Detection of Epstein-Barr Virus Genes and gene products in Nasopharyngeal Carcinoma

Kim, Won Il,Han, Kyoung Ja,Lee, Kyo Young,Kang, Chang Suck,Shim, Sang In CATHOLIC MEDICAL CENTER 1994 Bulletin of the Clinical Research Institute Vol.22 No.1

Epstein-Barr virus (EBV) is associated with infectious mononucleosis, Burkitt's lymphoma, Hodgkin's disease and undifferentiated nasopharyngeal carcinoma (NPC). The EBV-encoded RNAs (EBERS: EBERI & EBER2), two latent gene products, are the most abundant RNAs expressed in vitro, but their function and the significance of the intranuclear location is not established. Latent membrane protein (LMP-1) is an EBV latent gene product and the expression of LMP-1 in epithelial cells transforms them morphologically. Many studies on the relation between EBV and NPC using the serology, the hybridization technique of nucleic acid or polymerase chain reaction (PCR) were performed. This study was performed to detect EBV in nasopharyngeal carcinoma and to analize the expression and the localization of EBV gene products at the cellular level. Authors analyzed 40 cases of nasopharyngeal carcinomas using EBERS probe set (cDNA oligonucleotide probe for EBERs) by DNA-RNA hybridization and LMP specific monoclonal IgG antibodies, CSI-4, by immunohistochemical stain. The results were as follows: 1. Mean age of nasopharyngeal carcinoma patients was 52.3 and the male to female sex ratio of nasopharyngeal carcinoma was 4.7:1. 2. The EBERS were demonstrated in the malignant epithelial cells from 23 (57.5%) of 40 patients with nasopharyngeal carcinoma. Recognition of EBERS expression was facilitated by its chnracteristic location in the nucleus with nucleolar sparing. The EBERS detection rates in the male was significantly higher than in the female (P=0.044). There were significant differences between histological subtypes in the EBERS detection rates (X^2=8.224, P=0.004); nonkeratinizing carcinoma (76.9%), undifferentiated carcinoma (68.7%), keratinizing squamous cell carcinoma (18.2%). 3. Seven (17.5%) of forty nasopharyngeal carcinoma specimens showed a LMP-speciflc staining with the monoclonal antibodies, CSI-4. All the seven cases were positive for EBERs by in situ hybridization. Staining with anti-LMP antibody was localized to the cell membrane and cytoplasm of malignant epithelial cells. All the LMP positive cases were undifferentiated carcinoma, so that the LMP detection rate in undifferentiated carcinoma was 43.75% (7/16). In conclusion, above results implies that EBV infection is closely associated with the development of nasopharyngeal carcinoma. We suggest that the EBERs transcript is an appropriate target for EBV detection with in situ hybridization in formalin-fixed paraffin-embedded carcinoma specimens.

Mortality Characteristic and Prediction of Nasopharyngeal Carcinoma in China from 1991 to 2013

Xu, Zhen-Xi,Lin, Zhi-Xiong,Fang, Jia-Ying,Wu, Ku-Sheng,Du, Pei-Ling,Zeng, Yang,Tang, Wen-Rui,Xu, Xiao-Ling,Lin, Kun Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.15

Background: To analyze the mortality distribution of nasopharyngeal carcinoma in China from 1991 to 2013, to predict the mortality in the ensuing five years, and to provide evidence for prevention and treatment of nasopharyngeal carcinoma. Materials and Methods: Mortality data for Nasopharyngeal Carcinoma in China from 1991 to 2013 were used to describe its epidemiological characteristics, such as the change of the standardized mortality rate, sex and age differences, urban-rural differences. Trend-surface analysis was used to study the geographical distribution of the mortality. Curve estimation, time series, gray modeling, and joinpoint regression were used to predict the mortality for the ensuing five years in the future. Results: In China, the standardized mortality rate of Nasopharyngeal Carcinoma increased with time from 1996, reaching the peak values of $1.45/10^5$ at the year of 2002, and decreased gradually afterwards. With males being 1.51 times higher than females, and the city had a higher rate than the rural during the past two decades. The mortality rate increased from age 40. Geographical analysis showed the mortality rate increased from middle to southern China. Conclusions: The standardized mortality rate of Nasopharyngeal Carcinoma is falling. The regional disease control for Nasopharyngeal Carcinoma should be focused on Guangdong province of China, and the key targets for prevention and treatment are rural men, especially after the age of 40. The mortality of Nasopharyngeal Carcinoma will decrease in the next five years.

