Management of Clinically and Mammographically Occult Benign Papillary Lesions Diagnosed at Ultrasound-Guided 14-Gauge Breast Core Needle Biopsy.

OBJECTIVES: To determine how to manage clinically and mammographically occult benign papillary lesions diagnosed at ultrasound (US)-guided 14-gauge breast core needle biopsy (CNB) by evaluating their upgrade rates. METHODS: From our pathologic database of US-guided 14-gauge breast CNB, 69 benign papillomas and 9 atypical papillomas with available subsequent excisional findings (surgery or vacuum-assisted removal with additional US follow-up for ≥2 years) or US follow-up alone (≥2 years) were included in this study. We analyzed their upgrade rates by using excisional or US follow-up findings, with no change at 2 years as the reference standard. Patient age, lesion size, lesion distance from the nipple, multiplicity, imaging-histologic concordance, and histologic findings were compared between groups with and without upgrades by statistical analysis. RESULTS: Surgical excision was performed in 53 (67.9%) of 78 benign papillary lesions and revealed 5 upgrades (11.4%) to atypical papillomas in 44 benign papillomas and 2 upgrades (22.2%) to ductal carcinomas in situ in 9 atypical papillomas. Among 12 benign papillomas (15.4%) with vacuum-assisted removal and US follow-up (≥2 years), 1 (8.3%) was upgraded to atypical papilloma. The remaining 13 benign papillomas (16.7%) were followed with US and were stable after a 2-year follow-up period. There were no significant differences in the variables between the groups. CONCLUSIONS: Uniform surgical excision is not a reasonable management strategy for clinically and mammographically occult benign papillary lesions diagnosed at US-guided 14-gauge breast CNB. Clinically and mammographically occult benign papillary lesions may be subsequently managed by vacuum-assisted removal or imaging follow-up if atypia is not found.

Mammography, US, and MRI for Preoperative Prediction of Extensive Intraductal Component of Invasive Breast Cancer: Interobserver Variability and Performances.

BACKGROUND: Interobserver variability and performances of imaging studies for predicting an extensive intraductal component (EIC) of invasive breast cancer have not been well established. MATERIALS AND METHODS: Two independent readers retrospectively reviewed every preoperative mammography, ultrasonography (US), and magnetic resonance imaging (MRI) studies of 145 breast cancers in 144 patients with surgically confirmed EIC status and recorded the EIC presence for each study, using our own descriptors referred to in prior articles. Agreement and performance of each study for the prediction of an EIC were assessed. The reference standard was surgical pathologic findings. RESULTS: Of 145 breast cancers, an EIC was present in 49 cancers (33.8%) in 49 patients. Overall agreement was perfect on mammography (κ = 0.944), and substantial in US (κ = 0.691) or in MRI (κ = 0.627), and moderate to perfect agreement was found on most descriptors (κ = 0.443-0.81), except some US descriptors (κ = 0.23-0.396). The sensitivity of each study showed no significant differences in both readers (0.73-0.82). For the specificity, mammography was better than US in 2 readers (0.69/0.5; P = .001; 0.72/0.6; P = .007, respectively), and MRI better than US in 1 reader (0.79/0.5; P = .039). Performances between the readers showed no significant differences in each study. CONCLUSION: According to our data, mammography, US, and MRI are valid and reproducible methods for the preoperative prediction of an EIC of invasive breast cancer. However, US shows low agreement on some descriptors and lower performance than mammography or MRI.

Cyclooxygenase-2 expression in proliferative Ki-67-positive breast cancers is associated with poor outcomes.

In order to investigate the implications of cyclooxygenase-2 (COX-2) expression in combination with Ki-67 on breast cancer outcomes, the COX-2 and Ki-67 expression levels and other clinicopathologic parameters were investigated in 861 breast cancers. Clinicopathological parameters and survival were investigated in association with the expression levels of both COX-2 and Ki-67 using univariate and multivariate analyses. COX-2 expression was positive in 493 (57.3%) of invasive tumors. COX-2 was associated with favorable markers, but was not related to survival outcome by itself. However, COX-2 in proliferative tumors [COX-2(+)/Ki-67(+)] were significantly associated with unfavorable factors and the worst survival, but COX-2 in non-proliferative tumors [COX-2(+)/Ki-67(-)] showed significantly favorable parameters and better outcomes. COX-2(-)/Ki-67(any) showed intermediate prognosis. The statistical significance was maintained in stage-matched and multivariate analyses. The results of present study suggest that COX-2 expression is a common event in breast cancers and may play in a different ways by the proliferation status of the tumor cells. Further studies should be carried out to verify the role of COX-2 by proliferative conditions of breast tumor cells.

