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This carcinoma was one of the earliest cancers linked to a prior viral infection, Epstein-Barr Virus (EBV). This carcinoma accounts for 18% of all malignancies in Hong Kong, but accounts for only 2% of malignancies in the United States.

These cancers most frequently occur near the opening of the eustachian tube in the fossa of Rosenmuller. This location leads to localized symptoms of hearing loss and otitis media. As the tumor invades the surrounding tissues, there may be headaches, nose bleeds, and cranial nerve deficits. The aggressive nature of this cancer is evident as 50-80% of patients present with cervical lymph node metastases and 25% have bilateral lymph node involvement. In these cases of initial lymph node presentation, the surgeon must find the primary focus of carcinoma. Even in patients with a normal appearing nasopharynx, random biopsies may yield a diagnosis in up to 70% of cases.

EBV, the etiologic agent of infectious mononucleosis, is a well established cause of the cancer. The EBV DNA has been identified in the tumor and PCR has identifed viral sequences in metastatic deposits within lymph nodes. Serum antibodies directed against the viral proteins may help to identify these metastatic deposits.

This tumor is treated with irradiation with the undifferentiated cancers responding the best and keratinizing cancers having the least response.


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AGE RANGE-MEDIAN There is a bimodal age incidence with peaks occurring between 15 and 25 years and between 60 and 69 years
Males are favored by 2.5-3:1



Malignancies arising in oncocytic schneiderian papillomas: a report of 2 cases and review of the literature.

Maitra A, Baskin LB, Lee EL.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Arch Pathol Lab Med 2001 Oct;125(10):1365-7 Abstract quote

Oncocytic schneiderian papillomas (OSPs) are uncommon benign neoplasms that arise from the sinonasal schneiderian epithelium. Malignancies arising in OSPs are rare, and, to our knowledge, only 14 such instances have been reported in the medical literature.

We report 2 additional cases--a small cell carcinoma and a sinonasal undifferentiated carcinoma arising in OSPs and presenting synchronously with the benign neoplasm. The potential for malignant transformation in OSPs is small, but warrants that these papillomas be completely excised to exclude a coexisting carcinoma.

Clinically underdetected asymptomatic and symptomatic carotid stenosis as a late complication of radiotherapy in Chinese nasopharyngeal carcinoma patients.

Lam WW, Yuen HY, Wong KS, Leung SF, Liu KH, Metreweli C.

Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

Head Neck 2001 Sep;23(9):780-4 Abstract quote

BACKGROUND: Carotid artery stenosis is a late complication of radiotherapy to the neck region. This complication has, however, a significant impact with increased risk of stroke causing mortality and morbidity. Clinicians' awareness of this complication and early detection is therefore important.

METHODS: Eighty patients with nasopharyngeal carcinoma (NPC) who had received radiotherapy were recruited for color Doppler ultrasonography of the carotid arteries. fifty-eight patients with newly diagnosed NPC who had never received any radiotherapy were recruited as controls. All patients with significant carotid stenosis were referred to the neurology clinic for further assessment.

RESULTS: Twenty-four patients were found to have more than 50% diameter reduction in the extracranial carotid artery. Clinical assessment by a neurologist showed 9 of 24 patients had a history of transient ischemic attack, amaurosis fugax, or stroke. Seven of these patients had clinically detectable neck bruit.

CONCLUSIONS: Clinicians attending to patients after radiotherapy for head and neck cancers should be aware of this long-term complication of radiotherapy. A detailed clinical history and incorporation of auscultation of carotid arteries in routine follow-up of postradiotherapy patients are recommended.

Association between HLA-A/-B antigens and -DRB1 alleles and nasopharyngeal carcinoma in Tunisia.

Mokni-Baizig N, Ayed K, Ayed FB, Ayed S, Sassi F, Ladgham A, Bel Hadj O, El May A.

Institut de Carcinologie Salah Azaiz, Tunis, Tunisie.