비인강암의 방사선치료 결과 및 생존율에 관한 예후인자 분석

정영연(Young Yeon Jung),김옥배(Ok Bae Kim),김진희(Jin Hee Kim) 대한방사선종양학회 2005 Radiation Oncology Journal Vol.23 No.2

목 적: 비인강암 환자들을 대상으로 방사선치료 성적을 후향적으로 분석하여 방사선치료의 효과 및 생존에 영향을 주는 요인들을 알아보고자 이 연구를 시행하였다. 대상 및 방법: 1987년부터 2002년까지 계명대학교 동산의료원 방사선종양학과에서 비인강암으로 확진되어 근치적 방사선치료를 받은 43명을 대상으로 하였다. 대상 환자는 AJCC 병기 제 II기, III기, IV기가 각각 12명(27.9%), 13명(30.2%), 18명(41.9%)이었고, 조직병리학적으로는 편평세포암이 15명(34.9%), 비케라틴형성암이 8명(18.6%), 미분화암이 17명(39.5%), 림프상피종이 3명(7.0%)이었다. 치료방법은 방사선단독요법 31명(72.1%),동시 항암화학방사선요법 5명(11.6%), 전보조항암화학요법 7명(16.3%)이었다. 항암화학요법을 받은 12명 중 11명은 Cisplatin과 5-Fluorouracil을 4회, 1명은 Cisplatin과 Taxotere를 6회 치료받았다. 총조사선량은 61.2∼84 Gy였고 중앙값은 70.4 Gy였다. 생존 환자의 추적기간은 2∼197개월이었고 중앙값은 84개월이었다. 결 과: 방사선치료 6개월 후 39명(90.7%)은 완전관해를, 4명(9.3%)은 부분관해를 보였다. 전체 환자의 5년 생존율 및 무병생존율은 각각 50.7%, 48.9%였으며 중앙생존기간은 73개월, 57개월이었고, 단변량분석에서 연령, T-병기, 전체병기 및 치료방법에 따라서 유의한 차이를 보였다(p<0.05). 다변량분석 결과, 5년 생존율 및5년 무병생존율에 영향을 주는 변수로는 연령, N-병기 및 전체병기가 통계적으로 유의하였으며(p<0.05), T1-3 병기와 T4병기 간에 유의한 차이를 보였다(p<0.01). 방사선치료 후 재발은 국소재발 단독 3명(7.0%), 원격전이 단독 11명(25.6%), 국소 및 원격전이 동시재발 1명(2.3%)이었다. 결 론: 비인강암의 생존에 영향을 주는 예후 인자는 연령, T-병기(T1-3과 T4), N-병기 및 전체병기임을 알 수 있었고 원격전이가 주된 실패 양상으로 분석되어 원격전이를 감소시키기 위해 적극적인 전신 항암화학요법이 필요하며 보다 효과적인 항암제와 투여방법에 관한 연구가 필요할 것으로 생각된다. Purpose: This retrospective study was conducted to analyze the treatment results and to evaluate the prognostic factors affecting the survival of nasopharyngeal carcinoma patients. Materials and Methods: From 1987 to 2002, we analyzed 43 patients who had nasopharyngeal carcinomas that were histologically confirmed and who had also completed the planned radiation therapy course at Keimyung University Dongsan Medical Center. According to the 6th edition of American Joint Committee on Cancer staging system, 12 patients (27.9%) were at Stage II, 13 (30.2%) were at Stage III and 18 (41.9%) were at Stage IV. Histopathologically, there were 15 (34.9%) squamous cell carcinomas, 8 (18.6%) nonkeratinizing carcinomas, 17 (39.5%) undifferentiated carcinomas, and 3 (7.0%) lymphoepitheliomas. Among the total 43 patients, 31 patients (72.1%) were treated with only radiation therapy. Neoadjuvant chemotherapy was performed on 7 patients (16.3%) and concurrent chemoradiotherapy was performed on 5 patients (11.6%). Cisplatin and 5-Fluorouracil were administered to 11 patients for 4 cycles, and Cisplatin and Taxotere were administered to 1 patient for 6 cycles. The range of the total radiation dose delivered to the primary tumor was from 61.2 to 84 Gy (median 70.4 Gy). The follow-up period ranged from 2 to 197 months with median follow-up of 84 months. Results: The local control rate at 6 months after radiation therapy was 90.7%. The five year overall survival and disease free survival rates were 50.7% and 48.9%, respectively. On the multivariate analysis, the age, T-stage (T1-3 vs T4), N-stage and AJCC stage were the statistically significant prognostic factors affecting survival (p<0.05). The patterns of failure were as follows: local failure only in 3 patients (7.0%), local and systemic failure in 1 patient (2.3%), and distant metastasis only in 11 patients (25.6%). Conclusion: The prognostic factors affecting the outcome of nasopharyngeal carcinoma were age, T-stage (T1-3 vs T4), N-stage and stage. Because systemic metastasis was the main failure pattern noted for nasopharyngeal carcinoma, systemic chemotherapy is needed to decrease the rate of distant metastasis for nasopharyngeal carcinoma. In addition, research for more effective chemotherapeutical regimens and schedules is also needed.

