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Purpose The programmed death ligand 1 (PD-L1) SP142 assay with a 1% immune cell (IC) cutoff is approved for the selection of advanced triple-negative breast cancer (TNBC) patients for atezolizumab treatment. We aimed to evaluate the interobserver concordance of PD-L1 scoring and inter-assay variability of various PD-L1 assays in TNBC. Methods Thirty patients with primary TNBC were selected, and SP142, SP263, 22C3, and E1L3N assays were performed. PD-L1 staining in ICs and tumor cells (TCs) was scored by 10 pathologists who were blinded to the assay. The interobserver concordance among pathologists and the inter-assay variability of the four PD-L1 assays were analyzed. For SP142, the intraobserver concordance among the six pathologists was analyzed after training. Results The adjusted means of PD-L1 IC scoring ranged from 6.2% to 12.9% for the four assays; the intraclass correlations showed moderate (0.584-0.649) reader concordance. The PD-L1 IC scoring with a 1% cutoff resulted in identical scoring in 40.0%-66.7% of cases and a poor to moderate agreement (Fleiss κ statistic [FKS] = 0.345-0.534) for the four assays. The SP142 assay had the widest range of positive rate (56.5%-100.0%), lowest number of cases with identical scoring, and lowest FKS at 1% cutoff. Pairwise comparison of adjusted means showed significantly decreased PD-L1 staining in SP142 compared with the other assays in both ICs and TCs. As for the intraobserver concordance in the SP142 assay, the overall percent agreement was 87.8% with a 1% IC cutoff. After training, the proportion of cases with identical scoring at a 1% IC cutoff increased to 70.0%; the FKS also increased to 0.610. Conclusion The concordance of PD-L1 IC scoring among pathologists was low, at the 1% cutoff for the SP142 assay without training. SP142 showed the lowest PD-L1 expression in both IC and TC.

Background Despite surgical resection, early lung adenocarcinoma has a recurrence rate of 20–50%. No clear predictive markers for recurrence of early lung adenocarcinoma are available. Targeted next-generation sequencing (NGS) is rarely used to identify recurrence-related genes. We aimed to identify genetic alterations that can predict recurrence, by comparing the molecular profiles of patient groups with and without recurrence. Methods Tissues from 230 patients with resected stage I–II lung adenocarcinoma (median follow-up: 49 months) were analyzed via targeted NGS for 207 cancer-related genes. The recurrence-free survival according to the number and type of mutation was estimated using the Kaplan–Meier method. Independent predictive biomarkers related to recurrence were identified using the Cox proportional hazards model. Results Recurrence was observed in 64 patients (27.8%). In multivariate analysis adjusted for age, sex, smoking history, stage, surgical mode, and visceral pleural invasion, the CTNNB1 mutation and fusion genes (ALK, ROS1, RET) were negative prognostic factors for recurrence in early-stage lung adenocarcinoma (HR 4.47, p = 0.001; HR 2.73, p = 0.009). EGFR mutation was a favorable factor (HR 0.51, p = 0.016), but the CTNNB1/EGFR co-mutations were negative predictors (HR 19.2, p p = 0.02). Conclusions: Targeted NGS can provide valuable information to predict recurrence and identify patients at high recurrence risk, facilitating selection of the treatment strategy among close monitoring and adjuvant-targeted therapy. Larger datasets are required to validate these findings.

Venous ulcers, ischemic wounds and skin lesions from autoimmune diseases are some examples of unhealing wounds. Practitioners treating such wounds should consider the possibility of skin metastasis of neoplasms, especially in patients with cancer. Treatment of cutaneous metastasis in cancer must include both surgical resection and chemotherapy. Here we present a patient who had lung cancer with skin metastasis. Though incidence of metastasis from lung cancer is known to be as low as 1% to 12%, its prognosis is poor. Also, the clinical features of these skin lesions tend to vary, often resulting in them being misdiagnosed as benign lesions. The diagnosis of malignancy for this particular case was delayed. After the metastatic lesion was diagnosed as such, surgical resection was performed and the defect caused by wide excision was covered by a superior gluteal artery perforator flap. Though the patient was administered an anticancer drug, the wound healed well after the operation.

Purpose Triple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressive and metastatic behavior and the lack of available targeted therapies. Therefore, therapeutic strategies are needed to improve TNBC patient management. Recently, atezolizumab and nab-paclitaxel chemotherapy has been approved by the Food and Drug Administration for the first-line treatment of patients with locally advanced and metastatic TNBC. The programmed death-ligand 1 (PD-L1) immunohistochemical SP142 assay was also approved as a companion diagnostic device for selecting TNBC patients for atezolizumab treatment. This study aimed to evaluate and compare the analytical performance of the PD-L1 22C3/SP263 assays in comparison with the SP142 assay for ≥ 1% immune cells (ICs). Methods Immunohistochemical expression for the PD-L1 22C3/SP263 assays, in comparison with the SP142 assay, was analyzed for the ≥ 1% ICs in 95 TNBCs. Results At the 1% cut-off value, the proportions of positive cases were 52.6% for the SP142 assay in infiltrating ICs and 50.5% and 52.6% for the 22C3 and SP263 assays in tumor cells, respectively. The PD-L1 SP263 assay had the highest while the PD-L1 22C3 assay had the lowest total positive expression rate at all cut-off values. The concordance rate between the assays was highest at a 1% cut-off value and decreased when the cut-off value increased. The concordance rate between the SP142 and SP263 assays at 1% cut-off was high, while in comparison, the concordance rate between the SP142 and 22C3 assays at 1% cut-off was relatively lower. Conclusion This study demonstrates that although the 22C3 assay at a 1% cut-off value compared with the PD-L1 SP142 assay at the clinically relevant cut-off shows comparable but not interchangeable analytical performance, the analytical performance of the SP263 assay at a 1% cut-off value shows interchangeable performance with the PD-L1 SP142 assay at the clinically relevant cut-off.

With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.

Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I–IIIA EGFR-mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic alterations using the Kaplan–Meier method and Cox proportional regression analysis. The relapse rate was 25.2% (33/131). Five-year RFS of stages IA, IB, II, and IIIA were 82%, 75%, 35%, and 0%, respectively (p &lt, 0.001). RFS decreased with the number of co-mutations (p = 0.025). Among co-mutations, the CTNNB1 mutation was associated with short RFS in a multivariate analysis (hazard ratio: 5.4, 95% confidence interval: 2.1–14.4, p = 0.001). TP53 mutations were associated with short RFS in stage IB–IIIA (p = 0.01). RFS was shorter with EGFR exon 19 deletion (19-del) than with mutation 21-L858R in stage IB–IIIA tumors (p = 0.008). Among 19-del subtypes, pL747_P753delinS (6/56, 8.9%) had shorter RFS than pE746_A750del (39/56, 69.6%), the most frequent subtype (p = 0.004).

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey&rsquo, s blood parameters were analyzed on days &minus, 7, &minus, 3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.

Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer.The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases). MEL-18 amplification was validated by fluorescence in situ hybridization (FISH) analysis. The MEL-18 effect on trastuzumab response was confirmed by in vitro cell viability assays and an in vivo xenograft experiment (n = 7 per group). Gene expression microarray and receptor tyrosine kinase array were performed to identify the trastuzumab resistance mechanism by MEL-18 loss. All statistical tests were two-sided.MEL-18 was exclusively amplified in approximately 30-50% of HER2+ breast tumors and was associated with a favorable clinical outcome (disease-free survival: P = .02 in HER2+ cases, METABRIC; P = .04 in patients receiving trastuzumab). In MEL-18-amplified HER2+ breast cancer, MEL-18 depletion induced trastuzumab resistance by increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization. MEL-18 epigenetically silenced ADAM10/17 expression in cooperation with polycomb-repressive complex (PRC) 1 and PRC2. Combination treatment with an ADAM10/17 inhibitor and trastuzumab could overcome MEL-18 loss-mediated trastuzumab resistance in vivo (BT474/shMEL-18 xenograft: trastuzumab, mean [SD] tumor volume = 406.1 [50.1] mm3, vs trastuzumab + GW280264 30 mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm3, P.001). Consistently, trastuzumab-treated patients harboring concomitant MEL-18 amplification and low ADAM17 expression showed prolonged relapse-free survival (P = .02 in our cohort, n = 213).MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer.

Background Although lung adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutations is common in never smokers, one-third of the patients are ever-smokers. We aimed to investigate the effect of cumulative smoking dose(CSD) on clinical outcomes, including progression-free survival (PFS) and overall survival (OS), in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-tyrosine kinase inhibitors (TKIs). Methods We retrospectively analyzed 142 patients with EGFR-mutation positive advanced or recurrent lung adenocarcinoma who were administered gefitinib, erlotinib, afatinib, and osimertinib. These patients were classified based on their CSD as never smokers, light smokers (≤10 pack-years [PYs]), moderate smokers (11–30 PYs), and heavy smokers (> 30 PYs). PFS and OS were analyzed according to smoking subgroups via Kaplan-Meier curves. Results Among the 142 patients, 91 (64.1%), 12 (8.5%), 22 (15.5%), and 17 (12%) were never, light, moderate, and heavy smokers, respectively. CSD was inversely associated with median PFS in a statistically significant dose-dependent manner (11.8 months (mo), 11.0 mo, 7.4 mo, and 3.9 mo; p

Background EGFR mutation testing is an essential step for the therapeutic decision in newly diagnosed advanced NSCLC patients and usually performed by using DNA extracted from biopsied tumor tissue with a turnaround time(TAT) of 2-3 weeks. Plasma liquid biopsy using ctDNA is minimally invasive and less time-consuming, but shows limited usefulness due to low sensitivity. We conducted a prospective study to demonstrate clinical usefulness of bronchoalveolar lavage fluid (BALF) liquid biopsy using extracellular vesicle(EV)-derived DNA in advanced NSCLC patients by comparing the sensitivity and TAT with conventional tissue biopsy and plasma liquid biopsy Methods The analysis set for liquid EGFR genotyping is 224 BALF samples and 110 plasma samples obtained from newly diagnosed 224 advanced non-squamous NSCLC patients. EGFR genotyping was done through peptide nucleic acid(PNA)-mediated real-time PCR after extracting BALF EV DNA and plasma cfDNA separately. The sensitivity, specificity, and concordance rate of BALF liquid biopsy were calculated in comparison to matched tissue genotyping and plasma liquid biopsy. In addition, TAT was compared between BALF liquid biopsy and tissue genotyping. Results Tissue genotyping revealed 93 EGFR mutant cases (41.5%) and 131 wild-type cases (58.5%). The sensitivity, specificity, positive predictive value, negative predictive value, and concordance rate of BALF liquid biopsy to tissue genotyping were 97.8%, 96.9%, 96.8%, 98.4%, and 97.7%, respectively. BALF liquid biopsy showed almost identical performance with standard tissue genotyping, while only 5 cases were mismatched each other. On the other hand, plasma liquid biopsy using cfDNA (n=110) revealed 48.5% sensitivity, 86.3% specificity, and 63.6% concordance rate in comparison to tissue genotyping. The mean turnaround times of BALF liquid biopsy was significantly shortened to 2.6±2.0 days in contrast to 13.9±12.4 days of tissue genotyping. (p Conclusion BALF liquid biopsy can be developed as a novel platform for EGFR mutation testing in advanced NSCLC with almost identical performance with conventional tissue genotyping and significantly shorten TAT to 1-2 days. Citation Format: In Ae Kim, Jae Young Hur, Hee Joung Kim, Wan Seop Kim, Kye Young Lee. BALF liquid biopsy provides a novel platform for speedy and accurate EGFR mutation testing in advanced NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1196.

Background: The BRAFV600E mutation in papillary thyroid carcinoma (PTC) is particularly prevalent in Korea, and a considerable number of wild-type BRAF PTCs harbor RAS mutations. In addition, subsets of other genetic alterations clearly exist, but their prevalence in the Korean population has not been well studied. Recent increased insight into noninvasive encapsulated follicular variant PTC has prompted endocrine pathologists to reclassify this entity as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP). This study analyzed the genetic alterations among the histologic variants of PTC, including NIFTP. Methods: Mutations of the BRAF and RAS genes and rearrangement of the RET/PTC1, NTRK1, and ALK genes using 769 preoperative fine-needle aspiration specimens and resected PTCs were analyzed. Results: Molecular alterations were found in 687 (89.3%) of 769 PTCs. BRAFV600E mutation (80.8%) was the most frequent alteration, followed by RAS mutation and RET/PTC1, NTRK1, and AL...

