Wan Seop Kim

Surgical Results of Thyroid Nodules according to a Management Guideline Based on the BRAFV600E Mutation Status

CONTEXTnIn Korea, where PTC comprises about 90-95% of the reported thyroid cancers, the prevalence of BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is above 80%.nnnOBJECTIVEnWe analyzed the surgical result according to a management guideline based on the BRAF(V600E) mutation status of thyroid nodules.nnnDESIGNnA total of 865 thyroid nodules were prospectively analyzed for their cytology and BRAF(V600E) mutation status by pyrosequencing. For the patients who had a diagnosis of atypical cells of undetermined significance (ACUS), we recommended surgery when there was positivity for BRAF(V600E) mutation or the nodules were clinically suspicious.nnnRESULTSnAmong 865 cases, 504, 141, 54, 140, 10, and 16 were diagnosed as benign, ACUS, suspicious for malignancy, malignant, suspicious for follicular neoplasm, and nondiagnostic, respectively. None of the 504 benign, 45 (31.9%) of the 141 ACUS, 46 (85.2%) of the 54 suspicious for malignancy, 129 (92.1%) of the 140 malignant, and one (10%) of the 10 suspicious for follicular neoplasm cases showed BRAF(V600E) mutation. Surgery was recommended to all 45 patients with BRAF(V600E) mutation-positive ACUS nodules; among them, 30 patients underwent surgery, 29 had PTC, and one had nodular hyperplasia. All the patients diagnosed as suspicious for malignancy or malignant were advised to undergo an operation, and they turned out to have PTCs regardless of their BRAF(V600E) mutation status.nnnCONCLUSIONSnWe found that performing BRAF(V600E) mutation analysis on the fine-needle aspiration biopsy specimens was of great help to make a therapeutic decision for thyroid nodules when the fine-needle aspiration biopsy results were equivocal.

FDG PET/CT metabolic tumor volume and total lesion glycolysis predict prognosis in patients with advanced lung adenocarcinoma

PurposeWe 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.MethodsThis 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 (MTVxa0×xa0mean 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. ResultsUnivariate 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 (Pxa0=xa00.001), high whole TLG (Pxa0=xa00.027), and stage IV (Pxa0=xa00.006) were independent predictors of poor progression-free survival. High whole MTV (Pxa0<xa00.001), high whole TLG (Pxa0=xa00.001), and EGFR mutation-negative (Pxa0=xa00.001) were independent prognostic predictors for poor overall survival. In a survival analysis of stage I/II patients, none was an independent prognostic predictor. No significant differences were found in FDG PET/CT parameters for EGFR mutation-negative and EGFR mutation-positive patients.ConclusionsAssessment of MTV and TLG by FDG PET/CT in advanced lung adenocarcinoma patients provides useful information regarding prognosis.

BRAF and RAS mutations in follicular variants of papillary thyroid carcinoma.

Follicular variants of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often cause a diagnostic dilemma. Therefore, many FVPTCs are interpreted as “indeterminate” in preoperative fine-needle aspiration (FNA). The aim of this study was to analyze the genotypic changes in BRAF codons 600 and 601, as well as the N, H, and KRAS codons 12, 13, and 61 in FVPTCs and investigate the usefulness of preoperative BRAF and RAS mutation analysis as an adjunct diagnostic tool along with routine FNA. Surgically resected thyroid nodules were reviewed to establish the histological diagnosis of FVPTC. All preoperative FNA diagnoses were categorized according to the Bethesda Reporting System. Mutations in BRAF codons 600 and 601, and N, H, KRAS codons 12, 13, and 61 were analyzed by pyrosequencing. Of 132 cases, 81 (61.4xa0%) had a point mutation in one of the BRAF V600E, BRAF K601E, or RAS oncogenes; BRAF V600E in 43(32.6xa0%), BRAF K601E in three (2.3xa0%), and RAS in 35 (26.5xa0%) cases. All mutations were mutually exclusive. Of 78 cases with an FNA indeterminate category diagnosis, 51 (65.4xa0%) were positive for mutations: 24 for BRAF V600E, 3 for BRAF K601E, and 24 for the RAS gene. The KRAS mutation was more frequently found than the HRAS mutation, comprising 22.9xa0% of the RAS mutations, and all KRAS mutations were located at codon 61. This study demonstrated that either BRAF or RAS mutations were present in two thirds of FVPTCs and these mutations were mutually exclusive.

