Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

'Revertant' DCIS in human axillary breast carcinoma metastases.

Recent experimental evidence obtained in Scid mice has suggested that the metastatic process is in large part epigenetically regulated and undergoes partial reversion once the metastatic process is completed: the metastatic colonies become more engaged in the process of growing in situ than actively metastasizing. Based on this experimental evidence, examples were sought of metastatic human cancers where similar reversion to an in situ growth state was occurring. Review of 200 cases of metastatic human breast cancer revealed a 21 per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth pattern within axillary nodal metastases. The revertant DCIS areas were characterized by an intact and circumferential basement membrane, as demonstrated by extracellular laminin and type IV collagen immunoreactivity. These revertant DCIS areas could be distinguished from primary DCIS, however, by the absence of surrounding myoepithelial cells in the former, identified in the latter by their positive maspin, S-100, and smooth muscle actin immunoreactivity. The pattern of revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non-comedo) (6 per cent), or well-differentiated (non-comedo) (2%), exhibited complete 100 per cent concordance with the primary DCIS pattern. The concordance of histological patterns held true for even the subtypes of DCIS determined by architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear size by digital image analysis and Her-2/neu, p53, and Ki-67 status in the revertant DCIS also exhibited complete concordance with the primary DCIS counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER-negative/EGFR-positive and exhibited significant nodal involvement (mean number, 9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean number, 4; mean area, 15 per cent) (P < 0.01) These findings suggest that reversion of the metastatic phenotype may also be occurring within autochthonous human metastasis.

Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy.

BACKGROUND: The relationship between the microscopic margins of resection and ipsilateral breast recurrence (IBR) after breast-conserving therapy for carcinomas with or without an extensive intraductal component (EIC) has not been adequately defined. METHODS: Of 1,790 women with unilateral clinical Stage I or II breast carcinoma treated with radiation therapy as part of breast-conserving therapy, 343 had invasive ductal histology evaluable for an extensive intraductal component (EIC), had inked margins that were evaluable for an review of their pathology slides, and received > or = 60 Gray to the tumor bed; these 343 women constitute the study population. The median follow-up was 109 months. All available slides were reviewed by one of the study pathologists. Final inked margins of excision were classified as negative > 1 mm (no invasive or in situ ductal carcinoma within 1 mm of the inked margin); negative-1 mm, or close carcinoma < or = 1 mm from the inked margin but not at the margin); or positive (carcinoma at the inked margin). A focally positive margin was defined as invasive or in situ ductal carcinoma at the margin in three or fewer low-power fields. The first site of recurrent disease was classified as either ipsilateral breast recurrence (IBR) or distant metastasis/regional lymph node failure. RESULTS: Crude rates for the first site of recurrence were calculated first for all 340 patients evaluable at 5 years, then separately for the 272 patients with EIC-negative cancers and the 68 patients with EIC-positive cancers. The 5-year rate of IBR for all patients with negative margins was 2%; and for all patients with positive margins, the rate was 16%. Among patients with negative margins, the 5-year rate of IBR was 2% for all patients with close margins (negative < or = 1 mm) and 3% for those with negative > 1 mm margins. For patients with close margins, the rates were 2% and 0% for EIC-negative and EIC-positive tumors, respectively; the corresponding rates for patients with negative margins > 1 mm were 1% and 14%. The 5-year rate of IBR for patients with focally positive margins was 9% (9% for EIC-negative and 7% for EIC-positive patients). The 5-year crude rate of IBR for patients with greater than focally positive margins was 28% (19% for EIC-negative and 42% for EIC-positive patients). CONCLUSIONS: Patients with negative margins of excision have a low rate of recurrence in the treated breast, whether the margin is > 1 mm or < or = 1 mm and whether the carcinoma is EIC-negative or EIC-positive. Among patients with positive margins, those with focally positive margins have a considerably lower risk of local recurrence than those with more than focally positive margins, and could be considered for breast-conserving therapy.

Breast-duct endoscopy to study stages of cancerous breast disease.

BACKGROUND: In breast-cancer research, we lack reproducible non-invasive access to breast tissue. Breast cancer is thought to start in the lining of the milk duct or lobule. We have had no direct access to this area other than in tissue removed surgically or by fine-needle aspiration. Our objective was to explore an intraductal approach to studying breast cancer and precancerous changes by duct cannulation and endoscopy. METHODS: In this pilot study, women in a university hospital were asked to participate. Nine patients with previously diagnosed ductal carcinoma-in-situ (DCIS) or invasive breast cancer who were about to undergo mastectomy under general anaesthesia agreed. After the patient was asleep but before the operation, we spent 15 minutes cannulating their ducts, obtaining washings, and attempting endoscopy. The ducts that had been cannulated were marked by instillation of dye or other materials, the nipple was sutured shut, and the mastectomy proceeded as planned. The mastectomy specimen underwent extensive histopathological examination. FINDINGS: We were successful in intraductal cannulation and endoscopy in seven of the nine patients. In five of the nine, we obtained epithelial cells in the washings. In one the cells were consistent with proliferative disease, in three there was atypical epithelium, and in one there was frank DCIS. With several different contrast materials injected into separate duct orifices, DCIS was confined to a single duct system. INTERPRETATION: We found that the intraductal approach is feasible for the study of the early changes of breast cancer Technical difficulties include identification of the breast duct orifices, determining the distensibility of the duct, and developing a reliable technique to obtain washings.

