Estrogen receptor expression in benign breast epithelium and breast cancer risk.

BACKGROUND: Estrogen exposure is a major risk factor for breast cancer. Increased estrogen responsiveness of breast epithelium may enhance this effect. We examined the relationship between breast cancer diagnosis and 1) the presence and absence of estrogen receptor expression in benign breast epithelium, 2) the level of expression and 3) its variation during the menstrual cycle, and 4) other established risk factors. e.g., age, age at menarche, parity, and family history. METHODS: We measured estrogen receptor expression (as % of positive cells) by immunohistochemistry in normal breast epithelium from 376 women undergoing diagnostic or therapeutic breast surgery. Data on established risk factors were collected prior to surgery and those on menstrual cycle dates at the time of surgery. Logistic regression was used to assess risks (odds ratios [ORs]). RESULTS: The crude OR for breast cancer in women with estrogen receptor-positive breast epithelium versus those without was 3.16 (95% confidence interval [CI] = 1.89-5.28), with an OR of 2.49 (95% CI = 1.25-4.96) for premenopausal and an OR of 3.32 (95% CI = 1.43-7.68) for postmenopausal women. The ORs remained high and statistically significant after controlling for age and other breast cancer risk factors. The level of estrogen receptor expression was higher in patients with breast cancer than in control subjects and it was related to breast cancer risk in postmenopausal women (P trend <.005). Expression declined as expected in premenopausal control subjects as the menstrual cycle progressed but rose in breast cancer patients (P trend <.015). CONCLUSIONS: The overexpression of estrogen receptors in normal breast epithelium may augment estrogen sensitivity and hence the risk of breast cancer.

The normal breast epithelium of women with breast cancer displays an aberrant response to estradiol.

Breast epithelial response to estradiol may play an important role in breast cancer etiology. We have examined the relationship between serum estradiol and progesterone levels and normal breast epithelial expression of estrogen receptor (ER) alpha, progesterone receptor (PgR), and epithelial proliferation (as reflected by the Ki-67 labeling index) in 121 women (50 newly diagnosed breast cancer cases and 71 benign breast disease controls). Simultaneous samples of grossly normal breast tissue and venous blood were obtained from women undergoing breast surgery. Serum estradiol and progesterone levels were measured by radioimmunoassay; breast epithelial ER, PgR, and Ki-67 expression was measured by immunohistochemistry. Linear regression, controlled for patient age and ductal and lobular composition of the tissue, showed that the breast epithelium of control women displayed an inverse correlation between serum estradiol and ER-alpha, which was not seen in case women (P for the difference in regression slopes = 0.001). PgR expression displayed a significant positive correlation with serum estradiol in cases, but not in controls. Epithelial proliferation had no relationship to either estradiol or progesterone in both cases and controls but showed an inverse relationship with ER in controls and a direct relationship in cases (P for the difference in regression slopes = 0.066). These results suggest a dysregulation of hormonal response in the normal breast epithelium of high-risk women, with lack of regulation of ER by estradiol, increased estrogen responsiveness as reflected by PgR expression, and a dissociation of ER expression and proliferative response.

Increased risk of breast cancer in splenectomized patients undergoing radiation therapy for Hodgkin's disease.

PURPOSE: Second malignancies have been reported among patients who were treated by radiation therapy or chemotherapy alone or in combination. Studies have implied an increased risk of breast cancer in women who received radiotherapy as part of their treatment for Hodgkin's disease. This review was performed to determine if there is an association between splenectomy and subsequent breast cancer. METHODS AND MATERIALS: One hundred and thirty-six female patients with histologically proven Hodgkin's disease were seen in the Division of Radiation Oncology between 1962 and 1985. All patients received mantle or mediastinal irradiation as part of their therapy. The risk of breast cancer was assessed and multiple linear regression analysis was performed on the following variables: patient age, stage, dose and extent of radiation field, time after completing radiation therapy, splenectomy, and chemotherapy. RESULTS: Breast cancer was observed in 11 of 74 splenectomized patients and in none of 62 patients not splenectomized. The mean follow-up was 13 years in splenectomized patients and 16 years, 7 months in nonsplenectomized patients. Nine patients developed invasive breast cancer and two developed ductal carcinoma in situ. Splenectomy was the only variable independently associated with an increased risk of breast cancer (p < 0.005) in multiple linear regression analysis; age, latency, and splenectomy considered together were also associated with an increased risk of breast cancer (p < 0.01). CONCLUSION: Our data show an increased risk of breast cancer in splenectomized patients who had treatment for Hodgkin's disease. A multiinstitutional survey may better define the influence of splenectomy relative to developing breast cancer in patients treated for Hodgkin's disease. The risk of breast cancer should be considered when recommending staging laparotomy, and we recommend close follow-up examination including routine mammograms for female patients successfully treated for Hodgkin's disease.

