Vahit Ozmen

Feasibility of Surgical Management in Patients with Granulomatous Mastitis

Abstract:  Granulomatous mastitis (GM) is a rare inflammatory breast disease of unknown etiology. Although it usually presents with sinus formation and abscesses, it may mimic the clinical characteristics of breast cancer. The aim of this study was to identify the clinical, radiologic, and pathologic characteristics of patients with GM and to show the results of surgical treatment in these patients. A chart review was performed for patients that were treated with a diagnosis of GM at the Breast Unit, Department of Surgery, Istanbul Medical Faculty, University of Istanbul, between September 1998 and January 2003. Eighteen patients were eligible for this study. The median age was 41.5 years (range 16–80 years). Seventeen patients were evaluated by both ultrasonography and mammography; whereas one young patient only had ultrasonography. Three patients were further examined with color Doppler ultrasonography and magnetic resonance imaging (MRI). Fourteen patients (78%) presented with a mass as the chief symptom, with a median size of 3.9 cm (range 1–8 cm), whereas four patients presented with fistula in their breasts. None of the radiologic techniques distinguished benign disease from cancer in any of the 14 patients that presented with a mass except one patient with normal mammography findings. Ultrasonography was only helpful to localize the abscess associated with a fistula tract in one patient. Therefore fine‐needle aspiration biopsy (FNAB) was performed in six patients, followed by surgical excisional biopsy. The remaining eight patients with a clinical suspicion of malignancy underwent wide surgical excision with frozen section analysis under general anesthesia. All of the FNAB and frozen section evaluations revealed benign findings. All of the 18 patients underwent a wide excisional biopsy and had a definitive histopathologic diagnosis of GM. The median follow‐up was 36 months (range 6–60 months). Only one patient had a recurrent disease, which was diagnosed at 12 months. GM is a rare breast disease that mimics cancer in terms of clinical findings. Preoperative radiologic diagnosis might be difficult. Complete surgical excision is the treatment of choice. 

Breast Cancer in Limited-Resource Countries: Diagnosis and Pathology

Abstract:  In 2002 the Breast Health Global Initiative (BHGI) convened a panel of breast cancer experts and patient advocates to develop consensus recommendations for diagnosing breast cancer in countries with limited resources. The panel agreed on the need for a pathologic diagnosis, based on microscopic evaluation of tissue specimens, before initiating breast cancer treatment. The panel discussed options for pathologic diagnosis (fine‐needle aspiration biopsy, core needle biopsy, and surgical biopsy) and concluded that the choice among these methods should be based on available tools and expertise. Correlation of pathology, clinical, and imaging findings was emphasized. A 2005 BHGI panel reaffirmed these recommendations and additionally stratified diagnostic and pathology methods into four levels—basic, limited, enhanced, and maximal—from lowest to highest resources. The minimal requirements (basic level) include a history, clinical breast examination, tissue diagnosis, and medical record keeping. Fine‐needle aspiration biopsy was recognized as the least expensive reliable method of tissue sampling, and the need for comparing its clinical usefulness with that of core needle biopsy in the limited‐resource setting was emphasized. Increasing resources (limited level) may enable diagnostic breast imaging (ultrasound ± mammography), use of tests to evaluate for metastases, limited image‐guided sampling, and hormone receptor testing. With more resources (enhanced level), diagnostic mammography, bone scanning, and an onsite cytologist may be possible. Mass screening mammography is introduced at the maximal‐resource level. At all levels, increasing breast cancer awareness, diagnosing breast cancer at an early stage, training individuals to perform and interpret breast biopsies, and collecting statistics about breast cancer, resources, and competing priorities may improve breast cancer outcomes in countries with limited resources. Expertise in pathology was reaffirmed to be a key requirement for ensuring reliable diagnostic findings. Several approaches were again proposed for improving breast pathology, including training pathologists, establishing pathology services in centralized facilities, and organizing international pathology services.

