Benign mucocele-like lesion of the breast: how to differentiate from mucinous carcinoma before surgery.

The aim of the study was to improve the pre-operative diagnosis of mammary mucinous lesions. All mucinous lesions detected by fine needle aspiration (FNA) and confirmed by histological examination were reviewed by cytological findings, mammographic appearances and sonographic findings. Twenty aspirates had corresponding pathology, including 12 mucinous carcinomas, two mucocele-like lesions (MLL) with atypical ductal hyperplasia, three MLL with ductal hyperplasia and three simple MLL. Simple MLL and mucocele-like with ductal hyperplasia showed scant cellularity, no or rare intact single tumour cells, monolayered arrangement and absence of nuclear atypia. In contrast, most mucinous carcinomas showed higher cellularity, more single tumour cells, three-dimensional clusters, and mild to marked nuclear atypia. However, MLL with atypical ductal hyperplasia showed cytological features overlapping with mucinous carcinoma. MLL had a non-specific mammographic appearance and showed a cystic lesion on sonography. Mucinous carcinoma appeared as a solid mass on sonography and as a distinct nodule on mammography. Based on the combination of FNA cytology and image findings, benign MLL can be correctly distinguished from mucinous carcinoma before surgery.     

Changed expression of 9-O-acetyl GD3 (CDw60) in benign and atypical proliferative lesions and carcinomas of the human breast

 Expression of gangliosides is affected in various ways by malignant cell transformation. In the present study, we investigated the expression of CDw60, a constituent of O-acetylated disialogangliosides, in benign and atypical proliferative breast diseases, and preinvasive and invasive carcinomas by immunohistochemistry and thin-layer chromatography (TLC). In normal ducts, antibodies to CDw60 (mAb M-T21) reacted to membranes of the Golgi apparatus in the juxtaluminal cell compartment. A similar polarized distribution of Golgi cisterns in epithelial cells was observed in several benign lesions, i.e., fibroadenomas, intraductal papillomas, and gynecomastia. In contrast, blunt duct adenosis and duct hyperplasia exhibited an abnormal cytosolic and cell surface staining, whereas atypical duct hyperplasia showed randomly dispersed immunoreactive Golgi cisterns, indicating loss of epithelial polarity. In mammary carcinomas and in two breast carcinoma cell lines (MCF-7 and EFM-19) the neoplastic cells contained CDw60-immunolabelled Golgi complexes, which were distributed in a disorderly fashion throughout the cytoplasm, thus reflecting a loss of epithelial polarity. Additionally, only well differentiated ductal carcinomas in situ or invasive ductal carcinomas disclosed a strong cell surface labelling, which was absent in lower differentiated carcinomas of the same types. In all carcinomas, the intensity of CDw60 immunostaining decreased with progressing loss of differentiation (grade of dedifferentiation), as demonstrated by staining intensity in paraffin sections and by evaluation of the relative amounts of extracted 9-O-acetyl GD3 by TLC. Our results indicate that abnormal CDw60 expression is already detectable in benign proliferative breast lesions with different risk rates to develop into malignant lesions. Downregulation of CDw60 expression in poorly differentiated invasive carcinomas may be the consequence of loss of cell functions usually associated with poor prognosis. Received: 19 February 1998     

乳腺导管上皮内瘤变32例影像诊断分析

目的：探讨全数字化乳腺X线摄影与磁共振成像检查相结争对乳腺导管上皮内瘤变（DIN）的诊断价值。方法：对32例经乳腺平板数字X线摄影及磁共振检查并且病理证实为乳腺导管上皮内瘤变的病例进行回顾性分析。结果：32例DIN中,普通导管上皮增生（UDH）17例,DIN1A2例;DIN1B1例;乳腺导管原位癌（DIN1C--DIN3）12例。采用全数字化X线乳腺摄影与MRI相结合诊断乳腺增生18例,乳腺导管原位癌11例,3例未能明确诊断。结论：平板数字X线乳腺摄影及磁共振成像综合诊断,对乳腺导管原位癌的旱期发现具有重要意义．显著提高患者的生存质量。     