Chlorpropamide-induced changes in patients with hyperparathyroidism.

Ten patients with primary hyperparathyroidism were placed on a constant 30 mEq of calcium and 120 meq of sodium diet, and alterations in their calcium balance in response to standard oral doses of chlorpropamide were studied over a 4 day control period and a 4 day treatment period. The 10 patients treated with chlorpropamide significantly increased the urinary excretion of calcium and sodium and decreased the excretion of cyclic adenosine monophosphate (AMP). The serum calcium was lowered in six of the patients treated with chlorpropamide, and three of these patients, who had diabetes mellitus and either refused or were too ill for parathyroidectomy, continued to receive chlorpropamide for periods of 9 to 36 months. These three patients experienced prolonged lowering of the serum calcium level and became less confused, lethargic, and fatigued. The interrelationships between the chlorpropamide-induced changes in excretion of calcium, sodium, and cyclic AMP still must be clarified.

Neuropsychologic deficits associated with primary hyperparathyroidism.

Although neuropsychologic dysfunction has been recognized as a symptom of primary hyperparathyroidism since the earliest descriptions of the disease, the nature of the memory, learning, and cognition deficits has been poorly defined. To assess the nature and extent of the deficits, 10 patients with hyperparathyroidism without specific neuropsychologic complaints and 10 normocalcemic patients were tested with a battery of psychologic tests before and after operation. Postoperative test scores for the Wechsler Logical Memory and Associate Learning, Wechsler Memory Digit Span, and the Similarities subtest of the Wechsler Adult Intelligence Scales, which test short-term verbal memory and cognition, showed statistically significant improvement for the patients with hyperparathyroidism. The patients with hyperparathyroidism improved on the Wechsler Memory Quotient an average of 17%. Tests measuring conceptual tracking, short-term visual memory, graphic skills, and fine motor coordination were unchanged. The results suggest that dominant hemispheric functions are disrupted by hyperparathyroidism. Improved neuropsychologic function can be expected after parathyroidectomy and, since the deficit is difficult to assess before operation, may be an indication for operation in the patient without symptoms.

Pathogenesis-based treatment of recurring subareolar breast abscesses.

BACKGROUND: When a subareolar breast abscess (SBA) is incised and drained, an extraordinarily high frequency of recurrence is noted. METHODS: To develop a pathogenesis-based treatment plan, 24 women with a total of 84 abscesses were monitored. RESULTS: In nine women SBA was under the left areola, under the right, in 7 and in eight the SBA occurred either simultaneously or sequentially under both areolae. In 11 of 24 patients a chronic lactiferous duct fistula also existed. In four of 24 patients four SBAs were treated with antibiotics; alone; all recurred. In 16 of 24 patients initial treatment was incision and drainage plus antibiotics; all recurred. When the abscess plus the plugged lactiferous duct was excised, there were no recurrences; however, in four patients a new abscess in a different duct occurred, which was treated by en bloc resection of all subareolar ampullae, without further recurrence. Patients with a fistulous tract had the fistula, its feeding abscess, and its plugged lactiferous duct excised, without recurrence. In first time SBA the organism was usually staphylococcus; in recurrences mixed flora was isolated. Pathologic findings ranged from squamous metaplasia with keratinization of lactiferous ducts to chronic abscess. CONCLUSIONS: The cause of SBA is plugging of lactiferous duct within the nipple by keratin. To prevent recurrence the abscessed ampulla with its plugged proximal duct needs excision.

