Kensaku Yamaga

High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas

Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group of genes and is important in cell cycle regulation. Overexpression of EZH2 protein has been associated with biological malignancy of prostate cancer and several other cancers. The aim of the present study was to evaluate the expression of EZH2 protein in human oral normal mucosa, dysplasia and oral squamous cell carcinoma (OSCC) with clinicopathological profiles. EZH2 expression was assessed by Western blotting and immunohistochemistry in 3 OSCC cell lines, 10 normal mucosae, 50 dysplasias and 102 OSCCs. The labeling indices (LIs) of EZH2, Ki-67, P53, and the apoptotic index (AI) were evaluated by immunohistochemistry and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Western blot analysis detected EZH2 protein as a single band at 91kDa in the 3 OSCC cell lines, but it was almost absent in non-tumoral oral mucosae. The LI of EZH2 was highest in the OSCCs, followed by the dysplasias (p<0.05) and normal mucosae (p<0.05) with significant difference. The LI of EZH2 correlated with the clinical stage, tumor size, lymph node metastasis and LIs of Ki-67 and P53, but not with the AI in OSCCs, and inversely correlated with the histological differentiation of OSCCs. The survival rate calculated by the Kaplan-Meier method revealed that OSCC patients with higher EZH2 expression showed poorer prognosis than those with a lower EZH2 expression (p<0.01). These results suggest that overexpression of EZH2 is correlated with malignant potential and poor prognosis in OSCCs. EZH2 might serve as a novel biomarker for predicting prognosis in patients with OSCCs.

Expression of minichromosome maintenance 7 (MCM7) in small lung adenocarcinomas (pT1): Prognostic implication.

Minichromosome maintenance (MCM) proteins, essential molecules in the initiation and elongation of DNA replication, have been considered to be good indicators of cell proliferation. We examined the expressions of MCM7 and Ki-67 in lung adenocarcinomas (ACs) with a diameter less than 3cm (pT1), to clarify their pathobiological significance. Immunohistochemistry was conducted to obtain labeling indices (LIs%) for MCM7, MCM2 and Ki-67 in 100 surgically removed pT1 ACs. The LIs were compared with clinicopathological profiles and overall survival rates. The mean LIs of MCM7 and Ki-67 were 20.2+/-15.2% and 13.7+/-11.2%, the value being higher in the former than in the latter (P<0.01). MCM7 LIs were significantly correlated with sex, histological grade, histological subtype, tumor size, LIs of Ki-67, MCM2 and P53 (P<0.05). LIs of MCM7 and Ki-67 were significantly higher in the 84 non-bronchioloalveolar carcinomas than in the 16 bronchioloalveolar carcinomas (P<0.01). Kaplan-Meier survival curves showed that patients with higher MCM7 LIs had poorer prognosis in the 100 pT1 ACs as well as in the 73 stage I ACs. Multivariate Cox regression analysis confirmed that the LIs of MCM7, but not the LIs of MCM2 and Ki-67, was an independent prognostic marker in the 73 stage I ACs. These results suggest that MCM7 is an independent prognostic marker, being more reliable than MCM2 or Ki-67 in human pT1 ACs as well as in human stage I ACs.

Minichromosome maintenance 2 (MCM2) immunoreactivity in stage III human gastric carcinoma: clinicopathological significance

BackgroundThe origin licensing factor minichromosome maintenance 2 (MCM2) has recently been identified as a critical regulator of proliferation in both normal and neoplastic cells. This study examined whether MCM2 expression was of prognostic relevance in patients with stage III gastric carcinoma and whether the expression of this marker showed any correlation with clinicopathological characteristics. In addition, we evaluated whether the expression of this proliferation marker was correlated with that of another marker, Ki-67, in gastric carcinoma.MethodsWe examined the immunohistochemical expression of MCM2, Ki-67, and p53 in 103 surgically removed stage III gastric carcinomas, which consisted of 60 intestinal-type and 43 diffuse-type carcinomas. The labeling indices (LIs) of MCM2 and Ki-67 in cancer cells were compared with clinicopathological characteristics, p53 expression, and overall survival rates.ResultsThe mean MCM2 and Ki-67 LIs were 69.1 ± 11.8% and 48.2 ± 14.5%, respectively, in the intestinal carcinomas, and 43.7 ± 9.9% and 24.9 ± 11.0%, respectively, in the diffuse carcinomas. The LIs of these proteins revealed no significant association with clinicopathological characteristics or with p53 expression in the carcinomas. Kaplan-Meier survival curves showed that, in the patients with diffuse carcinoma, those with higher MCM2 LIs had a poorer prognosis (P < 0.05), but the MCM2 LI was not correlated with prognosis for those with intestinal carcinoma (P = 0.25). Ki-67 expression had no significant correlation with prognosis in either intestinal-type or diffuse-type carcinomas. Multivariate Cox regression analysis confirmed that MCM2 was an independent prognostic factor in patients with diffuse carcinoma.ConclusionOur data suggest that MCM2 is a useful prognostic marker in patients stage III diffuse-type gastric carcinoma.

