Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity.

Using contact-dependent three-dimensional coculture systems and serum-free conditions, we compared the ability of estrogen receptor (ER)-alpha(+) tamoxifen-sensitive premalignant (EIII8) or tumorigenic (MCF-7), ER-alpha(+) tamoxifen-resistant (EIII8-TAM(R)) or ER-alpha(-) MDA-MB-231 breast cancer cells to interact and undergo epithelial morphogenesis on association with breast tumor-derived fibroblasts. Although all breast cancer cell lines interacted with tumor fibroblasts, EIII8 and its intrinsically tamoxifen-resistant counterpart EIII8-TAM(R) cells were most receptive and responded with dramatic, albeit, aberrant epithelial morphogenesis. EIII8 cells underwent epithelial morphogenesis when cocultured with fibroblasts from ER-alpha(-)/PgR(-) or ER-alpha(+)/PgR(+) breast tumors; however, EIII8 cells cocultured with ER-alpha(-)/PgR(-) tumor-derived fibroblasts exhibited decreased tamoxifen sensitivity compared with cells cocultured with ER-alpha(+)/PgR(+) tumor fibroblasts. Fibroblast-induced tamoxifen resistance was accompanied by mitogen-activated protein kinase and Akt hyperactivation, reduced sensitivity to U0126 or LY294002, and ER-alpha hyperphosphorylation in the activation function-1 domain. The intrinsic tamoxifen resistance of EIII8-Tam(R) cells correlated with constitutive ER-alpha hyperphosphorylation that was unaffected by the tumor fibroblasts. Our results suggest that tumor fibroblast-induced tamoxifen resistance of EIII8 cells is not mediated by epidermal growth factor receptor or insulin-like growth factor (IGF)-1R axes because no correlation was found between expression levels of IGF-1, IGF-2, phosphorylated IGF-1R, or epidermal growth factor receptor, and tamoxifen sensitivity of EIII8 fibroblast cultures.

Can a practicing surgeon detect early lymphedema reliably?

BACKGROUND: Lymphedema may be identified by simpler circumference changes as compared with changes in limb volume. METHODS: Ninety breast cancer patients were prospectively enrolled in an academic trial, and seven upper extremity circumferences were measured quarterly for 3 years. A 10% volume increase or greater than 1 cm increase in arm circumference identified lymphedema with verification by a lymphedema specialist. Sensitivity and specificity of several different criteria for detecting lymphedema were compared using the academic trial as the standard. RESULTS: Thirty-nine cases of lymphedema were identified by the academic trial. Using a 10% increase in circumference at two sites as the criterion, half the lymphedema cases were detected (sensitivity 37%). When using a 10% increase in circumference at any site, 74.4% of cases were detected (sensitivity 49%). Detection by a 5% increase in circumference at any site was 91% sensitive. CONCLUSIONS: An increase of 5% in circumference measurements identified the most potential lymphedema cases compared with an academic trial.

Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated with preoperative chemotherapy correlates with breast cancer outcome.

BACKGROUND: The benefits of primary tumor downstaging and assessment of chemoresponsiveness have resulted in expanded applications for induction chemotherapy. However, the pathologic evaluation and prognostic significance of response in preoperatively treated lymph nodes have not been defined. METHODS: The axillary lymph nodes of 71 patients with locally advanced breast cancer treated with induction chemotherapy were evaluated for histological evidence of tumor regression as defined by the presence of nodal fibrosis, mucin pools, or aggregates of foamy histiocytes. RESULTS: Complete pathologic response in the breast and axilla occurred in 10 patients (14%); 19 (26.8%) had evidence of tumor regression in 1 or more lymph nodes. Patients without nodal metastases and no evidence of tumor regression had the best outcome (median disease-free survival, 31.5 months; relapse rate, 27%). Patients with residual nodal metastases and no evidence of treatment effect had the worst outcome (median disease-free survival, 19.8 months; relapse rate, 55%). The median disease-free survival was 22.1 months, and the relapse rate was 32% for patients with histopathologic evidence of tumor regression in the axillary lymph nodes. CONCLUSIONS: Detection of treatment effect in axillary lymph nodes after induction chemotherapy identifies a subset of patients with an outcome intermediate between that of completely node-negative and node-positive patients. The axillary lymph nodes of patients receiving preoperative chemotherapy should be routinely analyzed for the presence of these features.