Immunoreactive hormones in human breast tissues.

Samples of breast tissue obtained at biopsy or mastectomy from women with benign breast disease and infiltrating duct or anaplastic carcinoma were maintained for 2 weeks in organ culture synthetic medium 199 without additional serum or hormones. Media were changed every 48 hours. Media withdrawn from the tissues were assayed for insulin, prolactin (Prl), and parathyroid hormone (PTH). In addition, tissue explants were extracted in acid-alcohol and assayed for insulin by standard radioimmunoassay (RIA) procedures. At day 0 portions of breast tissue from patients with malignant or benign disease were fixed in Bouin solution; they were then embedded in paraffin; and serial sections were obtained for histologic and immunocytochemical examination. The dissection media assayed for insulin and PTH by RIA showed that the hormones were present in media from patients with benign as well as malignant disease. However, there was no significant difference between the two groups of women. Only traces of Prl were detected in media. The amount of insulin present in certain tissue explants appeared to increase with time in culture. Immunocytochemical studies showed that insulin-like or PTH-like immunostaining appeared most often in malignant tumor tissue and was observed infrequently or not at all in patients with benign disease. Prl-positive cells were rare. These data suggest that breast tissues contain and may synthesize significant amounts of certain hormones that may influence the growth and proliferation of breast cells.

Immunocytochemical localization of insulin- and somatostatin-like material in human breast tumors.

Four types of human breast lesions and C3H mouse mammary adenocarcinomas (type A) were examined for the immunocytochemical localization of cells containing hormone-like substances. Insulin- or somatostatin-like immunoreactive material was observed in scattered single cells and nests of tumor cells in seven of eight infiltrating duct carcinomas, and in the majority of tumor cells from an anaplastic carcinoma. A few somatostatin-immunoreactive cells were observed in only one of seven fibroadenomas studied. No immunoreactive cells were observed in mouse adenocarcinomas or in human breast dysplasias. These results suggest that cells with hormone-like immunoreactivity may be a common feature in two types of malignant human breast tumors.

Needle localization of occult breast lesions.

Excision of mammographically demonstrated breast lesions that are clinically occult remains a surgical challenge. Eighteen lesions were preoperatively localized (all but 1 with the Frank hooked wire technique). Eleven lesions were evaluated with specimen radiography. Three lesions proved to be malignant at biopsy and 15 were benign. We found hooked wire needle placement to be extremely accurate, enabling rapid excision of the suspicious mass with excision of rather small areas of the breast with no significant cosmetic defect. Mean anesthetic time for breast biopsy alone was slightly less than time for biopsy with needle localization, which was less than that when specimen radiography was employed. In the absence of a discrete lesion, specimen radiography is a useful adjunct. Needle localization is simple, accurate, rapid, and requires no special apparatus. Its widespread use should lead to the identification of more breast carcinomas in a potentially curable state.

Hyperparathyroidism and pregnancy.

BACKGROUND: Hyperparathyroidism during pregnancy can carry significant morbidity to both mother and fetus. Surgery is the definitive treatment of choice although medical management is occasionally warranted. This report looks at 6 cases of hyperparathyroidism during pregnancy and reviews the morbidity and mortality of this entity. METHODS: We retrospectively reviewed all parathyroidectomies performed over a 21-year period (May 1975 to May 1996). A total of 750 cases were performed. In 6 cases, hyperparathyroidism occurred during pregnancy. Serum calcium was measured in all patients before and after parathyroidectomy. RESULTS: A total of 6 of 750 patients (0.8%) were found to have hyperparathyroidism during pregnancy. In this review, fetal mortality rate was 17% (1 of 6). Two infants experienced neonatal tetany. Maternal morbidity included 1 woman who developed hypercalcemic crisis and acute pancreatitis. Two patients presented with hyperemesis gravidarum, 2 were asymptomatic, and 1 had recurrent urinary tract infection. CONCLUSION: Hyperparathyroidism during pregnancy, while rare, remains a preventable cause of fetal morbidity and mortality. Based on our case series and review of the literature, surgery is the definitive treatment of choice and is considered safe and effective if performed during the second trimester of pregnancy. Those involved with the care of the pregnant patient need to be diligent to diagnose and treat this entity promptly.

