Prospective Evaluation of the Feasibility of Sentinel Lymph Node Biopsy in Breast Cancer Patients with Negative Axillary Conversion after Neoadjuvant Chemotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Tumor response to neoadjuvant chemotherapy (NAC) may adversely affect the identification and accuracy rate of sentinel lymph node biopsy (SLNB). This study was conducted to evaluate the feasibility of SLNB in node-positive breast cancer patients with negative axillary conversion after NAC. MATERIALS AND METHODS: Ninety-six patients with positive nodes at presentation were prospectively enrolled. 18Fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and ultrasonography were performed before and after NAC. A metastatic axillary lymph node was defined as positive if it was positive upon both 18F-FDG PET and ultrasonography, while it was considered negative if it was negative upon both 18F-FDG PET and ultrasonography. RESULTS: After NAC, 55 cases (57.3%) became clinically node-negative, while 41 cases (42.7%) remained node-positive. In the entire cohort, the sentinel lymph node (SLN) identification and false-negative rates were 84.3% (81/96) and 18.4% (9/49), respectively. In the negative axillary conversion group, the results of SLNB showed an 85.7% (48/55) identification rate and 16.7% (4/24) false-negative rate. CONCLUSION: For breast cancer patients with clinically positive nodes at presentation, it is difficult to conclude whether the SLN accurately represents the metastatic status of all axillary lymph nodes, even after clinically negative node conversion following NAC.

Long-Term Survival Analysis of Korean Breast Cancer Patients at a Single Center: Improving Outcome Over Time

PURPOSE: The prognosis of breast cancer has been consistently improving. We analyzed our cohort of breast cancer patients with a long-term follow up at a single center over time. MATERIALS AND METHODS: A total of 1889 patients with known cancer stages were recruited and analyzed between January 1991 and December 2005. Patients were classified according to the time periods (1991-1995; 1996-2000; 2001-2005). To determine intrinsic subtypes, 858 patients whose human epidermal growth receptor-2 status and Ki67 were reported between April 2004 and December 2008 were also analyzed. RESULTS: At a median follow up of 9.1 years, the 10-year overall survival (OS) rate was 80.5% for the entire cohort. On multivariate analysis for OS and recurrence-free survival (RFS), the time period was demonstrated to be a significant factor independent of conventional prognostic markers. In the survival analysis performed for each stage (I to III), OS and RFS significantly improved according to the time periods. Adoption of new agents in adjuvant chemotherapy and endocrine therapy was increased according to the elapsed time. In the patients with known subtypes, OS and RFS significantly differed among the subtypes, and the triple-negative subtype showed the worst outcome in stages II and III. CONCLUSION: In the Korean breast cancer cohort with a long-term follow up, our data show an improved prognosis over the past decades, and harbor the contribution of advances in adjuvant treatment. Moreover, we provided new insight regarding comparison of the prognostic impact between the tumor burden and subtypes.

Does Liver Resection Provide Long-Term Survival Benefits for Breast Cancer Patients with Liver Metastasis? A Single Hospital Experience

PURPOSE: Liver resection with colorectal liver metastasis widely accepted and has been considered safe and effective therapeutic option. However, the role of liver resection in breast cancer with liver metastasis is still controversial. Therefore, we reviewed the outcome of liver resection in breast cancer patients with liver metastases in a single hospital experiences. MATERIALS AND METHODS: Between January 1991 and December 2006, 2176 patients underwent breast cancer surgery in Gangnam Severance Hospital. Among these patients, 110 cases of liver metastases were observed during follow-up and 13 of these patients received liver resection with potential feasibility to achieve an R0 resection. RESULTS: The median time interval between initial breast cancer and detection of liver metastasis was 62.5 months (range, 13-121 months). The 1-year and 3-year overall survival rates of the 13 patients with liver resection were 83.1% and 49.2%, respectively. The 1-year and 3-year overall survival rates of patients without extrahepatic metastasis were 83.3% and 66.7% and those of patients with extrahepatic metastasis were 80.0% and 0.0%, respectively (p=0.001). CONCLUSION: Liver resection for metastatic breast cancer results in improved patient survival, particularly in patients with solitary liver metastasis and good general condition.

