Hye Seung Han

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

CONTEXT In 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%. OBJECTIVE We analyzed the surgical result according to a management guideline based on the BRAF(V600E) mutation status of thyroid nodules. DESIGN A 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. RESULTS Among 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. CONCLUSIONS We 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.

Differential, stage‐dependent expression of Hsp70, Hsp110 and Bcl‐2 in colorectal cancer

Background: The presence of hypoxic cells in solid tumors has been suggested to contribute to the malignant progression of various tumors. Recently, we reported an activation of heat shock transcription factor (HSF) and expression of heat shock proteins (Hsp) in murine tumor cells by hypoxia.

Detection and typing of HPV genotypes in various cervical lesions by HPV oligonucleotide microarray

OBJECTIVES This study was conducted to evaluate a clinical efficacy of human papillomavirus (HPV) oligonucleotide microarray (Biomedlab Co., Seoul, South Korea) for the detection of HPVs in various cervical lesions. RESULTS HPV DNAs from 234 patients were analysed by two methods. Among those, 212 patients were classified into 5 groups according to the histologic diagnosis: chronic cervicitis, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, and invasive cervical carcinoma. PCR-RFLP could detect 7 types of high-risk HPVs (HPV 16/18/31/33/35/52/58) and HPV microarray could detect 15 types of high-risk HPVs (HPV 16/18/31/33/35/39/45/51/52/56/58/59/66/68/69) and 7 types of low-risk HPVs (HPV 6/11/34/40/42/43/44).HPV genotyping by HPV oligonucleotide microarray revealed that HPV16 was the most frequent type (30.2%) in all specimens tested and was significantly more frequent in CIN III and invasive carcinomas than other lesions. METHODS HPV DNAs were detected in 158 and 174 of the 234 cervical samples by PCR-RFLP and HPV microarray, respectively. The correlation between the two methods was good in detecting HPVs in general (kappa index = 0.69) and HPVs 31 and 52 (kappa index = 0.70 and 0.70, respectively) and excellent in detecting HPVs 16, 18, 33, 35, and 58 (kappa index = 0.90, 0.88, 0.92, 0.77, and 0.84, respectively). Double HPV infection was detected in 10 cases and one triple infection was detected. By combining cytology and HPV testing, the sensitivity was improved to 87.5, 95.5, 96.1, and 97.2% in CIN I, CIN II, CIN III, and carcinoma, respectively. CONCLUSIONS This results suggest that HPV oligonucleotide microarray is a highly comparable method to the previously used PCR-RFLP method for the detection of HPVs in cervical specimens. Genetic informations for HPV infection in cervical specimens may offer new strategies in manipulating the patients harboring cervical intraepithelial neoplasia and cervical carcinoma.

Microsatellite Alterations at Selected Tetranucleotide Repeats Are Associated With Morphologies of Colorectal Neoplasias

BACKGROUND & AIMS Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) occurs during microsatellite instability (MSI) that is not associated with major defects in DNA mismatch repair (MMR) but rather the reduced (heterogenous) expression of the MMR protein hMSH3; it occurs in sporadic colorectal tumors. We examined the timing of development of EMAST during progression of colorectal neoplasias and looked for correlations between EMAST and clinical and pathology features of tumors. METHODS We evaluated tumor samples from a cohort of patients that had 24 adenomas and 84 colorectal cancers. EMAST were analyzed after DNA microdissection of matched normal and tumor samples using the polymorphic tetranucleotide microsatellite markers MYCL1, D9S242, D20S85, D8S321, and D20S82; data were compared with clinical and pathology findings. Traditional MSI analysis was performed and hMSH3 expression was measured. RESULTS Moderately differentiated adenocarcinomas and poorly differentiated adenocarcinomas had higher frequencies of EMAST (56.9% and 40.0%, respectively) than well-differentiated adenocarcinomas (12.5%) or adenomas (33.3%) (P = .040). In endoscopic analysis, ulcerated tumors had a higher frequency of EMAST (52.3%) than flat (44.0%) or protruded tumors (20.0%) (P = .049). In quantification, all tumors with >3 tetranucleotide defects lost MSH3 (>75% of cells); nuclear heterogeneity of hMSH3 occurred more frequently in EMAST-positive (40.0%) than in EMAST-negative tumors (13.2%) (P = .010). CONCLUSIONS EMAST is acquired during progression of adenoma and well-differentiated carcinomas to moderately and poorly differentiated carcinomas; it correlates with nuclear heterogeneity for hMSH3. Loss of hMSH3 corresponds with multiple tetranucleotide frameshifts. The association between EMAST and ulcerated tumors might result from increased inflammation.