High expression of enhancer of zeste homologue 2 indicates poor prognosis in patients with soft tissue sarcomas.

Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group of genes, is associated with malignancy in several human cancers. The purpose of this study was to examine the association between EZH2 expression and clinicopathological factors as compared to Ki-67 expression in human soft tissue sarcomas. Expression of EZH2 and Ki-67 was immunohistochemically determined in paraffin-embedded sections from 104 soft tissue sarcomas. High expression of both EZH2 and Ki-67 was significantly correlated with distant metastasis (P<0.01), histologic grade (P<0.01) and poor prognosis (P<0.01), but not with clinicopathological factors such as age, sex, and tumor location and size. Although EZH2 expression was significantly correlated with Ki-67 expression (rs=0.65, P<0.01), multivariate analysis showed that high expression of EZH2, but not of Ki-67, was an independent factor of poor prognosis (relative risk = 2.79; P=0.02). These data suggest that expression of EZH2 is a novel and reliable prognostic marker of human soft tissue sarcomas.

Detailed analysis of a superficial CD34‑positive fibroblastic tumor: A case report and review of the literature

Superficial cluster of differentiation (CD)34-positive fibroblastic tumor (SCPFT) is a rare mesenchymal neoplasm of borderline malignancy. It is characterized by a superficial location, marked cellular pleomorphism, an extremely low incidence of mitotic figures, and strong CD34 immunohistochemical positivity. As SCPFT is a recently described neoplasm, its characteristics are yet to be fully elucidated. To the best of our knowledge, no detailed studies regarding the imaging findings and cytogenetic analyses of SCPFTs exist. The present study describes a typical case of an 18-year-old man who developed an SCPFT measuring 87×70×80 mm in the subcutaneous adipose tissue of his right thigh. Computed tomography (CT) revealed a well-marginated tumor without calcification, and the enhancement on CT was weak. The tumor demonstrated abnormal uptake on 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography (PET), with a maximum standardized uptake value of 2.57. Magnetic resonance imaging (MRI) revealed a clearly defined tumor that exhibited homogeneous low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted imaging, with small lobulated structures. Histopathologically, the tumor was composed of irregular spindle-to-oval-shaped cells with eosinophilic glassy cytoplasm and hyperchromatic, bizarre and pleomorphic nuclei that frequently exhibited intranuclear pseudoinclusions. Immunohistochemically, the tumor cells were diffusely and strongly positive for CD34. The Mindbomb E3 ubiquitin protein ligase 1 labeling index was 8.6%. Ultrastructurally, the tumor cells exhibited irregular or convoluted nuclei with abundant euchromatin-prominent nucleoli. The cytoplasmic organelles consisted of scattered, abundant rough endoplasmic reticulum, mitochondria, lysosomes, ribosomal rosettes and aggregated lipid globules. Of 18 metaphase cells identified, 2 demonstrated translocation between chromosomes 2 and 5 in cytogenetic studies. To the best of our knowledge, this is the first study describing imaging data (CT, MRI and PET-CT) and chromosomal aberrations for SCPFT.

Proliferative fasciitis mimicking a sarcoma in a child: a case report.

Proliferative fasciitis (PF) is a benign, discrete proliferation of fibroblasts or myofibroblasts in soft tissue. Proliferative fasciitis mostly occurs in adults and is often confused with a sarcoma because of its rapid growth and peculiar histological features. We report a case of PF mimicking a sarcoma which developed in a 13‐year‐old boy, who noticed a painful tumor, with gradual enlargement, in his right lower leg. Magnetic resonance imaging revealed that the tumor measured 34 mm × 20 mm × 41 mm and was located in the subcutaneous tissue. The tumor was surgically resected. Pathologically, the tumor was composed of a proliferation of atypical spindle cells, admixed with larger ganglion‐like cells. Immunohistochemically, the tumor cells were positive for vimentin, cytokeratin, smooth muscle actin, HHF‐35 and Fli‐1. The tumor was subsequently diagnosed as a PF, although it was difficult to differentiate from a sarcoma. Five years after surgery, the postoperative course has been uneventful with no recurrence or metastasis.

Increasing great toe pain in a patient with soft tissue swelling and nail enlargement. Osteoid osteoma in the distal phalanx of the great toe.

