N. O’Higgins

A pathologic assessment of adequate margin status in breast-conserving therapy

BackgroundThe definition of a clear margin in breast-conserving therapy is uncertain. The purpose of this study was to correlate the tumor-margin distance of the excision specimen with the presence of residual tumor at reoperation. We also analyzed predictors of compromised margins and of residual disease.MethodsAll patients who underwent breast-conserving therapy for invasive disease from 1999 to 2003 were reviewed. Pathologic characteristics and the precise tumor distance from the radial margin were recorded. A radial margin was compromised if invasive or (ductal) in situ carcinoma was <5 mm from the margin.ResultsOf the 612 patients who underwent breast conservation, 211 (34%) had compromised margins, and 39 had undetermined margins. Of the 161 patients who had a reoperation for compromised margins, 87 (54%) had residual disease. Residual disease after reoperation was present in 58% (56 of 96), 56% (9 of 16), and 45% (22 of 49) of those with tumor-margin distances <1 mm, ≥1 and <2 mm, and ≥2 and <5 mm, respectively. There was a progressive decline in residual disease for each millimeter until a rate of 22% for tumor-margin distances of ≥4 mm and <5 mm was reached. Pathologic size (P = .004), an extensive intraductal component (P = .002), referral from a symptomatic rather than a population-based screening program (P = .02), and the absence of a preoperative diagnosis by core biopsy (P < .0001) were predictive of compromised margins. Only young age (<45 years) was predictive of finding residual disease on reoperation (P = .02).ConclusionsA total of 45% of patients who had tumor 2 to 5 mm from the radial margin had residual disease on reoperation. Our results support a policy of requiring a 5-mm margin in patients undergoing breast-conserving therapy for invasive disease.The definition of a clear margin in breast-conserving therapy is uncertain. The purpose of this study was to correlate the tumor-margin distance of the excision specimen with the presence of residual tumor at reoperation. We also analyzed predictors of compromised margins and of residual disease. All patients who underwent breast-conserving therapy for invasive disease from 1999 to 2003 were reviewed. Pathologic characteristics and the precise tumor distance from the radial margin were recorded. A radial margin was compromised if invasive or (ductal) in situ carcinoma was <5 mm from the margin. Of the 612 patients who underwent breast conservation, 211 (34%) had compromised margins, and 39 had undetermined margins. Of the 161 patients who had a reoperation for compromised margins, 87 (54%) had residual disease. Residual disease after reoperation was present in 58% (56 of 96), 56% (9 of 16), and 45% (22 of 49) of those with tumor-margin distances <1 mm, ≥1 and <2 mm, and ≥2 and <5 mm, respectively. There was a progressive decline in residual disease for each millimeter until a rate of 22% for tumor-margin distances of ≥4 mm and <5 mm was reached. Pathologic size (P = .004), an extensive intraductal component (P = .002), referral from a symptomatic rather than a population-based screening program (P = .02), and the absence of a preoperative diagnosis by core biopsy (P < .0001) were predictive of compromised margins. Only young age (<45 years) was predictive of finding residual disease on reoperation (P = .02). A total of 45% of patients who had tumor 2 to 5 mm from the radial margin had residual disease on reoperation. Our results support a policy of requiring a 5-mm margin in patients undergoing breast-conserving therapy for invasive disease.

The accuracy of ultrasound, stereotactic, and clinical core biopsies in the diagnosis of breast cancer, with an analysis of false-negative cases.

Objective:Preoperative core biopsy in breast cancer is becoming the standard of care. The aim of this study was to analyze the various methods of core biopsy with respect to diagnostic accuracy and to examine the management and outcome of those patients with false-negative biopsies. Methods:All patients undergoing core biopsy for breast abnormalities over a 5-year period (1999–2003) were reviewed. The accuracy rates for each method of core biopsy, the histologic agreement between the core pathology and subsequent excision pathology, and the length of follow-up for cases of benign disease were studied. Patients whose biopsies were benign but who were subsequently diagnosed with cancer underwent detailed review. Results:There were 2427 core biopsies performed over the 5-year period, resulting in a final diagnosis of cancer in 1384 patients, benign disease in 954 patients, and atypical disease in 89 patients. Biopsy type consisted of 1279 ultrasound-guided cores, 739 clinically guided cores, and 409 stereotactic-guided cores. The overall false-negative rate was 6.1%, with specific rates for ultrasound-, clinical-, and stereotactic-guided cores of 1.7%, 13%, and 8.9%, respectively. False-negative biopsies occurred in 85 patients, and in 8 of these patients the diagnosis was delayed by greater than 2 months. In all other false-negative cases, “triple assessment” review allowed prompt recognition of discordant biopsy results and further evaluation. Conclusion:Ultrasound guidance should be used to perform core biopsies in evaluating all breast abnormalities visible on ultrasound. Adherence to principles of triple assessment following biopsy allows for early recognition of the majority of false-negative cases.