Factors influencing the outcome of breast cancer patients with 10 or more metastasized axillary lymph nodes.

BACKGROUND: The purpose of this study was to investigate prognostic factors in breast cancer patients with metastasis of ten or more lymph nodes (pathologic N3a). METHODS: We conducted a retrospective analysis of the cases of 304 breast cancer patients with pathologic N3a disease who had undergone definitive surgery between 1986 and 2006, and investigated the correlation between clinicopathologic characteristics and treatment outcomes. RESULTS: With a median follow-up period of 55 months, the 5-year disease-free survival rate was 42.9% and the overall survival rate was 57.8%. Univariate analysis showed that the factors associated with poor disease-free survival were: age < 35 years (P = 0.001), history of neoadjuvant chemotherapy (P < 0.001), T4 stage (P < 0.001), 20 or more positive lymph nodes (P < 0.001), presence of lymphovascular invasion (P = 0.003), and negative progesterone receptor expression (P = 0.003). Multivariate analysis showed the factors with independent prognostic significance to be: history of neoadjuvant chemotherapy (hazard ratio [HR] 3.163; 95% confidence interval [CI], 2.025-4.941; P < 0.001), 20 or more positive nodes (HR 1.598; 95% CI, 1.063-2.402; P = 0.024), and presence of lymphovascular invasion (HR 1.636; 95% CI, 1.009-2.654; P = 0.046). Factors associated with poor overall survival in univariate analysis were: age < 35 years (P = 0.033), history of neoadjuvant chemotherapy (P < 0.001), T4 stage (P = 0.001), 20 or more positive lymph nodes (P < 0.001), and negative progesterone receptor expression (P = 0.013). Multivariate analysis showed these factors to be: history of neoadjuvant chemotherapy (HR 2.900; 95% CI, 2.011-4.182; P < 0.001), and 20 or more positive nodes (HR 1.956; 95% CI, 1.419-2.696; P < 0.001). CONCLUSION: Cases of breast tumors with extensive nodal metastasis were found to be heterogeneous in terms of prognosis. History of previous neoadjuvant chemotherapy and higher numbers of metastatic lymph nodes were found to be the two most important prognostic markers for pathologic N3a disease. New strategies such as biologic therapy and novel combinations should be considered for application in patients with poor prognosis, rather than conventional treatment.

The impact of a focally positive resection margin on the local control in patients treated with breast-conserving therapy.

OBJECTIVE: The aim of the study was to investigate the parameters affecting positive margin and the impact of positive margin on outcomes after breast-conserving therapy in patients with breast cancer. METHODS: Characteristics and survival of 705 patients attempted breast-conserving therapy between January 1994 and December 2004 were retrospectively analyzed using χ(2) tests, the Kaplan-Meier methods and multivariate analyses. RESULTS: Ninety-five (13.5%) showed positive margins at initial resection. Among them, 28 (4.0%) had negative margin on the initial frozen section; however, they finally turned out a focally positive margin with intraductal carcinoma on the permanent pathology. Positive margin at initial resection was significantly associated with lobular histology (P = 0.001), four or more involved lymph nodes (P = 0.015) and the presence of extensive intraductal component (P < 0.001). A focally positive margin did not influence local (P = 0.250; 95% confidence interval, 0.612-6.592) or regional failure (P = 0.756; 95% confidence interval, 0.297-5.311). Patients with a focally positive margin showed an advanced nodal stage and received a higher dose of irradiation and more systemic therapy. Nodal involvements were the most significant factor for locoregional failure. CONCLUSIONS: Although the achievement of negative margins is the best way to reduce local failure, patients with a focally positive margin and favorable risk factors such as node negativity and older age could have an option of close follow-up with adequate boost irradiation and adjuvant therapy instead of conversion to total mastectomy.

Clinicopathologic features and outcomes of metaplastic breast carcinoma: comparison with invasive ductal carcinoma of the breast.

