Seong Jin Cho

Frequent hepatocyte growth factor overexpression and low frequency of c-Met gene amplification in human papillomavirus–negative tonsillar squamous cell carcinoma and their prognostic significances ☆

Human papillomavirus (HPV) is an important prognostic factor for tonsillar squamous cell carcinoma (TSCC). HPV-positive and HPV-negative TSCCs are considered distinct in terms of prognosis and sensitivity to chemo/radiotherapy. However, to date, no study has thoroughly evaluated the individual prognostic factors for these 2 disease subgroups. Hepatocyte growth factor (HGF)-Met signaling pathway can be a predictive marker for prognosis or therapy response, especially in HPV-negative TSCC. We therefore investigated the prognostic values of HGF and c-Met expression in TSCC according to HPV status. Immunohistochemical analyses of HGF and c-Met protein expression and silver in situ hybridization of c-Met gene copy number were performed in 79 formalin-fixed, paraffin-embedded specimens. In HPV-negative TSCC, HGF overexpression, regional lymph node category, and ipsilateral cervical nodal metastasis predicted decreased overall survival (OS) (P = .017, P = .024, and P = .003, respectively). The latter 2 were also independent prognostic factors for progression-free survival (P = .023 and P = .002, respectively). In HPV-positive TSCC, heavy alcohol consumption and advanced primary tumor category were predictive of progression-free survival, whereas no independent prognostic factor for OS was identified. HGF overexpression had a significant effect on OS in HPV-negative TSCC but not in HPV-positive TSCC. HPV-negative/HGF-high expression tumors exhibited the worst survival outcomes, whereas HPV-positive/HGF-low expression tumors had the most favorable prognosis. c-Met expression and c-Met gene amplification were not associated with survival outcomes in TSCC patients. In conclusion, HGF may be a potential prognostic marker in HPV-negative TSCC, whereas c-Met exhibited limited clinical significance in TSCC.

TWIST1 promoter methylation is associated with prognosis in tonsillar squamous cell carcinoma.

Tonsillar squamous cell carcinomas (TSCC) frequently present with locally advanced diseases and cervical metastases, which are associated with poor prognoses. Epithelial-mesenchymal transition (EMT) is critical for tumor invasiveness and metastatic potential. Recent studies have shown that TWIST1-inducing EMT is overexpressed and hypermethylated in several cancers, indicating disease progression. The aim of the present study was to determine the clinical and prognostic significance of TWIST1 hypermethylation and EMT-related protein expression in TSCC. Methylation levels of TWIST1 promoter were analyzed by quantitative real-time methylation-specific polymerase chain reaction. Immunohistochemical analyses of TWIST1, Snail, and SMAD nuclear interacting protein-1 (SNIP1) were performed in 65 formalin-fixed, paraffin-embedded blocks of surgically resected specimens. TWIST1 promoter hypermethylation was found in 27.7% (18/65) of TSCCs. TWIST1 promoter hypermethylation was associated with poor differentiation (P = .012). Contralateral cervical lymph node metastasis was more frequently observed in TWIST1-methylated tumors (P = .029). High protein expressions of TWIST1, Snail, and SNIP1 were observed in 14 TSCC specimens (21.5%), 21 TSCC specimens (32.3%), and 38 TSCC specimens (58.5%), respectively. SNIP1 expression correlated significantly with TWIST1 methylation (P = .001), whereas TWIST1 protein expression did not. Contralateral cervical lymph node metastasis was an independent risk factor of the decreased overall survival rate (P = .002). TWIST1 methylation (P = .031) and pN stage (P = .037) were independent factors of poor prognoses affecting disease-free survival. TWIST1 promoter hypermethylation may be a useful molecular marker for predicting prognoses and contralateral cervical lymph node metastases in patients with TSCC.

P2X7 Receptor Expression in Coexistence of Papillary Thyroid Carcinoma with Hashimoto's Thyroiditis

Background This study was aimed at investigating the relation of P2X7 receptor (P2X7R) expression with the clinicopathological features of papillary thyroid carcinoma (PTC) coexisting with Hashimotos thyroiditis (HT). Methods We examined 170 patients (84, PTC with HT; 86, PTC without HT). P2X7R expression was examined by immunohistochemical methods. The staining intensity and patterns were evaluated and scored using a semi-quantitative method. Results The PTC with HT group was more likely to contain women and had less extrathyroid extension, lymph node (LN) metastasis, lymphovascular invasion, and recurrence than the PTC without HT group. Patients positive for P2X7R had significantly higher frequencies of lymphovascular invasion, extrathyroid extension, LN metastasis, and absence of HT. As shown by multivariate analysis, the expression of P2X7R was significantly higher if HT was absent and extrathyroid extension was present. In the PTC with HT group, the expression of P2X7R was significantly higher in patients with tumor multifocality, lymphovascular invasion, and extrathyroid extension. In the PTC without HT group, the expression of P2X7R was significantly higher in women and those having tumor multifocality. Conclusions Coexistence of PTC with HT is associated with good prognostic factors, and P2X7R expression in PTC was correlated with poor prognostic factors and the absence of HT.

