Jung Han Yoon

FDG PET/CT for the Detection and Evaluation of Breast Diseases: Usefulness and Limitations

Positron emission tomography (PET) with fluorine 18 fluorodeoxyglucose (FDG) is used to diagnose, stage, and monitor breast cancer. FDG PET has the capability to depict abnormal metabolic activity before any anatomic change occurs; however, in the absence of identifiable anatomic structures on PET images, it may be impossible to identify the location of areas of increased radionuclide uptake. In such cases, the coregistration of PET images with images from computed tomography (CT) may help improve diagnostic accuracy and lead to better clinical management of patients with breast cancer. Although FDG PET/CT may have limited diagnostic value for detecting small primary breast tumors, well-differentiated breast cancer, or regional lymph node involvement, it is superior to conventional imaging modalities for detecting distant metastases and recurrences and for monitoring the response to therapy.

High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor‐infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma

CX3CL1 is the only CX3C chemokine that can chemoattract T cells, natural killer (NK) cells, and dendritic cells (DCs). The role of CX3CL1 in breast carcinoma remains unknown.

The Role of Lymphovascular Invasion as a Prognostic Factor in Patients with Lymph Node-Positive Operable Invasive Breast Cancer

Purpose Lymphovascular invasion (LVI) is an important prognostic factor in patients with lymph node-negative patients with invasive breast cancer. However, the prognostic value of LVI it is unclear and controversial about its prognostic value in patients with lymph node-positive breast cancer patients. So, we report the an analysis of the prognostic significance of LVI in a large cohort study of patients with lymph node-positive patients with invasive breast cancer. Methods We retrospectively reviewed 967 patients with invasive breast cancer that had undergone surgical treatment at our hospital, from January 2004 to December 2007. Among these thempatients, 349 patients with lymph node-positive breast cancer patients are were included in this study. We evaluated clinical and pathological data in these patients, we compared with 5-year overall survival and disease-free survival between an LVI-present group and an LVI-absent group. Results The median follow-up was 48 months (range, 12-78 months), and the mean age of the patients was 48 years (range, 23-78 years). LVI was present in 192 patients (55%) of with tumors and was associated with age ≤40 years (p=0.009), high histologichistological grade (p=0.007), estrogen receptor status (p=0.001), tumor size ≥2 cm (p<0.001), and number of involved lymph nodes (p<0.001), but not with progesterone receptor status, HER2 status, p53 status, or tumor multiplicity. LVI was a significant independent prognostic factor for disease-free survival (p<0.001) and overall survival (p=0.006). By multivariate analysis revealed that LVI (p=0.003), number of involved lymph nodes (≥4; p=0.005), and high histological grade (II and III; p=0.02) was were an independent significant predictors of disease-free survival and overall survival in the whole group of patients. Conclusion In this case, we demonstrated that LVI is a significant predictor of poor prognosis in patients with lymph node-positive patients with primary invasive breast cancer, LVI is a significant predictive predictor value of poor prognosis. So, LVI should be considered in the therapeutic strategy as a decision making tool in the adjuvant chemotherapy setting.

Quantitative promoter hypermethylation profiles of ductal carcinoma in situ in North American and Korean women: Potential applications for diagnosis

To investigate the diagnostic potential of DNA methylation-based markers in tissuesamples of DCIS, we examined the prevalence and extent of methylation in breastductal carcinoma in situ (DCIS) samples from North American and Korean women.Quantitative multiplex-methylation specific PCR (QM-MSP) of ten genes wasperformed. The methylation level of APC1, Cyclin D2, HIN-1, RASSF1A, and Twistsingly, and cumulative methylation of all ten genes was significantly higher in DCIScompared to normal tissues for both groups. A three-gene panel (APC1, HIN-1, andRASSF1A), QM-MSP distinguished between DCIS and normal breast tissues with asensitivity of 94 to 96% and a specificity of 81 to 87 %. Methylation levels of thesethree genes in DCIS were higher than those of hyperplasia or adjacent normal appearingtissues in Korean women. Comparing North American and Korean DCIS, statisticallysignificant differences in methylation levels were found for CDH1, ER α and RAR- β.Quantification of gene methylation combined with immunohistochemistry in a smallsubset of tumors suggested that methylation may precede loss of protein expression forER-α. Our study demonstrated that methylation profiles of DCIS between NorthAmerican and Korean women were similar. Methylation status of a panel of genesmeasured in a quantitative manner accurately discriminated between normal and DCIStissues of both groups. For both North American and Korean women, QM-MSPanalysis of a key panel of genes may be useful as an ancillary tool for DCIS detection inbreast tissues.

