THE ROLE OF E2/P RATIO IN THE ETIOLOGY OF FIBROCYSTIC BREAST DISEASE, MASTALGIA AND MASTODYNIA.

- The aim of the study was to assess the role of the estradiol and progesterone relationship during the late luteal phase and the occurrence of fibrocystic breast disease (FBD). The concentration of estradiol/progesterone was measured in the group of women with FBD as study group (n=50) and control group of women without FBD (n=40). All women had regular ovulation cycles. Blood samples for estradiol (E2), progesterone (P) and prolactin determination were obtained in the morning at 8 am on days 21 and 24 of menstrual cycle. Significant mastalgia and mastodynia history in women with FBD was obtained with yes or no questionnaire. FBD diagnosis was confirmed with ultrasound (size and number of simple cysts). In the control group, a reduced E2/P ratio was noticed from day 21 to day 24 of the cycle (from 14.8±11.5 pg/mL to 9.1±6.1 pg/mL; p<0.05), which was not recorded in the group of women with FBD (study group). Even the slightest disturbance of the E2/P ratio may contribute to the occurrence of FBD with clinical manifestations of mastalgia and mastodynia.

Examining the Associations among Fibrocystic Breast Change, Total Lean Mass, and Percent Body Fat.

Fibrocystic breast change (FBC) is extremely common and occurrs in 90% of women during their lives. The association between body composition and risk of breast cancer is well established. We hypothesized that the effect might exist during the development of FBC. Our aim was to examine the relationships of total lean mass (TLM) and percent body fat (PBF) with FBC in a general female population. In total, 8477 female subjects aged 20 years or older were enrolled in the study at the Tri-Service General Hospital in Taiwan from 2011 to 2016. Comprehensive examinations including biochemical data, measurements of body composition and breast ultrasound were performed. PBF was positively associated with the presence of FBC (OR = 1.039, 95%CI: 1.018-1.060), and TLM showed the opposite result (OR = 0.893, 95%CI: 0.861-0.926). Condition of metabolic syndrome (MetS), diabetes (DM) and fatty liver modified the association between PBF and FBC (P < 0.001, P = 0.032 and P = 0.007, respectively). Female subjects diagnosed with MetS, DM, and fatty liver had higher risk of developing FBC than control subjects (OR = 1.110, 95%CI: 1.052-1.171; OR = 1.144, 95%CI: 1.024-1.278; OR = 1.049, 95%CI: 1.019, 1.080). Those with higher PBF (for highest quartile versus lowest, OR = 2.451, 95%CI: 1.523-3.944) or lower TLM (for highest quartile versus lowest, OR = 0.279, 95%CI: 0.171-0.455) had increased risk of developing FBC. In conclusion, increased PBF and reduced TLM were likely to predict the risk of the presence of FBC in a general female population.

Increased bone mineral density in aged rats with spontaneous mammary dysplasia.

Spontaneous mammary tumors were seen in seven of the 12 breeding female rats aged 2 years. All mammary tumors were diagnosed as mammary dysplasia (MD). Bone mineral contents (BMC) and bone mineral density (BMD) of their lumbar vertebrae and femur were determined using dual energy X-ray absorptiometry (DXA). In rats with MD, body weight (BW), BMD of the lumbar vertebrae and BMC of the femur were significantly higher than in the rats without MD. Although corpus luteum (CL) and follicles were seen in the ovaries of all animals, the number of CL in rats with MD was significantly lower than the rats without MD. It was suggested that high BMD, BW and decreased CL promoted mammary tumors.

Lhermitte-Duclos disease and Cowden's syndrome. Report of two cases.

OBJECTIVE AND IMPORTANCE: Lhermitte-Duclos disease, or dysplastic cerebellar gangliocytoma is a rare entity characterized by a hamartomatous lesion in the posterior fossa. Cowden's syndrome, or hamartoma-neoplasia syndrome is a rare underdiagnosed autosomal dominant genodermatosis with high incidence of malignant tumors. Several recent reports suggest that Lhermitte-Duclos disease may be a component of Cowden's syndrome. CLINICAL PRESENTATION: We report two cases of Lhermitte-Duclos and Cowden disease occurring in adult patients. A 40-year-old woman had symptoms of raised intracranial pressure and macrocephaly. She displayed the stigmata of fibrocystic breast disease, thyroid goitre. Clinical examination showed mucocutaneous lesions. Her mother, brother and uncle had manifestations of Cowden's disease. An asymptomatic 38-year-old male had bilateral optic nerve drusen related to a cerebellar neoplasm. He exhibited manifestations of Cowden's syndrome and his familial history confirmed this hypothesis. INTERVENTION: The first patient was operated on for Lhermitte-Duclos disease. A conservative strategy was performed for the second patient and the clinical and imaging follow-ups were uneventful over 5 years. CONCLUSION: We stress the possibility that Lhermitte-Duclos and Cowden disease might be a peculiar form of phakomatosis. A conservative strategy can be chosen without neurological signs because of slow tumor growth. However, these patients should be carefully examined and followed up because of the risk of future malignancy.