The spectrum of vascular tumors ranges from hemangioma (HEM), to epithelioid hemangioendothelioma (EHE) and to angiosarcoma (AS). To the best of our knowledge, the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for vascular tumors has never been comprehensively studied. The present study investigated the usefulness of FDG-PET for pathologically diagnosed vascular tumors. The present study included 26 patients with vascular tumor (male:female, 17:9; age, 60.9±14.4 years; 7 HEM, 6 EHE and 13 AS) who underwent FDG-PET between January 2007 and May 2014 at the Seoul National University Bundang Hospital (Seongnam, Korea) and Konkuk University Medical Center, (Seoul, Korea). Representative FDG uptake was measured as the maximum standardized uptake value (SUVmax) over the lesion with the highest FDG uptake. Disease progression was clinically defined as the aggravation of known lesions or novel lesion development during follow-up on computed tomography, magnetic resonance imaging, or FDG-PET. FDG-PET revealed multi-organ involvement only in AS (6/13 [46.2%]), whereas HEM and EHE involved a single organ. Tumor SUVmax was significantly greater in AS (6.32±4.84) compared with EHE (3.10±2.68) and HEM (2.33±0.76) (P=0.0284). There was no difference in tumor SUVmax between HEM and EHE (P>0.05). Disease progression was primarily noticed in AS (9/13 [69.2%]). Only 1 patient with EHE (1/6=16.7%) and no patients with HEM (0/7=0%) experienced disease progression. Mortality was reported only in patients with AS (4/13 [30.8%]). Using the cutoff SUVmax of 3.0, the two-year progression-free survival rate of 14 patients with tumor SUVmax

Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories-mutations, gene rearrangements, and amplifications-and propose expanded guidelines on molecular testing of lung cancers.

ObjectiveThe current paradigm in the treatment of patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a diagnostic lobectomy rather than complete thyroidectomy and postoperative radioiodine treatment. Consequently, preoperative diagnosis of NIFTP is considered to be important.MethodsWe performed the comprehensive analysis for diagnosis of preoperative 20 NIFTPs in comparison with 41 invasive encapsulated follicular papillary thyroid carcinomas (I-EFVPTCs) using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and molecular analysis for BRAF and RAS mutations.ResultsK-TIRADS 3 was identified as the most common sonographic diagnosis in both NIFTP and I-EFVPTC. Unlike I-EFVPTC, K-TIRADS 5 was not identified in NIFTP. AUS/FLUS was the most common cytopathological diagnosis and none of the cases were classified as malignant category in both groups, although the difference in distribution was not significant between the groups. BRAF mutation was not found in NIFTP but was present in 9.8% of cases in I-EFVPTC. The frequency of RAS mutation in I-EFVPTCs was twice as high as that of NIFTP. Wild-type BRAF and RAS in NIFTP was significantly higher than I-EFVPTC.ConclusionThe existence of overlapping features between the groups was evident, hence conclusive distinction between radiology, cytology and molecular analysis could not be achieved. Apparently, the diagnosis of NIFTP based on comprehensive analysis was not confirmable but could perceive or at least favor the diagnosis of NIFTP.

// Seung Eun Lee 1 , Seong-Hwan Chang 2 , Wook Youn Kim 1 , So Dug Lim 1 , Wan Seop Kim 1 , Tea Sook Hwang 1 and Hye Seung Han 1 1 Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea 2 Department of Surgery, Konkuk University School of Medicine, Seoul, Korea Correspondence to: Hye Seung Han, email: // Keywords : TERT, CTNNB1, hepatocellular carcinoma, intratumoral genetic heterogeneity, Pathology Section Received : May 05, 2016 Accepted : September 12, 2016 Published : September 19, 2016 Abstract Genetic alterations of TERT and CTNNB1 have been documented in hepatocellular carcinoma. TERT promoter mutations are the earliest genetic events in the multistep process of hepatocarcinogenesis related to cirrhosis. However, analyses of TERT promoter and CTNNB1 mutations in hepatocellular carcinoma tumor samples have not been performed in the Korean population, where hepatitis B virus-related hepatocellular carcinoma is prevalent. In order to identify the role of TERT promoter and CTNNB1 mutations in the hepatocarcinogenesis and pathogenesis of recurrent hepatocellular carcinoma, we performed the sequence analyses in 140 hepatocellular nodules (including 107 hepatocellular carcinomas), and 8 pairs of matched primary and relapsed hepatocellular carcinomas. TERT promoter and CTNNB1 mutations were only observed in hepatocellular carcinomas but not in precursor lesions. Of 109 patients with hepatocellular carcinoma, 41 (39.0%) and 15 (14.6%) harbored TERT and CTNNB1 mutations, respectively. TERT promotermutations were significantly more frequent in hepatocellular carcinomas related to hepatitis C virus infection (5/6; 83.3%) compared to tumors of other etiologies ( P = 0.001). In two cases, discordance in TERT promoter mutation status was observed between the primary and the corresponding recurrent hepatocellular carcinoma. The two patients with discordant cases had early relapses. In conclusion, we identified TERT promoter and CTNNB1 mutations as the most frequent somatic genetic alterations observed in hepatocellular carcinoma, indicating its pivotal role in hepatocarcinogenesis. Furthermore, we suggest the possibility of intratumoral genetic heterogeneity of TERT promoter mutations in hepatocellular carcinoma as indicated by the discordance in TERT promoter mutations between primary and corresponding recurrent hepatocellular carcinoma.