Imaging mass spectrometry in papillary thyroid carcinoma for the identification and validation of biomarker proteins.

Direct tissue imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization and time-of-flight (MALDI-TOF) mass spectrometry has become increasingly important in biology and medicine, because this technology can detect the relative abundance and spatial distribution of interesting proteins in tissues. Five thyroid cancer samples, along with normal tissue, were sliced and transferred onto conductive glass slides. After laser scanning by MALDI-TOF equipped with a smart beam laser, images were created for individual masses and proteins were classified at 200-µm spatial resolution. Based on the spatial distribution, region-specific proteins on a tumor lesion could be identified by protein extraction from tumor tissue and analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using all the spectral data at each spot, various intensities of a specific peak were detected in the tumor and normal regions of the thyroid. Differences in the molecular weights of expressed proteins between tumor and normal regions were analyzed using unsupervised and supervised clustering. To verify the presence of discovered proteins through IMS, we identified ribosomal protein P2, which is specific for cancer. We have demonstrated the feasibility of IMS as a useful tool for the analysis of tissue sections, and identified the tumor-specific protein ribosomal protein P2. Graphical Abstract

Interobserver Variability in Diagnosing High-Grade Neuroendocrine Carcinoma of the Lung and Comparing It with the Morphometric Analysis

Background Distinguishing small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is difficult with little information about interobserver variability. Methods One hundred twenty-nine cases of resected SCLC and LCNEC were independently evaluated by four pathologists and classified according to the 2004 World Health Organization criteria. Agreement was regarded as unanimous if all four pathologists agreed on the classification. The kappa statistic was calculated to measure the degree of agreement between pathologists. We also measured cell size using image analysis, and receiver-operating-characteristic curve analysis was performed to evaluate cell size in predicting the diagnosis of high-grade neuroendocrine (NE) carcinomas in 66 cases. Results Unanimous agreement was achieved in 55.0% of 129 cases. The kappa values ranged from 0.35 to 0.81. Morphometric analysis reaffirmed that there was a continuous spectrum of cell size from SCLC to LCNEC and showed that tumors with cells falling in the middle size range were difficult to categorize and lacked unanimous agreement. Conclusions Our results provide an objective explanation for considerable interobserver variability in the diagnosis of high-grade pulmonary NE carcinomas. Further studies would need to define more stringent and objective definitions of cytologic and architectural characteristics to reliably distinguish between SCLC and LCNEC.

Primary pure squamous cell carcinoma of the thyroid: Report and histogenic consideration of a case involving a BRAF mutation

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 2u2003months 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.

ERG Immunohistochemistry as an Endothelial Marker for Assessing Lymphovascular Invasion

Background ERG, a member of the ETS family of transcription factors, is a highly specific endothelial marker. We investigated whether the use of ERG immunostaining can help pathologists detect lymphovascular invasion (LVI) and decrease interobserver variability in LVI diagnosis. Methods Fifteen cases of surgically resected colorectal cancers with hepatic metastasis were selected and the most representative sections for LVI detection were immunostained with ERG, CD31, and D2-40. Eight pathologists independently evaluated LVI status on hematoxylin and eosin (H&E) and the corresponding immunostained sections and then convened for a consensus meeting. The results were analyzed by kappa (κ) statistics. Results The average rate of LVI positivity was observed in 43% with H&E only, 10% with CD31, 29% with D2-40, and 16% with ERG. Agreement among pathologists was fair for H&E only (κ=0.27), D2-40 (κ=0.21), ERG (κ=0.23), and was moderate for CD31 (κ=0.55). Consensus revealed that ERG nuclear immunoreactivity showed better visual contrast of LVI detection than the other staining, with improved agreement and LVI detection rate (κ=0.65, LVI positivity rate 80%). Conclusions The present study demonstrated a superiority with ERG immunostaining and indicated that ERG is a promising panendothelial marker that might help pathologists increase LVI detection and decrease interobserver variability in LVI diagnosis.