Association of cyst type with risk factors for breast cancer and relapse rate in women with gross cystic disease of the breast.

The concentration of potassium (K+) and sodium (Na+) was measured in breast cyst fluid (BCF) from 611 cysts greater than 3 ml aspirated in 520 women with gross cystic disease of the breast. These women were enrolled, from 1983 on, in a cohort study aimed at assessing the relationship between cyst type, as defined by the K+/Na+ ratio in BCF, and the risk of breast cancer. The inverse relationship between K+ and Na+ and the bimodal distribution of the K+/Na+ ratio in BCF were confirmed. Type I cysts were defined as cysts with a K+/Na+ greater than 1.5 in BCF. Among women with type I cysts, a higher proportion of women with one or no births, of women with a history of apocrine cysts, of current smokers, and of women who do not drink coffee was found, as compared to women with other types of cysts. The risk of cyst relapse was significantly higher among women with type I cysts than among women with other types of cysts and among women with multiple cysts at presentation. These findings indicate that type I BCF is a marker of "active" gross cystic disease of the breast and suggest that it may be associated with increased breast cancer risk.

A Study of Using Massage Therapy Accompanied with Stretching Exercise for Rehabilitation of Mammary Gland Hyperplasia.

PURPOSE: To apply massage therapy accompanied with stretching exercises for treatment of mammary gland hyperplasia, evaluate the clinical outcome in patients, and estimate the therapy as a novel treatment method for mammary hyperplasia. METHODS: 28 adult female patients were selected and treated with massage therapy and stretching exercises focusing on skeleton muscles of chest, abdomen, and axilla. The mammary gland oxyhemoglobin (OxyHb) and deoxyhemoglobin (DeoxyHb) levels were detected before and after treatment after 15, 30, and 45 days. RESULTS: In this cohort, pretreatment OxyHb (mean ± SD) is 1.32 ± 0.14 (medium-high), and DeoxyHb is 0.87 ± 0.13 (normal). All patients were clinically diagnosed with benign mammary gland hyperplasia and mastitis. The posttreatment OxyHb levels are 1.23 ± 0.09 (normal-medium, 15-day), 1.16 ± 0.08 (normal, 30-day), and 1.05 ± 0.04 (normal, 45-day), and DeoxyHb levels are 0.90 ± 0.11 (normal, 15-day), 0.94 ± 0.18 (normal, 30-day), and 0.98 ± 0.12 (normal, 45-day). Patients were diagnosed with decreased hyperplasia 15 and 30 days after treatment and with no symptom of hyperplasia in mammary gland 45 days after treatment. CONCLUSION: Mammary gland hyperplasia is closely correlated with pathological changes of skeletal muscles and could be significantly improved by massage therapy and stretching exercises targeting neighboring skeletal muscles.

Time-domain optical mammography SoftScan: initial results.

RATIONALE AND OBJECTIVES: Near-infrared (NIR) technology appears promising as a noninvasive technique for breast cancer screening and diagnosis. The technology capitalizes on the relative transparency of human tissue in this spectral range and its sensitivity to the main components of the breast: water, lipid, and hemoglobin. In this study, the authors report quantitative measurements of these components and the functional contrast between healthy and diseased tissue. MATERIALS AND METHODS: A four-wavelength time domain optical imaging system was used to perform noninvasive NIR measurements in the breast of 49 women both pre- and postmenopausal, ages 24-80. Algorithms based on a diffusive model of light transport provided absolute bulk and local values of breast constituent concentrations. RESULTS: Important variations in the functional and structural NIR properties of the breast were observed. Demographics trend were noticed in accordance with breast physiology. In the 23 cases imaged with suspicious masses, the optical images were consistent with the mammographic findings. Substantial contrast between masses and adjacent tissue is observed. Moreover, consistent differences between malign and benign cases are found with optical imaging. CONCLUSION: The results of this pilot study illustrate the sensitivity of optical techniques to the composition of the breast. In addition, preliminary data suggest that benign and malignant tumors can potentially be noninvasively differentiated with optical imaging. Moreover, statistically significant discrimination based on deoxy-hemoglobin content between malign and benign cases was found with optical imaging (P = .0184, one-tailed t test).