凋亡相关基因p53、bcl-2在乳腺导管非典型增生中表达的研究

为观察凋亡相关基因-p53,bcl-2在乳腺导管非典型增生及乳腺癌中的表达,探讨其与乳腺癌组织发生的关系。本实验应用原位杂交方法检测凋亡相关基因p53,bcl-2mRNA,应用免疫组织化学方法检测p53蛋白在44例乳腺导管非典型增生组织中的表达,并与6例乳腺导管单纯性增生及26例乳腺癌对比分析,实验结果为,p53mRNA在乳腺导管单纯性增生组织中呈较强表达（66.7%),在乳腺导自欺欺人这非典型增生组织中阳性表达为40%（轻度;55.6%,中度：41.7%,重度;26.1%)。在癌组织中的表达率为19.2%(导管内癌：21.4%,浸润性导管癌：16.7%),p53蛋白在导管单纯性增生组无表达,在导管非典型增生组阳性表达为24%（轻度：11.1%,中度;25%,重度;34.8%)。在癌组织中的阳性表达为38.4%(导管内癌：35.7%,浸润性导管癌：41.7%),bcl-2mRNA在单纯性增生组无表达,在非典型增生组中阳性表达为轻度：11.1%,中度：16.7%,重度：39.1%,在乳腺癌组织中阳性表达为导管内癌;78.6%,浸润性导管癌83.3%。实验结果表明,在乳腺导管重度非典型增生组织中可检测到p53基因有较高的表达缺失,突变及bcl-2mRNA过表达。     

Histochemistry of estrogen sulfatases in human breast diseases

Two estrogen sulfatases, arylsulfatase C-estrone sulfatase (ASC-ES) and d-equilenin sulfatase (EqS) were demonstrated histochemically in the normal human female breast, in benign breast diseases and in infiltrating mammary ductal carcinomas to study their significance in the pathogenesis of epithelial proliferations. By hydrolyzing estrone sulfate, the amount of which in female blood is about ten times greater than that of estradiol or estrone, estrogen sulfatases can produce a high local concentration of estrogens. A simultaneous azo-coupling method for histochemical demonstration of ASC-ES is described in the present study; EqS was demonstrated by a previously described method. Estrogen sulfatases were not found in the normal female breast. Both estrogen sulfatases were found in epithelial cells in some examples of mastopathic disease and in fibroadenomas, while ASC-ES was found in periductal fibroblasts. In some cases of infiltrating ductal carcinomas, estrogen sulfatases were present in carcinoma cells. In most of these tumors ASC-ES activity was observed in fibroblasts around infiltrative cell cords. There was no correlation between the presence of estrogen sulfatases and of hormone receptors in carcinomas. It is concluded that estrogen sulfatases play no role in the early stages of benign or malignant epithelial proliferations. However, the induction of estrogen sulfatases may promote epithelial proliferation in some cases if estrogen receptors are present in epithelial cells.     

Quantitative DNA patterns in human preneoplastic breast lesions

In 12 cases of human mammary carcinoma in which a preneoplastic atypical ductal hyperplasia was also identified, quantitative DNA (QDNA) measurements of thionein-stained samples from both lesions were performed using the Cell Image Analysis 100 system. The QDNA values in the preneoplastic and neoplastic lesions from each case showed concordance (six as euploid and six as aneuploid/hyperdiploid). Such congruence suggests a stable inheritance of the somatic mutation(s) that is involved in carcinogenesis and that affects ploidy. If this relationship between concurrent preneoplasia and neoplasia in the ipsilateral breast is confirmed, it offers the possibilities of (1) identifying individuals at risk for developing neoplasias with defined biologic characteristics and (2) developing therapeutic regimens more appropriate to the risk assessment of each patient. It may be possible to conceive of a rational preventive regimen for cancer of the breast.     

Automated image morphometry of lobular breast carcinoma

OBJECTIVE: To analyze the role of automated image morphometry (AIM) in distinguishing infiltrating lobular carcinoma (ILC) of the breast from benign, borderline and infiltrating ductal carcinoma (IDC). STUDY DESIGN: Only histopathologically proven lobular carcinoma, ductal carcinoma, borderline lesions and benign breast lesions were selected for the study. There were 19 cases of ILC and 30 cases of IDC, 20 cases of benign lesions (fibroadenoma, 18; fibrocystic disease, 1; and fibroadenosis, 1); 10 cases were borderline lesions (mild epithelial hyperplasia, 3; moderate epithelial hyperplasia, 2; florid epithelial hyperplasia 4; intraductal papillary carcinoma, 1). In all cases hematoxylin and eosin-stained slides were used for AIM. At least 100 cells from each case were subjected to analysis randomly with an image cytometer with Leica Quantimet 600 software (Cambridge, England). Nuclear area, diameter, perimeter, convex perimeter, convex area and roundness were measured in each case with random, unbiased selection of cells and 40 x objectives (one pixel = 0.46 microm). AIM data on the cases were analyzed in relation to final cytologic diagnosis. RESULTS: All the nuclear morphometric features of ILC were much lower than those of IDC and borderline lesions, whereas nuclear morphometric data on ILC were only marginally more than those on benign cases. ANOVA showed that mophometric data were significant (P < .05) in all the variables between ILC and IDC. However, there was no significant difference between ILC, and borderline and benign cases. CONCLUSION: Image morphometry may be useful in distinguishing ILC from IDC on cytologic smears. However, morphometric data may not be helpful in distinguishing benign and borderline lesions from ILC.     