Histopathologic analysis of atypical lesions in image-guided core breast biopsies.

Appropriate follow-up of patients with needle core breast biopsies (NCBB) showing atypical hyperplasia remains unclear because previous studies show that subsequent open biopsies in variable proportions of these patients reveal ductal carcinoma in situ (DCIS) or even invasive carcinoma, indicating significant sampling artifact. NCBB with diagnoses of atypia were morphologically classified into groups as follows: I, ALH (n = 24); II, ADH with minimal cytologic atypism (n = 90); III, atypia, other (9 columnar, 2 apocrine, 11 atypical papillary); IV, severe ADH/borderline DCIS (n = 31). Mammographic and histologic features, including the number of foci of atypia in the NCBB and the calcification span, were then correlated with presence of DCIS or invasive tumor in subsequent open excisions. Open excisional biopsies showed more severe lesions in 12% of Group I-III cases (8% in Group I, 9% in Group II, and 27% in Group III), of which 15 were DCIS and one was an invasive tubular carcinoma (0.3 cm). Of the DCIS, 60% (n = 9) were < or =5 mm, and 13 of 15 (87%) were low grade. The NCBB cavity was immediately adjacent to the more severe lesions in 88% (n = 14) of cases, in keeping with sampling error. The subset showing severe ADH with borderline nuclear features in contrast was associated with a high likelihood (63%) of DCIS in follow-up excisions. NCBB with atypical papillary features also showed a high frequency of DCIS (4/11, 36%) in subsequent open excisions. Other factors associated with more severe lesions on open biopsy included the number of atypical foci in the NCBB (>4, P <.05) and the mammographic calcification span (>2.0 cm, P <.0001). Atypical lesions diagnosed in NCBB samples are radiographically and morphologically heterogeneous, accounting for the variable frequency of DCIS or invasive neoplasm identified in subsequent open excisions, which are usually focal, low grade, and a consequence of sampling artifact (i.e., adjacent to the NCBB cavity). DCIS is more likely if microcalcifications are mammographically extensive or if atypia is multifocal or is associated with borderline cytologic features.

Office-based ultrasound-guided cryoablation of breast fibroadenomas.

BACKGROUND: Fibroadenomas commonly found by palpation and routine mammography account for approximately 20% of open surgical breast biopsies. Alternatives to open surgery include tumor removal using an automated coring device and tumor ablation using heating or cooling elements. We report our initial experience with cryoablation of biopsy-proven benign fibroadenomas. METHODS: A table-top cryoablation system employing a 2.4-mm cryoprobe was used to treat biopsy-proven benign fibroadenomas up to 4 cm in maximum diameter in a prospective nonrandomized fashion. The cryoprobe was placed under ultrasound guidance. Using a treatment algorithm based on fibroadenoma size, all tumors were subjected to two freeze cycles with an interposing thaw. Skin appearance and temperature, probe temperature, iceball size, and patient comfort were closely monitored during the procedure. Follow-up examinations including ultrasonography and photographs were scheduled for up to 12 months postablation. RESULTS: Fifty patients with 57 core biopsy-proven benign fibroadenomas were treated. Seven early cases were treated in an ambulatory surgery center setting. The remaining procedures were completely office-based using only local anesthetic. Tumor diameter varied from 7 mm to 42 mm (mean 21 mm). The iceball engulfed the target lesion in each case. Transient postoperative side effects were local swelling and ecchymosis. Postoperative discomfort rarely required medication beyond acetaminophen or ibuprofen. Lesions showed progressive shrinkage and disappearance over 3 to 12 months. No skin injury was noted and appearance remained excellent. Patient satisfaction was excellent. CONCLUSIONS: With office-based use of ultrasound-guided cryoablation for fibroadenomas there was little or no pain, target lesions were reduced in size or eliminated, scarring was minimal, cosmesis outstanding, and patient satisfaction was excellent. Cryoablation offers a useful office-based alternative to surgical excision of benign fibroadenomas.