Increased False Negative Rates in Sentinel Lymph Node Biopsies in Patients with Multi-Focal Breast Cancer

There are few data about the reliability of sentinel node biopsy in patients with multi-focal breast cancer. The aim of this study was to determine the factors affecting the identification and accuracy of the sentinel node, comparing multifocality with other variables, using peritumoral isosulfan blue dye injection technique alone. Between 1998 and 2001, 122 patients with clinically negative nodes from a single institute were eligible for sentinel lymph node biopsies (SLNBs). All patients underwent conventional axillary lymph node dissection (ALND). SLNs were identified in 111 of 122 (91%) cases, and analyzed by hematoxylin and eosin. Twenty-one patients with multi-focal breast cancer were determined by clinical or pathologic examination (gross or microscopic). Success in locating the sentinel node was unrelated to patients age, tumor size, type, location, histological or nuclear grade, multifocality, or a previous surgical biopsy. SLNBs accurately predicted the status of the axilla in 104 of the 111 patients (93.7%), while 18 of the 21 patients with multi-focal breast cancer (85.7%) had successful lymphatic mapping. The false negative (FN) rate was 11.3% among patients with successful SLNBs. Multifocality and tumor size (>2 cm) were associated significantly with decreased accuracy and increased FN rates (for multifocality, p = 0.007 and p = 0.006, and for tumor size >2 cm, p = 0.04 and p = 0.05, respectively) in binary logistic regression analysis, whereas excisional biopsy, tumor location in the upper outer quadrant and patients age did not significantly affect the accuracy and FN rates in univariate analysis. These results suggest sentinel lymph node biopsy using peritumoral isosulfan blue injection method alone can accurately predict axillary status in patients with clinically negative nodes, but patients with multi-focal disease and large tumor size may not be ideal candidates.

Breast cancer risk factors in Turkish women – a University Hospital based nested case control study

BackgroundBreast cancer has been increased in developing countries, but there are limited data for breast cancer risk factors in these countries. To clarify the risk for breast cancer among the Turkish women, an university hospital based nested case-control study was conducted.MethodsBetween January 2000 and December 2006, a survey was prospectively conducted among women admitted to clinics of Istanbul Medical Faculty for examination and/or treatment by using a questionnaire. Therefore, characteristics of patients diagnosed with breast cancer (n = 1492) were compared with control cases (n = 2167) admitted to hospital for non-neoplastic, non-hormone related diseases.ResultsBreast cancer risk was found to be increased in women with age (≥ 50) [95% confidence interval (CI) 2.42–3.18], induced abortion (95% CI 1.13–1.53), age at first birth (≥ 35) (95% CI 1.62–5.77), body mass index (BMI ≥ 25) (95% CI 1.27–1.68), and a positive family history (95% CI 1.11–1.92). However, decreased breast cancer risk was associated with the duration of education (≥ 13 years) (95% CI 0.62–0.81), presence of spontaneous abortion (95% CI 0.60–0.85), smoking (95% CI 0.61–0.85), breast feeding (95% CI 0.11–0.27), nulliparity (95% CI 0.92–0.98), hormone replacement therapy (HRT) (95% CI 0.26–0.47), and oral contraceptive use (95% CI 0.50–0.69). On multivariable logistic regression analysis, age (≥ 50) years (OR 2.61, 95% CI 2.20–3.11), induced abortion (OR 1.66, 95% CI 1.38–1.99), and oral contraceptive use (OR 0.60, 95% CI 0.48–0.74) were found to be associated with breast cancer risk as statistically significant independent factors.ConclusionThese findings suggest that age and induced abortion were found to be significantly associated with increased breast cancer risk whereas oral contraceptive use was observed to be associated with decreased breast cancer risk among Turkish women in Istanbul.

Validation of breast cancer nomograms for predicting the non-sentinel lymph node metastases after a positive sentinel lymph node biopsy in a multi-center study

OBJECTIVE In the study, our aim was to evaluate the predictability of four different nomograms on non-sentinel lymph node metastases (NSLNM) in breast cancer (BC) patients with positive sentinel lymph node (SLN) biopsy in a multi-center study. METHODS We identified 607 patients who had a positive SLN biopsy and completion axillary lymph node dissection (CALND) at seven different BC treatment centers in Turkey. The BC nomograms developed by the Memorial Sloan Kettering Cancer Center (MSKCC), Tenon Hospital, Cambridge University, and Stanford University were used to calculate the probability of NSLNM. Area under (AUC) Receiver Operating Characteristics Curve (ROC) was calculated for each nomogram and values greater than 0.70 were accepted as demonstrating good discrimination. RESULTS Two hundred and eighty-seven patients (287) of 607 patients (47.2%) had a positive axillary NSLNM. The AUC values were 0.705, 0.711, 0.730, and 0.582 for the MSKCC, Cambridge, Stanford, and Tenon models, respectively. On the multivariate analysis; overall metastasis size (OMS), lymphovascular invasion (LVI), and proportion of positive SLN to total SLN were found statistically significant. We created a formula to predict the NSLNM in our patient population and the AUC value of this formula was 0.8023. CONCLUSIONS The MSKCC, Cambridge, and Stanford nomograms were good discriminators of NSLNM in SLN positive BC patients in this study. A newly created formula in this study needs to be validated in prospective studies in different patient populations. A nomogram to predict NSLNM in patients with positive SLN biopsy developed at one institution should be used with caution.

