Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions.

The 78 kDa glucose-regulated stress protein GRP78 is induced by physiological stress conditions such as hypoxia, low pH, and glucose deprivation which often exist in the microenvironments of solid tumors. Activation of this stress pathway occurs in response to several pro-apoptotic stimuli. In vitro studies have demonstrated a correlation between induced expression of GRP78 and resistance to apoptotic death induced by topoisomerase II-directed drugs. We were interested in characterizing this protein in human breast lesions for potential implications in chemotherapeutic intervention. Surgical specimens of human breast lesions and paired normal tissues from the same patients were flash frozen for these studies. Total RNA and/or protein were extracted from these tissues and used in northern and/or western blot analyses, respectively, to quantify the relative expression of GRP78. Northern blot analysis indicated that 0/5 benign breast lesions, 3/5 estrogen receptor positive (ER+) breast tumors, and 6/9 estrogen receptor negative (ER-) breast tumors exhibited overexpression of GRP78 mRNA compared to paired normal tissues, with fold overexpressions ranging from 1.8 to 20. Western blot analyses correlated with these findings since 0/5 benign breast lesions, 4/6 ER+ breast tumors, and 3/3 ER- breast tumors overexpressed GRP78 protein with fold overexpressions ranging from 1.8 to 19. Immunohistochemical analysis of these tissues demonstrated that the expression of GRP78 was heterogeneous among the cells comprising different normal and malignant glands, but confirmed the overexpression of GRP78 in most of the more aggressive ER- tumors. These results suggest that some breast tumors exhibit adverse microenvironment conditions that induce the overexpression of specific stress genes that may play a role in resistance to apoptosis and decreased chemotherapeutic efficacy.

Endoscopic axillary exploration and sentinel lymphadenectomy.

BACKGROUND: Minimally invasive approaches have changed the practice of surgery in several specialties. The purpose of this study was to develop a reproducible endoscopic technique for the evaluation of the axilla in breast cancer patients. METHODS: A total of 23 patients with biopsy-proven breast carcinoma were enrolled. Patients were positioned in the supine position with the ipsilateral arm abducted at 90 degrees. A 1-cm skin incision was made at the superior aspect of the axilla. Dissection was carried bluntly to the lateral border of the pectoralis major. A balloon distention device was inserted into the tract and distended under endoscopic vision to create a working space. Insufflation was initiated up to a pressure of 8 mmHg. A 30 degrees laparoscope was introduced for visualization of axillary contents. One or two additional 5-mm cannulas were placed as needed under direct visualization. Manipulation of axillary contents was performed, and in 19 patients a sentinel node identification technique was applied. RESULTS: In all patients, using insufflation and minimal instrument dissection, the axillary vein, long thoracic, and thoracodorsal nerves were found in their usual anatomical locations. Utilizing blunt and sharp dissection, the axilla was thoroughly inspected, and individual lymph nodes were easily identified and extracted. In 11 of 19 patients, a sentinel node or blue dye was identified using isosulfan blue. There was a procedure concordance of 84%, and there were no complications. CONCLUSIONS: We describe a novel endoscopic technique for the evaluation of the axilla in breast cancer patients. This technique allows (a) creation of a minimally invasive working space within the axilla, (b) recognition of key axillary anatomic landmarks, and (c) instrument manipulation within the axilla to identify and extract lymph nodes, and apply the sentinel node technique. This is the first report of a minimally invasive approach to axillary exploration to employ sentinel lymph node mapping.

Breast MRI as an adjunct in the diagnosis of a carcinoma partially obscured on mammography.

The role of unenhanced breast MRI as an adjunct to mammography in the diagnosis of a breast carcinoma presenting as architectural distortion partially obscured by dense tissue on film-screen mammography is illustrated.

Lobular carcinoma in situ: observation without surgery as an appropriate therapy.