Prognostic Factors for Patients with Bone-Only Metastasis in Breast Cancer

PURPOSE: Bone is the most frequent site of metastasis among breast cancer patients. We investigated prognostic factors affecting survival following bone-only metastasis in breast cancer patients. MATERIALS AND METHODS: The medical records of breast cancer patients who were treated and followed at Gangnam Severance Hospital retrospectively reviewed to identify patients with bone-only metastasis. RESULTS: The median time from the diagnosis of bone-only metastasis to the last follow-up or death was 55.2 [95% confidence interval (CI), 38.6-71.9] months. The Kaplan-Meier overall survival estimate at 10 years for all patients was 34.9%. In the multivariate Cox regression model, bisphosphonate treatment [hazard ratio=0.18; 95% CI, 0.07-0.43], estrogen receptor positivity (hazard ratio=0.51; 95% CI, 0.28-0.94), and solitary bone metastasis (hazard ratio=0.32; 95% CI, 0.14-0.72) were significantly associated with longer overall survival in the bone-only recurrence group. Among the treatment modalities, only bisphosphonate treatment was identified as a significant prognostic factor. CONCLUSION: Identifying the factors influencing breast cancer mortality after bone-only metastasis will help clarify the clinical course and improve the treatment outcome for patients with breast cancer and bone-only metastasis. Bisphosphonates, as a significant prognostic factor, warrant further investigation.

Clinical Outcomes of Ductal Carcinoma In Situ of the Breast Treated with Partial Mastectomy without Adjuvant Radiotherapy

PURPOSE: Some recent trials suggest that postoperative adjuvant radiotherapy (RT) may be safely omitted after breast-conserving surgery (BCS) for some patients with ductal carcinoma in situ (DCIS). In this study, we reviewed clinical outcomes of patients with DCIS treated with partial mastectomy (PM) without adjuvant RT. MATERIALS AND METHODS: Medical records of 28 patients (29 breasts) with DCIS who were treated with PM, but without RT, between April 1991 and December 2010 were retrospectively analyzed. Based on established criteria (2.0 cm or less in size and no comedonecrosis), 18 patients were treated without RT after PM. Seven patients (8 breasts) who did not receive RT due to refusal were also included in this study. Three other patients were excluded because data concerning comedonecrosis were not available. RESULTS: For the 25 patients included in this study, the mean age of the 18 patients who met the criteria was 47.9+/-6.2 years, and 47.6+/-12.7 years for the 7 patients who did not. The mean sizes of the primary tumors were 0.6+/-0.4 cm and 0.9+/-0.3 cm, respectively, in these two groups. Among these 25 patients (26 breasts) treated without RT, we observed no ipsilateral breast tumor recurrence or mortality within a mean follow-up of 84 months. CONCLUSION: Based on this small number of cases, patients with DCIS, who were selected for tumor size less than 2 cm and absence of comedonecrosis, may be treated successfully with BCS; adjuvant RT may be omitted.

Preventive Effects of Zoledronic Acid on Bone Metastasis in Mice Injected with Human Breast Cancer Cells

Bisphosphonates are used routinely to reduce bone-related events in breast cancer patients with bone metastasis. We evaluated the effects of zoledronic acid, a third generation, nitrogen-containing bisphosphonate, to prevent bone metastasis in breast cancer. Zoledronic acid or vehicle alone was administered to nude mice either simultaneously or after intracardiac injection of human breast cancer MDA-MB-231 cells. Nude mice treated with zoledronic acid at early time points showed a lower incidence of bone metastases than did vehicle-treated nude mice, but these differences were not statistically significant. Only 37.5% of mice treated with zoledronic acid at the time of tumor cell inoculation developed bone metastases compared to over 51.8% of mice receiving vehicle alone (P = 0.304). Cell count of apoptosis confirmed by immunohistochemical staining in metastatic bone tissue significantly increased in the zoledronic acid-treated groups compared to non-treated group (1,018.3 vs 282.0; P = 0.046). However, metastatic tumor cells, which invade soft tissue around the bone, did not show extensive apoptosis; there were no differences between the zoledronic acid-treated and control groups. These results suggest that zoledronic acid increases apoptosis of metastatic breast tumor cells in the bone and could therefore reduce metastatic tumor burden. These results support the use of zoledronic acid to reduce the incidence of bone metastasis in breast cancer.