Prevalence and risk of colorectal neoplasms in asymptomatic, average-risk screenees 40 to 49 years of age

BACKGROUND A paucity of information exists regarding colorectal neoplasm in asymptomatic, average-risk individuals 40 to 49 years of age. OBJECTIVE To evaluate the prevalence and risk factors of colorectal neoplasms in those in their 40s. DESIGN Cross-sectional study. SETTING Results offered to subjects of a health care provider that offers screening services as part of an employer-provided wellness program. PATIENTS A consecutive series of 1761 asymptomatic, average-risk screenees 40 to 59 years of age. INTERVENTION First screening colonoscopy. RESULTS The prevalence of overall colorectal neoplasm in subjects of ages 40 to 44 years, 45 to 49 years, 50 to 54 years, and 55 to 59 years increased significantly with increasing age (13.7%, 20.2%, 21.0%, and 23.8%, respectively; P < .001). The prevalence of advanced adenomas in subjects of ages 40 to 44 years, 45 to 49 years, 50 to 54 years, and 55 to 59 years increased significantly with age (1.9%, 3.0%, 3.2%, and 5.9%, respectively; P = .004). Multivariate analysis of data from the 40- to 49-year age group identified an increased risk of colorectal neoplasm associated with ages 45 years and older (odds ratio [OR], 1.68; 95% CI, 1.20-2.35), male sex (OR, 1.76; 95% CI, 1.15-2.69), presence of abdominal obesity (OR, 1.57; 95% CI, 1.12-2.21), and metabolic syndrome (OR, 1.56; 95% CI, 1.03-2.35), whereas for advanced adenomas, abdominal obesity (OR, 2.37; 95% CI, 1.06-5.27) and metabolic syndrome (OR, 2.83; 95% CI, 1.23-6.53) were the independent risk factors. LIMITATIONS Single-center study and the cohort composed of ethnic Korean subjects who lived in the same geographic region. CONCLUSION In average-risk individuals 40 to 49 years of age, men with abdominal obesity or metabolic syndrome might benefit from screening colonoscopy starting at 45 years of age to detect colorectal neoplasm.

Effect of submucosal fibrosis on endoscopic submucosal dissection of colorectal tumors: Pathologic review of 173 cases

Endoscopic submucosal dissection (ESD) is now commonly performed as a treatment for colorectal tumors. However, little is known about the relationship between submucosal fibrosis and the outcome of the colonic ESD procedure. The aims of this study were to investigate the relationship between the degree of submucosal fibrosis in colorectal tumors and the outcomes of ESD for these tumors and to evaluate the risk factors for submucosal fibrosis.

Cytologic Evaluation of Low Grade Transitional Cell Carcinoma and Instrument Artifact in Bladder Washings

OBJECTIVE To identify key cytologic features for the separation of low grade transitional cell carcinomas (TCCs) from nonneoplastic lesions in bladder washings. STUDY DESIGN The cytomorphologic features of 95 bladder washing specimens showing papillary fragments, which included 50 low grade TCCs and 45 nonneoplastic lesions, were reviewed retrospectively. RESULTS Bladder washings from low grade TCCs showed papillary and irregular groups of cells with ragged borders, cytoplasmic homogeneity and subtle nuclear changes, such as increased nuclear/cytoplasmic ratio and irregular nuclear border. Bladder washings after instrumentation from nonneoplastic lesions of the bladder showed cellular specimens with cohesive, ball-shaped and papillary clusters with smooth borders lined with a denser-staining cytoplasmic collar. Reactive urothelial cells often displayed loose aggregates with irregular borders but no cytoplasmic collar. CONCLUSION In bladder washing cytology, nuclear changes and cytoplasmic homogeneity play a major role in the diagnosis of carcinoma.

Diagnosis of gastric epithelial neoplasia: Dilemma for Korean pathologists.

The histopathological diagnosis of gastric mucosal biopsy and endoscopic mucosal resection/endoscopic submucosal dissection specimens is important, but the diagnostic criteria, terminology, and grading system are not the same in the East and West. A structurally invasive focus is necessary to diagnose carcinoma for most Western pathologists, but Japanese pathologists make a diagnosis of cancer based on severe dysplastic cytologic atypia irrespective of the presence of invasion. Although the Vienna classification was introduced to reduce diagnostic discrepancies, it has been difficult to adopt due to different concepts for gastric epithelial neoplastic lesions. Korean pathologists experience much difficulty making a diagnosis because we are influenced by Japanese pathologists as well as Western medicine. Japan is geographically close to Korea, and academic exchanges are active. Additionally, Korean doctors are familiar with Western style medical terminology. As a result, the terminology, definitions, and diagnostic criteria for gastric intraepithelial neoplasia are very heterogeneous in Korea. To solve this problem, the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists has made an effort and has suggested guidelines for differential diagnosis: (1) a diagnosis of carcinoma is based on invasion; (2) the most important characteristic of low grade dysplasia is the architectural pattern such as regular distribution of crypts without severe branching, budding, or marked glandular crowding; (3) if nuclear pseudostratification occupies more than the basal half of the cryptal cells in three or more adjacent crypts, the lesion is considered high grade dysplasia; (4) if severe cytologic atypia is present, careful inspection for invasive foci is necessary, because the risk for invasion is very high; and (5) other structural or nuclear atypia should be evaluated to make a final decision such as cribriform pattern, papillae, ridges, vesicular nuclei, high nuclear/cytoplasmic ratio, loss of nuclear polarity, thick and irregular nuclear membrane, and nucleoli.

Differential expression of Bcl-2, Bcl-XL and p53 in colorectal cancer

Aims:  The balance between proliferation and apoptosis is often disturbed in cancer. The aim of this study was to investigate the possible role of Bcl‐2 gene family members and p53 as prognostic factors in a series of colorectal cancer.

Prognostic Significance of TERT Promoter Mutations in Papillary Thyroid Carcinomas in a BRAF(V600E) Mutation-Prevalent Population.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.