Advances and Challenges in Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma

Qu, Song,Liang, Zhong-Guo,Zhu, Xiao-Dong Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.5

Nasopharyngeal carcinoma is an endemic disease within specific regions in the world. Radiotherapy is the main treatment. In recent decades, intensity-modulated radiation therapy has undergone a rapid evolution. Compared with two-dimensional radiotherapy and/or three-dimensional conformal radiotherapy, evidence has shown it may improve quality of life and prognosis for patients with nasopharyngeal carcinoma. In addition, helical tomotherapy is an emerging technology of intensity-modulated radiation therapy. Its superiority in dosimetric and clinical outcomes has been demonstrated when compared to traditional intensity-modulated radiation therapy. However, many challenges need to be overcome for intensity-modulated radiation therapy of nasopharyngeal carcinoma in the future. Issues such as the status of concurrent chemotherapy, updating of target delineation, the role of replanning during IMRT, the causes of the main local failure pattern require settlement. The present study reviews traditional intensity-modulated radiation therapy, helical tomotherapy, and new challenges in the management of nasopharyngeal carcinoma.

림프절로 전이된 비인두 미분화 암종의 세침흡인 세포학적 소견 -주로 방추형 세포의 양상을 나타낸 1례-

민동원,이광길,Min, Dong-Won,Lee, Kwang-Gil 대한세포병리학회 1993 대한세포병리학회지 Vol.4 No.1

We describe a case of fine needle aspiration cytology of metastatic nasopharyngeal carcinoma in the lymph node of the neck presenting a predominantly spindle cell pattern. A 36 year-old male patient complained of dysesthesia on the right face and a palpable neck mass. Fine needle aspiration was done on the neck mass. Tumor cells were present in syncytial groups or singly with mainly spindle shaped nuclei, vesicular chromatin, thin and regular nuclear membrane, occasional prominent nucleoli and a few fool of cellular cohesiveness. The cytoplasm was scant and pale with ill-defined borders. Mature lymphocytes were present in the background of aspirates and within the tumor cell clusters. Histologically, the tumor of nasopharynx showed several areas of spindle cell pattern. Because the tumor cells showed a predominantly spindle shape with vesicular nuclear chromatin, the differential diagnosis of spindle cell sarcoma or granuloma of epithelioid clils were considered, but the characteristic morphology of the nuclei with vesicular chromatin and prominent nucleoli, and cellular cohesiveness were important in making the diagnosis of nasopharyngeal carcinoma. The possibility of metastatic carcinoma should always be considered in fine needle aspiration cytology of the lymph node in the neck because the incidence of metastatic carcinoma, particularly of the nasopharyngeal carcinoma in the lymph nodes of the neck is relatively high.