The Prevalence of Ovarian Cancer in Korean Women at High-Risk for Hereditary Breast-Ovarian Cancer / 한국유방암학회지

PURPOSE: Few studies have reported ovarian cancer risks in Korean patients with the BRCA1/2 mutation. We investigated the prevalence of ovarian cancer in Korean women at high risk for hereditary breast-ovarian cancer (HBOC) syndrome and reviewed the clinicopathological factors of ovarian cancer. METHODS: Female subjects who were enrolled in the Korean Hereditary Breast Cancer study were included. The questionnaire included a personal and family history of cancer. The BRCA1/2 mutation and CA-125 level were tested at the time of enrollment. A transvaginal ultrasonogram (TVUS) was recommended for subjects with an elevated CA-125 level. RESULTS: A total of 1,689 patients were included. No ovarian cancer was newly diagnosed by CA-125 level or TVUS during the enrollment. The prevalence of ovarian cancer was 1.71% in BRCA1/2 mutation carriers and 0.39% in non-carriers. Among 11 patients with ovarian cancer, five had the BRCA1 mutation and one had the BRCA2 mutation. The most common histopathological type was serous cystadenocarcinoma. No difference in clinicopathological findings between BRCA1/2 mutation carriers and non-carriers was observed. CONCLUSION: The prevalence of ovarian cancer was 58-fold elevated in women at high-risk for HBOC syndrome and 146-fold elevated in the BRCA1 subgroup, compared with the Korean general population. Further investigation with a long-term follow-up is required to evaluate BRCA1/2 gene penetrance.

Correlation of Early Systemic Recurrence with In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay in Stage II and III Breast Cancer Patients Treated with Doxorubicin-Based Chemotherapy / 한국유방암학회지

PURPOSE: An in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) was designed to require only a limited number of cells and shorten test turnaround time with a high success rate. This study investigated the correlation between in vitro doxorubicin sensitivity of tumor cells and early systemic recurrence, defined as recurrence within 2 years after surgery. METHODS: From January 2004 to March 2007, the ATP-CRA for doxorubicin was tested in 128 patients among breast cancer patients treated at Gangnam Severance Hospital, Seoul, Korea. The American Joint Committee on Cancer stages for all patients were II and III. All patients received doxorubicin-based chemotherapy. Selected patients were divided into a chemosensitive group and a non-chemosensitive group, according to a 40% cell death rate as a cut-off value. We analyzed the relationship between chemosensitivity and early systemic recurrence in patients with breast cancer. RESULTS: The mean age of the patients investigated was 44.6-years-old, the mean follow-up period was 39.9 months, and recurrence free survival was 38.6 months. Thirteen recurrences were observed during follow-up. Among 13 patients with a recurrence, eight had a recurrence within 2 years (early recurrence). All of the early recurring patients belonged to the non-sensitive group. Doxorubicin sensitivity results measured by ATP-CRA were related with early recurrence free survival in patients with breast cancer (p=0.030). The mean cell death rate derived from the ATP-CRA for the early recurrence group tended to be lower than that of the non-early recurrence group, but the difference was not statistically significant (p=0.05). CONCLUSION: Doxorubicin sensitivity measured by ATP-CRA was well correlated with in vivo drug responsibility to predict early recurrence against doxorubicin-based adjuvant chemotherapy in patients with breast cancer.

