Mahmut Muslumanoglu

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.

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.

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.

Comparison of different injection sites of radionuclide for sentinel lymph node detection in breast cancer: single institution experience.

Background: There are still ongoing controversies about several aspects of lymphatic mapping and sentinel lymph node biopsy for breast cancer, including injection site of radioisotope and blue dye. This study aims to evaluate the success rate of different radiocolloid injection techniques in the detection of sentinel lymph nodes (SLN) in early breast cancer. Study Design: One hundred ninety-two women with early breast cancer were included. For SLN mapping with lymphoscintigraphy (LSG), 5 different injections were used. Group A (36 patients) had 4 peritumoral (PT), group B (n = 36) had 1 subdermal (SD) injection of Tc-99m rhenium sulfide colloid over the tumor quadrant. Group C (59 patients) had 1 PT and 1 SD combined injections. In group D (56 patients), lymphatic mapping was performed with 2 intradermal periareolar (ID-PA) injections. In group E (n = 41), 2 ID-PA and 1 PT combined injections were performed. Early dynamic and delayed images were obtained. A surgical gamma probe was used to explore the SLNs. Surgical specimens were evaluated histopathologically. The SLN identification rate, false negative rate, and comparison of groups were evaluated by statistical methods. Results: The SLN identification rate by LSG in groups A, B, C, D, and E were 72%; 92%, 93.2%, 98%, and 95%, respectively. The highest detection rates for the axilla (98%) and mammary internal (MI) drainage (22%) were obtained with ID-PA injections and a peritumoral injection, respectively. Seventy of 192 patients (36.4%) had positive axillary lymph nodes. The only statistically significant difference was between the PT and SD injection groups in axillary SLN identification rate by LSG (P = 0.016). Conclusion: The success rate was superior with intradermal periareolar injection compared with PT and SD injection to visualize the axillary SLN. However, PT deep injection combined with ID-PA injections may be more favorable to demonstrate the primary internal mammary (IM) lymphatic drainage.

Comparison of subdermal and peritumoral injection techniques of lymphoscintigraphy to determine the sentinel lymph node in breast cancer

Purpose: The purpose of this study was to evaluate 2 different injection techniques for lymphoscintigraphy to determine the axillary sentinel lymph node (SLN) in patients with breast cancer. Methods: Thirty-six patients with early breast cancer were studied prospectively. Both peritumoral (PT) and subdermal (SD) injections were performed on each patient with Tc-99m rhenium sulfide colloid. PT injections were done 1 to 8 days before surgery and SD injections were done on the day of operation. An intraoperative gamma probe was used to explore the axillary SLNs prior to tumor excision and axillary dissection. All surgical specimens were evaluated histopathologically. Results: In 19 of 36 patients, the same lymphatic drainage sites were observed with both techniques. Of these, 17 patients showed only axillary, 1 showed axillary and internal mammary (IM), and 1 showed axillary and subclavicular drainage sites. With PT injections 26 of 36 patients (72%), and with SD injections 33 of 36 patients (92%), showed axillary drainage and axillary SLNs. With PT injections 9 patients, and with SD injections only 2 patients, did not show any drainage site. During the operation with a gamma probe, axillary SLNs were excised in 35 patients (success rate, 97%). IM drainage was seen in 8 of 36 patients who underwent PT injections and in 3 of 36 with SD injections. Conclusion: The success rate was found to be higher with the SD injection technique than with PT injections to visualize the axillary SLN. To increase the visualization of both axillary and IM SLNs, it may be useful to perform lymphoscintigraphy with SD and PT injections together.

Comparison of Intermittent Pneumatic Compression with Manual Lymphatic Drainage for Treatment of Breast Cancer-Related Lymphedema

BACKGROUND The aim of this prospective controlled study was to assess the efficacy of two different combination treatment modalities of lymphedema (LE). Manual lymphatic drainage (MLD) and compression bandage combination (complex decongestive therapy) have been compared with intermittent pneumatic compression (IPC) plus self-lymphatic drainage (SLD). METHODS AND RESULTS Both MLD with compression bandage (complex decongestive therapy) group (Group I, n=15) and IPC with SLD group (Group II, n=15) received treatment for LE 3 days in a week and every other day for 6 weeks. Arm circumferences were measured before and the 1st, 3rd, and 6th weeks of the treatment. EORTC-QLQ and ASES-tests were performed to assess the quality of life before and after 6 week-treatment. Patients in both groups had similar demographic and clinical characteristics. Even though both treatment modalities resulted in significant decrease in the total arm volume (12.2% decrease in Group II and 14.9% decrease in Group I) (p<0.001), no significant difference (p=0.582) was found between those two groups. Similarly, ASES scores were significantly (p=0.001) improved in both Group I and II without any significant difference between the groups. While emotional functioning, fatigue, and pain scores were significantly improved in both groups, global health status, functional and cognitive functioning scores appeared to be improved only in patients of group I. CONCLUSIONS Different treatment modalities consisting of MLD and compression bandage(complex decongestive therapy) or IPC and SLD appear to be effective in the treatment of LE with similar therapeutic efficacy in patients with breast cancer. However, combination modalities including IPC and SLD may be the preferred choices for their applicability at home.