Thrombosis at the left ventricular outflow tract occurs without any detectable heart disease or predisposing factors only extremely rarely. A 48-year-old male visited Konkuk University Medical Center with loss of consciousness one month prior to presentation. Before he visited our hospital, he had been diagnosed with a cardiac tumor, which was located between the left atrium and posterior aortic root, and which was adjacent to both the aortic and mitral valves. Cardiac transplantation was recommended at the other hospital because of the high risk of cardiac dysfunction induced by both aortic and mitral valvular dysfunction after surgical resection. Based on preoperative transthoracic echocardiography, cardiac computed tomography, cardiac magnetic resonance imaging, and intra-operative transesophageal echocardiography, we considered it to be a benign tumor. Complete resection was achieved and the pathology confirmed organizing thrombus. We report a case of organizing thrombus mimicking a cardiac tumor, which was located at the mitral-aortic intervalvular fibrosa of the left ventricular outflow tract without any heart disease.

Advisory services are widely used in the field of medicine in many countries. Doctors commonly use consultations, especially in surgical pathology practice. In the United States, the Association of Directors of Anatomic and Surgical Pathology has defined various kinds of pathology consultations and devised regulations to control the quality of each type [1-3]. In Korea, pathologic consultations by doctors have also been performed in daily practice. However, most of these consultations have been conducted informally, without regulations or proper fees. Therefore, Korean pathologists agreed with the necessity for an official pathology advisory service system and organized the Medical Advisory Committee (MAC) as a subdivision of the Korean Society of Pathologists (KSP) in 2003. The MAC has been officially providing various kinds of advisory services, focusing on diagnostic pathology, since 2003. They have restrained the extent of users and contexts of pathologic consultations and have established detailed regulations. According to these regulations, certain individuals or institutions can use the consultation services: health and medical institutions run by government agencies such as the Ministry of Health and Welfare or community health centers; investigative authorities such as departments of prosecution or police departments; judicial offices; the Korean Medical Association; private insurance companies; specific institutions or individuals who are allowed to use the services of the KSP; and the members of the KSP. The contents of consultations are defined by the third provision of the regulations of the medical advisory services (MAS): classification and evaluation of the grade of malignant or premalignant lesion; confirmation of a pathologic diagnosis, including review of slides or pathologic reports; pathologic review of controversial cases among pathologists or clinicians; consultation about rare diseases; and other medical questions allowed by the MAC. The consultation process is quite simple (Fig. 1). After a client requests a pathologic consultation with the KSP, the advisory manager who is appointed by the MAC reviews the contents of the consultation. Then, he or she designates a specific pathologist as a consultant, considering his or her experience and subspecialty in pathologic fields. The appointed pathologist must have more than 10 years of experience as a surgical pathologist of the specific subspecialty. There must be no conflicts of interest between the consultant and client. After reviewing the consulted case, the assigned pathologist should report the result to the advisory manager within 2 weeks. Then, the advisory manager informs the clients of the result. Fig. 1. Schematic flow chart of the medical advisory service system of the Korean Society of Pathology (KSP). In this review, we discuss the medical advisory service system of Korea provided by the KSP and comprehensively review the consultation cases from 2003 to 2014.

Background: Corneal allotransplantation is a well-known technique to treat corneal blindness. However, the problem of organ scarcity in transplantology has become profound. One promising alternative could be xenograft using pig as an organ donor. Full thickness corneal xenotransplantation needs total immunosuppression. This study is an investigation of the efficacy of α1,3-ga lactosyltransferase gene-knockout (GTKO) transgenic pig-to-nonhuman primate lamellar corneal transplantation with minimal immunosuppression. Methods: We conducted 10 lamellae corneal xenotransplantation between 2016 and 2019. Clinically acceptable graft size (diam eter 7.5 mm, thickness 500 um). The dexamethasone subconjunctival injection (1.5 mg/0.3 mL) was administered for minimal immunosuppression immediately after surgery and eye drops of 0.5% levofloxacin and 1% prednisolone acetate were applied four times a day for 1 week, gradually tapered. No eye drops were added after two months. Three cases are alive without graft rejection. We examined the remaining seven cases for the histopathological features and Immunologic profiles. Results: As a result, three of the ten xenografts survival is significantly longer 1,239, 589, and 316 days. Corneal opacity result ed in graft failure, and terminated in seven cases. Rejected grafts showed extensive polymorphic cellular infiltration, different degrees of epithelial layer irregular attenuation, stromal neovascularization, and inflammatory cell infiltrations including lym phocytes, plasma cells, eosinophils, neutrophils. Stromal irregularity, fibrosis and edema are observed in two of seven cases resulting in a single case of sub epithelial detachment. Immunologic profiles of the recipients with rejected grafts shows minimal increase in anti-Gal antibody IgG and IgM but increase in anti-Gal IgG is seen in one case. Four cases have different systemic in flammatory conditions with regards to plasma C3a and D-dimer levels. The anterior stromal surface of the graft showed epitheli al nests and fibrous proliferation. Conclusions: The GTKO transgenic pig to NHP lamella xeno corneal transplantation could be a promising substitute for human corneal allograft. Lamella xeno corneal transplantation may be a feasible option with minimal immunosuppression.

Background: Targeted next-generation sequencing (NGS) is widely applied in personalized therapy of NSCLC patients by identifying driver oncogenes. Another important application of targeted NGS analysis is to predict recurrence in resected early stage NSCLC patients. We investigated targeted NGS analysis to identify the genetic alterations related to the recurrence in resected EGFR-mutated lung adenocarcinoma. Methods: Tissues from 130 patients who had complete resection of stage I to IIIA EGFR mutated adenocarcinoma (median follow-up: 45 months), were analyzed by targeted NGS with 170 cancer-related genes. The DFS according to the numbers and types of gene alterations were estimated using the Kaplan-Meier method. The independent biomarkers related to recurrence were identified by Cox proportional hazard regression analysis. Results: The relapses after surgical resections were observed in 32 patients of 130 (24.6%). The relapses were associated not with sex and smoking history but with visceral-pleural invasion (p=0.001), lympho-vascular invasion (p=0.002), and stage(p=0.001). Relapse rates were increased in order by L858R (11/59, 18.6%), exon 19 deletion (16/56, 28.6%), compound EGFR mutation (3/10, 30%) and exon 20 mutation (2/5, 40%), but there was no statistical difference. 13 of 16 (81%) relapse patients with 19 deletion had E746_A750 del. It indicates that the hot spot of exon 19 deletion related to recurrence is E746_A750 del. In the aspect of the number of mutations, the patients with single mutation were 68(51.5%). 44(33.8%) had dual mutation, 13(10.8%) had triple mutation. DFS was associated with the number of genetic mutations (p=0.025). The 5-year DFS rates were 83%, 62% and 25% for single, dual and triple mutation respectively(p Conclusions: The number of co-occurring mutations, CTNNB1 mutation and del E746_A750 in exon19 was negative prognostic factors for DFS in resected EGFR-mutated lung adenocarcinoma. We recommend that the targeted NGS should be performed to identify the genetic alterations so we can predict the outcome and plan adjuvant chemotherapy or EGFR tyrosine kinase inhibitor therapy to patients with a higher risk of recurrence. Citation Format: In Ae Kim, Hee Jung Kim, Jae Young Hur, Seung En Lee, Jung Hoon Park, Song Am Lee, Jae Jun Hwang, Wan Seop Kim, Kye Young Lee. Targeted NGS analysis to predict recurrence in resected EGFR- mutated lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5896.