Biopsychosocial Predictors of the Quality of Life in Breast Cancer Patients / 한국유방암학회지

PURPOSE: The purpose of this study was to identify biopsychosocial predictors of the quality of life in breast cancer patients. Disease factors (disease stage, type of surgery, type of treatment, family history), personal factors (age, education level, income), and psychosocial factors (psychological symptoms, optimism, self-esteem, husband's support, cancer coping) were included in biopsychosocial predictors. METHODS: A total of 128 breast cancer patients were recruited. Subjects were assessed by the Optimism Scale, the Selfesteem Scale, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC QLQ-BR23), the Symptom Checklist-90-Revision (SCL-90-R), and the Korean Cancer Coping Questionnaire (KCCQ). RESULTS: Disease factors and personal factors were not different between the high and low quality of life group. But the psychosocial factors were significantly different. Somatization, anxiety, depression, interpersonal sensitivity, hostility, and phobic anxiety showed significantly lower scores in the high quality of life group than the low group. Optimism, self-esteem and husband's support showed significantly higher score in the high quality of life group than the low group. In a stepwise multiple regression analysis, not disease factors and personal factors but the psychosocial factors significantly predicted the quality of life in breast cancer patients. Especially, somatization and depression significantly predicted the quality of life. CONCLUSION: Among psychosocial factors, somatization and depression were the most significant predictors of the quality of life in breast cancer patients. These results supported psychosocial intervention should be needed to breast cancer patients, in order to improve the quality of life.

Erratum: Author's Name Correction / 한국유방암학회지

One of the authors' names was misprinted. The author list should be corrected as follows. Seok Kyoung Choi, Joon Jeong, Seung Ah Lee, Seung Hyun Hwang, Sung Gwe Ahn, Woo Hee Jung1, Hy-De Lee

Heterogeneous Chemosensitivity of Breast Cancer Determined by Adeonsine Triphosphate Based Chemotherapy Response Assay / 한국유방암학회지

PURPOSE: Breast cancer is heterogeneous disease and the response to chemotherapeutic agents is also heterogeneous from patient to patient. Chemotherapy response assay is in vitro test that is performed to evaluate the degree of tumor growth inhibition by chemotherapy drugs. In this study, we performed the chemotherapy response assay using adenosine triphosphate (ATP-CRA) in breast cancer patients and assessed the clinical availability. METHODS: Sixty five breast cancer patients were enrolled in this study. Cancer cells were evenly divided and treated with commonly used chemotherapeutic drugs in breast cancer (doxorubicin, epirubicin, 5-fluorouracil, paclitaxel, docetaxel, vinorelbine, and gemcitabine). To verify in vitro ATP-CRA indirectly, we analyzed the correlation between cell death rate (CDR) of doxorubicin and epirubicin, and between doxorubicin and paclitaxel. We also analyzed the mean CDR of doxorubicin, epirubicin and paclitaxel by HER2 status. RESULTS: We could successfully perform the ATP-CRA in 60 patients (95.2%). In all cases, we can get the results within 7 days. The range of CDR was very wide, from 0 to more than 50%, except gemcitabine. Epirubicin showed the highest mean CDR (39.9%) and doxorubicin, paclitaxel in order. According to the chemosensitivity index, paclitaxel is the most frequently first-ranked and doxorubicin, epirubicin in order. Correlation coefficient between the cell death rate of doxorubicin and epirubicin is 0.4210 and 0.1299 between paclitaxel and doxorubicin. In HER2 positive group, mean CDR of paclitaxel, epirubicin and doxorubicin was higher than in HER2 negative group, even though epirubicin and doxorubicin were not statistically significant (p=0.018, p=0.114, p=0.311, respectively). CONCLUSION: ATP-CRA showed heterogeneous results in individual patients. ATP-CRA was successful and can be performed within short time period. According to our in vitro study, it showed similar results with in vivo study but for the clinical use, the prospective randomized controlled trial should be preceded.