치료 후 액와 림프절의 전이를 보인 비인강암 1례

홍현준(Hyun Jun Hong),이원일(Won Il Lee),박미나(Mi-Na Park),정은지(Eun Ji Chung),김용태(Yong Tai Kim),최은창(Eun Chang Choi) 대한두경부종양학회 2009 대한두경부 종양학회지 Vol.25 No.1

Nasopharyngeal carcinomas are epithelial neoplasm derived from nasopharyngeal mucosa. Nasopharyngeal carcinoma involved cervical lymph nodes frequently. However, nasopharyngeal carcinoma with metastatic axillary node after concurrent chemoradiotherapy was reported rarely. We report the patients who was a 34-year-old man diagnosed as nasopharyngeal carcinoma. He was treated by concurrent chemo-radiotherapy. But axillary node metastasis was found after treatment in 2 years. After surgical resection of axillary lymph node, there is no evidence of disease.

무병 생존 상태로 경과 관찰 중이던 비인두암 환자에서 새롭게 발견된 후인두 내 림프상피암종에 대한 증례: 미분화형 비인두암의 재발에 대한 논쟁

박유영,이은정,조재구,우정수 대한이비인후과학회 2019 대한이비인후과학회지 두경부외과학 Vol.62 No.3

Lymphoepithelial carcinoma is a rare subtype of head and neck malignancy. Histologically, it is an undifferentiated carcinoma accompanied by a prominent reactive lymphoplasmacytic infiltrate. We report a case of anewly found lymphoepithelial carcinoma in the retropharynx of a patient who had been diagnosed and treated as nasopharyngeal carcinoma with multiple metastasis; the case could not be ruled out as a recurrence of nasopharyngeal carcinoma ac-cording to recent World Health Organization pathology guideline.

Survivin Gene Functions and Relationships between Expression and Prognosis in Patients with Nasopharyngeal Carcinoma

Cai, Jun-Hong,Fu, Sheng-Miao,Tu, Zhi-Hua,Deng, Li-Qun,Liang, Zhu,Chen, Xin-Ping,Gong, Xuan-Ju,Wan, Li-Hua Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.6

This study aimed to investigate the relationship between prognosis and protein and mRNA expression of an apoptotic inhibitor gene, survivin, in patients with nasopharyngeal carcinoma. Furthermore, functions of the survivin gene in the CNE2 nasopharyngeal carcinoma cell line were assessed. Immunohistochemistry and in situ hybridization were used in detecting the survivin protein and mRNA in 44 nasopharyngeal carcinoma specimens, and 30 chronic nasopharyngitis samples as controls. Survivin gene expression in CNE2 cell line was suppressed with an shRNA (short hairpin RNA). The positive ratios of expression for survivin protein and mRNA in nasopharyngeal carcinoma were 79.5% and 75.0% respectively, obviously higher than in the control group (p<0.01), and there is very good consistency between the two methods. The mean survival time of patients with higher survivin protein or mRNA expression was shorter than in patients with lower levelsv(p<0.01). Proliferation of the CNE2 cell line was distinctly inhibited by the shRNA. The results indicate that overexpression of the survivin gene plays an important role in onset and development of nasopharyngeal carcinoma, and it may be helpful for prognostic appraisal.

