Results of needle aspiration cytology in proliferative fibrocystic disease of the breast (author's transl)

The accuracy of needle aspiration cytology in fibrocystic disease of the breast was evaluated in 101 cases with microscopically proved proliferative fibrocystic disease. The morphology of the obtained cytosmears was described. In about 50% of the cases a cytological diagnosis of proliferating fibrocystic disease is possible with accuracy. The needle aspiration is therefore a new method for intensive follow-up of patients with a high risk of develop carcinoma of the breast. The accuracy is increased in cases with well developed proliferation of the glandular cells. In cases with intraductal and intracystic proliferations, the results were better than in cases with adenosis.     

Argyrophilic nucleolar organiser regions (AgNORs) in breast lesions

Nucleolar organiser regions (NORs) demonstrated by argyrophilia of NOR-proteins are indicator of cellular proliferative activity. The NORs can be identified in the nuclei as brown or black dots with silver colloidal staining technique in formalin fixed paraffin sections and in cytology smears. Seventy-five cases including 45 tissue sections and 30 fine needle aspiration cytology (FNAC) smears of benign and malignant lesions of breast have been studied to evaluate the significance and practical application of AgNOR count per nucleus. Out of 45 tissue sections 15 belonged to fibrocystic disease, 10 fibro-adenomas and 20 carcinomas and of the 30 FNAC smears, 10 were fibrocystic disease, 8 fibro-adenomas and 12 carcinomas. In fibrocystic disease the mean AgNOR count was 1.60 (FNAC group-0.75, tissue section-1.61). In fibro-adenomas it was 1.61 (FNAC-1.63, tissue section-1.59). The mean count in carcinoma was 12.10 (FNAC-12.08, tissue section-12.10). The difference in AgNOR count in fibrocystic disease and fibro-adenoma was not significant, but that between benign breast lesion and carcinoma was significant. No difference was observed between FNAC and tissue section groups in benign or malignant lesions. The simple staining technique can be used as an additional criterion to differentiate the benign and malignant lesions of breast.     

Benign disease of the breast in Ile-Ife: a 10 year experience and literature review

This study is a 10 year review of the benign diseases of the breast in Ile-Ife, Nigeria. A total of 362 cases were found. Three hundred and forty (95%) of the diseases occurred in females while 18 (5%) occurred in males giving a female-male ratio of 19:1. Fibroadenoma was the commonest lesion followed by fibrocystic disease. They accounted for 59.1% and 16.5% of benign breast diseases respectively. Acute and acute-on-chronic mastitis constituted 7.2%. These three lesions made up over 82% of the cases. Gynaecomastia was the commonest benign male breast disease and accounted for 3.8% of all the cases of benign breast disease. Apart from the atypical hyperplasia form of fibrocystic disease, benign diseases of the breast are not major predisposing lesions to malignant breast diseases.     

Bulletin of breast disease: results of the 1990-1994 quinquennium

All mammary lesions diagnosed at the Institute of Pathological Anatomy of the University of Modena have been systematically filed since 1990 and reported in a bulletin, which is issued twice a year and delivered to health operators. So far, 5.188 cases of breast lesions, comprising 1.999 non-neoplastic pathologies, 1.040 benign tumors, 1.943 primary malignant neoplasms and 206 recurrences, have been filed. During the quinquennium 1990-1994, a progressive numerical reduction in diagnoses of non-neoplastic lesions coupled to an increase of benign tumors has been observed, whereas the number of primary malignant tumors has not changed. In particular, a statistically significant increase in diagnoses of carcinoma-in-situ and of fibrocystic disease associated with moderate-risk lesions (atypical hyperplasias) has been detected, whereas the number of cases of single fibrocystic disease has decreased. This reduction, however, is not significant. A slight increase of breast carcinomas smaller than 1 cm and 2 cm, coupled to a decrease of those exhibiting dimensions between 2 and 5 cm, has been found. The collection and systematic analysis of cases of mammary lesions appears to represent a useful tool to study the incidence of different breast pathologies in the general populations. It can also be viewed as a simple way to test the reliability of diagnostic methods used for selection of surgical cases.     

Breast disease: Etiology, prevention, and rehabilitation.