Impact of Grade, Hormone Receptor, and HER-2 Status in Women with Breast Cancer on Response to Specific Chemotherapeutic Agents by in vitro Adenosine Triphosphate-based Chemotherapy Response Assay

This study was designed to assess whether histological and biological factors of breast cancer can predict chemoresponse to specific agents. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA) was employed to retrieve chemoresponse to 5-fluorouracil (5-FU), doxetaxel, doxorubicin, epirubicin, and paclitaxel in 49 patients. Tumors with high histologic and nuclear grade have higher response rate to doxorubicin (P<0.05) and palitaxel (P<0.05). Estrogen receptor (ER)-negative tumors respond well to doxorubicin (P=0.038), and progesterone receptor (PR)-negative tumors to 5-FU (P=0.039), doxetaxel (P=0.038), doxorubicin (P=0.000), epirubicin (P=0.010), and paclitaxel (P=0.003). Among the breast cancer subtypes determined by ER, PR, and HER-2 immunohistochemical stains, the HER-2+/ER- subtype has a higher response rate to doxorubicin (P=0.008). This in vitro result suggests that the combination of histologic and nuclear grade, hormone receptor, and HER-2 status can be a predictive factor of response to specific chemotherapy agents. Further in vivo study should be followed for clinical trials.

Validation of Radiation Volume by Analysis of Recurrence Pattern in Breast-conserving Treatment for Early Breast Cancer / 한국유방암학회지

PURPOSE: To assess the appropriateness of radiotherapy volume for patients receiving breast-conserving treatment (BCT) through analysis of recurrence pattern and factors affecting recurrence. METHODS: From 1991 to 1996, 362 patients who received BCT were retrospectively evaluated. The radiation volume was the involved breast alone in the patients with less than 4 positive axillary lymph nodes (LNs), and breast and supraclavicular fossa in patients with 4 or more positive axillary LNs. The median follow-up period was 123 months (range, 3-169 months). RESULTS: Ten-year overall, disease-free, local recurrence-free, and regional recurrence-free survival rates were 86.2%, 82.2%, 95.9%, and 95.2%, respectively. Among 310 patients receiving radiotherapy on the breast alone, 15 (4.8%) had regional recurrence. In particular, patients with inner quadrant lesions had high regional recurrence rates (11/98, 11.2%) (p<0.001). CONCLUSION: These low local recurrence rates may reveal that the current radiotherapy technique was successful. However, in cases of inner quadrant lesions, there were a considerable number of regional recurrences, even in N0 cases. This may suggest a potential role for irradiation on regional LNs in this group.

Population-based Breast Cancer Statistics in Korea during 1993-2002: Incidence, Mortality, and Survival

In 2002, breast became the most common cancer site in Korean women. Using national breast cancer incidence data during 1993-2002, crude, age-standardized, and age-specific rates for incidence and mortality were calculated. Survival was examined for cases diagnosed during 1993-2002 and followed up to 2004. Observed survival was calculated using the life table method and relative survival using the Ederer II method. Age-standardized incidence rates in female increased from 14.5 in 1993 to 26.2 per 100,000 in 2002. Age-specific incidences showed peaks in women in their forties. Mortality rates increased from 3.7 in 1993 to 4.6 per 100,000 in 2002 and showed peaks in women in their fifties. Five-year relative survival for female breast cancer diagnosed during 1993-2002 was 82.2%. When we examined the secular trends using cases diagnosed 1993-1999 for complete 5-yr follow-up, the 5-yr relative survival increased from 75.2% in 1993 to 83.5% in 1999. The data from this study will provide valuable information to plan and evaluate actions against breast cancer including national breast cancer screening.

Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-beta were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-beta expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.

Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-beta were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-beta expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.

Detection of micrometastasis in fixed paraffin-embedded Sentinel Lymph Nodes of Breast cancer using RT-PCR / 한국유방암학회지