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Lung cancer is the leading cause of cancer-related death in Korea, accounting for approximately 20% of all cancer deaths [1]. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers, and the majority of patients with NSCLC present at an advanced cancer stage (stage III or IV) [2]. In the last decade, several studies have been performed on the molecular stratification of NSCLC in order to provide targeted treatment based on activating or driver mutations in these tumors. Activating mutations in the epidermal growth factor receptor gene (EGFR) can be used as therapeutic targets for treatment of NSCLC. In the Iressa Pan-Asia Study, tumors with EGFR mutations showed a 71.2% clinical response to first-line treatment with gefitinib, while tumors with wild-type EGFR showed only a 1.1% response [3]. Since then, several randomized control studies have shown an association between activating EGFR mutation and response to EGFR tyrosine kinase inhibitors (TKIs) [4-9]. Patient selection is important for using EGFR TKIs as the first-line treatment. At present, analysis of EGFR mutations is the accepted method for identifying patient response to EGFR TKIs. Direct DNA sequencing is a standard method for identifying mutations and is commonly used in the Asia-Pacific region [10]. Any routinely available pathological specimen can be used for analyzing EGFR mutations, including formalin-fixed, paraffin-embedded tissues from surgical resections; small tissue biopsies; or cell block preparations. Several publications have reported the prevalence of EGFR mutations in patients with NSCLC [10-14]. The rates of EGFR mutations are higher in Asian countries than in Western countries. Further, rates of EGFR mutations in Korean patients range from 17.4% to 51.3% [10,15-22]. Therefore, we performed a nationwide study of EGFR mutations in Korean patients with NSCLC in order to provide reliable information on the incidence and characteristics of EGFR mutations. This study was led by the Korean Cardiopulmonary Pathology Study Group.

Gigantomastia is a rare condition characterized by excessive breast growth. It has been reported that the majority of gigantomastia cases occur during either pregnancy or puberty. We were presented with a rare case of gigantomastia associated with neither pregnancy nor puberty, and successfully treated it with reduction mammaplasty and free nipple graft. This idiopathic gigantomastia is the very first case in Korea, and adds to the worldwide total of 9 reported cases.

BACKGROUND Limited data are available on the current status of cytology practices in Korea. This nationwide study presents Korean cytology statistics from 2015. METHODS A nationwide survey was conducted in 2016 as a part of the mandatory quality-control program by the Korean Society for Cytopathology. The questionnaire was sent to 208 medical institutions performing cytopathologic examinations in Korea. Individual institutions were asked to submit their annual cytology statistical reports and gynecologic cytology-histology correlation data for 2015. RESULTS Responses were obtained from 206 medical institutions including 83 university hospitals, 87 general hospitals, and 36 commercial laboratories. A total of 8,284,952 cytologic examinations were performed in 2015, primarily in commercial laboratories (74.9%). The most common cytology specimens were gynecologic samples (81.3%). Conventional smears and liquid-based cytology were performed in 6,190,526 (74.7%) and 2,094,426 (25.3%) cases, respectively. The overall diagnostic concordance rate between cytologic and histologic diagnoses of uterine cervical samples was 70.5%. Discordant cases were classified into three categories: category A (minimal clinical impact, 17.4%), category B (moderate clinical impact, 10.2%), and category C (major clinical impact, 1.9%). The ratio of atypical squamous cells of undetermined significance to squamous intraepithelial lesion was 1.6 in university hospitals, 2.9 in general hospitals, and 4.9 in commercial laboratories. CONCLUSIONS This survey reveals the current status and trend of cytology practices in Korea. The results of this study can serve as basic data for the establishment of nationwide cytopathology policies and quality improvement guidelines in Korean medical institutions.

Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative RET/PTC1 rearrangement analysis in BRAF and RAS wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection of the RET/PTC1 rearrangement by real-time reverse transcription-polymerase chain reaction (RT-PCR) using fresh and routine air-dried TPC1 cells were evaluated. The correlation of RET/PTC1 rearrangement between fine-needle aspiration (FNA) and paired formalin-fixed paraffin-embedded (FFPE) specimens was analyzed. RET/PTC1 rearrangements of 76 resected BRAF and RAS wild-type classical PTCs were also analyzed. Results of RT-PCR and the Nanostring were compared. When 100 fresh and air-dried TPC1 cells were used, expression of RET/PTC1 rearrangement was detectable after 35 and 33 PCR cycles, respectively. The results of RET/PTC1 rearrangement in 10 FNA and paired FFPE papillary thyroid carcinoma (PTC) specimens showed complete correlation. Twenty-nine (38.2%) of 76 BRAF and RAS wild-type classical PTCs had RET/PTC1 rearrangement. Comparison of RET/PTC1 rearrangement analysis between RT-PCR and the Nanostring showed moderate agreement with a κ value of 0.56 (p = 0.002). The RET/PTC1 rearrangement analysis by RT-PCR using routine air-dried FNA specimen was confirmed to be technically applicable. A significant proportion (38.2%) of the BRAF and RAS wild-type PTCs harbored RET/PTC1 rearrangements.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome characterized by activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursor cells in bone marrow, liver, spleen, or lymph nodes. We report a case of Epstein-Barr virus (EBV)-associated HLH unusually presenting as an ileal mass. A 23-year-old man presented initially with persistent fever unresponsive to antibiotics and pancytopenia. A bone marrow aspiration and biopsy were used to diagnose the patient with aplastic anemia and HLH. A relatively well-defined low-density mass was radiologically noted in the terminal ileum, along with enlarged lymph nodes, and was suspected to be malignant lymphoma or an abscess. The ileocecectomy specimen revealed a transmural hemorrhagic infarction with numerous activated macrophages phagocytosing erythrocytes, plasma cells, and lymphocytes, and he was diagnosed with EBV-associated HLH. The patient received an allo-unrelated peripheral blood stem-cell transplantation and expired due to graft-versus-host disease following liver failure. The present case is very unique, in that EBV-associated HLH presented with an unusual ileal mass resulting from hemorrhagic infarction in a patient with aplastic anemia, suggesting variability in the biological behavior of EBV-associated disease.