Human breast cancer progression can be regulated by dominant trans-acting factors in somatic cell hybridization studies.

Human breast cancer is often characterized by a progression to an ER (estrogen receptor)-negative, estrogen-independent, antiestrogen-resistant, EGFR (epidermal growth factor receptor)-positive, and highly metastatic phenotype. The molecular and biochemical mechanisms behind this progression are not well defined. Most studies of breast cancer have focused on one or another aspect or this progression but have not found a common pathway. By constructing stable and complete human-human somatic cell fusions between a highly metastatic, undifferentiated, ER-negative line of melanoma lineage and the estrogen-dependent, ER-positive MCF-7 line, this study produced hybrids that were ER negative, highly expressive of EGFR, estrogen independent, estrogen unresponsive, fully tumorigenic, and highly metastatic. ER negativity was on the basis of complete suppression of ER transcription as evidenced by Northern blot analysis and nuclear run-on assay, not on the basis of gene rearrangement. EGFR positivity was not due to gene amplification or rearrangement but rather to increased EGFR transcription. Mechanisms, including ras activation, fibroblast growth factor 4 expression, and human DNA methyltransferase activation causing ER promoter methylation, which are respectively known to induce estrogen-independent growth, induce spontaneous metastasis, and decrease ER levels in breast carcinoma experimentally, were not mechanisms operating in the hybrids. This model demonstrates that many of the common denominators of human breast carcinoma progression can be regulated by dominant trans-acting factors.

A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer.

BACKGROUND: Randomized clinical trials have clearly demonstrated that the use of radiation therapy (RT) following breast-conserving surgery (CS) substantially reduces the risk of local recurrence. However, the low rate of local recurrence after CS and RT for patients without known risk factors, and the recent increase in the detection of smaller cancers due to mammographic screening have led to the speculation that a subgroup of patients who have a low risk of local recurrence without RT might be identified. In 1986, we initiated a one-arm, prospective clinical trial of CS alone for treatment of highly selected breast cancer patients without known risk factors for local recurrence. METHODS: The study had a sequential design with a planned accrual of 90 patients. Criteria for entry into the trial were: a unicentric, clinical TI infiltrating ductal, mucinous or tubular carcinoma without an extensive intraductal component or lymphatic vessel invasion; a wide excision with a pathologically-documented negative margin of at least 1 cm; and histologically negative axillary lymph nodes. No adjuvant RT or systemic therapy was administered. Seventy-six per cent of the lesions were detected by mammography alone. The median gross pathologic tumor size was 0.9 cm. The median patient age was 67 years. RESULTS: Eighty-seven patients were enrolled in the trial before it closed prematurely in 1992 because the predefined stopping boundary was crossed (i.e., the sixth local recurrence was observed). At that time, the average annual local recurrence rate was 4.2%. With a median follow-up of 56 months, there are now 14 patients (16%) with local recurrence as their site of first failure (average annual local recurrence rate: 3.6%). Four patients without local recurrence developed distant metastases. Three patients have died, one of metastatic breast cancer and two of unrelated causes. CONCLUSIONS: Even in a highly selected group of patients with early-stage breast cancer, there is a substantial risk of early local recurrence for those treated with wide excision alone.

Surgical techniques in breast conservation.

The surgical treatment of breast cancer has changed dramatically in the last 30 years. The era of the Halsted radical mastectomy has passed, and less deforming surgeries have come into use. Partial mastectomy in association with axillary lymph node dissection has become a viable alternative for stage 1 and 2 carcinomas; more advanced tumors may be treated with breast conservative surgery when neoadjuvant chemotherapy is utilized. Further, the use of mammography in screening for breast cancer has led to an increase in the diagnosis of ductal carcinoma in situ (DCIS), another lesion for which breast conservation is often indicated.

Mammographically detected recurrent nonpalpable carcinoma developing in a transverse rectus abdominus myocutaneous flap. A case report.

BACKGROUND: Breast reconstruction is performed with increasing frequency and has become important in the treatment of mastectomy patients. METHODS: The development of recurrent carcinoma after a mastectomy and transverse rectus abdominus myocutaneous (TRAM) flap procedure is described. RESULTS: The lesion was nonpalpable and was detected by mammography. CONCLUSION: This case raises questions about the practice of not performing postreconstruction mammography for detection of local recurrence after mastectomy.

Recurrent breast cancer following immediate reconstruction with myocutaneous flaps.

