Eung Seok Lee

Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis.

Numerous studies have investigated the clinical significance of BRAF mutation in papillary thyroid carcinoma (PTC). However, there have been conflicting data on the usefulness of BRAF mutation as a prognostic marker of PTC. To address this controversy, the frequency of the BRAF mutation and the associations between BRAF mutation and clinicopathologic parameters in PTC were evaluated by meta‐analysis.

Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid

Numerous studies have investigated the clinical significance of BRAF mutation in papillary thyroid carcinoma (PTC). However, there have been conflicting data on the usefulness of BRAF mutation as a prognostic marker of PTC. To address this controversy, the frequency of the BRAF mutation and the associations between BRAF mutation and clinicopathologic parameters in PTC were evaluated by meta‐analysis.

Clinicopathological and molecular characteristics of Epstein–Barr virus‐associated gastric carcinoma: A meta‐analysis

There is conflicting data regarding the clinicopathological significance of the risk factors associated with Epstein–Barr virus (EBV)‐associated gastric carcinoma (EBVaGC). To address this controversy, we performed a meta‐analysis for the clinicopathological and molecular characteristics of EBVaGC. The relevant published studies were reviewed according to the defined selection criteria. The effect sizes of the outcome parameters were estimated by an odds ratio or a weighted mean difference. This meta‐analysis included 48 studies that encompassed a total of 9738 patients. The frequency of EBVaGC was 8.8%, and EBVaGC was significantly associated with ethnicity. It was more predominant in men and in younger individuals. Interestingly, EBVaGC was more prevalent in Caucasian and Hispanic patients than in Asian ones. EBVaGC developed most often in the cardia and body, and it generally showed the diffuse histological type. EBV was highly prevalent in the patients with lymphoepithelial carcinoma. EBVaGC was closely associated with remnant cancer and a CpG island methylator‐high status, but not with Helicobacter pylori infection, a TP53 expression, and p53 mutation. In addition, EBVaGC was not significantly associated with the depth of invasion, lymph node metastasis, or the clinical stage. The clinicopathological and molecular characteristics of EBVaGC are quite different from those of conventional gastric adenocarcinoma. However, further study is needed to determine the effect of EBV on the survival of EBVaGC patients.

Prognostic relevance of immunohistochemically detected lymph node micrometastasis in patients with gastric carcinoma

Micrometastases consisting of one to a few cells in lymph nodes resected during gastrectomy are difficult to identify using conventional hematoxylin and eosin (H&E) stains. It has been shown that immunostaining for cytokeratins is effective in detecting lymph node micrometastasis in a variety of human tumors, but only a few previous reports demonstrated its use in the treatment of patients with early and advanced gastric carcinoma, and those reports had conflicting results.

BRAF mutation and AKAP9 expression in sporadic papillary thyroid carcinomas

Aim: We aimed to determine the BRAF mutation and AKAP9 expression in papillary thyroid carcinomas (PTCs). Methods and Results: In this study, we analysed 100 sporadic PTC specimens and we detected mutation in 62.2% of the conventional type PTCs (51/82), in 50% of the follicular variant type PTCs (3/6), in 50% of the diffuse sclerosing variant type PTCs (1/2), and in 30% of the microcarcinomas (3/10). All mutations involved a T→A transversion at the nucleotide 1796. The cases with BRAF mutation were significantly associated with extrathyroidal extension. We also evaluated the expression of AKAP9 protein by immunohistochemistry. The AKAP9 protein was seen as a single perinuclear dot in all the PTCs. Therefore, 58% of the specimens harboured the BRAF mutation and no case had AKAP9‐BRAF fusion in the sporadic PTCs. Conclusion: Our results suggest that the BRAF mutation can be a useful diagnostic and prognostic marker and a target for exploring novel cancer therapies to treat PTCs. AKAP9‐BRAF fusion may be a very rare event in sporadic PTCs.

A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinomas

KIT is expressed not only in tumors derived from hematopoietic stem cells, melanocytes, germ cells, mast cells, and interstitial cells of Cajal, but also in other malignancies such as chromophobe renal cell carcinoma. This pattern of KIT expression prompted us to investigate the expression and mutation of c-kit gene exons 9, 11, 13, 17, and intron 17 in the different subtypes of renal cell carcinomas (n=66) and non-neoplastic kidneys (n=12). We found that KIT showed strong immunoreactivity in the cytoplasm of papillary renal cell carcinomas (100%), but on the cell membranes of chromophobe renal cell carcinomas (100%). Interestingly, a specific point mutation of the c-kit intron 17 (T->A) was found only in papillary renal cell carcinomas (94%). Our study demonstrates that the expression pattern and one mutation of c-kit may distinguish papillary renal cell carcinomas.

The hypermethylation and protein expression of p16 INK4A and DNA repair gene O6-methylguanine-DNA methyltransferase in various uterine cervical lesions.