Accuracy of cytologic interpretation of pancreatic neoplasms by fine needle aspiration and pancreatic duct brushings

OBJECTIVE: To investigate the accuracy of fine needle aspiration (FNA) specimens and pancreatic duct brushings in the detection of pancreatic lesions and to compare the results with follow-up biopsy and/or surgical interpretation. STUDY DESIGN: We reviewed a total of 57 specimens (37/20), 37 FNA specimens and 20 pancreatic duct brushings, from 45 patients treated at Froedtert Memorial Lutheran Hospital, affiliated with the Medical College of Wisconsin, Milwaukee, over a 4-year period. The FNA and brushing samples were categorized as follows: positive for malignancy (21/3 = 24), suspicious for malignancy (8/7 = 15) and atypical (8/10 = 18). The results were then correlated with the tissue diagnosis. RESULTS: The 24 cytologic samples positive for malignancy included 23 (20/3) pancreatic ductal carcinoma (CA) and 1 (1/0) neuroendocrine CA; in the suspicious category, 11 (6/5) were pancreatic ductal CA; 2 (0/2) mucinous neoplasms and (2/0) neuroendocrine neoplasms; in the atypical category; 2 (2/0) suggestive of mucinous neoplasia, 1 (1/0) suggestive of serous neoplasia and 9 (2/7) favor reactive; and 6 (3/3) without further categorization. Tissue diagnoses were available in 26 cases: 12 (10/2) cases positive for malignancy, 8 (5/3) suspicious for malignancy and 6 (5/1) atypical. The 12 cytologically positive cases confirmed by histology showed 10 ductal CA, 1 neuroendocrine CA and 1 negative. All 8 cases (100%) suspicious for malignancy revealed positive results, including 5 ductal CA, 1 neuroendocrine neoplasm, 1 mucinous cystic neoplasm and 1 lymphoma. Of the 6 atypical lesions, 1 showed ductal CA, 2 mucinous cystic neoplasm and 3 chronic pancreatitis. CONCLUSION: Pancreatic FNA and duct brushings [table: see text] are accurate methods in identifying pancreatic lesions, particularly ductal CA. Accuracy can be improved in the case of mucinous and other lesions with adequate cellularity of the smear and recognizing the limitations of brush samples in the case of mucinous cystic lesions. False negative results may occur in cases of poor representation of malignant cells or poor sampling.     

Stereotaxic fine needle aspiration cytology of clinically occult malignant and premalignant breast lesions

Stereotaxic fine needle aspiration (FNA) cytology was used to study clinically occult (nonpalpable) breast lesions in 114 consecutive patients with mammographically suspicious findings prior to excisional biopsy. The aspirate contained insufficient material for cytologic evaluation in 15 cases (13.2%), which were histologically diagnosed as benign (7 cases), atypical hyperplasia (7 cases) or carcinoma in situ (1 case). The cytologic findings indicated a benign lesion in 77 cases (67.5%), which were histologically diagnosed as benign (71 cases) or atypical ductal hyperplasia (6 cases). The cytologic sample showed atypia in eight cases (7.0%), which were histologically diagnosed as severe atypical ductal hyperplasia (three cases), carcinoma in situ (one case) or proliferative fibrocystic disease (four cases). In the eight cases (7.0%) cytologically interpreted as probably malignant, histology confirmed six invasive carcinomas, one carcinoma in situ and one fibrocystic disease. Of six cases (4.4%) cytologically reported as malignant, five were histologically diagnosed as invasive carcinoma and one as carcinoma in situ. Overall, stereotaxic FNA cytology reported as malignant or probably malignant 14 of the 15 cases with a histologic confirmation of malignancy, for a sensitivity of 93.3%. Cytology correctly identified 78 of the 83 histologically negative cases, for a specificity of 94.0%. The 16 cases histologically diagnosed as ductal hyperplasia, which carries a high risk for subsequent malignancy, were studied in detail in an effort to define histologic and cytologic criteria for this entity. Using selected histologic criteria, 11 of these cases were graded as showing mild-to-moderate atypical hyperplasia and 5 as showing severe atypical hyperplasia. Three of the latter cases were similarly identified by an analogous cytologic grading; the other two cases had insufficient cytologic samples. The total results in this series of 114 cases support the use of stereotaxic FNA cytology in the diagnosis of these nonpalpable breast lesions, examples of which are illustrated. In particular, it may help to raise the low specificity yielded by mammography alone, which would represent a significant advance for the patient in terms of the accuracy, expediency and reduced cost of diagnosing these lesions.     