As immediate breast reconstruction with rectus abdominis and latissimus dorsi myocutaneous flaps has become a recognized technique for patients requiring mastectomy, concerns have arisen regarding the detection and treatment of locoregional recurrence of breast cancer. Because most recurrences develop in the residual native skin of the chest wall following a mastectomy, breast reconstruction procedures involving the placement of a subpectoral prosthesis are unlikely to interfere with postoperative cancer surveillance. Myocutaneous flaps, however, transpose blocs of soft tissues into the mastectomy site. This study was done to evaluate the influence of a myocutaneous flap on the subsequent diagnosis and treatment of locoregional recurrence of breast cancer. Data were obtained from 161 patients with breast cancer who had immediate reconstruction with a myocutaneous flap between 1982 and 1990. Of the 161 patients reviewed, 120 had primary mastectomy with immediate reconstruction; 41 patients had salvage mastectomy and immediate reconstruction after failed conservative surgery and radiation therapy. Modified radical mastectomy was performed on all patients. Either a rectus abdominis (n = 65) or latissimus dorsi (n = 97) myocutaneous flap breast reconstruction was performed. Recurrent tumor was observed in 17 of the 161 patients reviewed (10.6 percent). Fourteen of the 17 recurrences occurred in 120 patients having primary mastectomy and immediate reconstruction for a rate of 11.7 percent; 3 of 41 patients (7.3 percent) who had salvage mastectomy and flap reconstruction developed recurrences. Of the 17 recurrences, 6 patients were stage II, 10 were stage III, and 1 was stage IV. All 17 patients who developed a recurrence had invasive breast cancer, with infiltrating and inflammatory tumors predominating. All locoregional recurrences of breast cancer developed within the native skin and subcutaneous tissues adjacent to the mastectomy and flap reconstruction site. Recurrences were seen as rapidly as 2 weeks or as long as 3.8 years (mean 1.4) after the mastectomy and flap reconstruction. Overall mean follow-up for the entire group of 161 patients was 5.4 years. Thirteen of the 17 patients (76.5 percent) developed distant metastases either concomitantly with the locoregional recurrence or within 4.3 years (mean 1.7). From an oncologic viewpoint, the technique of myocutaneous flap breast reconstruction with rectus abdominis or latissimus dorsi flaps appears to be a safe one. An analysis of locoregional recurrence of breast cancer in patients undergoing primary mastectomy or salvage mastectomy with myocutaneous flap breast reconstruction did not show concealment by the flap of any recurrent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Reconstruction of the radiated partial mastectomy defect with autogenous tissues.

As conservative surgery and radiation therapy have become accepted treatments for early-stage breast cancer, increasing attention has focused on the cosmetic results of this technique. When partial mastectomy--a term which encompasses a diversity of excisional techniques--is followed by radiation therapy, breast defects characterized by parenchymal loss, nipple-areola complex distortion, and cutaneous abnormalities can occur. From 1981 to 1990, eight patients sought reconstructive correction of a radiated partial mastectomy deformity. Patients were from 42 to 70 years of age (mean 49 years). All had breast cancer, except for one patient with diffuse and chronic breast abscesses. Six patients were reconstructed with latissimus dorsi flaps and two with rectus flaps. No patient underwent reconstruction sooner than 1 year after completion of radiation therapy; for the entire group, a mean of 2.6 years elapsed from completion of radiation therapy to flap reconstruction of the breast. Mammograms were obtained on all the breast cancer patients before and after the myocutaneous flap procedure. Follow-up extended from 1 to 9 years after reconstruction (mean 3.6 years) and included both physical examination and serial mammographic evaluations. Myocutaneous flap reconstruction with either latissimus or rectus flaps achieved an aesthetic improvement of the partial mastectomy deformity in all eight patients. Complications consisted only of seroma formation in two patients following latissimus flap reconstruction. Mammographic evaluation revealed fibrofatty degeneration of the soft tissues of both types of flaps, a change that occurs as early as 6 months after operation and appears as a radiolucent area. The feasibility of mammography as a screening adjunct for recurrent cancer in this group of patients is demonstrated. Advantages of this technique of autogenous tissue reconstruction are improvement of contour deformities associated with conservative surgery and radiation therapy, preservation of normal, sensate breast skin, enhancement of symmetry with the contralateral breast, and avoidance of a prosthesis.

The in situ carcinomas of the breast.

In situ carcinoma of the breast is being diagnosed with greater frequency on breast biopsies. Of the two types of CIS, lobular carcinoma in situ is considered a marker for increased risk of developing breast cancer in either breast, and treatment options are based on different philosophies of careful follow-up vs preventive surgery. Ductal carcinoma in situ is a direct precursor to invasive carcinoma and the variety of treatments available reflect the need to completely excise this lesion. Several trials are now in progress to define the roles of surgery, radiation, and hormonal manipulation in the treatment of both types of CIS.