Oncology 2001;61(1):55-8 Abstract quote

Using serologic and molecular methods, 45 nasopharyngeal carcinoma (NPC) patients were typed for HLA class I and class II and were compared to 100 unrelated normal Tunisians.

Our results showed that the antigen frequency of HLA-B13 and allelic frequencies of DRB1*03, DRB1*15 were significantly higher in the NPC patients than in the control group (15.5 vs. 4; 26.4 vs. 11.5, and 14.4 vs. 6.5%, respectively) probably indicating a positive association with NPC. Moreover, we observed that HLA-A23 was absent in our NPC sample and was present in 18% of normal controls, and HLA-DRB1*11 was less frequent among the patients compared to the controls (5.5 vs. 14%) suggesting a protective effect of this association with NPC.



Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma.

Gallo O, Masini E, Bianchi B, Bruschini L, Paglierani M, Franchi A.

Department of Oto-Neuro-Ophthalmologic Surgery, University of Florence Medical School, Florence, Italy.

Hum Pathol 2002 Jul;33(7):708-14 Abstract quote

Prostaglandins play a critical role in tumor development and growth by regulating numerous biologic processes, including tumor angiogenesis, with clear prognostic and therapeutic implications.

The aim of this study was to investigate the prognostic relevance of cyclooxygenase-2 (COX-2) pathway activation in head and neck squamous cell carcinoma (HNSCC). COX-2 activity was analyzed in 52 consecutive patients by assessing protein expression and prostaglandin E(2) (PgE(2)) levels and was then correlated to vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. We evaluated the prognostic impact of these parameters by Kaplan-Meier and Cox survival analysis. COX-2 expression by tumor cells was closely correlated to VEGF expression and to tumor vascularization. According to Kaplan-Meier analysis, patients with COX-2 tumor overexpression and with higher PgE(2) tumor levels had significantly shorter overall survival estimates (P = 0.022 and P = 0.033, respectively). Analogously, patients with more-vascularized tumors had worse survival than those with less-vascularized cancers (P = 0.032). Cox multivariate analysis demonstrated that the most significant prognostic factors were presence of lymph node metastasis, tumor vascularization, COX-2 protein expression, and PgE(2) tumor levels.

This study demonstrates a close correlation between COX-2 pathway, VEGF expression, and tumor angiogenesis in HNSCC. In addition, COX-2 overexpression and higher tumor vascularization appear to predict a shorter survival in patients with head and neck cancer.


Tissue specific distribution of Epstein-Barr virus (EBV) BZLF1 gene variants in nasopharyngeal carcinoma (NPC) bearing patients.

Sacaze C, Henry S, Icart J, Mariame B.

Unite de Physiopathologie Cellulaire et Moleculaire, UPR 2163 du CNRS, CHU Purpan, Avenue de Grande-Bretagne, 31059 Cedex 03, Toulouse, France

Virus Res 2001 Dec 4;81(1-2):133-42 Abstract quote

Using EBV BNLF1 gene polymorphism, we have recently shown that, in NPC bearing patients, lymphocytes and tumor cells of the same individual were infected by different viruses.

It appeared as a rule that EBV infection was by multiple strains in these immunocompetent, HIV negative patients. Our data did not detect any evident association between tumor cells and a particular BNLF1 variant. In the present paper, we extend our analysis to the BZLF1 gene of the viruses present in different sites of the same patients. Only two main variants of the BZLF1 gene were identified.

Despite this very weak polymorphism of this locus, our results entirely confirm the very frequent occurrence of multistrain infections in these patients, and the presence of different EBV strains in tumor cells and lymphocytes from the same individual. However, in contrast to our results concerning the BNLF1 gene, the BZLF1 variants appeared to be cell type specific, one being associated mainly with epithelial or tumor cells and the other with lymphocytes. The possible reasons for this distribution are discussed.

Comparative analysis of the expression of the Epstein-Barr virus (EBV) anti-apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV-related lymphoid diseases.