Increased Lymph Node Positivity in Multifocal and Multicentric Breast Cancer

BACKGROUND Multifocal and multicentric (MF/MC) breast cancers have been reported to be associated with increased lymph node metastases. The limited data on this issue prompted us to investigate the pathologic and clinical differences between unifocal and MF/MC breast cancer. STUDY DESIGN Between 1990 and 2002, 1,322 patients with operable invasive breast cancer underwent a definitive operation at our Breast Clinic. Patients with MF/MC breast cancer (n=147, 11%) were compared with patients with unifocal breast cancer (n=1,175; 89%) in terms of pathologic and clinical characteristics. RESULTS Patients with MF/MC were found to have a higher frequency of lymph node metastases when the largest diameter was used as a tumor size estimate for MF/MC cancer (unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 48% and 67%, respectively; p=0.05 and p=0.003, respectively). When the combined diameter assessment was used, the frequency of lymph node positivity was similarly higher in MF/MC patients versus unifocal patients (unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 49% and 61%, respectively; p=0.08 and p=0.046, respectively). At a median followup of 55 months (range 12 to 153 months), 5-year disease-free survival (DFS; unifocal, 88% versus MF/MC, 82%, p=0.14) and overall survival (OS) rates (unifocal, 92% versus MF/MC, 93%, p=0.43) did not show any significant difference between two groups. CONCLUSIONS Our data suggest that breast tumors with multiple foci have a different biology, with an increased metastatic potential to axillary lymph nodes, regardless of tumor size, that reflects an advanced stage. The clinical relevance of the currently used TNM classification system, which uses the diameter of the largest nodule, is supported by our findings.

Abstract S2-03: Early follow up of a randomized trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer; Turkish study (protocol MF07-01)

Introduction: Previous reports of carefully selected patients presenting with stage IV breast cancer (BC) suggest that surgery on the primary tumor may result in improved survival, but this remains unproven. The MF07-01 trial is a phase III randomized controlled trial of BC women with distant metastases at presentation who receive loco-regional (LR) treatment for intact primary tumor compared with those who do not receive such treatment. Aim: The primary objective of the trial is to compare overall survival (OS) in women treated with or without initial LR resection prior to systemic therapy for de novo stage IV BC. Materials and Methods: At the discretion of the surgeon, LR treatments consisted of either mastectomy or breast conserving surgery with level I-II axillary clearance in clinically or sentinel lymph node positive patients. Radiation therapy to whole breast was required following breast conserving surgery. At the discretion of the medical oncologist standard systemic therapy of either endocrine treatment or chemotherapy (plus trastuzumab for HER2 +) was given to all patients either immediately after randomization (no surgery group) or after surgical resection of the intact primary tumor (surgery group). After consideration of previous retrospective studies, the assumed OS difference between the two groups was determined to be 18% (35% in LR treatment group versus 17% in no-LR treatment group). A 10% drop out rate including lost to follow up was assumed. By using a one sided log-rank test with a 95% confidence (α = 0.05) and a 90% power (β = 0.9), sample size calculation revealed that 271 patients were needed to be randomized. Results: There were 140 women in the surgery group and 138 in the no-surgery group. The mean follow up time was 21.1 ± 14.5 months. The mean age was 51.6 ± 13.2 years and the groups were comparable regarding age, BMI, ER/PR, Her 2, Triple negative, tumor type and size between the groups (all p>0.05). Metastatic patterns included bone only in 45.7%, organ except bone in 28.8%, and bone plus organ in 25.5%. There were a total of 86 (31%) deaths. At 54 months the survival rate was 35% in the surgery group and 31% in the no surgery group (p = 0.24). However, OS was statistically higher in bone only, ER/PR positive and patients younger than 50 years but was lower in the triple negative patients (p Conclusion: In early follow-up of this trial comparing surgery of the primary tumor with no surgery in stage IV BC at presentation OS was similar but there were important subgroup differences; in particular those with solitary bone metastasis have a significant survival benefit and patients with bone metastasis only have a trend toward improved survival with initial surgery. Further follow-up will expand on these important findings. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-03.