A case of pedunculated hepatic hemangioma mimicking submucosal tumor of the stomach

Hepatic hemangioma is the most common benign tumor of the liver. Most such hemangiomas are small, asymptomatic, and have an excellent prognosis. Giant hepatic hemangioma has been reported in the literature, but the exophytic and pedunculated forms of hepatic hemangioma are rare. A 56-year-old woman was referred to our hospital under the suspicion of having a gastric submucosal tumor. Abdominal computer tomography (CT) scans showed a pedunculated mass from the left lateral segment of the liver into the gastric fundus, exhibiting the atypical CT findings of hepatic hemangioma. We therefore decided to perform laparoscopic resection based on the symptoms, relatively large diameter, inability to exclude malignancy, and risk of rupture of the exophytic lesion. The pathology indicated it to be a cavernous hemangioma of the liver. Herein we report a case of pedunculated hepatic hemangioma mimicking a submucosal tumor of the stomach due to extrinsic compression of the gastric fundus.

Pulmonary endometriosis resected by video‐assisted thoracoscopic surgery

Abstract:u2003 Catamenial haemoptysis is a rare condition caused by thoracic endometriosis that presents as tracheobronchial or pulmonary endometriosis. The authors report a 31‐year‐old woman with a 1‐year history of catamenial haemoptysis, which was diagnosed by chest CT scan during menses and treated successfully by means of video‐assisted thoracoscopic surgery of the solitary pulmonary lesion. There was no evidence of recurrence 6u2003months after the operation. The authors suggest that video‐assisted thoracoscopic surgery is an effective therapy for catamenial haemoptysis caused by localized peripheral pulmonary endometriosis.

Comparison of HER2 gene amplification and KRAS alteration in eyelid sebaceous carcinomas with that in other eyelid tumors.

Eyelid sebaceous carcinoma (SC) represents a highly aggressive malignancy. Despite the poor prognosis, genetic alterations as potential molecular targets are not available. KRAS mutation and HER2 gene amplification may be candidates related to their genetic alterations. We examined the HER2 and KRAS alteration status in eyelid SCs and compared it with that in other eyelid tumors. The controversial topics of the human papillomavirus (HPV) and p16 expression were also investigated. HER2 amplification was determined by silver in situ hybridization, while immunohistochemistry was performed to study protein expressions in 14 SCs and controls, including 23 other eyelid malignancies and 14 benign tumors. Peptide nucleic acid-mediated PCR clamping and direct sequencing were used to detect KRAS mutations. HER2 protein overexpression was observed in 85.7% (12/14) of the SCs, of which two-thirds showed HER2 gene amplification. HER2 protein overexpression and HER2 amplification were found more frequently in eyelid SCs than in other eyelid tumors. All SCs harbored wild type KRAS genes. No HPV infections were identified in the SCs. Nevertheless, p16 overexpression was found in 71.4% (10/14) of SCs, irrespective of the status of HPV infection. Furthermore, p16 overexpression in eyelid SCs was also significantly higher than that in other eyelid tumors. HER2 protein overexpression, HER2 gene amplifications, and wild type KRAS genes are common in eyelid SCs. HER2 gene amplification may represent potential therapeutic targets for the treatment of eyelid SCs.

Cribriform-morular variant of papillary thyroid carcinoma: a study of 3 cases featuring the PIK3CA mutation.

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is an unusual neoplasm with a considerably important association with familial adenomatous polyposis in young women, characterized by a peculiar histologic morphology with mixed cribriform, papillary, solid, tall columnar, and morular patterns. However, it can also occur sporadically. The molecular pathogenesis of sporadic CMV-PTC is not completely understood. We report cases of 3 patients with sporadic CMV-PTC with PIK3CA mutations. Using sequencing analyses and immunohistochemistry, we examined KRAS, BRAF, PIK3CA, and CTNNB1 mutations and related proteins, including β-catenin, PTEN, CD10, estrogen receptor, progesterone receptor, cytokeratin 19, and cyclin D1 in 3 CMV-PTCs. The 3 patients were teenaged girls. The tumors were solitary and encapsulated without cervical lymph node metastasis. They showed no recurrence for more than 6 years after the operation. Three tumors were diffusely positive for β-catenin, cyclin D1, and PTEN. The biphasic immunohistochemical patterns between the morular and nonmorular components were identified; the nonmorular components were positive for estrogen receptor, progesterone receptor, and cytokeratin 19, whereas the morular components showed CD10 positivity. All tumors harbored the same mutation in exon 9, codon 545 of the PIK3CA gene (p.E545A), whereas the KRAS, BRAF, and CTNNB1 mutations were not detected. This is the first study identifying the PIK3CA mutation specifically in sporadic CMV-PTC. The presence of the PIK3CA mutation and the wild-type KRAS, BRAF, CTNNB1 genes, and the intact PTEN expression in 3 sporadic CMV-PTCs may suggest the possible contribution of the PIK3CA mutation in its tumorigenesis.