PURPOSE: Metaplastic breast carcinoma (MBC) is rare. Its clinicopathologic features and prognosis are uncertain. The aim of this study was to evaluate the clinicopathologic characteristics and outcomes in comparison with invasive ductal carcinoma (IDC). MATERIALS AND METHODS: We reviewed the data of 29 patients with MBC and 4,851 patients with IDC, who received surgery at Yonsei University Severance Hospital between 1980 and 2008. Various clinicopathologic features, recurrence free, and overall survival were investigated and compared to each other. RESULTS: Stage IV cases at diagnosis were more common in MBC (10.3%) than in IDC (0.9%). The incidence rates of triple negative breast cancer (TNBC) were significantly higher in MBC (84.0%) than in IDC (20.1%). Larger tumors (> 2 cm) and lower tendency of axillary metastasis were frequently observed in MBC. Only one of 24 preoperative core needle biopsies (CNB) correctly diagnosed MBC. There was no significant difference in survival between the two groups. CONCLUSION: MBC was characterized by a higher incidence of TNBC, larger tumor size, and lower tendency of axillary metastasis, and was difficult to diagnose with CNB. Although the incidence of stage IV disease at diagnosis was higher in MBC, the survival rates of stage I-III were comparable to those of IDC.

Clinicopathological characteristics of mucinous carcinoma of the breast in Korea: comparison with invasive ductal carcinoma-not otherwise specified.

Clinicopathological characteristics and prognostic factors of mucinous carcinoma (MC) were compared with invasive ductal carcinoma-not otherwise specified (IDC-NOS). Clinicopathological characteristics and survivals of 104 MC patients were retrospectively reviewed and compared with those of 3,936 IDC-NOS. The median age at diagnosis was 45 yr in MC and 47 yr in IDC-NOS, respectively. The sensitivity of mammography and sonography for pure MC were 76.5% and 94.7%, respectively. MC showed favorable characteristics including less involvement of lymph node, lower stage, more expression of estrogen receptors, less HER-2 overexpression and differentiated grade, and better 10-yr disease-free survival (DFS) and overall survival (OS) (86.1% and 86.3%, respectively) than IDC-NOS (74.7% and 74.9%, respectively). Ten-year DFS of pure and mixed type was 90.2% and 68.8%, respectively. Nodal status and stage were statistically significant factors for survival. MC in Koreans showed similar features to Western populations except for a younger age of onset than in IDC-NOS. Since only pure MC showed better prognosis than IDC-NOS, it is important to differentiate mixed MC from pure MC. Middle-aged Korean women presenting breast symptoms should be examined carefully and evaluated with an appropriate diagnostic work-up because some patients present radiologically benign-like lesions.

Clinicopathological characteristics of male breast cancer.

PURPOSE: To investigate clinicopathological characteristics and outcomes of male breast cancer (MBC). PATIENTS AND METHODS: We retrospectively analyzed the data of 20 MBC patients in comparison with female ductal carcinoma treated at Yonsei University Severance Hospital from July 1985 to May 2007. Clinicopathological features, treatment patterns, and survival were investigated. RESULTS: MBC consists of 0.38% of all breast cancers. The median age was 56 years. The median symptom duration was 10 months. The median tumor size was 1.7 cm, 27.8% showed node metastasis, and 71.4% were estrogen receptor positive. All 20 cancers were arisen from ductal cells. No lobular carcinoma was found. The incidence of stages 0, I, II, and III in patients were 2, 10, 4, and 3, respectively. All patients underwent mastectomy. One with invasive cancer did not receive axillary node dissection and stage was not exactly evaluated. Adjuvant treatments were determined by pathologic parameters and stage. Clinicopathological parameters and survival rates of MBC were comparable to those of female ductal carcinoma. CONCLUSION: The onset age of MBC was 10 years older and symptom duration was longer than in female patients. No difference in outcomes between MBC and female ductal carcinoma suggests that the biology of MBC is not different from that of females. Therefore, education, an appropriate system for early detection, and adequate treatment are necessary for improving outcomes.

The changes of estrogen receptor-beta variants expression in breast carcinogenesis: Decrease of estrogen receptor-beta2 expression is the key event in breast cancer development.

BACKGROUND AND OBJECTIVES: Although more than five variant forms of estrogen receptor-beta (ERbeta) have been identified, their role has not been identified. This study was carried out to investigate the changes of ERbeta variants in breast cancer development. METHODS: Using reverse transcription polymerase chain reaction (RT-PCR) and triple primer PCR (TP-PCR), the expression levels of ERbeta variants mRNA were measured in 66 paired normal and cancer tissues. The relative expression level of ERbeta variants were compared between normal and cancer tissues, and also compared according to various clinicopathological parameters. RESULTS: Among ERbeta variants, ERbeta2 and ERbeta5 consist of the major proportion of ERbeta expression both in normal and cancer tissues. The ERbeta and ERbeta2 expression levels decreased significantly in the cancers compared with corresponding normal tissues, particularly in ERalpha-expressing cancers. However, ERbeta5 expression level increased significantly in the cancers, especially in those of postmenopausal patients. The relative increase of ERbeta5 expression in cancer tissues was associated with favorable differentiation. CONCLUSIONS: Decrease of ERbeta2 is thought to be the key reason for the decrease in ERbeta expression in cancer tissues, and it is particularly associated with the development of ERalpha-expressing breast cancer.