A theoretical model is presented that takes etiological factors into account in describing behavioral and constitutional factors associated with fibrocystic disease and breast cancer. The model identifies 5 variables: genetic background and familial history; life cycle events; dietary habits; use of exogenous estrogens; and psychological factors, including life stresses, anxiety or tension, and depression. Most of the variables are hypothesized to increase the risk of breast pathology by inducing physiological changes—specifically, by fostering endocrinopathy or immunosuppression. Supportive research is cited, and the relationship between fibrocystic disease and breast cancer is detailed. Implications for prevention and for rehabilitation of women with breast disease are described. (91 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Urinary incontinence in castrated bitches. Part 1: Significance, clinical aspects and etiopathogenesis

INTRODUCTION AND AIMS: The aim of this study was to study patients suffering from mammary nodules, fibrocystic disease and mastodynia. Having established the absence of malignant disease, the effect of EP (oestroprogestin) was evaluated in the treatment of fibrocystic disease with mastalgia. METHODS: From January 1990 to December 1995 a total of 1921 women underwent breast examination at the "Centro di Fisiopatologia della Mammella" in the Division of Gynecology and Obstetrics of Iseo Municipal Hospital. Subjects were aged between 9 and 84 years old. The experimental protocol included a retrospective study of a group of 89 patients suffering from chronic fibrocystic disease with mastalgia with a 3-month follow-up. The clinical examination was commenced by recording the patient's history and the measurement of the thickness of the gland and the evaluation of mastalgia represented important stages of the eco-clinical assessment. The setting for the study was the breast pathology out-patient clinic of the Division of Gynecology and Obstetrics. These women regularly attended our outpatient clinics for the following reasons: depistage, mastodynia, mammary secretion, self-diagnosis of mammary nodules, checkups in patients during follow-up after surgery for genital neoplasia. All patients underwent clinical, echographic and often mammography/X-ray. Patients were selected on the basis of the following criteria: absence of malignant pathology and presence of chronic fibrocystic disease with mastalgia. Of those admitted to the study (no. = 89), only 59 completed the course. In addition to the absence of malignant pathology and the presence of chronic fibrocystic disease with mastalgia, the following parameters were assessed: measurement of the thickness of the mammary gland involving QSE before and after 3-month treatment with EP. The EP used were: gestodene 0.075 mg and etynylestradiol 0.03 mg-Minulet, or etynylestradiol 0.02 mg and dexogestrel 0.150 mg-Securgin and Mercilon. RESULTS: The response to treatment was classified according to the 4 levels of the Cardiff Breast Score (CBS). The results were relatively good: 35.59% of patients showed a reduction in symptoms; 25.42% showed a marked improvement, and 18.64% a remission of symptoms. No effect was reported in 20.33% of patients. CONCLUSIONS: In conclusion, it may be said that EP treatment for 3 months can at least be proposed in patients with chronic fibrocystic disease and mastalgia given that a reduction and improvement in symptoms was seen in 60% of patients.     

Immunohistochemical analysis of apocrine breast lesions. Consistent over-expression of androgen receptor accompanied by the loss of estrogen and progesterone receptors in apocrine metaplasia and apocrine carcinoma in situ

Apocrine phenotype is observed in a spectrum of breast epithelial lesions spanning from benign metaplasias to apocrine carcinoma. Apocrine metaplasia is a common finding in fibrocystic change of the female breast. In situ and invasive apocrine carcinomas are rare variants of ductal carcinoma. All breast apocrine lesions were shown to be associated with increased androgen hormones metabolism. We have evaluated 10 cases of apocrine metaplasia, 3 cases of in situ apocrine carcinoma and 10 cases of invasive apocrine carcinomas using immunostaining method for steroid hormone receptors (estrogen, progesterone, androgen), p53, bcl-2 and BRST-2. Paraffin embedded tissue and avidin-biotin peroxidase complex system were used. Androgen receptor (AR) expression is consistently increased in all cases of apocrine metaplasia when compared with surrounding normal, non-apocrine breast epithelium. This androgen receptor over-expression is accompanied by the loss of immuno-detectable estrogen and progesterone receptor, and also the loss of bcl-2. An identical pattern of immuno-reactivity is seen in in situ apocrine carcinomas, but it is observed with less frequency in invasive apocrine carcinomas, which only infrequently express AR as the only steroid hormone receptor.     