We report on a case of malignant pleural effusion as initial metastatic presentation of occult gastric cardia cancer in a young woman. To the best of our knowledge, this is the first report of gastric adenocarcinoma metastasized to pleura as an initial presentation. Location of cardia and signet ring cell histology may contribute to the manifestation. Utilization of positron emission tomography-computed tomography was helpful for proper diagnosis. For patients with such distinct clinical presentations, it would be appropriate to consider gastric cancer as one of the possible primary sites.

A primary ductal adenocarcinoma (PDA) of the lacrimal gland is a rare distinct subtype of an epithelial tumor arising in the lacrimal gland. PDA is the counterpart of salivary duct carcinoma (SDC) resembling an invasive ductal carcinoma (IDC) of the breast. In our case, PDA revealed histopathological and immunohistochemical results corresponding to SDC. Interestingly, the tumor cells showed intracytoplasmic vacuoles containing dense eosinophilic hyaline globules at light microscopy. Ultrastructurally, the tumor cells exhibited microvilli-lined intracytoplasmic lumen containing homogenous electron-dense secretory products. A previous study demonstrated that numerous intracytoplasmic lumens of tumor cells are favored breast malignant tumor, similar to the histopathology of PDA, rather than benign lesion. This characteristic finding may be meaningful to diagnose high grade epithelial tumors including PDA.

Matrix metalloproteinases (MMPs) are matrix-degrading enzymes that play a pivotal role in aggressive behaviours, such as rapid tumour growth, invasion, and metastasis, of several types of solid tumours. In particular, stromal MMP-2 plays important roles in the progression of malignant tumours, but most clinical studies have focused on tumoural MMP-2 and -9 expression, and not stromal MMP-2 expression. One hundred and seventy-seven cases diagnosed as invasive ductal carcinoma of the breast between 2000 and 2005 were included in this study. Expressions of tumoural MMP-2 and -9 and stromal MMP-2 were analysed by immunostaining on a tissue microarray. Subsequently, the associations between those results and various clinicopathological parameters were evaluated. Stromal MMP-2 expression correlated significantly with clinicopathological parameters such as advanced T category, larger tumour size, high histological grade, tumour necrosis, ER- and PR-negative, and HER-2-positive (all p < 0.05). In univariate and multivariate analyses, overall survival was linked with stromal MMP-2 expression as well as dual expression of stromal MMP-2 and tumoural MMP-2 and -9 (all p < 0.05). Stromal MMP-2 expression may play a crucial role in predicting aggressive clinical behaviour in breast cancer patients.

Tumour-to-tumour metastasis is a rare phenomenon, although double primary neoplasms are fairly common. Since it was first described by Berent in 1902, fewer than 200 cases have been reported in the...

Here, we present a rare case of cardiac parasitic infection found in an adult female patient who had the symptoms of dyspnea upon exertion. She was diagnosed with a double-chambered right ventricle due to infundibular hypertrophy confirmed by transthoracic echocardiography and cardiac computed tomography. We performed surgery of infundibulectomy around the pulmonary valve. In the end, histopathological findings of the resected infundibular muscle demonstrated trichinellosis, a type of roundworm infection.

We evaluated p53, KRAS, BRAF and CTNNB1 mutation and p53, WT1, p16 and beta-catenin expression in 31 ovarian high-grade serous adenocarcinoma. Twenty-five (80.6%) tumors contained functional mutations of p53; three frameshift, four nonsense and 19 missense mutations. None of the tumors showed KRAS, BRAF or CTNNB1 mutation. In all 18 tumors with missense mutations, ≥60% of tumor cells were strongly positive for p53 immunostaining whereas all tumors with frameshift or nonsense mutations were completely negative. Missense mutation was correlated with diffuse and strong imunoreaction and frameshift/nonsense mutation was correlated with completely negative immunoreaction (P = 0.000). Tumors with wild-type p53 revealed a wide range of immunostaining patterns. In 27 (87.1%) and 18 (58.1%) tumors, ≥50% of tumor cells were moderate to strongly positive for WT1 and p16, respectively. A considerable intratumoral heterogeneity for p16 expression was present. None of the tumors demonstrated nuclear beta-catenin expression. p53 mutations appear to be a powerful molecular marker for ovarian high-grade serous adenocarcinoma. Using p53 with an appropriate interpretation criteria together with WT1, p16 and beta-catenin, most of the high-grade serous adenocarcinoma could be distinguished from other ovarian tumors.