Routine use of positron-emission tomography/ computed tomography for staging of primary colorectal cancer: Does it affect clinical management?

BackgroundThe use of positron emission tomography-computed tomography (PET/CT) for the preoperative staging of patients with colon and rectal cancer has increased steadily over the last decade. The aim of this study was to evaluate the effect of PET/CT on the preoperative staging and clinical management of patients with colorectal cancer.MethodsBetween December 2010 and February 2012, 64 consecutive patients with colorectal cancer were evaluated with both PET/CT scans and conventional preoperative imaging studies. We prospectively recorded the medical reports of these patients. The PET/CT findings were compared with conventional imaging studies and the rate of over-staging or down-staging and changes in clinical management were evaluated. The correlation of the PET/CT with the conventional imaging was compared by a kappa agreement coefficient. Differences in the accuracy for N and T staging were assessed by χ 2 and related-samples marginal homogeneity tests.ResultsThirty-nine (60.9%) patients had rectal cancer and 25 (39.1%) had colon cancer. Based on PET/CT, additional lesions were found in 6 (9.4%) of the patients: hilar and paratracheal lesions in 4 patients, hepatic in 1 and supraclavicular in 1 patient. In four of six patients, detailed imaging studies or biopsies revealed chronic inflammatory changes. Hepatic and supraclavicular involvement was confirmed in two patients. Therefore, the false positivity rate of PET/CT was 6.25%. Based on the additional PET/CT, 2 (3.2%) patients had a change in surgical management. A chemotherapy regimen was administered to the patient with a 1.5 cm hepatic metastasis near the right hepatic vein; for another patient with an identified supraclavicular lymph node metastasis, a simultaneous excision was performed.ConclusionsRoutine use of PET/CT for preoperative staging did not impact disease management for 96.8% of our patients. The results of our study conclude that PET/CT should not be routinely used for primary staging of colorectal cancer. More studies are required for identifying the subgroup of patients who might benefit from a PET/CT in their initial staging.

Genetic alterations of the WWOX gene in breast cancer

FRA3B and FRA16D are the most sensitive common chromosomal fragile site loci in the human genome and two tumor suppressor genes FHIT (Fragile Histidine Triad) and WWOX (WW domain-containing oxidoreductase gene) map to this sites. The WWOX gene is composed of 9 exons and encodes a 46-kD protein that contains 414 amino acids. Loss of heterozygosity, homozygous deletions, and chromosomal translocations affecting WWOX has been reported in several types of cancer, including ovarian, esophageal, lung and stomach carcinoma, and multiple myeloma. The aim of this study was to determine the role of WWOX as a tumor suppressor gene in patients with breast cancer. Tumor and adjacent non-cancerous tissue samples were obtained from 81 patients with breast cancer. DNA was isolated from all tissue samples, and all exons and flanking intronic sequences of the WWOX gene were analyzed by PCR amplification and direct sequencing. We detected 14 different alterations in the coding sequence and one base substitution at the intron 6 splice site (+1 G-A). In addition to exonic and splice-site alterations, we detected 23 different alterations in the non-coding region of the gene. All coding region mutations identified in this study were in the exons between 4 and 9. We did not observe any alterations in exons 1–3. We conclude that mutations in critical region of the WWOX gene are frequent and may have an important role in breast carcinogenesis.

An ultrasensitive tumor enriched flow-cytometric assay for detection of isolated tumor cells in bone marrow of patients with breast cancer

BACKGROUND An ultrasensitive tumor enriched flow-cytometric assay was used to determine its feasibility in detection of isolated tumor cells (ITC) in bone marrow (BM) of patients with breast cancer. METHODS Epithelial cells were removed by magnetic microbeads conjugated with an anti-cytokeratin 7/8 monoclonal antibody to enrich tumor cells in BM samples. A specific gate for MCF-7 breast cancer cells (gate(MCF-7 cells)) was also taken into consideration in addition to a gate including all enriched BM cells (gate(enriched BM cells)) in flow-cytometric analysis to enhance the specificity of the method. RESULTS Nineteen patients with stage I/II were evaluated. Ten patients (53%) were found to have cytokeratin positive (CK(+)) cells according to the gate(enriched BM cells) whereas 6 patients (32%) had CK(+) cells when the gate(MCF-7 cells) was taken into account. CONCLUSIONS New strategies in nonmorphological ultrasensitive techniques might be useful to categorize patients with ITCs having different tumor morphology and characteristics.