PURPOSE: Sentinel lymph node (SLN) biopsy is considered a highly accurate and very economic method of assessing the axillary nodal status in breast cancer patients. Recently immunohistochemical (IHC) staining and reverse transcriptase polymerase chain reaction (RT-PCR) are commonly used to evaluate micrometastasis in the sentinel lymph node. However, most of the RT-PCR studies have been performed using fresh tissue. This study was conducted to assess micrometastasis in clinically node-negative breast cancer by using RT-PCR technique on the paraffin embedded sentinel lymph nodes. METHODS: Sixty patients who undergone SLN biopsy followed by axillary lymph node dissection due to breast carcinoma were evaluated from February 2000 to January 2001 at the Breast Cancer Center, Department of Surgery, Yongdong Severance Hospital. Serial sections were made from all sentinel lymph nodes for the H&E staining and for the IHC staining with monoclonal anti-cytokeratin antibody. RNA was extracted from the paraffin embedded sentinel lymph nodes and RT-PCR was performed using cytokeratin 19 mRNA, MUC-1 mRNA, and MAGE-A3 mRNA. RESULTS: In 32 out of 60 cases, beta-actin mRNA was detected after RT-PCR, and the 28 cases which had no product after RT-PCR for beta-actin were excluded from this study. Twenty five cases showed as being metastasis positive and 7 cases showed as being metastasis negative by serial section (SS) H&E staining. Three out of 25 negative cases tested for by SS H&E staining were found to be positive by IHC. Ten, six and, eight cases out of the 25 negative cases tested for by SS H&E were found to be positive by RT-PCR for cytokeratin 19, MUC-1, and MAGE-A3, respectively. Among the 22 cases that were found to be negative by both SS H&E staining and IHC staining, 9, 4, and 6 cases were converted to positive by RT-PCR for cytokeratin 19, MUC-1, and MAGE-A3, respectively. Using the combination of two or three markers for performing RT-PCR was more sensitive than any single marker to detect micrometastasis (p < 0.05). CONCLUSION: Even though we failed to extract RNA in 46% of the paraffin embedded tissues, it may be possible to detect micrometastasis by using RT-PCR with the paraffin embedded tissue. RT-PCR is far more sensitive than IHC for detecting microme tastasis, and when we combine multiple markers, the detection rate is higher than for any one marker.

Detection of micrometastasis in fixed paraffin-embedded Sentinel Lymph Nodes of Breast cancer using RT-PCR / 한국유방암학회지

PURPOSE: Sentinel lymph node (SLN) biopsy is considered a highly accurate and very economic method of assessing the axillary nodal status in breast cancer patients. Recently immunohistochemical (IHC) staining and reverse transcriptase polymerase chain reaction (RT-PCR) are commonly used to evaluate micrometastasis in the sentinel lymph node. However, most of the RT-PCR studies have been performed using fresh tissue. This study was conducted to assess micrometastasis in clinically node-negative breast cancer by using RT-PCR technique on the paraffin embedded sentinel lymph nodes. METHODS: Sixty patients who undergone SLN biopsy followed by axillary lymph node dissection due to breast carcinoma were evaluated from February 2000 to January 2001 at the Breast Cancer Center, Department of Surgery, Yongdong Severance Hospital. Serial sections were made from all sentinel lymph nodes for the H&E staining and for the IHC staining with monoclonal anti-cytokeratin antibody. RNA was extracted from the paraffin embedded sentinel lymph nodes and RT-PCR was performed using cytokeratin 19 mRNA, MUC-1 mRNA, and MAGE-A3 mRNA. RESULTS: In 32 out of 60 cases, beta-actin mRNA was detected after RT-PCR, and the 28 cases which had no product after RT-PCR for beta-actin were excluded from this study. Twenty five cases showed as being metastasis positive and 7 cases showed as being metastasis negative by serial section (SS) H&E staining. Three out of 25 negative cases tested for by SS H&E staining were found to be positive by IHC. Ten, six and, eight cases out of the 25 negative cases tested for by SS H&E were found to be positive by RT-PCR for cytokeratin 19, MUC-1, and MAGE-A3, respectively. Among the 22 cases that were found to be negative by both SS H&E staining and IHC staining, 9, 4, and 6 cases were converted to positive by RT-PCR for cytokeratin 19, MUC-1, and MAGE-A3, respectively. Using the combination of two or three markers for performing RT-PCR was more sensitive than any single marker to detect micrometastasis (p < 0.05). CONCLUSION: Even though we failed to extract RNA in 46% of the paraffin embedded tissues, it may be possible to detect micrometastasis by using RT-PCR with the paraffin embedded tissue. RT-PCR is far more sensitive than IHC for detecting microme tastasis, and when we combine multiple markers, the detection rate is higher than for any one marker.