Analysis of Mutations in Epidermal Growth Factor Receptor Gene in Korean Patients with Non-small Cell Lung Cancer: Summary of a Nationwide Survey

Background: Analysis of mutations in the epidermal growth factor receptor gene (EGFR) is important for predicting response to EGFR tyrosine kinase inhibitors. The overall rate of EGFR mutations in Korean patients is variable. To obtain comprehensive data on the status of EGFR mutations in Korean patients with lung cancer, the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists initiated a nationwide survey. Methods: We obtained 1,753 reports on EGFR mutations in patients with lung cancer from 15 hospitals between January and December 2009. We compared EGFR mutations with patient age, sex, history of smoking, histologic diagnosis, specimen type, procurement site, tumor cell dissection, and laboratory status. Results: The overall EGFR mutation rate was 34.3% in patients with non-small cell lung cancer (NSCLC) and 43.3% in patients with adenocarcinoma. EGFR mutation rate was significantly higher in women, never smokers, patients with adenocarcinoma, and patients who had undergone excisional biopsy. EGFR mutation rates did not differ with respect to patient age or procurement site among patients with NSCLC. Conclusions EGFR mutation rates and statuses were similar to those in published data from other East Asian countries.

Characteristics of Cutaneous Lymphomas in Korea According to the New WHO-EORTC Classification: Report of a Nationwide Study

Background Previously, cutaneous lymphomas were classified according to either the European Organization for the Research and Treatment of Cancer (EORTC) or the World Health Organization (WHO) classification paradigms. The aim of this study was to determine the relative frequency of Korean cutaneous lymphoma according to the new WHO-EORTC classification system. Methods A total of 517 patients were recruited during a recent 5 year-period (2006-2010) from 21 institutes and classified according to the WHO-EORTC criteria. Results The patients included 298 males and 219 females, and the mean age at diagnosis was 49 years. The lesions preferentially affected the trunk area (40.2%). The most frequent subtypes in order of decreasing prevalence were mycosis fungoides (22.2%), peripheral T-cell lymphoma (17.2%), CD30+ T-cell lymphoproliferative disorder (13.7%), and extranodal natural killer/T (NK/T) cell lymphoma, nasal type (12.0%). Diffuse large B-cell lymphoma accounted for 11.2% of cases, half of which were secondary cutaneous involvement; other types of B-cell lymphoma accounted for less than 1% of cases. Conclusions In comparison with data from Western countries, this study revealed relatively lower rates of mycosis fungoides and B-cell lymphoma in Korean patients, as well as higher rates of subcutaneous panniculitis-like T-cell lymphoma and NK/T cell lymphoma.

Bilateral Ovarian Metastases from ALK Rearranged Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) rearrangement, is a kind of driver mutation, accounts for 3%-5% of non-small cell lung cancer (NSCLC). NSCLC patients harboring ALK fusion genes have distinct clinical features and good response to ALK inhibitors. Metastasis from lung cancer to the ovary has rarely been known. We report a case of a 54-year-old woman with bilateral ovarian metastases from ALK rearranged NSCLC. She underwent bilateral salpingo-oophorectomy for ovary masses, which were progressed after cytotoxic chemotherapy although primary lung mass was decreased. Histopathological examination of the ovary tumor showed characteristic adenocarcinoma patterns of the lung and ALK rearrangement.