Nicholls J, Kremmer E, Meseda CA, Mackett M, Hahn P, Gulley ML, Brink A, Swinnen LJ, Greenspan J, De Souza Y, Grasser F, Sham J, Ng MH, Arrand JR.

Department of Pathology, The University of Hong Kong, Pok Fu Lam, Hong Kong.

J Med Virol 2001 Sep;65(1):105-13 Abstract quote

Epstein-Barr virus (EBV) has been identified in a wide range of neoplastic and non-neoplastic disorders. The EBV open reading frame BHRF1 encodes a protein with partial sequence and functional homology to the anti-apoptotic onco-protein Bcl-2 and may therefore have a role in the proliferation of EBV positive cells.

We have developed a rat monoclonal antibody against pBHRF1, which can detect BHRF1 in paraffin sections.

While a number of mutant versions of BHRF1 were recognised, the monoclonal did not detect the BHRF1 homologue encoded by Herpesvirus papio or two mutants with deletions in the BH2 region. This novel rat monoclonal antibody (6A9) was used to examine tissue sections from 39 cases of non-keratinising undifferentiated nasopharyngeal carcinoma (NPC), 6 cases of metastatic NPC, 7 cases of EBV-positive NPC with squamous differentiation from Chinese patients, 15 cases of EBV-positive post-transplant lymphoproliferative disorder (PTLD), 6 EBV-containing lymphoblastoid cell lines, and 2 cases of oral hairy leukoplakia (OHL). In 11 cases of undifferentiated NPC, RT-PCR data were available for comparison with the immunohistochemistry. Both cases of OHL and two cases of LCL were positive for BHRF1 but none of the PTLD showed positive staining. All cases of undifferentiated NPC were positive for Bcl-2 but only one BHRF1 positive cell was identified in 1 of 39 cases of primary undifferentiated NPC. The 6A9 antibody produced less background staining and no nuclear positivity compared with the commercially available mouse monoclonal 5B11.

It is concluded that BHRF1 can not be detected by immunohistochemistry in NPC and therefore it appears not to play a significant anti-apoptotic role in the progression of this EBV-associated tumour. The 6A9 monoclonal appears to be superior to 5B11 for the detection of pBHRF1 in tissue sections.

Expression of interleukin-18 by nasopharyngeal carcinoma cells: A factor that possibly initiates the massive leukocyte infiltration.

Hu H, Tang KF, Chua YN, Lu J, Feng P, Chew CT, Chan SH.
Hum Pathol. 2004 Jun;35(6):722-8. Abstract quote  

Interleukin-18 (IL-18) is a single-chain cytokine that is produced by various cells. With interleukin-12 (IL-12), it synergistically stimulates activated T cells and natural killer (NK) cells to produce interferon-gamma (IFN-gamma).

Nasopharyngeal carcinoma (NPC) is the most common form of nasal and nasopharyngeal malignancy, and in NPC tumor tissues there is an intense leukocyte infiltration comprising predominantly T cells and macrophages.

We previously showed an increased expression of IFN-gamma in the infiltrating T cells. To identify the cells that provide IL-12 and IL-18 for stimulating the expression of IFN-gamma in activated T cells, NPC cell lines CNE-2 and HK-1, as well as biopsies obtained from NPC and control individuals, were examined. CNE-2 and HK-1 cells were found to express messenger RNA encoding IL-18, but not IL-12. Secreted IL-18 was detected in the culture supernatant. Addition of a caspase-1 inhibitor decreased the secretion level, indicating that this IL-18 secretion was caspase-1 dependent. Moreover, the in vitro IL-18 production in NPC cell lines correlated with the NPC tumor cells in situ. NPC tumor cells in the biopsies produced IL-18, as detected by immunohistochemistry and immunofluorescent double staining. In contrast, IL-18 expression was not observed in the control biopsies.

We suggest that IL-18 secreted by NPC tumor cells plays a role in initiating the leukocyte infiltration process. IL-18 stimulates T cells and NK cells to produce IFN-gamma, which consequently activates macrophages and other immune cells to secrete chemokines to start a leukocyte recruitment cascade.
Microsatellite Instability in Nasopharyngeal and Lymphoepithelial Carcinomas of the Head and Neck.