Axillary sentinel node biopsy after neoadjuvant chemotherapy

INTRODUCTION The role of sentinel lymph node biopsy (SLNB) in patients with locally advanced breast cancer (LABC) with potentially sterilized axillary lymph nodes after neoadjuvant chemotherapy (NAC) remains unclear. PATIENTS AND METHODS Between 2002 and 2008, SLNB with both blue-dye and radioisotope injection was performed in 77 patients with LABC whose cytopathologically confirmed positive axillary node(s) became clinically negative after NAC. Factors associated with SLN identification and false-negative rates, presence of non-sentinel lymph node (non-SLN) metastasis were analyzed retrospectively. RESULTS SLNB was successful in 92% of the patients. Axillary status was predicted with 90% accuracy and a false-negative rate of 13.7%. Patients with residual tumor size >2 cm had a decreased SLN identification rate (p=0.002). Axillary nodal status before NAC (N2 versus N1) was associated with higher false-negative rates (p=0.04). Positive non-SLN(s) were more frequent in patients with multifocal/multicentric tumors (versus unifocal; p=0.003) and positive lymphovascular invasion (versus negative; p=0.0001). SLN(s) positive patients with pathologic tumor size >2 cm (versus <or=2 cm; p=0.004), positive extra-sentinel lymph node extension (versus negative; p=0.002) were more likely to have metastatic non-SLN(s). CONCLUSIONS SLNB has a high identification rate and modest false-negative rate in LABC patients who became clinically axillary node negative after NAC. Residual tumor size and nodal status before NAC affect SLNB accuracy. Additional involvement of non-SLN(s) increases with the presence of multifocal/multicentric tumors, lymphovascular invasion, residual tumor size >2 cm, and extra-sentinel node extension.

Risk Factors of Breast Cancer-Related Lymphedema

INTRODUCTION Secondary lymphedema is one of the major important long-term complications of breast cancer treatment. The aim of this study is to determine patient- and treatment-related risk factors of lymphedema in breast cancer patients. PATIENTS AND METHODS Patients, who had been operated on for primary breast cancer at Akdeniz University Hospital and followed regularly between August 1984 and December 2009 were included in the study. In order to evaluate the arm swelling objectively, measurements were performed with a flexible tape measure for both arms, and limb volume was calculated using a truncated cone volume formula. Participants, whose volume difference between the two arms was ≥ 5%, were considered as lymphedema-positive patients. The SPSS program (SPSS inc. Chicago, IL) was used for statistical analysis. RESULTS The mean age of 455 patients was 50.6 years and the median follow-up time was 53 months. Lymphedema was found in 124 (27%) patients. Most of the patients with a history of postoperative wound infection (52%) and lymphangitis (57%) had lymphedema (p=0.003 and p=0.002, respectively). Addition of radiation therapy increased lymphedema risk 1.83 times (p=0.007). The mean duration of the axillary drainage and number of the removed lymph nodes were 7.8 days and 19, respectively. The rate of lymphedema in patients with early stage breast cancer was less than patients with advanced breast cancer (24% and 35.3%, respectively, p=0.018). Most of the patients (92%) with lymphedema had a high body mass index (BMI ≥ 25 kg/m²), and obesity was another important factor for lymphedema (p<0.001). CONCLUSIONS The most important treatment and patient-related risk factors for breast cancer-related lymphedema were obesity (≥ 25 kg/m²), axillary lymph node dissection, postoperative radiotherapy, wound infection, history of lymphangitis, and duration of axillary drainage. Elimination or prevention of these risk factors may reduce the incidence of lymphedema.

Autophagy and Nuclear Changes in FM3A Breast Tumor Cells after Epirubicin, Medroxyprogesterone and Tamoxifen Treatment in vitro

Objective: Autophagy is a form of physiological programmed cell death which is observable after hormonal withdrawal. In this study, the FM3A murine breast tumor cell line was treated with epirubicin alone and with medroxyprogesterone acetate (MPA) or tamoxifen, to determine if structural and kinetic signs of autophagy may also occur in an enhanced manner during epirubicin sensitization via hormonal agents. Methods: One-week soft agar colony growth, 96-hour values of plating and pulse thymidine labeling and electron microscopical examinations were performed following treatment with MPA and tamoxifen alone or with epirubicin. Results: Tamoxifen induced signs of autophagy, which was enhanced when it was combined with MPA. Epirubicin also induced autophagy of secretory granules, which coalesced to form an intracytoplasmic lumen. Combining MPA with epirubicin enhanced the formation of apoptotic blebs and chromatin fragmentation. When epirubicin was combined with tamoxifen, peculiar nuclear structures were formed. Conclusions: Hormonal agents may modulate anthracycline activity towards specific patterns in eliciting cell death, via autophagy and/or as yet unknown nucleolus-specific interactions.