Intraoperative Examination of Sentinel Lymph Nodes Using Rapid Cytokeratin Immunohistochemical Staining in Breast Cancer Patients / 한국유방암학회지

PURPOSE: Sentinel lymph node (SLN) biopsy has become a new standard procedure in the treatment of patients with early breast cancer. Furthermore, many institutions have begun offering the sentinel lymph node biopsy without simultaneous axillary dissection as a possible standard procedure when the SLN was free from tumors. For appropriate intraoperative decision making on the presence of cancer cells in axillary lymph nodes, a fast and accurate method to assess the SLN is required. The authors performed a prospective investigation of the relative merits of rapid cytokeratin immunohistochemical (IHC) staining of the SLN removed during the operations of breast cancer patients. METHODS: Between December 2002 and August 2003, 38 patients with T1and T2 breast cancer were enrolled after undergoing successful sentinel lymph node biopsy. A total of 60 sentinel lymph nodes (mean number, 1.58) were biopsied and first examined by hematoxylin-eosin (H&E) staining. All the tumor free sentinel lymph nodes by H&E stained section were immunostained for cytokeratin using a rapid immunohistochemical assay (Cytokeratin (PAN), 1:50, Newcastle, UK) during the operation. Finally, the sentinel lymph nodes were submitted for paraffin embedding and serial section after surgery. Both H&E stained and cytokeratin immunostained sections were also performed. RESULTS: This technique has a turnaround time of less than 20 minutes during the operation. Rapid IHC staining revealed 4 positive sentinel lymph nodes that were negative for metastasis by H&E staining. Among these false negative 4 cases, two cases had problems with the frozen section of H&E staining and the other 2 cases had problems due to micrometastasis. This study showed a sensitivity of 88.89%, a specificity of 100%, an accuracy of 98.33%, and a negative predictive value of 98.08%. The false-negative case (1 of 52), which was negative on H&E staining and rapid IHC staining during the operation, was disclosed as positive only after a serial permanent section examination with IHC stain. CONCLUSION: The introperative examination of sentinel lymph nodes is a highly accurate and effective way of predicting the axillary lymph node status of patients with breast cancers. This may be a promising technique in deciding whether to spare axillary lymph node dissection for the patient in the operating room.

Predicting the Status of the Nonsentinel Lymph Nodes in early Breast Cancer Patients with Positive Sentinel Lymph Nodes / 한국유방암학회지

PURPOSE: The need for completion axillary lymph node dissection, even in early breast cancer patients with a positive sentinel lymph node, has been questioned. The purpose of this study was to determine the factors that predict the presence of metastasis in non-sentinel lymph nodes (NSLNs) when the sentinel lymph node (SLN) was positive. METHODS: Between December 1998 and June 2004, the records of 104 early breast cancer patients with a positive SLN and who underwent completion axillary lymph node dissection were reviewed. The clinicopathological features in SLN-positive patients were evaluated as possible predictors of metastatic NSLN. RESULTS: Forty four (42.3%) of the 104 patients with positive SLN had metastatic NSLNs. In a univariate analysis, unicentric multifocality (P=0.016), lymphovascular invasion (P=0.006) and SLN metastasis larger than 2 mm (P= 0.003) were associated with positive NSLN findings. The number of SLNs removed was significantly associated as a negative predictor (P=0.043). A multivariate analysis revealed that SLN metastasis >2 mm (P=0.021) and lymphovascular invasion (P=0.040) were independent predictors of metastatic NSLN. CONCLUSION: The likelihood of metastatic NSLNs correlates with the size of the largest SLN metastasis and the presence of lymphovascular invasion of the primary tumor. Even though in early breast cancer with positive SLNs, incorporating these factors may help determining which patients would benefit from additional axillary lymph node dissection.