CA 15-3 is predictive of response and disease recurrence following treatment in locally advanced breast cancer

BackgroundPrimary chemotherapy (PC) is used for down-staging locally advanced breast cancer (LABC). CA 15-3 measures the protein product of the MUC1 gene and is the most widely used serum marker in breast cancer.MethodsWe retrospectively investigated the role of CA 15-3 in conjunction with other clinico-pathological variables as a predictor of response and time to disease recurrence following treatment in LABC. Pre and post primary chemotherapy serum concentrations of CA 15-3 together with other variables were reviewed and related to four outcomes following primary chemotherapy (clinical response, pathological response, time to recurrence and time to progression). Persistently elevated CA 15-3 after PC was considered as consecutively high levels above the cut off point during and after PC.Results73 patients were included in this study. Patients received PC (AC or AC-T regimen) for locally advanced breast cancer. 54 patients underwent surgery. The median follow up was 790 days. Patients with high concentrations of CA 15-3 before PC treatment had a poor clinical (p = 0.013) and pathological (p = 0.044) response. Together with Her-2/neu expression (p = 0.009) and tumour lympho-vascular space invasion (LVI) (p = 0.001), a persistently elevated CA 15-3 post PC (p = 0.007) was an independent predictive factor of recurrence following treatment in LABC.ConclusionElevated CA 15-3 level is predictive of a poor response to chemotherapy. In addition, persistently elevated CA 15-3 levels post chemotherapy in conjunction with lympho-vascular invasion and HER2 status predict a reduced disease free survival following treatment in locally advanced breast cancer.

Granulomatous Appendicitis Revisited: Report of a Case

Background: Isolated granulomatous appendicitis is uncommon and previously was considered to be a form of localised Crohn’s disease. However more recent series have noted that relapse is rare after appendicectomy and concluded that the condition is a distinct entity unrelated to Crohn’s disease. Following a case of granulomatous appendicitis at St. Vincent’s University Hospital Dublin, the condition was reviewed and the results are detailed herein. Methods: A case of granulomatous appendicitis is presented with discussion of 4 previous cases encountered in our practice and the literature is reviewed. Results: The clinical presentation was sub-acute appendicitis with a mass palpable in the right iliac fossa. At operation an enlarged, inflamed appendix with a broad base was noted and appendicectomy performed. Histopathology showed numerous granulomata on microscopic examination. The yersinia serology tests were negative. Review of computerised histopathology records in the hospital for the last 7 years showed 4 additional cases of granulomatous appendicitis. This is a total of 5 of 1,615 appendicectomies (an incidence of 0.31%). In all cases, the post-operative course was uneventful and the patients have had no further complaints. Conclusion: This small series provides further evidence that granulomatous appendicitis is a distinct clinical entity unrelated to Crohn’s disease and is cured by appendicectomy. It should be suspected when there is a sub-acute onset of appendicitis and an enlarged, broad-based appendix is found at operation.

Expression of the breast cancer metastasis suppressor gene, BRMS1, in human breast carcinoma: lack of correlation with metastasis to axillary lymph nodes.

The BRMS1 (breast cancer metastasis suppressor 1) gene has been found to suppress metastasis in animal models without inhibiting primary tumor growth. The aim of this study was to measure expression of BRMS1 mRNA in a panel of human breast carcinomas and compare its expression with parameters of local dissemination such as tumor size and lymph node metastasis. We also compared expression of BRMS1 mRNA in normal breast tissue, fibroadenomas, primary breast cancers and axillary nodal metastases from primary breast cancers. BRMS1 mRNA was detected in 10/11 (90%) specimens of normal breast tissue, 12/16 (75%) fibroadenomas, 64/82 (78%) primary breast cancer and 11/15 (64%) lymph node metastases (p, NS). In the primary cancer, expression was independent of tumor size, tumor grade, metastasis to axillary nodes and hormone receptor status. Furthermore, similar levels of BRMS1 were found in normal breast tissue, primary breast carcinomas and lymph node metastases from primary breast cancer. Our results do not suggest a role for BRMS1 in suppressing metastasis to local lymph nodes in patients with breast cancer.

Safety guidelines for radiolocalised sentinel node resection

BackgroundSentinel node radiolocalisation procedures are associated with low levels of radiation exposure. Radioactive material is present in the operating theatre and pathology laboratory. In most hospitals there are no official regulations in place for sentinel node radiation exposure.AimTo establish guidelines on the safety of sentinel node mapping with emphasis on the management of radioisotopes.MethodsThe current literature regarding sentinel node procedures and radiation safety was reviewed. EU and US radiation safety regulations were scrutinised.ResultsPersonnel involved in sentinel node procedures are exposed to low levels of radiation. These levels are not high enough to require designated radiation workers in the theatre and pathology laboratory. Awareness of radiation safety and certain precautions during the procedure and processing of the specimen can further reduce levels of exposure.ConclusionAlthough low levels of radiation exposure are associated with sentinel node procedures, awareness of radiation safety and adherence to regulations, along with close interdepartmental co-operation, are recommended for further reduction in radiation exposure and safe application of this technique.