Accumulation of hormones in breast cyst fluid.

The concentration of some immunoreactive peptide hormones in breast cyst fluid and serum from a series of patients with cystic breast disease were compared. The concentrations of the two pituitary gonadotropins, LH and FSH, were consistently higher in serum than in cyst fluid, confirming earlier more limited observations. The mean PRL concentration, on the other hand, was elevated in cyst fluid though the variability was great. The cyst fluid serum ratio of hCG was elevated in the patient group as a whole. However, the results suggested the presence of two subpopulations; group I, in which the cyst fluid and serum hCG levels were essentially indistinguishable and in the range found in normal serum, and group II, in which the cyst fluid hCG concentration was consistently greater than the normal serum range. Analysis of hormone concentrations in multiple cysts aspirated at the same time showed a remarkable degree of agreement in the cyst hormone levels in most of the patients. The greatest variability in the levels was seen with hCG, were a small numer of subjects showed a very large spread in the values.

Danazol in the treatment of mammary dysplasia.

While employing danazol in the management of women with endometriosis, a voluntary comment patients frequently offerd was that breast pain, nodularity and premenstrual engorgement were alleviated. Because of this unexpected finding, our attention was directed to the treatment of women with mammary dysplasia, particularly fibrocystic disease of the breast. Since the incidence of mammary cancer increases rapidly with age, we obtained xerommamograms in all suspected cases to exclude such a possibility. Danazol was employed in dosages varying from 100 to 400mg per day for 3 to 6 months, depending on the severity of the disorder. More than 75% of patients experienced marked improvement or elimination of the nodularity and engorgement, and many women were spared unnecessary surgery. When surgical interference was deemed necessary in cases of multiple nodosities, danazol treatment helped to identify for biopsy a dominant nodule that did not respond to therapy. Danazol has much to offer in the treatment of benign breast disease, and represents an important advance over 'traditional' hormonal regimens proposed in the past.

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

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

Clinical and biochemical studies on methylxanthine-related fibrocystic breast disease.

The results of this study show that the consumption of methylxanthines through dietary sources appears to be associated with the etiologic development of benign fibrocystic disease in the American woman. Complete abstention from methylxanthine consumption resulted in complete resolution of the disease in 82.5% and significant improvement in 15% of those studied. Thus 97.5% showed clinical benefit from total methylxanthine abstention. The results of a clinical questionnaire answered by 500 women consuming methylxanthines, one half of whom had fibrocystic breast disease, suggest that women with fibrocystic disease may have a genetic predisposition for both benign breast disease and cancer. Biochemical studies implicate increased sensitivity of the adenylate cyclase system to catecholamines in patients with fibrocystic disease. Methylxanthines are known to increase circulating catecholamines.

The "luteal breast": hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.

The pathophysiology, malignant potential, and hormonal therapy for benign breast disease remain controversial. This report investigates the anatomic and endocrinologic correlates of luteal phase mastodynia patients, compared with asymptomatic control subjects. Objective sonographic evidence of fibrocystic disease (FCD) was found in one-half of both mastodynia and control groups. Endocrine abnormalities observed in the mastodynia group included (1) significantly lower luteal phase progesterone and (2) prolactin hyperresponsiveness to thyroid-releasing factor. The presence or absence of anatomic FCD was not correlated with endocrine abnormalities. These data suggest that (1) cyclic mastalgia may be the end result of a dyshormonal milieu resembling the inadequate luteal phase; (2) FCD may be hormonally independent; and (3) cyclic mastalgia and FCD are different, if often coexistent, factors in benign breast disease syndromes.

Influence of hormonal status of patients with cystic disease on the composition of cyst fluid and breast cancer risk.

The relationship between the composition of breast cyst fluid (BCF), the menstrual status and in addition some endocrine events in the history of patients (n = 131) with gross cystic breast disease was investigated. The dehydroepiandrosterone (DHA) levels in type II (K+/Na+ < 1) cysts of the follicular group were significantly higher compared to the type II cysts of the luteal or postmenopausal groups. For testosterone a significant difference existed between the type I (K+/Na+ > or = 1) follicular and type I postmenopausal groups. Estrone levels were significantly higher in type I BCF of patients in the luteal phase compared to both the follicular and postmenopausal type I cysts. Progesterone levels were lowest in the postmenopausal subgroups (both in type I and II cyst). Significant correlations were found between the number of pregnancies and the levels of DHA-sulfate and also progesterone in BCF. DHA levels were correlated with the period of lactation. The K+/Na+ ratios were the lowest in women who lactated for the longest period. The estrone was lowest in BCF of current oral contraceptive (o.c.) users while the estradiol was lowest in patients who had never used o.c. A history of previous o.c. use was associated with a significantly high mean DHA level. A significantly higher DHA and lower testosterone level were demonstrated in BCF of patients who had some previous gynecological interventions. The composition of BCF and the "life of cysts" and thus the rate of breast cancer risk may depend on hormonal status during the menstrual cycles or postmenopause and also on endocrine history of patients.