Comparison of stage-specific outcome of breast cancer based on 5th and 6th AJCC staging system.

BACKGROUND AND OBJECTIVES: To investigate the appropriateness of the new staging system (AJCC 6th edition) for breast carcinoma. METHODS: We reviewed the clinicopathologic data of 1,768 breast cancer patients, and their disease stages were re-categorized by the new system. The overall survival (OS) and distant relapse free survival (DRFS) rates were compared between those patients whose stages by the old system (AJCC 5th edition) remained the same (the remainders) and those patients whose stages moved up (the upstaged cases) as well as between the subgroups in the new system. RESULTS: The 10-year DRFS rates of the upstaged cases in each stage were poorer than those of the remainders, and statistical significance was demonstrated for stage IIB and stage IIIA. The 10-year OS rates were also poorer in the upstaged cases, and statistical significance was demonstrated for stage IIIA. Subgroup analysis within the new system between the node-negative versus node-positive subgroups in stages IIA and IIB showed a significant OS difference. The DRFS difference was also shown between the subgroups in stage IIA. CONCLUSIONS: The new staging system seems to more accurately reflect disease outcome, however, a re-evaluation might be required to reflect the impact of nodal involvement upon the new staging system.

Overexpression of cyclooxygenase-2 is associated with breast carcinoma and its poor prognostic factors.

Cyclooxygenase is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. The inducible form, cyclooxygenase-2, is known to be overexpressed in various human cancers including the colon, stomach, and urinary bladder. In this study, we evaluated the overexpression of cyclooxygenase-2 in 64 cases of breast cancer and correlated the results with clinicopathologic parameters. Immunohistochemical staining for cyclooxygenase-2 demonstrated positivity of the tumor cells in 46 of 64 cases (72%). Cyclooxygenase-2 overexpression was significantly correlated with larger tumor size and advanced clinical stage. Cyclooxygenase-2 overexpression tended to be more frequently observed in cases with presence of lymph node metastasis and in cases without expression of estrogen and progesterone; however, there was no significant correlation statistically. Nuclear and histologic grade were not well correlated with cyclooxygenase-2 overexpression. When ductal carcinoma in situ was considered separately, 32 of 42 cases (76%) were positive for cyclooxygenase-2. We conclude that cyclooxygenase-2 is up-regulated in a high proportion of breast cancers. The overexpression of cyclooxygenase-2 was associated with larger tumor size and advanced clinical stage, although lymph node status, estrogen and progesterone expression, and nuclear and histologic grade were not significantly correlated. Therefore, cyclooxygenase-2 overexpression may be a feature of the aggressive phenotype and may be useful as a prognostic indicator in breast cancer.

Expression of estrogen receptor-beta in normal mammary and tumor tissues: is it protective in breast carcinogenesis?

Using messenger RNA (mRNA) in situ hybridization, we investigated estrogen receptor-beta (ERbeta) mRNA levels in normal mammary, benign breast tumor (BBT), breast cancer (BC), and metastatic lymph node tissues to verify the role of ERbeta in BC development and progression. ERbeta expression was significantly decreased in BC and metastatic lymph node tissues compared with normal mammary and BBT tissues (p < 0.01). The intensity and extent of ERbeta mRNA signals were also significantly lower in BC and metastatic lymph node tissues than in the normal mammary and BBT tissues (p < 0.01). An inverse relationship was found between ERbeta mRNA level and both histologic grade (p = 0.091) and progesterone receptor expression (p = 0.052) with marginal significance, but no significant association was noted between ERbeta expression in cancer tissues and the other clinico-pathologic data. The 3-year distant relapse-free survival probability was found to be independent of ERbeta expression. Collectively, ERbeta mRNA decreases in the process of BC development, but seems to be associated with poor differentiation.

Anti-HER2/neu peptide producing vector system for biologic therapy - is it possible to mass-produce the peptide?