Mammary ductal foam cells: macrophage immunophenotype

Mammary ductal foam cells are present in normal breast tissue as well as in a number of breast diseases. Such foam cells tend to be in particular abundance with fibrocystic changes of the breast. Foam cells may appear within duct lumens or plastered in cohesive masses along duct walls, simulating an epithelial structure. The nature and origin of these innocuous-appearing cells, based on morphologic studies, remain a controversy, for they appear to be of epithelial derivation. This study was undertaken to determine the nature of intraductal "foam" cells and their origin in the breast. Nine cases of adult fibrocystic disease were examined immunohistochemically with antibodies to cytokeratins (Mak-6, Cam 5.2), leukocyte common antigen, and the following macrophage antibodies: KP-1 (CD68), HAM 56, and MAC 387. The lysozyme and alpha-1-antitrypsin content of foam cells also was studied. The immunohistochemical data in this study confirm the macrophage character of these foam cells, which are positive for CD68, HAM 56, and MAC 387, lysozyme, and alpha-1-antitrypsin and negative for leukocyte-common antigen and cytokeratins.     

Differences and similarities in adjuvant chemotherapy in mouse and man

Supernatants obtained after incubation of tumor patient lymphocytes with the homologous tumor-associated antigen (TAA) elicit adherence inhibition in normal guinea pig peritoneal cells. From 37 tested patients with different carcinomas, the supernatants of 30 caused more than 10 per cent adherence inhibition (breast cancer 11/11, lung cancer 7/8, colon cancer 6/7, stomach cancer 6/11). Besides 40 healthy blood donors were tested to a panel of TAA. There was a reactivity more than 10 per cent only in 2 cases. The supernatants of 14 patients with nonmalignant disorders produced adherence inhibition more than 10 per cent in 2 cases. By incubation of tumor patient lymphocytes with the human encephalitogenic protein the supernatants of 19/27 patients elicited a positive reaction. The results suggest that anti-tumor immunity can be detected in an indirect heterologous adherence inhibition system.     

Standardized uptake value and quantification of metabolism for breast cancer imaging with FDG and L-[1-11C]tyrosine PET

The aims of the study were to compare the value of L-[1-11C]tyrosine (TYR) and [IBF]fluoro-2-deoxy-D-glucose (FDG) as tumor tracers in patients with breast cancer, to investigate the correlation between quantitative values and standardized uptake values (SUVs) and to estimate the value of SUVs for the evaluation of therapy. METHODS: Eleven patients with one or more malignant breast lesions and two patients with one or more benign breast tumors were studied with TYR and FDG. Doses of 300 MBq of TYR and 230 MBq of FDG were given intravenously. All PET sessions were performed using a Siemens ECAT 951/31 camera. Of 10 malignant tumors and the 3 benign lesions, glucose consumption and protein synthesis rate were quantified. All lesions were studied using SUVs based on body weight, body surface area and lean body mass, with and without correction for plasma glucose or tyrosine levels. RESULTS: All malignant tumors were visualized with both FDG and TYR, but the visual contrast was better with FDG. Increased uptake of the tracers was seen in patients with fibrocystic tissue and complicated the visual assessment and the outlining of tumor tissue. Uptake in fibrocystic disease was more prominent with FDG than with TYR. No difference in tumor/nontumor ratio between the two tracers could be established. FDG showed a false-positive result in one benign lesion. No major differences between the SUVs as defined above were found, although the best correlation between glucose consumption and the SUV was observed when the SUV was based on body surface area and corrected for plasma glucose level (r = 0.85-0.87). The SUV based on lean body mass was found to correlate best with protein synthesis rate (r = 0.83-0.94). CONCLUSION: In this group of patients, TYR appears to be a better tracer than FDG for breast cancer imaging, because of lower uptake in fibrocystic disease. SUVs correlate well with quantitative values, but future studies must determine whether treatment evaluation is also reliable with SUVs.     

How actual is the treatment with antiandrogen alone in patients with polycystic ovary syndrome?