Breast cancer and oral contraceptives: a review.

The relationship between oral contraceptive use and breast cancer was investigated in 22 major epidemiological studies, which are reviewed in this paper. The overall risk ratio was never found to increase when computed among all users vs. nonusers. Risk increases were found in some studies within specific subgroups; but in general, if any risk exists, it is not much more than one. Future studies should focus specifically on women under age 25, on women before a first full-term pregnancy and, to a lesser extent, on perimenopausal women and on women who have had a benign breast disease.

PIP: This paper reviews the findings of the 22 major epidemiologic studies that have investigated the relationship between breast cancer and oral contraceptive (OC) use. Although the findings are discrepant, they tend to rule out the hypothesis of a large increase in the risk of breast cancer in OC users compared to nonusers, at least among women over 25 years of age. Moreover, rates of breast cancer have not been shown to increase with increasing duration of OC use. In general, if a risk has been found, it has not exceeded 1. In certain specific subgroups, particularly women under age 25 years and women who used OCs before 1st pregnancy, the risk of breast cancer has been found to be increased in selected studies but not in other studies. To clarify these discrepant findings, it is recommended that future studies focus on women under age 25 years, on women before a 1st full-term pregnancy, and, to a lesser extent, on perimenopausal women and those who have had a benign breast disease. It should be kept in mind that widespread use of OCs may be too recent to assess possible carcinogenic effects. The absence of a consistent pattern of risk findings in the literature may in part reflect methodological inadequacies, including an sufficient number of cases or biased selection of subjects.

The relationship of estrogen and progesterone to breast disease.

The rising incidence of breast cancer, coupled with awareness of the effects of hormones on breast tissue, has resulted in fears that estrogen, progesterone or both incite or adversely affect benign and malignant breast disease. An intensive review of the hormone physiology of the breast and of the numerous studies on hormones and breast disease reveals that estrogen and especially oral contraceptives not only do not cause breast cancer but may have a slight protective effect. Also, the overwhelming evidence is that the risk of benign breast disease is substantially reduced in both current and prior users of oral contraceptives.

PIP: The rising incidence of breast cancer, coupled with awareness of the effects of hormones on breast tissue, has resulted in fears that estrogen, progesterone, or both incite or adversely affect benign and malignant breast disease. An intensive review of the hormone physiology of the breast and of numerous studies on hormones and breast disease reveals that estrogen and especially oral contraceptives (OCs) not only do not cause breast cancer but may have a slightly protective effect. Also, the overwhelming evidence is that the risk of benign breast disease is substantially reduced in both current and prior users of OCs.

Cytologic and clinicopathologic features of abnormal nipple secretions: 225 cases.

A case review of 225 patients with abnormal breast nipple secretions (NS) was done to determine diagnostically useful clinical and cytologic features. The cytologic specimens and medical records from all patients and 45 concurrent breast biopsies were reviewed. Nipple discharge was attributed to fibrocystic disease (FCD) in 81 cases, physiologic disturbances in 62, papillomas in 18, ductal carcinoma (CA) in 5, miscellaneous benign disorders in 14, and unknown causes in 45. Although cytologic examination of NS was very specific in identifying malignancy, the sensitivity of cytology was low. Carcinoma was diagnosed or suspected cytologically in only three of the five CA cases, with no false-positive cytopathologic interpretations. Malignant NS were usually unilateral, hemorrhagic, mass-associated, and in older patients. Males with nipple discharge had a significantly higher incidence of breast cancer (two of nine; 22%) than women with abnormal NS (3 of 216; 1.5%). Papilloma NS were generally unilateral and hemorrhagic; FCD and physiologic NS were mostly serous or milky. Benign NS were not cytologically distinguishable. We conclude that cytologic examination of NS is a specific but insensitive method to identify underlying malignancy. Additional clinical features, including patient age, laterality and character of NS, and radiographic findings, were found to be diagnostically useful.

Fine needle aspiration cytologic diagnosis of axillary accessory breast tissue, including its physiologic changes and pathologic lesions.