BACKGROUND: The finding of lobular carcinoma in situ (LCIS) in the breast has generally prompted treatment with unilateral or bilateral mastectomy. Most experts now feel that LCIS simply identifies a woman who is at high risk to develop future breast cancer and requires only close clinical and mammographic follow-up. This approach has been recommended at our institution for > 15 years. This study defines the natural history of a population of women with LCIS who were treated by observation alone. METHODS: Women with a pathologic diagnosis of LCIS were identified by tumor registry search. Records and pathology were reviewed. Radiographic-pathologic correlation was performed on women who had undergone mammographic-localized breast biopsies. One hundred forty-nine women with LCIS were identified. Eighty four were excluded from analysis because of synchronous invasive cancer or ductal carcinoma in situ (DCIS). The remaining 65 women formed the basis of this report. RESULTS: Sixty-five women with LCIS were treated from 1963 through 1990. Median follow-up was 83 months. No women were lost to follow-up. Median age at diagnosis was 48 years (range 37-81), and 32% had a family history of breast cancer. Clinical findings leading to biopsy were breast mass in 43, nipple discharge in three, and mammographic abnormality in 19. Mammographic-pathologic correlation showed that the focus of LCIS in these 19 women was not associated with the mammographic abnormality. Fourteen of 65 women underwent mastectomy after diagnosis of LCIS (nine ipsilateral, five bilateral). Fifty-one of 65 women elected observation alone. In the observation group, 13 of 51 women (25%) underwent a second breast biopsy for a clinical or mammographic abnormality during the follow-up period. The median interval to biopsy was 50 months. Pathology was benign in two, LCIS in seven, DCIS in one, and invasive cancer in three. All seven women with LCIS on subsequent biopsy continued with observation and none developed breast cancer. All four cancers were detected by mammography without an associated palpable mass. Three of four cancer masses were < 1 cm in diameter. The woman with DCIS was 47 years of age and developed DCIS 106 months after LCIS diagnosis. She was treated by total mastectomy and is disease free 108 months later. The three women with invasive cancer developed this at 41, 53, and 69 months after diagnosis of LCIS. All were < 50 years of age. All three cancers were in the same breast as the previous LCIS. Two women were treated by modified radical mastectomy, and the third had wide excision/axillary dissection followed by radiation therapy. They are alive and disease-free at 16, 82, and 116 months. CONCLUSIONS: Four of 51 women treated with observation alone after diagnosis of LCIS developed breast cancer. All were detected by screening at an early stage. LCIS appeared to be an incidental finding on biopsy of mammographic abnormalities. The policy of observation alone for the finding of LCIS spares women mastectomy. Furthermore, cancers that develop in follow-up are likely to be detected at an early stage and be amenable to curative therapy. Observation alone is appropriate treatment for women with LCIS.

Atypical hyperplasia: frequency and mammographic and pathologic relationships in excisional biopsies guided with mammography and clinical examination.

PURPOSE: To ascertain the frequency and pathologic relationships of atypical hyperplasia in biopsy specimens obtained after clinical and mammographic examination. MATERIALS AND METHODS: Clinical, mammographic, and histologic findings were prospectively correlated in 300 consecutive excisional biopsies. RESULTS: Atypical hyperplasia was detected in 26 (17%) of 154 biopsies with benign findings and 19 (13%) of 146 biopsies with malignant findings overall (P > .05). The frequency of atypical hyperplasia was only 4% (two of 55 specimens) in clinically prompted biopsies with benign findings but 24% (24 of 99 specimens) in mammographically prompted biopsies with benign findings (P = .002), increasing to 31% (21 of 68 specimens) in benign microcalcifications and 40% (18 of 45 specimens) in benign microcalcifications associated with adenosis. Atypical hyperplasia was found most often within (16 [62%] of 26 cases) or adjacent to (nine [35%] of 26 cases) another lesion that prompted biopsy. CONCLUSION: Most atypical hyperplasia is not a random finding in benign biopsy specimens but shows a statistically significantly greater frequency in association with microcalcifications detected with mammography only, especially those in areas of adenosis.

Breast biopsy in women 30 years old or less.

Forty women 30 years of age or less underwent breast biopsy at Roswell Park Cancer Institute between January 1980 and January 1989. Thirty-eight of the 40 women had a palpable breast mass. Thirty-one of these young women had self-detected breast masses, and the median duration before presentation was 6 months. Physical characteristics were described in 30 of the masses. Twenty-three were described as "fibroadenomas" or smooth, firm, and mobile. Seven masses were described as irregular. The median size of the breast mass was 1.5 cm (range: 0.5 to 9.0 cm). Mammography was performed in 20 patients, but results were reported as abnormal in only 6. Twenty of the masses were described histologically as fibroadenoma. Twelve were described histologically as "fibrocystic disease" or "stromal fibrosis." One case (2.5%) was invasive adenocarcinoma. Probability of serious underlying breast pathology in young women is low but not nil. Noninvasive and minimally invasive techniques are proposed by some authors as cost-efficient methods that may substitute for open biopsy in these patients. Unfortunately, false-negative results persist and are particularly unacceptable in these young women. During the same time period as our study, 54 women aged 30 years or less were referred to Roswell Park Cancer Institute with a previously diagnosed invasive breast cancer. The incidence of breast cancer in this biopsy series was 2.5%. The potential costs of misdiagnosed early breast cancer in young women negate any rationalization for less invasive biopsy techniques. Following aspiration to rule out a benign cyst, and a possible period of brief observation for spontaneous resolution (2 or 3 months), excisional biopsy is recommended for young women with a breast mass.

Results of salvage mastectomy for local recurrence after breast-conserving surgery without radiation therapy.

BACKGROUND: Between 1975 and 1987, 128 patients with infiltrating breast cancer, categorized as clinical Stage I and II disease, were treated by breast conservation surgery without radiation therapy. MATERIALS: After a median disease-free interval of 20 months (range, 8-64 months), 25 of 128 patients had local recurrence, for which salvage mastectomy was performed. The results of modified radial mastectomy as a salvage procedure were analyzed in these 25 patients. RESULTS: After a median disease-free interval of 52 months (range, 8-75 years) after the salvage procedure, 12 patients had chest wall and distant recurrences, whereas 13 patients remained free of disease. The 5-year actuarial disease-free and overall survival rates after the salvage mastectomy were 51% and 65%, respectively. CONCLUSIONS: Univariate analyses of factors affecting disease-free survival and overall survival showed that the size of the local recurrence (< or = 2 cm) (P = 0.009) and the number of pathologically positive axillary nodes at the time of the salvage procedure (fewer than four nodes) (P = 0.002) were associated with a better prognosis.