Simian virus 40 (SV40) is a polyomavirus that originates from the rhesus macaque and was discovered in 1960 as a contaminant of human polio vaccines produced in monkey cells.1 Recently, there has been considerable interest in the identification of SV40 in human tumors, including malignant mesothelioma (MM) and other rare tumors such as osteosarcoma, ependymoma, and choroid plexus tumors.2-6 Subsequently, it has been found that SV40 may play an important role in the etiology of these tumors.2-6 However, SV40 was not detected in malignant lymphomas in Korean patients.7 Oncogenesis driven by SV40 is mediated by the large tumor antigen (T-Ag) oncoprotein, which is capable of transforming different types of cells in the absence of other viral genes.8,9 T-Ag induces DNA synthesis in host cells and prolongs the onset of the S-phase through the inhibition of tumor suppressor proteins p53 and Rb.8 MM is a rare and extremely aggressive neoplasm that arises from the serosal surfaces of pleural, peritoneal, and pericardial cavities and is very likely associated with amphibole asbestos exposure.10,11 In recent years, the incidence of MM has been gradually increasing in concert with industrial development and increased exposure to asbestos.12 However, only a small number of people who have been exposed to asbestos during their lifetime will develop MM.11 This suggests that SV40 may act as an independent carcinogenic agent or as a cofactor of asbestos to augment the risk of MM.13 Studies investigating the relation of SV40 to MM have been inconsistent and differ by geographical location.6 The incidence of MM varies according to geographic location, and the highest incidence rates are reported from Australia, Belgium, and Great Britain.14 In Korea, the incidence of MM is very low compared with other developed countries, with only about one case per million in the last decade.14,15 However, the incidence is recently increasing. Korea has a higher proportion of females (33.8%) among MM cases compared with other nations such as Canada (15.4%) or Italy (27.6%), and most of the patients are diagnosed when they are in their 50s, which is younger compared to cases in other countries.15 Although the majority of MM patients have had occupational (36.8%) and/or environmental (20.4%) asbestos exposure, the remaining patients (42.8%) had no known asbestos exposure.15 The role of SV40 in the oncogenesis of MM following asbestos exposure has not yet been studied in a Korean population. The purpose of this study is to identify SV40 DNA and protein in tissues extracted from MM from a Korean population using quantitative polymerase chain reaction (PCR) and immunohistochemical staining.

Mutations of the epidermal growth factor receptor (EGFR) are the strongest predictive factor for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. EGFR TKIs are approved in Korea as a first-line treatment for lung cancer patients with mutated EGFR. Rapid and accurate EGFR mutation testing is essential for patient selection and establishing targeted therapies with EGFR TKIs. Thus, a standard set of guideline recommendations for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of guideline recommendations for EGFR mutation testing that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

In patients with colorectal cancer (CRC), the BRAF V600E mutation has been reported to be associated with several clinicopathological features and poor survival. However, the prognostic implications of BRAF V600E mutation and the associated clinicopathological characteristics in CRCs remain controversial. Therefore, we reviewed various clinicopathological features, including BRAF status, in 349 primary CRCs and analyzed the relationship between BRAF status and various clinicopathological factors, including overall survival. Similar to previous studies conducted in Eastern countries, the incidence of the BRAF V600E mutation in the current study was relatively low (5.7%). BRAF-mutated CRC exhibits distinct clinicopathological features from wild-type BRAF-expressing cancer independent of the microsatellite instability (MSI) status. This mutation was significantly associated with a proximal tumor location (P = 0.002); mucinous, signet ring cell, and serrated tumor components (P < 0.001, P = 0.003, and P = 0.008, respectively); lymphovascular invasion (P = 0.004); a peritumoral lymphoid reaction (P = 0.009); tumor budding (P = 0.046); and peritoneal seeding (P = 0.012). In conclusion, the incidence of the BRAF V600E mutation was relatively low in this study. BRAF-mutated CRCs exhibited some clinicopathological features which were also frequently observed in MSI-H CRCs, such as a proximal location; mucinous, signet ring cell, and serrated components; and marked peritumoral lymphoid reactions.

The role of telomerase reverse transcriptase (TERT) promoter mutations in differentiated thyroid cancer has been well established. These mutations have a significantly higher prevalence in aggressive thyroid tumors, including widely invasive oncocytic carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas. Interestingly, in some studies, TERT mutations were found to be more common in tumors with a BRAF(V600E) mutation. However, mutational analysis of TERT promoter mutations in thyroid tumors has not been previously performed for patients in Korea, where the BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is particularly prevalent. This study analyzed TERT promoter mutations in various thyroid tumors and examined their relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases.Using 242 preoperative fine-needle aspiration biopsy specimens (including 207 PTCs) with confirmed histopathological diagnosis of the biopsied thyroid nodules, the TERT promoter status (C228T and C250T) was analyzed, and the relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases was examined.Of 242 patients, 14.5% (30/207), 26.7% (4/15), 50% (1/2), and 60% (2/5) of PTCs, follicular thyroid carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas harbored a TERT(C228T) mutation, respectively. The TERT(C228T) mutation was associated with recurrence (p = 0.03). However, no association with other clinicopathologic factors in PTC was found. Coexistence of TERT(C228T) and BRAF(V600E) mutations was found in 13.0% of PTCs and was significantly associated with older age and advanced stage compared with the group negative for either mutation. The TERT(C228T) mutation status was an independent prognostic factor for recurrence-free survival (hazard ratio = 3.08 [confidence interval 1.042-9.079]; p = 0.042) in patients with PTC in multivariate analysis.Identification of TERT promoter mutations in preoperative fine-needle aspiration biopsy specimens may help in better characterizing the prognosis and triaging thyroid cancer patients for appropriate treatment.

Primary squamous cell carcinoma of the thyroid (SCC-T) is extremely rare. Its clinical presentation is similar to that of anaplastic carcinoma. Metastasis or extension from the head and neck area should be ruled out, as patients with SCC-T have a poorer prognosis than patients who have a thyroid extension from an adjacent tumor. An 87-year-old man presented with a longstanding painless mass in the right thyroid and had experienced 2 months of pain upon swallowing. A right lobectomy was performed with resection of thyroid cartilage, cricoid cartilage, a portion of the first to third tracheal ring and the right neck lymph node. A histological examination revealed pure SCC. The tumor cells showed diffuse immunoreactivity to CK5/6, CK19 and p63. Immunoreactivity to EMA and p53 was focally positive. TTF-1, galectin 3 and thyroglobulin immunoreactivity was restricted to the non-neoplastic thyroid tissue. Both tumor cells and non-neoplastic follicular cells were negative for CD5. The MIB-1 index was 36%. DNA extracted from the tumor identified a BRAF V600E mutation in exon 15 and a BRAF G468A mutation in exon 11, whereas DNA from non-tumorous cells did not contain a mutation. These molecular findings may suggest a direct transformation from papillary carcinoma to SCC-T.