Lobular carcinoma in situ and invasive cancer: the contralateral breast controversy.

We determined if the risk of relapse is increased in patients with the concomitant diagnosis of lobular carcinoma in situ (LCIS) and an invasive cancer, suggesting the need for a more aggressive surgical approach. A retrospective chart review was conducted from the University of Michigan's Cancer Registry of patients with LCIS and a simultaneous invasive cancer and patients with invasive cancer only diagnosed between 1981 and 1997. The two groups were compared statistically with the following variables: age at diagnosis, tumor stage, histopathologic type of cancer, type of surgery, first line of treatment, relapse status with dates, site of relapse, and vital status. Statistically significant differences were found in the distribution of age (mean p = 0.0484 and median p = 0.0216), and histopathologic type of cancer (p < 0.0001). No significant difference was noted in the overall survival between the two groups (p = 0.511). There was also a significant difference in the relapse-free survival curves between the groups (p = 0.032). The risk of relapse was almost double (1.92) for the cancer-only patients relative to patients with LCIS as a histologic component of cancer. There was no significant increase in contralateral or ipsilateral breast recurrence for patients with LCIS and an invasive cancer compared to an invasive cancer alone. This lends support to the use of breast conservation therapy for invasive cancer patients with a histologic component of LCIS. The significant difference in the types of cancer may support the theory of genetic progression of LCIS to cancer, but clearly further data are required to prove this hypothesis.

Histologic and radiographic analysis of ductal carcinoma in situ diagnosed using stereotactic incisional core breast biopsy.

BACKGROUND: Stereotactic incisional core breast biopsy (SCBB) is a highly specific technique for diagnosing ductal carcinoma in situ (DCIS) in patients with suspicious mammographic microcalcifications. However, its sensitivity for excluding the presence of coexisting occult invasive disease in this setting is not fully established. DESIGN: We correlated SCBB findings to subsequent lumpectomy/mastectomy (lx/mx) results in 122 cases of DCIS. In 29 of these cases, the SCBB showed microscopic invasion (n = 15) or foci that were suspicious for invasion (n = 14). Likelihood for invasive disease in subsequent lx/mx samples from each case then was compared with various parameters, including DCIS grade, extent and mammographic findings. RESULTS: Overall, 13% of cases in which the SCBB showed DCIS only (i.e., without any evidence of invasion), had invasive disease in the subsequent excision. This finding was significantly correlated with DCIS grade (low: 0/26 [0%], intermediate: 2/31 [6%], high: 10/36 [28%], P <.001). Invasive lesions were usually small (nine T1a, one T1b, and two T1c) and typically present within more extensive fields of DCIS (no invasion: 1.5 cm DCIS size; invasion: 2.8 cm mean DCIS size, P =.01). This was reflected by greater extent of involvement in the SCBB (5/8 cases with invasion had >15 ducts involved, versus 4/23 with <15 ducts involved, P =.03). SCBB that were suspicious or positive for microinvasion demonstrated invasion in most subsequent excision (susp: 7/14 [50%], microinv: 11/15 [73%]), generally of significant extent (11/18 T(1b-c)). CONCLUSIONS: 1. Patients with SCBB showing high grade DCIS and DCIS suspicious or positive for microinvasion have a significant and high likelihood, respectively, of harboring occult invasive neoplasm. They should accordingly be carefully evaluated radiographically, and possibly with sentinel node biopsy to facilitate axillary staging. 2. Likelihood of occult invasion is correlated with overall DCIS size/extent.