p16和cyclinD1在乳腺导管非典型增生癌变过程中的表达

目的 探讨乳腺导管非典型增生癌变过程中p16和cyclinD1的变化及其相互关系。方法 应用免疫组织化学方法检溯p16、cyclin成在乳腺各组病变中的蛋白表达情况。结果 乳腺导管单纯性增生、非典型增生组织中p16蛋白表达率明显高于乳腺癌组织,差异有显性。cyclinD1在中,重度非典型增生组表达最为明显,且与乳腺导管单纯性增生组及轻度非典型增生组比较,差异均有显性。p16、cyclinD1蛋白在乳腺各组病变中表达呈负相关关系。结论 p16、cyclinDl在乳腺增生性病变中呈现不同程度表达,其表达强度在一定程度上与细胞的恶性倾向有关,检测其表达水平可作为乳腺导管非典型增生组织恶性转化的一个客观检测指标。其中,cyclinD1蛋白可能是乳腺癌发生过程中的早期分子事件,可作为临床早期发现乳腺癌的免疫学指标。     

cyclin D1, cyclin E 在乳腺良、恶性病变中的表达及其与p16,p21waf1及Rb 蛋白的关系

为探讨cyclinD1,cyclinE在乳腺癌发生发展中的作用及其与细胞周期调控相关基因蛋白的关系,采用免疫组化检测17例非增生乳腺导管上皮、19例不同程度增生的导管上皮及59例乳腺癌中cyclinD1,cyclinE,p16,p21waf1及Rb基因蛋白的表达.结果显示1.非增生乳腺导管上皮除1例cyclinE过表达外均无cyclinD1和cyclinE的过表达.乳腺癌的cyclinD1和cyclinE的过表达率均明显高于良性乳腺组织(P<0.05).2.乳腺癌cyclinD1过表达与淋巴结转移呈正相关(P<0.05),瘤体直径大于5cm者cyclinE过表达呈增加趋势,但差异无显著性意义.3.CyclinD1和cyclinE的过表达呈正相关(P<0.05).4.从非增生乳腺导管上皮到增生直至乳腺癌,p16,p21与cyclinD1,cyclinE含量的比值逐渐递减,而p21含量高于cyclinD1的乳腺癌体积小、淋巴结转移率低(P<0.05).p21阳性率与cyclinD1过表达呈正相关(P<0.01),也随cyclinE的过表达呈上升趋势.Rb基因蛋白的强表达与cyclinD1过表达呈正相关(P<0.01).结果表明CyclinD1和cyclinE蛋白过表达频发于乳腺癌早期,它们可能与p16、p21waf1、pRb共同参与了乳腺癌的发生发展.     

Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice

To study the role of transforming growth factor alpha (TGF alpha) in normal mammary development and mammary neoplasia in vivo, we have generated transgenic mice in which a human TGF alpha cDNA is expressed under the control of the MMTV enhancer/promoter. Overexpression of TGF alpha in the mammary epithelium, as confirmed by in situ hybridization and immunohistochemistry, is associated with hyperplasia of alveoli and terminal ducts in virgin female and pregnant transgenic mice. A range of morphologic abnormalities including lobular hyperplasia, cystic hyperplasia, adenoma, and adenocarcinoma is seen in mammary tissue of transgenic females. In contrast, no morphologic abnormalities are seen in transgenic males in spite of TGF alpha overexpression in salivary glands and reproductive organs. TGF alpha can therefore act as an oncogene in vivo and appears to predispose mammary epithelium to neoplasia and carcinoma.     

