Han Suk Ryu

Early Stage Triple-Negative Breast Cancer: Imaging and Clinical-Pathologic Factors Associated with Recurrence

PURPOSE To determine the imaging and clinical-pathologic factors associated with recurrence in patients with early stage triple-negative breast cancer. MATERIALS AND METHODS This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The authors evaluated 398 patients with stage I or II triple-negative breast cancer (median age, 48 years; range, 21-81 years) who were treated between January 2003 and December 2008. Data collected included preoperative breast magnetic resonance (MR) images, mammographic density, patient age, symptoms, family history of breast cancer, histologic tumor characteristics, tumor grade, tumor size, lymphovascular invasion, lymph node involvement, surgery type, margin status, and adjuvant treatment received. Multivariate analysis was performed by using a Cox proportional hazards model, and recurrence-free survival was estimated with the adjusted Kaplan-Meier method. RESULTS Of the 398 patients, 63 (15.8%) had recurrent disease after a median follow-up of 6.1 years. The absence of preoperative MR imaging (hazard ratio [HR] with multivariate analysis = 2.66; 95% confidence interval = 1.49, 4.75; P < .001), dense breast tissue (HR = 2.77; 95% confidence interval = 1.39, 5.51; P = .004), family history of breast cancer (HR = 2.32; 95% confidence interval = 1.10, 4.90; P = .028), and lymphovascular invasion (HR = 1.83; 95% confidence interval = 1.11, 3.03; P = .019) were found to be independently associated with recurrence. These same factors were also found to be associated with recurrence-free survival. CONCLUSION The absence of preoperative MR imaging and the presence of dense breast tissue at mammography were associated with an increased risk of recurrence in patients with triple-negative breast cancer.

Liquid-Based Fine Needle Aspiration Biopsy of Papillary Thyroid Carcinoma: Logistic Regression Analysis with Conventional and New Cytomorphologic Features

Objective: The morphological interpretation of liquid-based preparation (LBP) remains a diagnostic challenge due to altered cytomorphology with technical reason. Only a few published accounts of the cytopathological features needed for diagnosis of papillary thyroid carcinoma (PTC) on an LBP exist. We utilized the SurePath LBP system to evaluate conventional and newly recognized cytomorphologic features on histologically confirmed PTC to identify their potent diagnostic significance compared to benign follicular neoplasm (BFN). Study Design: One-hundred and three cases of PTC and 84 BFNs were collected using preoperative fine needle aspiration biopsies. We evaluated and compared 16 cytomorphologic findings in PTC and BFN using an LBP. Results: Among the conventional criteria, papillary structures, fewer background colloids and macrophages, hobnail patterns (54.4% in PTC vs. 10.7% in BFN; p < 0.001) and swirling architecture (14.6% in PTC vs. 0% in BFN; p < 0.001; positive predictive value 100.0%) were significant diagnostic findings for PTC compared to BFN. The hobnail pattern was shown as a newly recognized strong diagnostic parameter for PTC (odds ratio 50.157, p < 0.001). Conclusion: The identified distinctive cytological criteria may be helpful in cases where conventional criteria for PTC are insufficient. Furthermore, application of these findings, along with classical criteria, may enhance the diagnostic accuracy of PTC by fine needle aspiration biopsy.

A Pilot Study Evaluating Liquid-Based Fine Needle Aspiration Cytology of Breast Lesions: A Cytomorphological Comparison of SurePath® Liquid-Based Preparations and Conventional Smears

Objective: Fine needle aspiration cytology (FNAC) is recommended by the World Health Organization as a diagnostic method for breast lesions. The morphological interpretation of liquid-based preparations (LBPs) remains a diagnostic challenge due to considerably altered cytomorphology. The aim of the current study was to compare cytomorphological characteristics of SurePath® (SP)-based LBP and conventional smear (CS) in breast FNACs. Study Design: The study included 77 benign and 60 malignant breast FNACs obtained by both SP and CS, all with tissue confirmation. Cases analyzed with both preparations were reviewed and compared, focusing on 10 cytomorphological features. Results: SP aspirates demonstrated notable cytomorphological alterations. Among them, a prominent three-dimensional configuration of cell clusters and frequent and conspicuous nucleoli were the most prominent characteristics of SP compared with CS. Overall diagnostic performances were comparable but were slightly lower for SP than CS (diagnostic accuracy of two reviewers; 87.6 and 90.5% for SP vs. 91.2 and 92.7% for CS, respectively). Conclusion: Although the reviewer should be aware of distinctive cytomorphological alterations, the SP technique is reliable for the evaluation of breast lesions with the advantage of easy interpretation and a diagnostic accuracy equivalent to CS.