Raised plasma endostatin levels correlate inversely with breast cancer angiogenesis

BACKGROUND Angiogenesis is essential for solid tumors, such as breast cancer, to grow. The effect of surgical removal of breast tumors on plasma endostatin and vascular endothelial growth factor (VEGF) levels was evaluated. Tumor tissues were analyzed for expression of Intratumoral microvessel density (IMVD) and endostatin. The effect of VEGF and endostatin in inducing apoptosis on human liver microvascular endothelial cells (HLMVEC) was investigated. MATERIALS AND METHODS Plasma from healthy volunteers, patients with fibroadenomas and breast cancer patients were assayed for endostatin and VEGF via immunoassay, pre-operatively and four weeks post-operatively. Expression of endostatin in tumor tissue was determined by Western blotting. IMVD was assessed following immunohistochemical staining with anti-CD34 antibody. RESULTS Plasma endostatin levels, in breast cancer patients, were significantly elevated (P = 0.015) in the post-operative (60.59 +/- 7.70 etag/ml) compared with the pre-operative group (30.62 +/- 4.54 etag/ml) and with normal age-matched controls (34.97 +/- 3.76 etag/ml). In patients with high pre-operative plasma endostatin value, IMVD was decreased to 20.1 +/- 3.2 counts compared with 41.9 +/- 5.4 counts in those with low pre-operative endostatin value (P = 0.006). Neither plasma endostatin nor VEGF levels correlated with routine clinico-pathological parameters. Endostatin induced endothelial cell apoptosis and modulated the cytoprotective effect of VEGF in HLMVEC survival. CONCLUSIONS Plasma endostatin levels are increased in patients following surgical removal of the primary tumor. The decreased IMVD seen in patients with higher endostatin levels may be due to the apoptosis-inducing effect of endostatin on microvascular endothelial cells.

Estrogen Receptor-β mRNA Is Associated with Adverse Outcome in Patients with Breast Cancer

Background/Aims: Estrogen receptor (ER) is the prototype therapy predictive marker in oncology. The ER is now known to exist in two main forms with similar overall structure: ER-α and ER-β. Both forms may be expressed in breast cancer. The aim of this study was to examine breast cancer outcome in relation to expression of ER-β. Methods: In this investigation, we measured the expression of ER-α protein and ER-β mRNA in 121 extracts of invasive breast cancer. Association of expression with clinical outcome was examined using Kaplan-Meier and Cox regression analyses. Results: While ER-α expression was associated with good patient outcome [hazard ratio (HR) for death from breast cancer 0.37; 95% confidence interval (CI) 0.17–0.84; p = 0.017], ER-β predicted poor outcome (HR for death from breast cancer 2.49; 95% CI 1.10–5.63; p = 0.028). Conclusion: Based on these findings, we conclude that ER-β may have a different biological role from that of ER-α in breast cancer.

Tamoxifen as the primary treatment in elderly patients with breast cancer.

BackgroundWith the increasing incidence of breast cancer in patients over 70 years, there is interest in the best therapeutic approach.AimsTo review the management of breast cancer in elderly women and to identify the factors involved in the decision to treat patients with tamoxifen as first line therapy.Patients and methodsBetween 1986 and 1999, 302 female patients aged ≥ 70 years presented with primary breast cancer, of whom 219 underwent surgery, 79 received tamoxifen as first line treatment and four received primary radiotherapy. A retrospective review was performed on these 79 patients and the outcome recorded.ResultsOf these 79 patients, data was available on 68. Follow-up ranged from one to 63 months (median 17 months). Co-morbidity was the principal reason for choosing first line tamoxifen therapy in 61% and patient preference in 11%. Tumour size was less than 5cm in 51%. In 25% tumour size decreased, in 24% it remained stable and in 27% it increased in size following tamoxifen therapy. Additional treatment was prescribed for 33% of patients.ConclusionIn the authors’ experience, for those elderly patients suffering considerable co-morbidity or who refuse surgical intervention, tamoxifen is an acceptable alternative.

Use of a Panel of Novel Genes for Differentiating Breast Cancer from Non-Breast Tissues

Existing serum markers for breast cancer such as CA 15-3, BR 27.29 and CEA lack sensitivity and specificity. The aim of this study was to evaluate the value of new putative breast-specific markers for differentiating breast cancer from non-breast tissues. Expression of mammaglobin A (MGA), B726P, small breast epithelial mucin (SBEM) and MUC1 was measured by RT-PCR. MGA mRNA was detected in 86/162 (60%) breast cancers but in only 1/32 (3%) non-breast tissues; B726P was detected in 44/108 (41%) breast cancers but in none of 20 non-breast tissues, while SBEM was present in 52/103 (51%) breast cancers but in only 1/26 non-breast cancer tissues. In contrast to these novel markers, the established breast cancer marker MUC1 was detected in 72/99 (73%) breast cancers and in 22/32 (59%) of non-breast tissues. Combining MGA with B726P separated breast cancer from non-breast tissue with a sensitivity of 71% and a specificity of 95% while combining MGA with SBEM differentiated breast cancer from non-breast tissues with a sensitivity of 76% and a specificity of 89%. Genes such as MGA, B726P and SBEM that are expressed relatively exclusively in breast tissue are potential new markers for breast cancer.