PurposeThis study is aimed at investigating the significance of gene promoter methylation status and protein expression of p16 INK4A and O6-methylguanine-DNA methyltransferase (MGMT) in the various uterine cervical lesions.Materials and methodsMethylation status by using methylation-specific polymerase chain reaction (MS-PCR) and protein expression by using immunohistochemistry for p16 INK4A and MGMT genes were performed in cervical squamous intraepithelial neoplasms (CIN), invasive squamous cell carcinomas (SCC), adenocarcinomas and non-neoplastic cervices.ResultsNone of 20 non-neoplastic cervices showed p16 INK4A and MGMT gene hypermethylation, whereas at least one of these genes was hypermethylated with 50.0% (5/10) of CIN I, 65.0% (13/20) of CIN II–III, 70.2% (33/47) of SCC and 85.0% (17/20) of adenocarcinoma. p16 INK4A protein was totally negative in non-neoplastic cervices, but positive with 90.0% of CIN I, 100% of CIN II–III and adenocarcinoma, and 78.7% of SCC. MGMT protein was expressed in 10% of non-neoplastic cervices, but significantly increased in SCC (42.5%) and adenocarcinoma (70.0%). The protein expression of p16 INK4A and MGMT was not related to their gene promoter methylation status.ConclusionsThe hypermethylation of p16 INK4A and MGMT genes in the uterine cervix may indicate the presence of malignant cells, and p16 INK4A immunostaining is useful in grading CIN and diagnosing invasive SCC and adenocarcinoma.

ΔNp63 protein expression in uterine cervical and endometrial cancers

PurposeTo investigate the significance of p63 expression in uterine cervical and endometrial cancers.Materials and methodsΔNp63 protein expression was studied in a variety of 127 cases of uterine cervical lesions (20 non-neoplastic cervices, 43 cervical intraepithelial neoplasia [CIN], 54 squamous cell carcinomas (SCCs), 40 adenocarcinomas, and 13 other histologic types) and 30 endometrioid type of endometrial adenocarcinomas by using immunohistochemistry. One SCC cell line (ME-180) and one adenocarcinoma cell line (HeLa) were also included.ResultsIn uterine cervix, the expression of ΔNp63 was increased with progression of CIN, and positive in all SCCs, transitional cell carcinomas, and adenoid basal carcinoma, but negative in all adenocarcinomas. Adenosquamous cell carcinoma and mixed neuroendocrine and squamous cell carcinoma were positive in squamous component, but not in adenocarcinoma and neuroendocrine carcinoma components. ME-180 cell line was positive, whereas HeLa cell line was negative. Endometrioid type of endometrial adenocarcinomas showed a positive staining in glandular (26.7%) and squamous component.ConclusionsImmunohistochemical staining for ΔNp63 is a powerful marker for squamous differentiation and useful in exclusion of glandular and neuroendocrine differentiation in uterine cervical cancers, but not always in endometrial cancers.

Human papillomavirus genotyping by oligonucleotide microarray and p16INK4A expression in uterine cervical intraepithelial neoplasm and in invasive carcinoma in Korean women

For evaluating the diagnostic significance of p16INK4A over‐expression in the uterine cervical intraepithelial neoplasm and in invasive carcinoma, human papillomavirus (HPV) was detected and genotyped by oligonucleotide microarray in archival tissues of 117 cervical specimens, including 47 invasive squamous cell carcinomas (SCC), 30 cases of cervical intraepithelial neoplasia (CIN), 20 adenocarcinomas, and 20 cases of non‐neoplastic cervix. The expression of p16INK4A protein was immunohistochemically studied in these cases and in five HPV‐positive and one HPV‐negative cervical cancer cell lines. HPV was detected in 50% of CIN, 61.7% of SCC, and 45.5% of adenocarcinomas. p16INK4A expression was seen in all 20 cases of adenocarcinoma, 78.7% (37/47) of SCC, and 96.7% (29/30) of CIN, but not in any cases of the non‐neoplastic cervix. There was no difference in p16INK4A expression between the HPV‐positive and HPV‐negative cervical lesions. All HPV‐positive and ‐negative cervical cancer cell lines expressed p16INK4A protein. In conclusion, the presence of p16INK4A expression in cervical squamous and glandular epithelium indicates the existence of dysplasia or malignancy in the uterine cervix, regardless of HPV infection.

Occurrence of c-kit+ tumor cells in hepatitis B virus-associated hepatocellular carcinoma

Progenitor cells, termed oval cells, are involved in the pathogenesis of hepatocellular carcinoma (HCC) in animal models. By immunolabeling for c-kit and CD34 in human hepatitis B virus-associated cirrhosis with HCC (50 cases) and those with cirrhosis alone (10 cases), we found c-kit+ tumor cells in tumor tissue in 40 of 50 HCCs. The proportion was less than 0.1% of total tumor cell volume in most HCCs. Immunostaining for c-kit also was detected in sinusoidal endothelial cells in 43 of 50 HCCs. The incidence of oval cell occurrence in the adjacent nonneoplastic tissue in cases of HCC was high (44/50). The occurrence of oval cells, c-kit+ tumor cells, and c-kit+ sinusoidal cells in cases of human hepatitis B virus-associated HCC suggests that oval cell proliferation might be associated with the development of human hepatitis B virus-associated HCC. Furthermore, the c-kit+ sinusoidal cells might have a role in angiogenesis and progression of human hepatitis B virus-associated HCC.