Carcinoma of the breast is the second most frequent tumour in African females. Breast carcinomas in African females appear about a decade earlier and follow a more aggressive clinical course than those in developed countries. To elucidate this difference we investigated 63 biopsied benign lesions of the female breast for their potential to malignant progression. We also performed histologic typing and grading of 184 female breast carcinomas received at the Muhimbili University Hospital in Dar es Salaam, Tanzania. Fibrocystic disease and fibroadenomas were the most frequent lesions. The majority of patients with fibrocystic disease had no proliferative lesion and thus were not at a significantly increased risk of developing breast carcinomas. For fibroadenomas, no indication for precancerous lesions was found. The vast majority of breast carcinomas investigated were invasive. As a striking feature, the majority of those studied (66%) were of the non-special type (NST), displaying a more aggressive behaviour than the remaining tumours of the special type (ST). In the group of ST tumours, cribriform types constituted 41% of the cases which may be a special feature of the carcinomas in African females. Among the NST, the tumours were either of grade II or grade III, whereas in ST, 25% of the cases were of grade I. Since histology observed in this study is comparable to that seen in patients from the Western society, late hospital presentation with advanced tumour stages may be a major reason for differences in clinical behaviour between African and Western females. A genetic factor, however, may be an important contributing factor.     

Articulated radial head replacement and elbow release for post head-injury heterotopic ossification

We observed an interstitial deletion of the long arm of chromosome 6 occurring as the sole anomaly in a benign fibrocystic disease of the breast, confirming its nonrandom occurrence in this type of condition, and we discuss the possible meaning of this observation.     

Danazol for benign breast disease

Three groups of women with benign breast disease were treated with danazol for 3 to 6 months. Doses of 100 mg per day were given to 40 patients, 200 mg to 55, and 400 mg to 35. The age range of the patients was 20 to 48 years. The patients were rechecked at 6-month intervals over a period of 48 months. Most of them were seen four or more times after completion of therapy. Elimination of nodularity occurred in about two thirds; three experienced no improvement, and partial resolution was obtained in the remainder. Untoward effects were minimal or trivial. Danazol proved to be an excellent hormonal agent in the management of fibrocystic disease of the breast.     

Ductal carcinoma in situ of the breast: correlation of pathologic and mammographic features with extent of disease

Optimal treatment of ductal carcinoma in situ (DCIS) of the breast requires an improved understanding of its pathologic extent and propensity for local recurrence. This study was performed to analyze mammographic and pathologic features of DCIS that might predict the extent of disease within the breast and facilitate treatment selection between lumpectomy alone, lumpectomy and radiotherapy, and mastectomy. At our institution, 60 cases of DCIS were diagnosed in 59 patients from June 1985 to February 1995 and form the basis of this retrospective study. Demographic and treatment-related information was obtained from hospital and tumor registry records. Mammograms were reviewed and size estimates of the abnormalities were determined. Pathologic slides from all cases were reviewed and classified according to size group, focality, nuclear grade, necrosis, and histologic subtype. DNA ploidy status and proliferation indices were available for 28 patients. Pathologically, 43 (72%) cases were < 15 mm, 14 (23%) were 16 to 40 mm, and 3 (5%) were > 40 mm. Five (8%) of the lesions were multicentric, 28 (47%) focal, and 27 (45%) multifocal. Thirty-three (55%) patients were treated by mastectomy, 16 (27%) by lumpectomy alone, and 11 (18%) by lumpectomy and radiation therapy. Mammographic size, histologic grade, presence or absence of necrosis, histologic subtype, DNA ploidy, and proliferative index were compared with pathologic size and focality by chi 2 analysis. Mammographic size correlated significantly with pathologic size (chi 2 = 11.3; P = 0.02) but underestimated the extent of disease in 9 cases. Although focality correlated significantly with pathologic size (chi 2 = 15.8; P = 0.003), the remaining histopathologic features did not significantly correlate with pathologic size or focality. Histopathologic features, including DNA studies, do not reliably predict the pathologic extent of DCIS, but mammographic size and focality do significantly correlate with pathologic size. Nevertheless, most cases of DCIS are small focal or multifocal lesions that are amenable to breast conservation approaches; further studies are needed to determine the appropriate use of lumpectomy, radiation therapy, and mastectomy in the treatment of DCIS.     

Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99m methoxyisobutylisonitrile scintimammography in the detection of breast tumours

The aim of this study was to compare, in breast cancer patients, the diagnostic accuracy of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) and scintimammography (SMM) using technetium-99m methoxyisobutylisonitrile (MIBI). A total of 20 patients (40 breasts with 22 lesions) were evaluated serially with MIBI and, on the following day, with FDG. For SMM, planar and single-photon emission tomography imaging in the prone position was performed starting at 10 min following the injection of MIBI (740 MBq). For PET, scans were acquired 45-60 min after the injection of FDG (370 MBq) and attentuation correction was performed following transmission scans. Results from SMM and PET were subsequently compared with the histopathology results. True-positive results were obtained in 12/13 primary breast cancers (mean diameter=29 mm, range 8-53 mm) with both FDG and MIBI. False-negative results were obtained in two local recurrences (diameter <9 mm) with both FDG and MIBI. In benign disease, FDG and MIBI did not localize three fibrocystic lesions, two fibroadenomas and one inflammatory lesion (true-negative), but both localized one fibroadenoma (false-positive). Collectively, the results demonstrate a sensitivity of 92%, and a specificity of 86%, for primary breast cancer regardless of whether FDG or MIBI was used. In contrast to MIBI scintigraphy, FDG PET scored the axillae correctly as either positive (metastatic disease) or negative (no axillary disease) in all 12 patients. The tumour/non-tumour ratio for MIBI was 1.97 (range 1.43-3.1). The mean standard uptake value (SUV) for FDG uptake was 2.57 (range 0.3-6.2). The diagnostic accuracy of SMM was equivalent to that of FDG PET for the detection of primary breast cancer. For the detection of in situ lymph node metastases of the axilla, FDG seems to be more sensitive than 99mTc-MIBI.     

Pseudoangiomatous hyperplasia of the mammary stroma: true entity or phenotype?

We report the clinical and pathologic features seen in 14 cases of pseudoangiomatous hyperplasia of the mammary stroma. The lesion manifested as a discrete palpable lump in twelve women and two men. The excisional biopsy specimens showed firm, circumscribed grey-tan lesions measuring from 3 to 5.5 cm in largest dimension. Histologic study revealed diffuse, anastomosing, enlongated slits with open lumina, covered by spindle cells with bland nuclei and no mitotic activity. Strong reactivity for vimentin and CD34 was noted. Smooth muscle actin was focally noted in most cases. Immunostains for other markers, including CD31 and factor VIII related antigen was negative. Spindle cells from two cases expressed both estrogen and progesterone receptors. In all the cases, there was some degree of glandular hyperplasia accompanying the stromal changes. Fibroadenoma or fibrocystic disease were also common features. Our study confirms that pseudoangiomatous hyperplasia of mammary stroma represents a proliferation of local myofibroblasts, likely related to a hormonal stimulus. The wide range of associated changes of breast parenchyma further indicates that this lesion may represent a local, non specific change rather than a true clinico-pathologic entity.     

Angiogenin expression and prognosis in primary breast carcinoma

Angiogenin is a protein originally isolated as an inducer of new blood vessel growth, and it has been reported to be an effective substrate for tumor cell adhesion. To understand the role of angiogenin in cancer progression, we evaluated the expression of angiogenin in 459 cases with primary breast carcinoma and in 40 benign breast specimens using an immunoassay. Higher angiogenin concentrations were observed in carcinomas in comparison with fibrocystic disease (mean, 17.3 versus 10.9 ng/mg; P = 0.008), but not with fibroadenomas. We selected 5 ng/mg cytosol protein of angiogenin as the normal cutoff for primary breast carcinoma. Eighty-eight percent of carcinomas expressed elevated angiogenin levels and 12% had low levels. We observed an association between elevated levels of angiogenin and low/ moderate histological grade (P = 0.001) and small tumor size (P = 0.026), but not with age, menopausal status, lymph node status, stage of disease, or hormonal receptor status. With a median follow-up of 31 months, breast cancer patients with elevated angiogenin levels had significantly longer disease-free survival (DFS) than patients with low angiogenin (log-rank, P = 0.003). This effect was equally observed in node-negative and node-positive cases. In a multivariate analysis of DFS, only angiogenin, tumor size, and histological grade showed statistical significance. A multivariate analysis of overall survival showed that angiogenin and tumor size were the only significant variables. Serum samples from the breast cancer patients at the time of surgery were available in 194 cases. We evaluated the levels of circulating angiogenin using the same immunoassay as in tumor tissue. Serum angiogenin levels were higher in cancer patients than in 40 healthy controls (mean, 401.2 versus 206.0 ng/ml; P < 0.0001). In breast cancer patients, we observed no correlation between the serum concentrations and the tissue levels of angiogenin (r = 0.115; P = 0.110). In addition, serum levels of angiogenin did not have a prognostic impact on the DFS of breast cancer patients (log-rank, P = 0.581). Our results indicate that elevated levels of tissue angiogenin, but not of circulating angiogenin, are a favorable prognostic factor in primary breast carcinoma, which is consistent with a role of angiogenin as a cancer cell substrate.     

