The transcription factors of embryonic stem cells, such as Oct4, Sox2, Nanog, Bmi1, and Klf4, are known to be associated with stemness, epithelial–mesenchymal transition and aggressive tumor behavior. This study was designed to evaluate the clinicopathological significance of their expression in breast cancer. Immunohistochemistry for Oct4, Sox2, Nanog, Bmi1, and Klf4 was performed in 319 cases of invasive breast cancer. The relationship between the expression of these markers and clinicopathologic features of the tumors, including breast cancer stem cell phenotype and epithelial–mesenchymal transition marker expression, and their prognostic value in breast cancer, were analyzed. Expression of Oct4 and Sox2 was commonly associated with high histologic grade and high Ki-67 index in the whole group and in the hormone receptor-positive subgroup. On the other hand, expression of Nanog, Bmi1, and Klf4 was inversely correlated with aggressive features of the breast cancer. Oct4 expression was associated with ALDH1 expression but not with epithelial–mesenchymal transition marker expression. In survival analysis, Oct4 expression was independently associated with poor prognosis in the whole group and in the hormone receptor-positive subgroup, but not in hormone receptor-negative subgroup. Particularly, Oct4 expression was associated with poor clinical outcome in patients with hormone receptor-positive breast cancer treated with tamoxifen. Our results indicate that Oct4 expression is associated with aggressive features, ALDH1 expression, tamoxifen resistance and poor clinical outcomes in hormone receptor-positive breast cancer, and thus may be useful as a predictive and prognostic marker in this subgroup of breast cancer.

Background: The immune microenvironment in ductal carcinoma in situ (DCIS) and its significance are not well established. This study was conducted to evaluate the immune microenvironment of DCIS including the composition of tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells and to compare it with that of invasive breast cancer. Materials and methods: A total of 671 cases including three different disease groups of pure DCIS, DCIS with microinvasion (DCIS-M), and invasive carcinoma were included in this study. CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ immune cells were detected with immunohistochemistry using tissue microarrays and were analyzed in relation to clinicopathologic characteristics and different disease groups. Results: In pure DCIS, high infiltrations of CD4+, CD8+, and FOXP3+ T cells and the presence of PD-L1+ immune cells were associated with high nuclear grade, comedo-type necrosis, hormone receptor (HR) negativity, and high Ki-67 proliferation index. All immune cell infiltrations were higher in invasive carcinoma than in pure DCIS regardless of the HR status. While CD4+ T cells were more abundant than CD8+ T cells in pure DCIS, CD8+ T cells were dominant in invasive carcinoma, especially in HR-negative tumors. Within individual cases of invasive carcinoma with DCIS component, all immune cell subset infiltration was higher in the invasive component than in the DCIS component; however, CD4+ TIL infiltration did not differ between the two components in HR-negative tumors. Comparing pure DCIS, DCIS-M, and DCIS associated with invasive carcinoma (DCIS-INV), CD4+ TIL infiltration revealed a gradual increase from pure DCIS to DCIS-M and DCIS-INV in the HR-negative group, whereas FOXP3+ TIL infiltration was significantly increased in DCIS-INV than in pure DCIS in the HR-positive group. The high infiltration of FOXP3+ TIL and the presence of PD-L1+ immune cells were associated with tumor recurrence in patients with pure DCIS. Conclusions: Our study showed that the immune microenvironment differs significantly not only between DCIS and invasive carcinoma but also between pure DCIS, DCIS-M, and DCIS-INV depending on the HR status.

PurposeThe management of benign intraductal papilloma (IDP) without atypia diagnosed on core needle biopsy (CNB) remains controversial. This study was performed to evaluate the rate of upgrading to malignancy or high-risk lesions after excision and to identify factors associated with upgrading using a large series of benign IDP cases without atypia.MethodsWe included patients who were diagnosed as having benign IDP without atypia on CNB and underwent surgical or vacuum-assisted excision between 2010 and 2015. We analyzed the clinical, radiologic, and histopathologic features of IDPs that were upgraded to malignancy or high-risk lesions after excision.ResultsA total of 511 benign IDPs without atypia diagnosed via CNB were identified, of which 398 cases were treated with excision. After reviewing these cases, four cases of high-risk lesions in adjacent tissue on CNB, two cases which were revealed as papilloma with atypia, and nine cases of malignancy in the same breast were excluded. In the remaining 383 cases, the rate of upgrading to malignancy and high-risk lesions after excision was 0.8% and 4.4%, respectively. The presence of concurrent contralateral breast cancer, the presence of symptoms, and multifocality were factors significantly associated with upgrading to malignancy on subsequent excision. Surgical excision rather than vacuum-assisted excision was significantly associated with upgrading to high-risk lesions or malignancy.ConclusionThe rate of upgrading to malignancy for benign IDP without atypia was very low, suggesting that close clinical and radiologic observation may be sufficient for patients with benign IDP without atypia on CNB under proper settings.

