in breast core biopsies performed for mammographic abnormalities even though LN is often not, in itself, responsible for the abnormal mammogram. The need for surgical excision following a diagnosis of LN on core biopsy is not well defined. We examined pathologic and mammographic findings in a consecutive series of cases diagnosed as LN to address this issue. Radiology/pathology records were reviewed for cases with a pathology diagnosis of pure LN during the period 1998-2001. Specifically excluded were cases with associated atypical ductal hyperplasia, ductal carcinoma in situ, invasive mammary carcinoma, or any history of breast malignancy. Thirty-five women 39-76 years of age (mean 52 years) were identified. Specimens were obtained as stereotactic core (31) or limited wire-guided biopsy (four). The diagnoses were lobular carcinoma in situ (12), lobular carcinoma in situ/ALH (10), and ALH (13). Fourteen patients did not undergo excisional biopsy and had no subsequent clinical follow-up to warrant additional biopsy (follow-up 6 months to 3 years). Five patients had no immediate excision, but eventually during clinical follow-up for LN (1 month to 3 years), two developed mammographic lesions in the ipsilateral (one patient) or contralateral breast (one patient) that led to diagnoses of invasive mammary carcinoma (lobular and composite ductal-lobular types, 10 and 8 mm, respectively); three patients had subsequent mammographic findings in the ipsilateral or contralateral breast leading to biopsies showing only LN (two patients) or no neoplastic pathology (one patient). The remaining 16 patients (all core biopsied) underwent immediate wire-guided excisions. Thirteen (81%) showed additional foci of LN, one (6.3%) with atypical ductal hyperplasia, and two (12.5%) with invasive lobular carcinoma (3 mm and <1 mm). Three (19%) had no residual disease; however, additional clinical follow-up in one of these patients revealed an invasive mammary carcinoma in the contralateral breast (false-negative mammography). Radiographic findings were calcifications and density/mass lesions in 27 and 8 cases, respectively. Of 27 cases presenting with Ca, 10 showed colocalization of LN and Ca. In the eight cases presenting with density/mass, incidental microscopic microcalcifications colocalized to LN were found in two cases. When present, histologic Ca was associated with LN in 12 of 29 cases studied (41%). Of the 21 patients with immediate or subsequent excision, five (24%) were found to have an associated invasive mammary carcinoma (two on immediate excision and three after short-term follow-up of up to 3 years). The bilaterality of cancer risk was expected; however, the number of invasive carcinomas was not. That the invasive carcinomas detected at follow-up were small implies that they might have been present (but occult) at initial presentation. We conclude that lobular carcinoma in situ detected on core biopsy is potentially a significant marker for concurrent and near-term breast pathology requiring complete intensive multidisciplinary clinical follow-up with specific individualization of patient care.