Patterns of occurrence of second primary non-mammary malignancies in breast cancer patients: results from 1382 consecutive autopsies.

An autopsy series on the patterns of occurrence of second primary non-mammary malignancies (SPNM) in breast cancer patients is presented. SPNM occurred in 11.4% of breast cancer patients at a mean interval of 83.9 months. Seventy-five per cent of them occurred by the first decade following breast cancer. The most common system of SPNM occurrence was the female genital system, followed by the gastrointestinal system. The single organs most commonly involved were the colon and rectum, ovary and uterine cervix. There was no evident association between administration of radiotherapy or chemotherapy for the breast cancer and the risk for SPNM development except in the case of post-radiation sarcomas at or near the site of post-mastectomy radiotherapy. Death was caused by the breast cancer in 28.7% of patients and by the SPNM in 53.5%. In 10.6% of the cases the SPNM was clinically interpreted as metastatic breast cancer until autopsy.

Flow cytometric DNA analysis of excised breast lesions: use of fresh tissue needle aspirates obtained under guidance with mammography of the specimen.

Eighty consecutive biopsy specimens were studied to determine whether DNA analysis could be performed on fine-needle aspirates of excised clinically occult breast lesions obtained under guidance with mammography of the specimen before fixation to offer the advantages of fresh-tissue analysis. With use of single aspirates, cytologic analysis was possible in 50 cases (62%); DNA analysis was possible in 75 cases (94%). These methods combined offered no statistically significant increase in sensitivity for detection of malignancy compared with cytologic analysis alone. Forty-one percent of the analyzable invasive carcinomas showed aneuploidy. Aneuploidy and high S phase fractions of the invasive carcinomas showed no substantial correlation with patient age, nodal status, and size or appearance of the mammographic lesion. Aneuploidy was also seen in zero of four analyzable lesions showing ductal carcinoma in situ, two of 13 showing atypical hyperplasia (15%), and one of the 28 remaining benign lesions (4%). The authors conclude that this mammographic intervention is an effective means of obtaining fresh tissue samples of clinically occult lesions for DNA analysis.

Factors affecting outcome in locally advanced breast cancer.

Patients presenting with locally advanced breast cancer (LABC) constitute a diverse group for which a variety of treatment modalities have been instituted. To assess which factors have a direct impact on outcome, we reviewed the medical records of 104 patients diagnosed with stage IIIA, stage IIIB and T3N0M0 breast carcinoma. When considered individually (univariate analysis), clinical stage, pathological stage, oestrogen receptor status and type of therapy were significant predictors for disease-free survival (DFS) and overall survival (OS). However, in a multivariate analysis, only clinical stage was a significant predictor for both DFS and OS, while ER status was a significant predictor for OS. There was a high degree of correlation between clinical and pathological staging. Nearly two-thirds of the patients developed a recurrence by 5 years. Loco-regional recurrence was the site of first recurrence in one-third of the patients by 5 years. The prognosis for patients presenting with LABC is poor, and they should be treated aggressively with loco-regional and systemic multimodality therapy. Although groups of patients with improved outcome could be identified by clinical or pathological staging, no group demonstrated an outcome good enough to be spared from multimodality therapy.

Tumor hormone receptor status and recurrences in premenopausal patients with node-negative breast carcinoma.

To ascertain the prognostic significance of tumor hormone receptor status in premenopausal patients with node-negative breast cancer, a retrospective review of 199 patients who met these criteria was conducted. Of these 199 patients, estrogen receptor (ER) data were available for 147. One hundred four patients (71%) had ER-negative disease and 22 (21%) exhibited local or distant recurrence with a median follow-up time of 85.4 months. Thirteen patients in this group had died of breast cancer. Of the 43 patients who had ER-positive disease, 5 (12%) had recurrences and 2 died of breast cancer. After observing patients for a longer period of time (median follow-up time, 85.4 months), no statistically significant differences in disease-free survival (DFS) or overall survival (OS) were demonstrated. However, as seen in our first analysis of this group at 45 months, tumor size after a median follow-up time of 85.4 months continues to have significant prognostic implications, regardless of ER status.

Breast cancer in women under 35 years of age.

A review was undertaken of 226 patients with primary breast carcinoma who were 35 years of age, or younger, from 1960 to 1987. Comparisons to other studies of young and older women were made for clinical, pathologic, and survival characteristics. Young patients with breast cancer share many of the same disease characteristics of tumor type, location, size, and nodal involvement as their older counterparts. Five- and 10-year survival rates were comparable for patients with stage I or stage II disease and negative axillary lymph nodes. However, patients with stage II disease and positive nodes appear to have a decreased survival compared with older patients.