Osteoid osteoma, a term first used by Jaffe [1] in 1935, is a relatively common osteoblastic lesion and occurs most commonly in the cortex of long bones, especially the femur and tibia [2, 3]. The essential feature in the central portion of the lesion (nidus) is the presence of differentiated osteoblastic activity [2]. It rarely occurs in the toes; only 27 cases of osteoid osteoma involving the phalanges of the toe have been reported. Furthermore, 13 of these 27 cases involved the great toe [3, 4]. The nidus in the toe is frequently in the cancellous or subperiosteal region [5]. A cancellous osteoid osteoma shows less surrounding sclerosis than does a cortical osteoid osteoma [6]. Furthermore, some case reports have suggested that the most characteristic clinical features of osteoid osteoma in the phalanx of the toe are soft tissue swelling, enlargement of the nail, and aching pain [3, 7]; erythema is occasionally present as well [3]. Rosborough [8] reported that both the enlargement and hypertrophy of the nail in osteoid osteomas might be explained by increased vascularity. In cases with these characteristics, both the swelling and erythema of the toe can be confused with infection, such as osteomyelitis [9]. MRI of an osteoid osteoma shows reactive inflammatory changes in the bone marrow and soft tissues around the tumor [10]. Therefore, the opportunity for misdiagnosis would be high if clinicians were to rely on MRI alone [3]. The patient in this case presented with pain and soft tissue swelling of his right toe for 10 months. He had no history of trauma or nocturnal pain. The present case was initially diagnosed as possible osteomyelitis because the great toe was enlarged, there was slight erythema, and the nail and soft tissue were hypertrophied (Fig. 1). A radiograph showed an

Increasing great toe pain in a patient with soft tissue swelling and nail enlargement

Osteoid osteoma, a term first used by Jaffe [1] in 1935, is a relatively common osteoblastic lesion and occurs most commonly in the cortex of long bones, especially the femur and tibia [2, 3]. The essential feature in the central portion of the lesion (nidus) is the presence of differentiated osteoblastic activity [2]. It rarely occurs in the toes; only 27 cases of osteoid osteoma involving the phalanges of the toe have been reported. Furthermore, 13 of these 27 cases involved the great toe [3, 4]. The nidus in the toe is frequently in the cancellous or subperiosteal region [5]. A cancellous osteoid osteoma shows less surrounding sclerosis than does a cortical osteoid osteoma [6]. Furthermore, some case reports have suggested that the most characteristic clinical features of osteoid osteoma in the phalanx of the toe are soft tissue swelling, enlargement of the nail, and aching pain [3, 7]; erythema is occasionally present as well [3]. Rosborough [8] reported that both the enlargement and hypertrophy of the nail in osteoid osteomas might be explained by increased vascularity. In cases with these characteristics, both the swelling and erythema of the toe can be confused with infection, such as osteomyelitis [9]. MRI of an osteoid osteoma shows reactive inflammatory changes in the bone marrow and soft tissues around the tumor [10]. Therefore, the opportunity for misdiagnosis would be high if clinicians were to rely on MRI alone [3]. The patient in this case presented with pain and soft tissue swelling of his right toe for 10 months. He had no history of trauma or nocturnal pain. The present case was initially diagnosed as possible osteomyelitis because the great toe was enlarged, there was slight erythema, and the nail and soft tissue were hypertrophied (Fig. 1). A radiograph showed an

Diagnotic Significance of Detection of Fusion Genes by Reverse Transcriptase-Polymerase Chain Reaction in Soft Tissue Tumors

軟部腫瘍の診断は，病理組織診断が最終診断となることが多いが，病理組織像が多彩で典型像を示さない例も多く，専門病理医でも診断に難渋する．近年，軟部腫瘍において多くの疾患特異的な融合遺伝子が同定され，診断へ応用されている．今回，RT-PCR法を用いた融合遺伝子の検出が軟部腫瘍の診断に有用であった症例を報告する．症例は滑膜肉腫2例，粘液型脂肪肉腫2例，悪性末梢神経鞘腫瘍1例，孤在性線維性腫瘍1例，類上皮肉腫1例であった．いずれも，臨床所見，術前生検の病理組織所見のみでは確定診断できなかった．滑膜肉腫，粘液型脂肪肉腫は特異的な融合遺伝子が検出された．悪性末梢神経鞘腫瘍，孤在性線維性腫瘍，類上皮肉腫は，特異的な融合遺伝子の存在は報告されていないが，鑑別診断となった融合遺伝子が存在する腫瘍を除外することで診断の補助となった．軟部腫瘍の診断において，融合遺伝子の検出は有用な手段となる．