Sixty-nine cases of axillary accessory breast tissue, including its physiologic changes and pathologic lesions, were diagnosed by fine needle aspiration cytology. The age of the patients ranged from 13 to 40 years, with a median of 25, and all were female. The cases presented with swellings in the left axilla in 16 cases, right axilla in 30 cases and both axillae in 23 cases. The common clinical diagnoses included accessory breast tissue (23.2%), lipomatous lesion (17.4%), lymphadenopathy (18.8%) and swellings not otherwise specified (30.4%). In 8.8% cases two of the possibilities were considered. The cytodiagnoses included axillary accessory breast tissue (47 cases), axillary breast tissue with pregnancy or lactational changes (15), cystic disease (4) and fibroadenoma (3). One of the cystic disease cases showed granulomatous inflammation. Although no case of carcinoma in axillary breast tissue was diagnosed during the study period, there were two cases of malignancy in axillary swellings (diagnosed as metastatic carcinoma) when no primary was detected in the breasts.

[Stereotaxic fine-needle aspirations of clinically latent breast cysts: an efficient and neat procedure]. / Les cytoponctions sous stéréotaxie des kystes mammaires infracliniques: une procédure efficace et élégante.

The purpose was to evaluate the interest of stereotaxic fine-needle aspiration for round opacities when the ultrasound and echoguided punctures are inefficient; especially when women are under menopausal hormonal replacement therapy. Sixty stereotactic guided fine-needle aspirations detected by mammography have been performed between january 1990 and august 1996. The stereotaxic procedure is performed with a DMR unit (GE with Stereotix II). Stereotaxic views are done to verify needle position. After aspiration, cytologic examination is realised. Cystic fluid was always obtained and cytologic examination proved benign cysts in all cases. In 50 cases, cysts completely disappeared. There were 2 relapses that received after a second. This method is reliable for evaluation of non palpable mammographically detected opacities. The use of this technique spares the patient a surgical biopsy. This procedure enables women under menopausal hormone replacement therapy to continue the treatment.

Significance of resistive index in color Doppler ultrasonogram: differentiation between benign and malignant breast masses.

The objective of this article is to evaluate the significance of resistive index in differentiation between benign and malignant breast lesions on duplex ultrasonographic examination. Resistive indices obtained in 106 breast lesions of 104 patients were included. Sixty-four were benign (mean age: 32.4 +/- 11.1 years), and 42 were malignant lesions (mean age: 47.8 +/- 11.4 years). The resistive index was classified as follows: below 0.49, from 0.5 to 0.59, 0.6 to 0.69, 0.7 to 0.79, and above 0.8. We analyzed and defined the optimal threshold value of RI between benign and malignant lesions. The mean values of the RI of benign and malignant lesions were 0.62 +/- 0.095 (range 0.44-0.86) and 0.74 +/- 0.097 (range, 0.50-0.92), respectively. The resistive index exceeded 0.7 in 80% of malignant lesions. The difference of the RI between malignant and benign lesions was statistically significant when the threshold value was 0.7 (P < 0.001). A resistive index over 0.7 may suggest malignant lesions. Due to the considerable overlap of the range of the RI, it may not be diagnostic in any single patient; however, it may be helpful in conjunct with gray-scale image.

The usefulness of Doppler angiography in differential diagnosis of benign and malignant breast lesions.

OBJECTIVE: To estimate the usefulness of Doppler angiography in differential diagnosis of benign and malignant breast tumors. SETTING: District special hospital, 1997-2000. PATIENTS: 195 women with breast lesions detected by mammography or palpation in the out-patient clinic; 120 (average age 40 years) had benign lesions, and 75 (average age 54 years), malignant tumors, all confirmed by histopathology. There were 125 healthy controls, both pre- and postmenopausal. METHODS: Areas of tumor in vivo and healthy breast tissue were scanned using the Doppler angiography option of an Acuson 128XP sonograph, with a 7-MHz transducer. The signals were recorded on videotape and transferred with a QuickCapture frame grabber board for PC analysis by HLImage 97 software (256 gray scale). Signal strength was given per 1 cm2. This result was taken as semi-quantitative perfusion of the tissue section. RESULTS: In malignant breast lesions perfusion was significantly greater than in benign ones. Furthermore, perfusion of malignant lesions was not dependent on the phase of the menstrual cycle (1st vs. 2nd phase). The maximum sensitivity and specificity were 72% and 72.5%, respectively, based on ROC curves. CONCLUSIONS: This computerized Doppler angiography system is useful for differentiating between benign and malignant breast lesions in combination with other findings. It would also be useful for surveillance of apparently benign lesions. A limitation is the complicated computer analysis.