PurposeAlthough microinvasive carcinoma is distinct from ductal carcinoma in situ (DCIS), the clinical significance of microinvasion in DCIS remains elusive. The purpose of this study is to evaluate the clinicopathological features and clinical outcomes of microinvasive carcinoma compared with pure DCIS.MethodsWe assessed 613 cases of DCIS and microinvasive carcinoma that were consecutively resected from 2003 to 2014 and analyzed clinicopathological variables, expression of standard biomarkers such as the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), p53, and Ki-67, and tumor recurrence.ResultsAmong the 613 cases, 136 (22.2%) were classified as microinvasive carcinoma. Microinvasive carcinoma was significantly associated with DCIS with a large extent, high nuclear grade, necrosis, and comedotype architectural pattern. ER and PR expressions were dominantly observed in pure DCIS, whereas positive HER2 status, p53 overexpression, and high Ki-67 proliferation indices were more frequently observed in microinvasive carcinoma. Lymph node metastasis was found in only four cases of microinvasive carcinoma with multifocal microinvasion. In the multivariate analysis, DCIS with a large extent, comedo-type architectural pattern, and negative ER status were found to be independent predictors of microinvasion. During follow-up, 12 patients had ipsilateral breast recurrence, and no differences in recurrence rates were observed between patients with DCIS and those with microinvasive carcinoma. The triple-negative subtype was the only factor that was associated with tumor recurrence.ConclusionMicroinvasive carcinomas are distinct from DCIS in terms of clinicopathological features and biomarker expressions but are similar to DCIS in terms of clinical outcomes. Our results suggest that microinvasive carcinoma can be treated and followed up as pure DCIS.

BackgroundThis study was performed to analyze cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and its impact on the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). MethodsFive thousand five hundred and forty-nine cases of thyroid fine-needle aspiration cytology (FNAC) diagnosed between 2012 and 2014 were included in this study. Diagnostic categories based on TBSRTC were compared with final surgical diagnoses, and the ROM in each category was calculated both when NIFTP was included in malignant lesions and when excluded from malignant lesions. ResultsOf the 5,549 thyroid FNAC cases, 1,891 cases underwent surgical resection. In final diagnosis, 1,700 cases were revealed as papillary thyroid carcinoma (PTC), and 25 cases were reclassified as NIFTP. The cytologic diagnoses of NIFTP were non-diagnostic in one, benign in five, atypia of undetermined significance (AUS) in 14, follicular neoplasm in two, and suspicious for malignancy in three cases. Collectively, NIFTP/encapsulated follicular variant of PTC (EFVPTC) were more frequently classified as benign, AUS, or follicular neoplasm and less frequently categorized as malignant compared to conventional PTCs. Exclusion of NIFTP from malignant diagnoses resulted in a slight decrease in malignancy rates in non-diagnostic, benign, AUS, follicular neoplasm, and suspicious for malignancy categories without any statistical significance. ConclusionsThe decrease in the ROM was not significant when NIFTP was excluded from malignant lesions. In thyroid FNACs, NIFTP/EFVPTCs were mostly classified into indeterminate categories. Therefore, it might be feasible to separate NIFTP/EFVPTC from conventional PTC on FNAC to guide clinicians to conservative management for patients with NIFTP/EFVPTC.

PurposeAlteration of biomarker status after primary systemic therapy (PST) is occasionally found in breast cancer. This study was conducted to clarify the clinical implications of change of biomarker status in breast cancer patients treated with PST.Materials and MethodsThe pre-chemotherapeutic biopsy and post-chemotherapeutic resection specimens of 442 breast cancer patients who had residual disease after PST were included in this study. The association between changes of biomarker status after PST and clinicopathologic features of tumors, and survival of the patients, were analyzed.ResultsEstrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status changed after PST in 18 (4.1%), 80 (18.1%), and 15 (3.4%) patients,respectively. ER and PR mainly underwent positive to negative conversion,whereas HER2 status underwent negative to positive conversion. Negative conversion of ER and PR status after PST was associated with reduced disease-free survival. Moreover, a decline in the Allred score for PR in post-PST specimens was significantly associated with poor clinical outcome of the patients. HER2 change did not have prognostic significance. In multivariate analyses, negative PR status after PST was found to be an independent adverse prognostic factor in the whole patient group, in the adjuvant endocrine therapy-treated subgroup, and also in pre-PST PR positive subgroup.ConclusionER and HER2 status changed little after PST, whereas PR status changed significantly. In particular, negative conversion of PR status was revealed as a poor prognostic indicator, suggesting that re-evaluation of basic biomarkers is mandatory in breast cancer after PST for proper management and prognostication of patients.

ObjectiveTo evaluate the impact of the adaptive iterative dose reduction (AIDR) three-dimensional (3D) algorithm in CT on noise reduction and the image quality compared to the filtered back projection (FBP) algorithm and to compare the effectiveness of AIDR 3D on noise reduction according to the body habitus using phantoms with different sizes.Materials and MethodsThree different-sized phantoms with diameters of 24 cm, 30 cm, and 40 cm were built up using the American College of Radiology CT accreditation phantom and layers of pork belly fat. Each phantom was scanned eight times using different mAs. Images were reconstructed using the FBP and three different strengths of the AIDR 3D. The image noise, the contrast-to-noise ratio (CNR) and the signal-to-noise ratio (SNR) of the phantom were assessed. Two radiologists assessed the image quality of the 4 image sets in consensus. The effectiveness of AIDR 3D on noise reduction compared with FBP were also compared according to the phantom sizes.ResultsAdaptive iterative dose reduction 3D significantly reduced the image noise compared with FBP and enhanced the SNR and CNR (p < 0.05) with improved image quality (p < 0.05). When a stronger reconstruction algorithm was used, greater increase of SNR and CNR as well as noise reduction was achieved (p < 0.05). The noise reduction effect of AIDR 3D was significantly greater in the 40-cm phantom than in the 24-cm or 30-cm phantoms (p < 0.05).ConclusionThe AIDR 3D algorithm is effective to reduce the image noise as well as to improve the image-quality parameters compared by FBP algorithm, and its effectiveness may increase as the phantom size increases.

Cancer stem cell (CSC) and ATP-binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre-therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5-fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX-4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y-box 2 (SOX2), leucine-rich repeat-containing G protein-coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX-4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease-free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX-4 therapy.