Effects of TESTIN Gene Expression on Proliferation and Migration of the 5-8F Nasopharyngeal Carcinoma Cell Line

Zhong, Zhun,Zhang, Fei,Yin, Shu-Cheng Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.6

Purpose: To investigate effects of the TESTIN (TES) gene on proliferation and migration of highly metastatic nasopharyngeal carcinoma cell line 5-8F and the related mechanisms. Materials and Methods: The target gene of human nasopharyngeal carcinoma cell line 5-8F was amplified by PCR and cloned into the empty plasmid pEGFP-N1 to construct a eukaryotic expression vector pEGFP-N1-TES. This was then transfected into 5-8F cells. MTT assays, flow cytometry and scratch wound tests were used to detect the proliferation and migration of transfected 5-8F cells. Results: A cell model with stable and high expression of TES gene was successfully established. MTT assays showed that the OD value of 5-8F/TES cells was markedly lower than that of 5-8F/GFP cells and 5-8F cells (p<0.05). Flow cytometry showed that the apoptosis rate of 5-8F/TES cells was prominently increased compared with 5-8F/GFP cells and 5-8F cells (p<0.05). In vitro scratch wound assays showed that, the width of the wound area of 5-8F/TES cells narrowed slightly, while the width of the wound area of 5-8F/ GFP cells and 5-8F cells narrowed sharply, suggesting that the TES overexpression could inhibit the migration ability. Conclusions: TES gene expression remarkably inhibits the proliferation of human nasopharyngeal carcinoma cell line 5-8F and reduces its migration in vitro. Thus, it may be a potential tumor suppressor gene for nasopharyngeal carcinoma.

비인두암의 국소 종양 치유와 생존율에 관한 예후 인자 분석

정웅기(Woong-Ki Chung),조재식(Jae-Shik Cho),박승진(Seung Jin Park),이재홍(Jae-Hong Lee),안성자(Sung Ja Ahn),남택근(Taek Keun Nam),최찬(Chan Choi),노영희(Young Hee Noh),나병식(Byung Sik Nah) 대한방사선종양학회 1999 Radiation Oncology Journal Vol.17 No.2