A useful immunohistochemical approach to evaluate intraductal proliferative lesions of the breast and to predict their prognosis

An examination was performed on 16 intraductal proliferative breast lesions diagnosed as intraductal papillomas (IP) or usual ductal hyperplasia (UDH), which were followed up for more than 3 years. An immunohistochemical marker panel combining myoepithelial markers, high-molecular-weight keratin (HMWK) and neuroendocrine markers was used. Two of 11 IP cases were re-evaluated as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). These cases developed breast cancer after the first operation. One IP case showed repeated recurrences. None of the other IP and UDH cases had breast cancer or recurrence. The ADH, DCIS and the recurrent IP showing a solid growth lacked myoepithelia, but the recurrent IP expressed HMWK, immunohistochemically. Interestingly, these three lesions were weakly positive for neuroendocrine markers. All other IPs and UDHs, including lesions having solid components, were negative for neuroendocrine markers, and most of them were positive for myoepithelial markers and/or HMWK. A combination of the above immunohistochemical markers seems useful to evaluate intraductal proliferative lesions and to predict their prognosis. In particular, intraductal proliferative lesions with solid components exhibiting positivity for neuroendocrine markers should be followed up carefully to monitor breast cancer risk or recurrence.     

Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland

We have examined the role of two mesenchymal ligands of epithelial tyrosine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promoted branching of the ductal trees but inhibited the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland could be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recombinant HGF and NRG. We thus show that two major postnatal morphogenic periods of mammary gland development are dependent on sequential mesenchymal- epithelial interactions mediated by HGF and NRG.     

Accuracy of touch imprint cytology of image-directed breast core needle biopsies

OBJECTIVE: To evaluate the accuracy of touch imprint (TI) cytology of image-directed core needle biopsy (CNB) specimens of nonpalpable breast lesions. STUDY DESIGN: Fifty-two consecutive CNBs from 44 patients were performed under mammographic or ultrasound guidance. Air- dried TIs of CNBs were stained with Diff-Quik. TI cellularity was considered adequate if six or more ductal cell groups were identified. CNBs and TIs were interpreted in a blinded fashion. RESULTS: TI cellularity was adequate in 37/52 (71%) cases, including 17/20 carcinomas and 20/32 benign lesions. Among 17 carcinomas, TIs were positive in 12, suspicious in 4 and atypical in 1. One case of lactational change was suspicious on TI, and 5/8 fibroadenomas were atypical. No benign lesions were called "carcinoma" on cytology. When lesions categorized as "carcinoma" or "suspicious" were considered positive and those classified as "atypical" or "benign" were scored as negative, TI sensitivity and specificity were 94% and 95%, respectively. When the "atypical" cases were grouped with the positive cases, TI sensitivity was 100%, with 75% specificity. CONCLUSION: With satisfactory cellularity, TIs of CNBs are highly accurate. When immediate evaluation of CNB specimens is important, TIs can potentially decrease the number of biopsy passes required and provide preliminary diagnoses.     

bcl-2癌基因蛋白在鼻咽癌以及单克隆癌细胞裸鼠体内连续传代中的表达

用免疫组织化学Ｓ－Ｐ方法,检测了４０例低分化鼻咽癌、３０例鼻咽癌克隆细胞裸鼠移植瘤、１０例慢性鼻咽炎及８例人胚鼻咽上皮组织石蜡包埋切片中抗凋亡基因ｂｃｌ－２癌蛋白的表达;并进一步检测了鼻咽癌克隆株在裸鼠体内演进中ｂｃｌ－２癌蛋白的表达以及与淋巴结转移之间的关系。结果表明：鼻咽癌及其裸鼠移植瘤组织中ｂｃｌ－２癌蛋白的表达率分别为６２．５％和７０％,慢性鼻咽炎中ｂｃｌ－２癌蛋白的表达率为１０％,人胚鼻咽上皮组织中不表达ｂｃｌ－２癌蛋白,鼻咽癌及其裸鼠移植瘤组织中ｂｃｌ－２癌蛋白的表达率明显高于慢性鼻咽炎组织中（Ｐ＜０．０１）;鼻咽癌克隆株演进中癌细胞ｂｃｌ－２癌蛋白的表达不断升高,其淋巴结转移率亦不断升高。提示：抗凋亡基因ｂｃｌ－２癌蛋白的表达可能和鼻咽癌的发生、演进及转移能力密切相关