Diagnosis of intraductal spread of breast cancer by high-resolution MR imaging: correlation between MR imaging and pathohistological findings

The main purpose of this study was to investigate pathohistological factors that affect the MR findings of intraductal spread (IDS) of breast cancer. The subjects of the present study were 42 breast cancer patients who were examined by MR imaging. Fat-suppressed high-resolution T1-weighted spin-echo images [350/13/1 (TR/TE/excitations), 16-cm FOV, 5-mm section thickness, and 512 x 256 matrix] were obtained one minute after the intravenous administration of Gd-DTPA. In this protocol, contrast determination time was 1 min 48 sec. Of the 42 cases, IDS was found to be located more than 1 cm from the primary focus in 22 cases (52%). Rates of sensitivity, specificity and accuracy of MR imaging for the detection of IDS were 82%, 80%, and 81%, respectively. The probable cause of misdiagnosis was parenchymal enhancement due to severe fibrocystic disease and normal menstrual cycle. In 21 of 42 cases, the MR findings were precisely correlated with the pathohistologic findings of almost the same cross-section. The MR findings of IDS varied greatly with observation of linear, band-like, branch-like, plate-like and minute ring enhancements. These findings closely reflected the size, aggregation pattern, and distribution of intraductal lesions. In particular, minute ring enhancement was only observed in 4 comedo-type lesions. This pattern of enhancement is considered to reflect elevated intraductal cellular density with necrosis in the central region.     

Mucinous lesions of the breast. A pathological continuum

Mucocele-like tumor and invasive mucinous carcinoma of the breast may represent the two ends of the pathological spectrum of mucinous lesions of the breast, respectively. Little data exists on mucinous lesions that may be considered intermediate between mucocele-like tumor and invasive mucinous carcinoma. We studied 23 consecutive cases of invasive mucinous carcinoma of the breast and observed the following associated intermediate mucinous lesions: mucin-filled ducts (MFD) with unremarkable epithelium in 15 cases (65%), MFD with typical ductal hyperplasia in 9 cases (39%), MFD with atypical ductal hyperplasia in 5 cases (22%), and MFD with intraductal carcinoma in 13 cases (57%; micropapillary or cribriform types). Eighteen cases (78%) contained MFD with one of these four lesions and five cases (22%) contained all four lesions. Twenty-three consecutive cases of infiltrating ductal carcinoma-not otherwise specified (IDC-NOS), 21 cases of intraductal carcinoma, and 50 consecutive cases of surgically-excised breast tissue with fibrocystic change (FC), were similarly reviewed. Only one case (4%) of IDC-NOS, 1 case of intraductal carcinoma, and two cases (4%) of FC, contained small foci of MFD with intraductal carcinoma, intraductal carcinoma, and unremarkable epithelium, respectively. Our findings suggest the presence of a spectrum of mucinous lesions of the breast which represents a pathological continuum.     

Cytosol cathepsin D in Thai women with breast cancer

The necessity of screening high-risk patients with breast cancer who may require more intensive systemic therapy especially in the node negative subgroup was generally accepted. Cathepsin D, an estrogen induced protease, has been shown to be implicated in the proliferation and invasion of breast cancers. Retrospective assessment of cytosol cathepsin D in 151 primary breast cancers was done together with ER, PR and other clinico-pathological parameters. No significant relationship was shown between cathepsin D concentrations or cathepsin D status using median value of 56 pmol/mg protein as cutoff level with most studied parameters. High cathepsin D status was found in 47 per cent of patients with fibrocystic disease of breast and 30 per cent in node-negative, ER-PR negative tumors. Survival analysis after 5 or 10 year follow-up and evaluation in a larger scale are necessary before including cytosol cathepsin D measurement as a routine clinical investigation for breast cancers.