A histomorphologic predictive model for axillary lymph node metastasis in preoperative breast cancer core needle biopsy according to intrinsic subtypes

The aim of this study is construction of a pathologic nomogram that can predict axillary lymph node metastasis (LNM) for each intrinsic subtype of breast cancer with regard to histologic characteristics in breast core needle biopsy (CNB) for use in routine practice. A total of 534 CNBs with invasive ductal carcinoma classified into 5 intrinsic subtypes were enrolled. Eighteen clinicopathological characteristics and 8 molecular markers used in CNB were evaluated for construction of the best predictive model of LNM. In addition to conventional parameters including tumor multiplicity (P < .001), tumor size (P < .001), high histologic grade (P = .035), and lymphatic invasion (P = .017), micropapillary structure (P < .001), the presence of small cell-like crush artifact (P = .001), and overexpression of HER2 (P = .090) and p53 (P = .087) were proven to be independent predictive factors for LNM. A combination of 8 statistically independent parameters yielded the strongest predictive performance with an area under the curve of 0.760 for LNM. A combination of 6 independent variables, including tumor number, tumor size, histologic grade, lymphatic invasion, micropapillary structure, and small cell-like crush artifact produced the best predictive performance for LNM in luminal A intrinsic subtype (area under the curve, 0.791). Thus, adding these combinations of clinical and morphologic parameters in preoperative CNB is expected to enhance the accuracy of prediction of LNM in breast cancer, which might serve as another valuable tool in determining optimal surgical strategies for breast cancer patients.

Cytomorphological Factors and BRAF Mutation Predicting Risk of Lymph Node Metastasis in Preoperative Liquid-Based Fine Needle Aspirations of Papillary Thyroid Carcinoma

Objective: Preoperative fine needle aspiration biopsy (FNAB) has become the initial diagnostic method for papillary thyroid carcinoma (PTC). Identification of cytomorphologic factors predicting lymph node metastasis (LNM) is clinically important for determining the appropriate treatment regimen due to the high rate of lymph node involvement in PTC at the time of diagnosis. Hobnail features (HF) have previously been described as potential histomorphologic features in the histological examination of PTC. This study evaluated the value of HF as a predictor of LNM. Study Design: Histologically confirmed FNABs (n = 111) of papillary thyroid microcarcinoma prepared by the liquid-based method were enrolled. Along with other cytomorphologic parameters, HF were evaluated for their value in predicting LNM. Results: Although HF were closely correlated with cytoplasmic vacuoles of tumor cells and background macrophages (p < 0.05), which were considered diagnostic indicators of PTC with cystic changes, HF were only found to be significantly correlated with LNM (p = 0.008). The BRAFV660E mutation was not associated with LNM. All combinations including HF were revealed as stronger predictors of LNM (odds ratios: 2.254-2.524, p < 0.05). Conclusions: HF, a distinctive cytomorphologic feature, may be used as a factor predicting LNM in preoperative FNAB of PTC.

SIRT1 induces tumor invasion by targeting epithelial mesenchymal transition-related pathway and is a prognostic marker in triple negative breast cancer

Absence of therapeutic targets poses a critical hurdle in improving prognosis for patients with triple negative breast cancer (TNBC). We evaluated interaction between SIRT1 and epithelial mesenchymal transition (EMT)-associated proteins as well as the role of combined protein expression as a predictor of lymph node metastasis and clinical outcome in TNBC through in vivo and vitro studies. Three hundred nineteen patients diagnosed with TNBC were chosen, immunohistochemical staining for SIRT1 and EMT-related markers’ expression was performed on tissue microarrays, and in vitro experiments with each of the three human TNBC cell lines were carried out. The cohort was reclassified according to the use of adjuvant chemotherapy, tumor size, and AJCC stage to analyze the prognostic role of SIRT1 and EMT-related proteins’ expression considering different therapeutic modalities and AJCC stages. Combination of four proteins including SIRT1 and three EMT-related proteins was revealed to be a statistically significant independent predictor of lymph node metastasis in the tumor size cohort as well as in the total patient population. Upon Cox regression analysis, increased expression level of the combined proteins correlated with decreased disease-free survival in the total patients as well as those who received adjuvant chemotherapy and those who had early stage breast cancer. In additional in vitro experiments, inhibition of SIRT1 expression with small interfering RNA (siRNA) suppressed tumor invasion in three different TNBC cell lines, and altered expression levels of EMT-related proteins following SIRT1 gene inhibition were identified on western blotting and fluorescence activated cell sorting (FACS) analysis; on the other hand, no change in expression levels of the cell cycle-related factors was observed. Our analysis showed the potential role of SIRT1 in association with EMT-related factors on tumor invasion, metastasis, and disease-free survival in TNBC, SIRT1, and associated EMT-related markers may offer a new prognostic indicator as well as a novel therapeutic candidate.