Renal angiomyolipoma (AML) is a benign but progressive tumor that occasionally requires non-surgical therapy and there appears to be a possibility that epidermal growth factor (EGF) is associated with pathogenesis of renal AML. The response to gefitinib, anti-epidermal growth factor receptor (EGFR) agent and a prime example of target therapy, reportedly has been correlated with the presence of mutations within the tyrosine kinase (TK) domain of EGFR or the expression of its truncated form, EGFR variant III. Therefore the purpose of the present paper was to investigate EGFR protein expression and gene mutations in exons 18, 19 and 21 in 40 renal AML. No EGFR gene mutations of TK domain were detected in any of the 40 cases studied and strong immunostaining was found in 5% of the renal AML cases. The present findings indicate that in renal AML, anti-EGFR treatment may not be promising but that there is a possibility that EGFR is associated with renal AML pathogenesis.

A subpopulation of breast cancer cells with cluster of differentiation (CD)44-positive and CD24-negative expression has been reported to have stem cell properties and to have a higher tumorigenic capacity than other cells. However, the clinicopathological characteristics of this subpopulation are not fully understood. In this study, we aimed to identify the correlations between the expression of CD44 and CD24 and clinicopathological parameters and overall survival. We studied specimens from 262 patients with invasive breast cancer. Immunohistochemical staining for CD44 and CD24 was performed using tissue microarrays. The clinicopathological factors were evaluated from the patients' medical records. In correlation analysis, CD44 expression was significantly associated with human epidermal growth factor receptor 2 (HER2)-negative status (P

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

Background Combination therapy, which reduces the dosage intensity of the individual drugs while increasing their efficacy, is not a novel approach for the treatment of cancer. Methylsulfonylmethane (MSM) is an organic sulfur compound shown to act against tumor cells. Tamoxifen is a commercially available therapeutic agent for breast malignancies. Methods In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis. Additionally, we also validated the molecular targets by which the drug combination regulated tumor growth and metastasis. Results We observed that the combination of MSM and tamoxifen regulated cell viability and migration in vitro. The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway. Our study also assessed the regulation of signaling molecules implicated in the growth, progression, differentiation, and migration of cancer cells, such as Jak2, STAT5b, insulin-like growth factor-1Rβ, and their phosphorylation status. Conclusions Study results indicated that this combination therapy inhibited tumor growth and metastasis. Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1445-0) contains supplementary material, which is available to authorized users.

Granular cell tumors are uncommon soft tissue neoplasm of nerve sheath origin, which are predominately benign. Granular cells can be found at any site in the body including the tongue, skin, subcutaneous tissue, breast, gastrointestinal, and urogenital systems. However, granular cell tumors have only been rarely described in the chest wall. Here we report a case of a granular cell tumor that occurred in the chest wall of a 59-year-old woman, along with a review of the literature.

Metastasis to the breast from medullary thyroid carcinoma (MTC) is extremely rare and the associate cytological findings have not been reported in Korea until now. We report a case of metastatic MTC presented as palpable neck and breast nodules in a 39-year-old woman. Fine needle aspiration of breast nodules showed a cellular smear with relatively homogenous, poorly cohesive tumor cells in a relatively clean background. The tumor cells were round to oval, with hyperchromatic nuclei, abundant cytoplasm and plasmacytoid in appearance. A few amorphous materials, possibly amyloid, were also noted. The patient underwent radical thyroidectomy, cervical lymph node dissection and excision of breast nodules. The primary thyroid mass was typical of MTC but metastatic breast tumors showed more homogenous and smaller tumor cells. The cellular origin of the breast tumors was confirmed by their immunoreactivity for calcitonin, chromogranin, synaptophysin and TTF-1. Distinguishing MTC from primary breast cancer via fine needle aspiration cytology of breast nodules is important in planning treatment. Detection of amyloid-like materials and immunohistochemical staining for calcitonin or TTF-1 is helpful in diagnosing metastatic MTC in breast nodules when clinically suspected.

Poorly differentiated ("insular") carcinoma of the thyroid shares insular, trabecular, and solid histological patterns that are different from those of papillary, follicular, medullary, and anaplastic varieties. This tumor is situated morphologically and biologically in the intermediate position between the well differentiated (papillary and follicular) and the totally undifferentiated (anaplastic) thyroid tumors. We report two cases of insular carcinoma of the thyroid, occurring in 39-year-old and 52-year-old women. Grossly, these cases showed a lobulated mass with fibrous septa. The histologic finding showed characteristic "insular" growth pattern with focal follicular or papillary areas. Thyroglobulin was demonstrated within cytoplasmic paranuclear vacuoles of the neoplastic cells. Calcitonin and amyloid were not demonstrated. The aspiration cytology showed high cellularity, low grade of atypia, presence of clusters, nests, and trabeculae of cells with poorly outlined cytoplasm. The ultrastructural finding showed primordial cells having cytoplasmic organelles such as rough endoplasmic reticulum, mitochondria, and free ribosomes. We believe that its separation from other types of thyroid carcinoma will lead to a more accurate estimate of its biologic behavior and a more appropriate therapeutic approach.

We investigated fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT)-assessed metabolic tumor volume (MTV) and total lesion glycolysis (TLG) as prognostic factors in lung adenocarcinoma patients. This retrospective study included 106 patients (19 stage I/II and 87 stage III/IV lung adenocarcinoma) who underwent FDG PET/CT before treatment. Standardized uptake value (SUV), MTV, and TLG (MTV × mean SUV) of each malignant lesion were measured. Whole MTV and whole TLG were the summation of all the MTV and TLG values in each patient. Survival analysis and FDG PET/CT parameters regarding epidermal growth factor receptor (EGFR) gene mutation status were evaluated. Univariate survival analysis of stage III/IV patients identified high whole MTV (≥90), high whole TLG (≥600), and stage IV as significant predictors of poor progression-free survival. For overall survival, high whole MTV (≥90), high whole TLG (≥600), EGFR mutation-negative, and stage IV were significant poor prognostic predictors. After multivariate survival analysis, high whole MTV (P = 0.001), high whole TLG (P = 0.027), and stage IV (P = 0.006) were independent predictors of poor progression-free survival. High whole MTV (P