목 적 : 비인두암 환자에서 항암화학요법과 방사선치료 후 국소종양제어율, 생존율, 무병생존율에 미치는 예후 인자를 알아보고자 하였다. 대상 및 방법 : 1986년 7월부터 1996년 6월까지 약 10년간 전남대학교병원에서 비인두암으로 확진되어 근치적 목적으로 치료를 받은 47명의 환자를 대상으로 후향적 분석을 시행하였다. 대상 환자의 연령 분포는 16세에서 80세까지였고 중앙 값은 52세였다. 성별 분포는 남자가 33명(70%), 여자가 14명(30%)이었다. WHO의 기준에 의한 조직학적 유형은 제1형(케 라틴형성 편평세포암)이 3례(6%), 제2형(비케라틴형성 편평세포암)이 30례(64%), 제3형(미분화암)이 13례(28%)였고 나머 지 1례(2%)는 조직학적 유형이 알려지지 않았다. 미국암합동위원회(1997)의 병기분류법에 따라 후향적으로 다시 분류한 병기는 T1, T2a, T2b, T3, T4에서 각각 11례(23%), 6례(13%), 9례(19%), 7례(15%), 14례(30%)였다. 그리고 림프절 침범 상태는 N0, N1, N2, N3에서 각각 7례(15%), 14례(30%), 21례(45%), 5례(10%) 있었다. 병기군별 분포는 Stage I, IIA, IIB, III, IVA, IVB에서 각각 2례(4%), 2례(4%), 10례(21%), 14 례(30%), 14례(30%), 5례(11%) 있었다. 방사선치료 전에 항암제 치료를 받은 환자는 42례이며 5례는 항암제 치료가 시행되지 않았다. 방사선치료는 선형가속기의 6MV와 10MV X-ray 및 9 MeV 전자선을 사용하였으며 원발 병소에 조사된 총방사선량은 6120- 7920cGy(중앙값: 7020cGy)였다. 항암화학요법은 Cisplatin+5-Fluorouracil(25명), Cisplatin+Pepleomycin(17명)으로 1회에서 3회까지 시행하였다. 국소종양제어율, 생존율, 무병생존율을 Kaplan-Meier법에 의하여 산출하였으며 두 군간의 생존율의 차이는 Generalized Wilcoxon test를 이용하여 검증하였다. 영향을 주는 인자의 다변량분석에는 Cox 모델을 이용하였다. 결 과 : 국소종양 제어율은 2년에 89%, 5년에 81%이었다. 5년 생존율은 60%(범위; 6-132개월, 중앙값; 32개월)이었다. 예후에 영향을 미치는 위험 인자로 연령, 성별, 두개신경침범, 병리조직학적 유형, 병기군, 항암화학요법, 항암화학요법과 방사선치료 사이의 간격, 방사선량, 방사선치료기간을 다변량분석에 포함시켰다. 국소종양제어율에는 두개신경침범(P=0.004)만이 의의 있는 것으로 나타났다. 생존율과 무병생존율에는 병기군(P=0.006, P=0.003)과 총방사선량(P=0.012, P=0.008)이 의의 있는 것으로 나타났다. 치료 후 합병증은 구강건조증, 치아손상, 이증상 등이 많았으며 2례의 갑상선기능저하증이 있었다. 결 론 : 비인두암에서 예후에 영향을 미치는 인자로서 국소종양제어율은 두개신경침범 여부가, 생존율 및 무병생존율에는 총방사선량 과 병기군, 특히 N 병기가 의의 있는 것을 알 수 있었다. 사용된 항암화학요법과 방사선치료는 심각한 부작용이 없이 효과적으로 이용될 수 있음을 알 수 있었다. Purpose : This study was performed to find out the prognostic fac tors affecting local control, survival and disease free survival rate in nasopharyngeal carcinomas treated with chemotherapy and radiation therapy. Materials and Methods : We analysed 47 patients of nasopharyngeal carcinomas, histologically confirmed and treated at Chonnam University Hospital between July 1986 and June 1996, retrospectively. Range of patients' age were from 16 to 80 years (median; 52 years). Thirty three (70%) patients was male. Histological types were composed of 3 (6%) of keratinizing, 30 (64%) of nonkeratinizing squamous cell carcinoma and 13 (28%) of undifferentiated carcinoma. Histological type was not known in 1 patient (2%). We restaged according to the staging system of 1997 American Joint Committee on Cancer. Forty seven patients we re recorded as follows: T1; 11 (23%), T2a; 6 (13%), T2b; 9 (19%), T3; 7 (15%), T4; 14 (30%), and N0; 7 (15%), N1; 14 (30%), N2; 21 (45%), N3; 5 (10%). Clinical staging was grouped as follows: Stage I; 2 (4%), IIA; 2 (4%), IIB; 10 (21%), III; 14 (30%), IVA ; 14 (30%) and IVB; 5 (11%). Radiation therapy was done using 6 MV and 10 MV X- ray of linear accelerator. Electron beam was used for the lymph nodes of posterior neck after 4500 cGy. The range of total radiation dose delivered to the primary tumor was fro m 6120 to 7920 cGy (median; 7020 cGy). Neoadjuvant chemotherapy was performed with cisplatin+5-fluorouracil (25 patients) or cisplatin +pepleomycin (17 patients) with one to three cycles. Five patients have not received chemotherapy. Local control rate, sur vival and disease free survival rate were calculated by Kaplan- Meier method. Generalized Wilcoxon test was used to evaluate the difference of survival rates between groups. Multivariate analysis using Cox proportional hazard model was done for finding prognostic factors. Results : Local control rate was 81% in 5 year. Five year survival rate was 60% (median survival; 32 months). We included age, sex, cranial nerve deficit, histologic type, stage group, chemotherapy, elapsed days between chemotherapy and radiotherapy, total radiation dose, period of radiotherapy as potential prognostic factors in multivariate analysis. As a result, cranial nerve deficit (P=0.004) had statistical significance in local control rate. Stage group and total radiation dose were sig nificant prognostic factors in survival (P=0.006, P=0.012), and in disease free survival rates (P=0.003, P=0.008), respectively. Common complications were xerostomia, tooth and ear problems. Hypothyroidism was developed in 2 patients. Conclusion : In our study, cranial nerve deficit was a significant prognostic factor in local control rate, and stage group and total radiation dose were significant factors in both survival and disease free survival of nasopharyngeal carcinoma. We have concluded that chemothe rapy and radiotherapy used in our patients were effective without any serious complication.