Low frequency of KRAS mutation in pancreatic ductal adenocarcinomas in Korean patients and its prognostic value.

Objectives Low prevalence and prognostic relevance of KRAS mutations in Korean pancreatic ductal adenocarcinomas (PDACs) need to be validated with sensitive detection method. Methods Peptide nucleic acid (PNA)–mediated polymerase chain reaction (PCR) clamping was used to precisely detect KRAS mutation in 72 paraffinized tumor samples and was validated by pancreatic cell lines to compare the efficiency of direct sequencing. Results The PNA-mediated PCR clamping detected mutant allele proportions of as low as 0.5% against a background of wild-type DNA and was 20-fold more sensitive than direct sequencing through the validation of pancreatic cell lines. Peptide nucleic acid–mediated PCR clamping detected KRAS mutations in 47.2% of 72 PDACs. Low tumor cellularity and low PCR amplification efficiency led to be undetected or failed by direct sequencing in pancreatic paraffinized samples. KRAS mutations were an independent worse prognostic factor predicting a reduced progression-free survival rate in the postoperative chemotherapy group. Conclusions Peptide nucleic acid clamp real-time PCR was a sensitive method for detecting KRAS status in paraffinized PDAC samples. We identified a low KRAS mutation rate among the Korean PDAC patients using PNA clamp real-time PCR, potentially implicating epidemiological characteristics. The low KRAS mutation rate and its prognostic role may suggest the further survival benefit in Korean PDAC patients.

Expression of HAT1 and HDAC1, 2, 3 in Diffuse Large B-Cell Lymphomas, Peripheral T-Cell Lymphomas, and NK/T-Cell Lymphomas

Background It has generally been proven that histone acetylation and deacetylation are involved in the malignant transformation. To date, however, this has rarely been studied in cases of malignant lymphoma. Methods We studied nine cases of reactive lymphoid hyperplasia, 78 cases of diffuse large B-cell lymphoma (DLBCL), 13 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 cases of extranodal NK/T-cell lymphoma, nasal type (NKTCL). Thus, we attempted to elucidate the associations of the degree of the expression of histone acetyltransferase 1 (HAT1), histone deacetylase (HDAC) 1, HDAC2, and HDAC3 with the clinical behaviors of above malignant lymphomas using the immunohistochemistry and a western blot analysis. Results The degree of the expression of HAT1 was higher in cases of DLBCL, PTCL-NOS or NKTCL as compared with reactive lymphoid hyperplasia (p<0.05). The degree of the expression of HAT1 was correlated with that of HDAC1 in cases of DLBCL or NKTCL (p<0.05). The degree of the expression of HAT1 and HDAC1 was correlated with a poor survival in cases of DLBCL or PTCL-NOS (p>0.05). Conclusions HAT1, HDAC1, and HDAC2 play a critical role in the development of malignant lymphomas. Both HAT1 and HDAC1 might be indicators for a poor prognosis in cases of DLBCL as cooperating factors.

Histopathologic Predictors of Lymph Node Metastasis and Prognosis in Tonsillar Squamous Cell Carcinoma

Background Risk factors for lymph node metastasis in tonsillar squamous cell carcinoma (TSCC) need to be established to determine the degree of surgery required to achieve high curative rates. However, little is known currently about the histopathological features predicting prognosis, specifically in TSCC. Methods This study included 53 patients who underwent surgical resection with neck dissection. Clinicopathological factors investigated included age, gender, alcohol use, tobacco consumption, tumor stage, adjacent structure involvement, cell differentiation, squamous dysplasia, in situ carcinoma associated with primary invasive cancer, carcinoma in situ skip lesions, necrosis, invasive front, depth of invasion, and lymphatic, muscle, or perineural invasion. Results Contralateral cervical metastasis was associated with higher T stages and soft palate invasion. Lymphatic and muscle invasion were associated with ipsilateral cervical metastasis. Advanced T stage, invasion to the base of tongue, and skip lesions were associated with decreased disease-free survival. Advanced T stage and skip lesions were associated with worse overall survival. Conclusions Advanced T stage and soft palate invasion may predict a high risk of contralateral nodal metastasis. T stage and skip lesion are worse prognostic factors in TSCC and should be commented in pathology reports.