A humanized monoclonal antibody against HER2 has been using in a clinical setting and has been shown to possess therapeutic properties. A mimetic peptide against HER2 was also reported to bind to the HER2 receptor with some therapeutic potential. Based on a previous report and the sequence of Herceptin, we designed oligonucleotides of anti-HER2 mimetic peptides, named V2 and V3 peptides, in order to develop a peptide- producing vector system for biologic therapy against HER2- overexpressing cancers. We also adopted the sequence of a previously reported mimetic peptide, V1 (Park BW et al. Nat. Biotechnol, 2000, 18:194-198), as a reference peptide. We examined the effects of the V2 and V3 peptides against the HER2-overexpressing cell lines, SK-BR-3 and T6-17. Transient transfection of the construct expressing V1 and V2 inhibited cell proliferation in HER2-overexpressing cell lines by 20 - 30%, but had no effect on the HER2-negative NIH3T3 cells. The proliferation inhibition shown by V2 was slightly better than that shown by V1. Recombinant peptides V2 and V3 were produced on a large scale in an E. coli system, and the V2 peptide showed anti-HER2-specific tumor cell proliferation inhibition of 10% to 30%. Current results suggest that anti-HER2 mimetic peptides, overexpressed by a constitutive promoter or produced in an E. coli system, could specifically inhibit the proliferation of HER2-expressing cancer cells. Further efforts to augment the biologic specificity and efficacy and to develop new technologies for the purification of the peptide from the E coli system are needed.

The role of sonography in patients with breast cancer presenting as an axillary mass.

OBJECTIVE: To compare sonography and mammography in terms of their diagnostic value in breast cancer cases which initially presented as an axillary mass without a palpable mass or other clinical symptoms. MATERIALS AND METHODS: Seven patients with enlarged axillary lymph nodes who first presented with no evidence of palpable breast lesions and who underwent both mammography and sonography were enrolled in this study. In six of the seven, the presence of metastatic adenocarcinoma was confirmed preoperatively by axillary needle aspiration biopsy; in four, subsequent sonographically-guided breast core biopsy performed after careful examination of the primary site indicated that primary breast cancer was present. In each case, the radiologic findings were evaluated by both breast sonography and mammography. RESULTS: Breast lesions were detected mammographically in four of seven cases (57%); in three of the four, the lesion presented as a mass, and in one as microcalcification. In three of these four detected cases, fatty or scattered fibroglandular breast parenchyma was present; in one, the parenchyma was dense. In the three cases in which lesions were not detected, mammography revealed the presence of heterogeneously dense parenchyma. Breast sonography showed that lesions were present in six of seven cases (86%); in the remaining patient, malignant microcalcification was detected at mammography. Final pathologic examination indicated that all breast lesions except one, which was a ductal carcinoma in situ, with microinvasion, were infiltrating ductal carcinomas whose size ranged from microscopic to greater than 3 cm. At the time of this study, all seven patients were alive and well, having been disease free for up to 61 months after surgery. CONCLUSION: In women with a palpable axillary mass confirmed as metastatic adenocarcinoma, breast sonography may be a valuable adjunct to mammography.

Impact of patient age on the outcome of primary breast carcinoma.

BACKGROUND AND OBJECTIVES: The poorer outcome amongst younger breast cancer patients continues to be an issue of debate. In order to clarify the prognostic value of patient age, we retrospectively analyzed the data of 1098 breast cancer patients. METHODS: Patients were divided into two groups based on the age 35 (Group I, women aged 35 or younger, and Group II, women aged over 35). Clinico-pathological parameters, 10-year loco-regional recurrence-free (10LRRFS), distant relapse-free (10DRFS), and overall (10OS) survival estimates were determined. RESULTS: Among the 1098 patients, approximately 16.7% (183) were allocated to Group I and the other 83.3% (915) to Group II. There were no significant differences between the two groups in terms of histopathologic features or mean follow-up. Group I had a poorer 10LRRFS of 86.8% (P = 0.036), 10DRFS of 57.7% (P < 0.0001), and 10OS of 68.3% (P = 0.0001), compared with 93.9, 76.2, and 81.4% for Group II, respectively. Group I also showed a poorer 10DRFS when matched for stage and lymph node status as well. With lymph node status and tumor size, a patient age of younger than 35 was determined to be an independent prognostic factor by multivariate analysis. CONCLUSIONS: These results indicate that patient age (younger than 35) shows an independent prognostic value and that survival differences by age may reflect differences in the tumor biology.