Distinctive role of SIRT1 expression on tumor invasion and metastasis in breast cancer by molecular subtype

The aim of this study was to evaluate silent mating type information regulation 2 homolog 1 (SIRT1) expression levels by subtype and evaluate its predictive power of axillary lymph node metastasis (LNM) and its association with clinical outcome. A total of 427 patients diagnosed with invasive ductal carcinoma were chosen, immunohistochemical staining for SIRT1 expression was performed on tissue microarrays, and in vitro experiments with each intrinsic subtype of human breast cancer cell line were carried out. Increased expression of SIRT1 in hormone receptor-positive breast cancer and HER2 breast cancer subtype significantly correlated with lower risks of LNM. On the contrary, in triple-negative breast cancer, increased SIRT1 expression was more frequently observed in LNM-positive subgroup than LNM-negative subgroup. Combination of statistically significant, independent parameters including SIRT1 revealed predictive performance for LNM with area under the curve of 0.602, 0.587, and 0.726 for hormone receptor-positive breast cancer, HER2 breast cancer, and triple-negative breast cancer subtype, respectively. Inhibition of SIRT1 expression with small interfering RNA suppressed tumor invasion in MDA-MB-231, specifically. This is the first study to examine SIRT1 expression in breast cancer by subtype, and we have observed the potentially different role of SIRT1 gene having tumor-suppressive or tumor-promoting influence depending on the subtype; thus, different associations between SIRT1 expression and prognosis by subtype should be considered in its target therapy.

A novel prognostic factor for hepatocellular carcinoma: protein disulfide isomerase

Background/Aims Protein disulfide isomerase (PDI) has been implicated in the survival and progression of some cancer cells, by compensating for endoplasmic reticulum stress by upregulating the protein-folding capacity. However, its prognostic role in patients with hepatocellular carcinoma (HCC) has not been investigated. Methods We collected HCC tissues from 83 HCC patients who underwent surgical resection for an immunohistochemical study of PDI. Overall survival (OS) was measured from the date of surgical resection until the date of death from any cause. Radiological progression was evaluated using the modified Response Evaluation Criteria in Solid Tumors in an independent radiological assessment. Results PDI expression was found to be increased in human HCC compared to adjacent nontumor tissues. Increased immunopositivity for PDI was associated with a high Edmondson-Steiner grade (p = 0.028). Univariate analysis of patients who had undergone surgical resection for HCC showed that tumor PDI upregulation is a significant risk factor for poor OS (p = 0.016; hazard ratio [HR], 1.980) and time to progression (TTP; p = 0.007; HR, 1.971). Multivariate analyses revealed that high PDI expression was an independent predictor of a shorter TTP (p = 0.015; HR, 1.865) and poor OS (p = 0.012; HR, 2.069). Conclusions Upregulated PDI expression is associated with aggressive clinicopathological features of HCC; thus, PDI might serve as an independent prognostic factor and a potential therapeutic target for HCC patients.

Combined Morphologic and Molecular Classification for Predicting Lymph Node Metastasis in Early-Stage Colorectal Adenocarcinoma

BackgroundIdentifying reliable predictors of lymph node (LN) metastasis is clinically important, particularly for optimizing treatments for early colorectal cancer (ECC) patients. This study evaluated risk-predictive models of LN metastasis using several pathologic and molecular ECC parameters.MethodsTissue specimens from 179 patients with histologically confirmed ECC were enrolled. A total of 20 clinicopathological characteristics, including tumor budding, micropapillary structure, and mucinous differentiation, and 22 protein expressions related to cancer invasion in central and invasive front areas were evaluated for their predictive value for LN metastasis.ResultsAlongside conventional histopathological parameters, tumor budding and mucinous differentiation at the invasive front of ECCs and micropapillary structure were found to be independent predictive factors for LN metastasis. Immunohistochemical expressions of CXCL12 and p38-MAPK at the invasive front were also found to be associated with regional LN metastasis in ECC. Analytic logistic models, using combinations of statistically independent parameters, revealed their abilities to predict LN metastasis in ECC. Further, receiver operating characteristic analysis using combinations of 6 or 7 independent variables represented predictive performances (area under curve of 0.956 or 0.960, respectively) for LN metastasis in ECC.ConclusionsThe combined histomorphologic and molecular factors tested here might be able to predict for LN metastasis in ECC.

Application of chemokine CXC motif ligand 12 as a novel diagnostic marker in preoperative fine-needle aspiration biopsy for papillary thyroid carcinoma.

Objectives: A panel composed of three immunomarkers, cytokeratin 19, HBME-1 and galectin-3, is recommended for improving the accuracy of diagnosing papillary thyroid carcinoma (PTC), but the results are sometimes inconsistent and difficult to interpret. We used immunocytochemistry to assess the utility of chemokine CXC ligand 12 (CXCL12) as a novel diagnostic marker for PTC employing paraffin-embedded cell blocks. Methods: We analyzed the expression of CXCL12 using immunocytochemical staining in 82 cases of thyroid lesions (47 PTCs and 35 thyroid lesions other than PTC). To determine the optimal cut-off value for the assessment of CXCL12 positivity, we used receiver operating characteristics (ROC). Results: ROC curves showed that the optimum diagnostic cut-off was 10% (area under the curve 0.950, 95% confidence interval 0.891-1.008), with exclusive CXCL12 expression in PTC compared to other thyroid lesions (p < 0.001). In total, more than 90% of the PTCs were associated with CXCL12 immunohistochemical staining, while only up to 11.4% of thyroid lesions other than PTC were positive for CXCL12. The follicular variant PTC showed 90% CXCL12 expression compared to 10.5% positivity in follicular neoplasm. Conclusion: Our findings indicate that CXCL12 may be an effective supplementary diagnostic marker for PTC in preoperative fine-needle aspiration cytology using the cell block method.