Basal-like breast cancer displays distinct patterns of promoter methylation

Recent microarray profiling studies on breast cancer have identified distinct subtypes that are associated with different clinical outcomes. Promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of breast cancer. We proposed that immunohistopathologic subtypes of breast cancer are likely to contain distinct promoter methylation patterns. A panel of 10 gene promoters was assessed by quantitative multiplex methylation-specific PCR in 114 invasive ductal carcinomas from Korea representing the three major subtypes [57 luminal, 24 human epidermal growth factor 2 (HER2), and 33 basal-like] based on immunohistochemical findings of estrogen receptor, progesterone receptor, HER2, cytokeratin 5/6, and epidermal growth factor receptor.The median methylation levels of HIN1, RASSF1A, and TWIST, and the average methylation ratio were significantly lower in basal-like subtype compared to luminal or HER2 subtypes. In contrast, BRCA1 methylation level was significantly higher in basal-like subtype than in luminal subtype. The methylation status of a panel of four genes (APC1, CDH, BRCA1 and RAR-b) inluminal and HER2 subtypes were dissimilar, where HER2 tumors showed a significantly higher level of methylation compared to luminal tumors. These results suggest that gene methylation in breast cancer can potentially serve as epigenetic biomarkers and may contribute further to current breast cancer classification.

The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER‐positive breast cancers

Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2‐negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER‐positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1‐deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.

Evaluation of promoter hypermethylation detection in serum as a diagnostic tool for breast carcinoma in Korean women

OBJECTIVE We have noted that quantitative multiplex-methylation specific PCR (QM-MSP) analysis of a key panel of genes may be useful as an ancillary tool for ductal carcinoma in situ (DCIS) detection in breast tissue. In this study, we investigated aberrant promoter hypermethylation of four genes as a means to detect epigenetic alterations specific to breast carcinoma in the serum of patients with DCIS and invasive ductal carcinoma (IDC). METHODS Two hundred forty-three serum samples from 89 patients with IDC, 30 patients with DCIS, and 125 age-matched healthy controls were examined. After DNA extraction and sodium bisulfite treatment, QM-MSP was performed for HIN-1, RASSF1A, RAR-beta, and Twist. RESULTS Overall significant differences in methylation levels were observed for HIN-1 (p=0.006), RAR-beta (p<0.001), RASSF1A (p=0.004), and Twist (p<0.001). All four genes showed significantly higher methylation frequencies in DCIS or IDC than in control subjects (p<0.001 for all comparisons). However, methylation frequencies were not significantly different between DCIS and IDC. In receiver-operating characteristic analysis, the two-gene combination (RAR-beta/RASSF1A) showed the best performance in distinguishing DCIS/IDC from control samples. The estimated specificity of this two-gene panel for detecting DCIS/IDC was 88.8%, and its sensitivity was 94.1%. CONCLUSIONS The quantitative detection of aberrant DNA methylation in serum samples may be a promising high throughput approach for the diagnosis of breast cancer including DCIS.

Papillary thyroglossal duct cyst carcinoma with synchronous occult papillary thyroid microcarcinoma.

This is a case report on papillary thyroglossal duct cyst (TGDC) carcinoma along with synchronous occult papillary thyroid microcarcinoma. A 46-year-old woman visited our hospital because she had an anterior midline neck mass below her hyoid bone. Preoperative ultrasound-guided fine-needle aspiration cytology revealed signs of papillary TGDC carcinoma. We performed a Sistrunk operation and a total thyroidectomy. Histopathological examination of the specimen revealed papillary carcinoma arising in the TGDC and papillary microcarcinoma of the thyroid gland without extrathyroidal extension. Surgeons should be aware of TGDC carcinoma during surgical planning and postoperative treatment and should differentiate this carcinoma from an anterior midline neck mass.

Stromal matrix metalloproteinase-14 expression correlates with the grade and biological behavior of mammary phyllodes tumors.

Phyllodes tumors (PTs) of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. Matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key aspects of tumoral growth, invasion, and metastasis, but little is known of their expression in PTs. The objective of this study was to assess the expression of MMPs and TIMPs in PTs and to determine their association with grade and clinical behavior of PTs. Eighty-two PTs (50 benign, 22 borderline, and 10 malignant) were studied. Automated immunohistochemical staining for MMP-1, -2, -7, -9, -11, -13, and -14 and TIMP-1, -2, and -3 was performed using tissue microarray blocks and the expression of MMPs and TIMPs was assessed in the stromal component. There were no significant differences in the expression of stromal MMPs and TIMPs in the 3 groups of PTs, except for MMP-14. There was a significant increase in stromal MMP-14 expression with increasing PT grade (P<0.01). The stromal MMP-14 expression in the borderline and malignant PTs was higher than that in benign PTs (P<0.05 and P<0.05, respectively). Furthermore, the expression of stromal MMP-14 was associated with a higher rate of recurrence (P<0.05). Our results show for the first time that stromal MMP-14 expression is associated with the grade and clinical behavior of PTs of the breast.

Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer

BackgroundMetalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification.MethodsTissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected.ResultsStatistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival.ConclusionWe found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.