Hypokalemia in a patient with pheochromocytoma.

OBJECTIVE: To report the occurrence of hypokalemia in a patient with pheochromocytoma. METHODS: We present a case report and discuss the possible role of hyperepinephrinemia as a cause of hypokalemia. RESULTS: A patient with pheochromocytoma had hypokalemia associated with vomiting, but hypokalemia recurred after repletion of potassium and cessation of vomiting. She had substantially increased epinephrine concentrations in the plasma and in the subsequently excised pheochromocytoma. Because evidence has shown that infusions of epinephrine induce hypokalemia in normal human subjects, the relationship between serum potassium and plasma epinephrine concentrations in 16 previous patients with pheochromocytoma and 4 patients with primary hyperepinephrinemia was studied. A significant negative correlation was noted. CONCLUSION: The presence of hypokalemia and its potential role in predisposing to arrhythmias in patients with pheochromocytoma merit further study.

Details of technique and results of staging laparotomy in the diagnosis of Hodgkin's disease.

The operative procedure for staging laparotomy in Hodgkin's disease is described in detail. Of 18 patients undergoing this procedure, staging laparotomy changed the stage of disease and subsequent therapy in 38%. Complications of the operation were minor, occurring in only two patients. Abnormal lymphangiography and splenomegaly proved unreliable clinical diagnostic findings. Most disturbing was the 100% incidence of amenorrhea in the women receiving pelvic irradiation following oophoropexy.

Prophylactic mastectomy: pathologic findings in high-risk patients.

BACKGROUND: According to recently published data, prophylactic mastectomy (PM) appears to prevent about 90% of the expected malignant neoplasms in women with a family history of breast cancer. OBJECTIVES: To identify the frequency of high-risk lesions in PM specimens and to determine occurrence of any new primary breast cancer following PM. DESIGN: We performed a retrospective study of women undergoing unilateral or bilateral PM. Medical charts and pathologic findings of 35 patients who underwent bilateral mastectomies at University Hospital, Syracuse, NY, from 1989 to 1996 were reviewed. Patients with biopsy-proven bilateral breast cancer were excluded. Patients were divided into 3 groups: (A) positive family history and no known breast cancer (n = 9), (B) positive family history and contralateral neoplasia (n = 13), and (C) negative family history and contralateral neoplasia (n = 13). These findings were compared with those found in reduction mammoplasty specimens from 10 women at standard risk of breast cancer. RESULTS: The mean age of the control group of women undergoing reduction mammoplasty was 38 years. The pathologic specimens demonstrated no significant pathologic findings in 9 and fibrocystic change in 1. In group A, the mean number of affected relatives was 3.1, and the mean age was 38 years. Two of these 9 women had atypical duct hyperplasia and 1 had atypical lobular hyperplasia in their breasts (ie, 33% with high-risk pathologic findings). Of the 13 group B women (mean age, 46.6 years; mean of 2.5 affected relatives and unilateral breast cancer), the contralateral PM specimen contained duct carcinoma in situ in one and invasive ductal cancer in a second (15% with occult malignant neoplasms). In 13 group C patients (mean age, 47.1 years), 3 (23.1%) of the contralateral PM specimens displayed atypical duct hyperplasia or atypical lobular hyperplasia. At a mean follow-up of 4.8 years, there have been no new breast malignant neoplasms in these 45 women. CONCLUSIONS: The occurrence of unilateral cancer in patients with family history of breast cancer is associated with a 15.4% probability of simultaneous occult malignant neoplasms in the contralateral breast. Patients with a strong family history but no evidence of breast cancer have a substantially similar rate of proliferative disease in their PM specimens as those women who have unilateral cancer but no significant family history.