*Departments of Otolaryngology daggerPathology, University of Pittsburgh Medical Center double daggerDepartment of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH.


Am J Surg Pathol. 2006 Oct;30(10):1250-1253 Abstract quote

Lymphoepithelial carcinoma (LEC) is a descriptive diagnosis for an undifferentiated carcinoma that has a typical morphologic appearance of large vesicular cells with prominent nucleoli and infiltrating lymphocytes.

Tumors with this histopathologic appearance in the head and neck can be categorized as either those that occur in endemic areas, such as Southeast Asia and are associated with Epstein-Barr virus (EBV) infection, or those that occur in other countries and are less commonly associated with EBV. The molecular changes in endemic EBV-related LEC have been fairly well studied and include both alterations in tumor suppressor genes and 1 report of high levels of microsatellite instability.

In nonendemic LECs arising in western countries, there is very little data related to molecular mutational profiles. In this study, we examined 19 cases of LEC from the United States for evidence of microsatellite instability at the DNA level and for alterations in the DNA mismatch repair (MMR) system at the immunohistochemical staining level. Only 3/19 cases showed high-level microsatellite instability and only 1 of these showed an alteration in the DNA MMR protein expression hMLH1.

These data suggest that alterations in DNA MMR system are not a common mechanism of tumorigenesis in LEC of the head and neck in a nonendemic country.

Induction of c-Met proto-oncogene by Epstein-Barr virus latent membrane protein-1 and the correlation with cervical lymph node metastasis of nasopharyngeal carcinoma.

Horikawa T, Sheen TS, Takeshita H, Sato H, Furukawa M, Yoshizaki T.

Department of Otolaryngology, School of Medicine, Kanazawa University, Japan.

Am J Pathol 2001 Jul;159(1):27-33 Abstract quote

Nasopharyngeal carcinoma (NPC) is distinctive in head and neck carcinomas for its close association with Epstein-Barr virus and its highly metastatic nature. Up-regulation of cell motility is essential for enhancement of metastatic potential. The expression of c-Met proto-oncogene, a high-affinity receptor for hepatocyte growth factor/scatter factor, has been reported to correlate with metastatic ability of the tumor cell.

We observed close association of c-Met expression with cervical lymph node metastasis (P = 0.0272) in 39 NPC specimens studied immunohistochemically

. Epstein-Barr virus-encoding latent membrane protein-1 (LMP-1) is a primary oncogene and is suggested to enhance the metastatic property of NPC. Previously, we reported that LMP-1 enhanced the motility of Madin-Darby canine kidney (MDCK) epithelial cells that was mediated by activation of Ets-1 transcription factor. Therefore, we examined the interrelationships of LMP-1, Ets-1, and c-Met. In immunohistochemical studies, the expression of LMP-1, Ets-1, and c-Met correlated significantly with each other in NPC (LMP-1 versus Ets-1, P < 0.0001; Ets-1 versus c-Met, P = 0.0012; LMP-1 versus Met, P = 0.0005). Transfection of LMP-1-expressing plasmid in MDCK cells induced c-Met protein expression. The c-Met protein was also induced by Ets-1 expression, and induction of c-Met by LMP-1 was suppressed by introducing a dominant-negative form of Ets-1 in LMP-1-expressing MDCK cells.

These results suggest that LMP-1 induces c-Met through the activation of Ets-1, which may contribute in part to the highly metastatic potential of NPC.


Segmentation of nasopharyngeal carcinoma (NPC) lesions in MR images.

Lee FK, Yeung DK, King AD, Leung SF, Ahuja A.

Diagnostic Radiology and Organ Imaging, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.

Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):608-20. Abstract quote

PURPOSE: An accurate and reproducible method to delineate tumor margins from uninvolved tissues is of vital importance in guiding radiation therapy (RT). In nasopharyngeal carcinoma (NPC), tumor margin may be difficult to identify in magnetic resonance (MR) images, making the task of optimizing RT treatment more difficult. Our aim in this study is to develop a semiautomatic image segmentation method for NPC that requires minimal human intervention and is capable of delineating tumor margins with good accuracy and reproducibility.

METHODS AND MATERIALS: The segmentation algorithm includes 5 stages: masking, Bayesian probability calculation, smoothing, thresholding and seed growing, and finally dilation and overlaying of results with different thresholds. The algorithm is based on information obtained from the contrast enhancement ratio of T1-weighted images and signal intensity of T2-weighted images. The algorithm is initiated by the selection of a valid anatomical seed point within the tumor by the user. The algorithm was evaluated on MR images from 7 NPC patients and was compared against the radiologist's reference outline.

RESULTS: The algorithm was successfully implemented on all 7 subjects. With a threshold of 1, the average percent match is 78.5 +/- 3.86 (standard deviation) %, and the correspondence ratio is 66.5 +/- 7%.

DISCUSSION: The segmentation algorithm presented here may be useful for diagnosing NPC and may guide RT treatment planning. Further improvement will be desirable to improve the accuracy and versatility of the method.

Prognostic implication of pretreatment plasma/serum concentration of Epstein-Barr virus DNA in nasopharyngeal carcinoma.

Lo YM.

Department of Chemical Pathology and Institute of Molecular Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, People's Republic of China.

Biomed Pharmacother 2001 Sep;55(7):362-5 Abstract quote

Recently, much interest has been focused on the diagnostic application and biology of tumor-derived DNA in the plasma and serum of cancer patients. Such interest has resulted in the demonstration of Epstein-Barr virus (EBV) DNA in the plasma/serum of patients with nasopharyngeal carcinoma (NPC).

Using quantitative real-time polymerase chain reaction (PCR) technology, circulating EBV DNA has been found not only to correlate with disease staging, but also to provide additional prognostic information. Following treatment, circulating EBV DNA analysis has been shown to provide useful information for the monitoring for tumor recurrence.

In addition to NPC, it is envisaged that circulating DNA technology will find wide applications in the detection and monitoring of many other types of malignancies.

Specific IgA antibodies to recombinant early and nuclear antigens of Epstein-Barr virus in nasopharyngeal carcinoma.

Hsu MM, Hsu WC, Sheen TS, Kao CL.

Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.

Clin Otolaryngol 2001 Aug;26(4):334-8 Abstract quote

Nasopharyngeal carcinoma is a common cancer in Taiwan. The Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma. The sera of patients with nasopharyngeal carcinoma have IgA antibodies to a variety of EBV latent and replicated antigens. Recently, an enzyme-linked immunosorbent assay (ELISA) kit, combining both the EBV early antigen (EA) and nuclear antigen (EBNA-1) became commercially available. The purpose of this study was to assess its clinical application.

Serum IgA antibodies to the EBV EA and EBNA-1 were measured by using the ELISA kit in various groups of subjects. Fluorescence antibody (FA) tests against EBV viral capsid antigen (VCA) and EA in the IgA and IgG classes were also studied for comparison. The DNA content analysis was also carried out to investigate the association with IgA antibody titres using ELISA. The sensitivity, specificity and accuracy of the ELISA test were 98.1%, 81.8% and 88.7% respectively. It was far better than any FA tests. The IgA antibody titres showed no association with DNA content analysis. Univariate analysis of various factors revealed that IgA antibody titres were statistically correlated to N stage (P = 0.0291) and M status (P = 0.001). However, there was no association with the age, sex, T stage and clinical stage. Multivariate analysis of various factors was found to be statistically significant in patients with T4 (P = 0.0133), N3 (P = 0.0244) or M1 (P = 0.001) respectively. Serial testing of antibody titres in 22 previously untreated patients found a trend of decreasing IgA antibody titres after initial treatment when the tumours disappeared (P = 0.0358).

The ELISA kit to identify specific IgA antibodies with the combination of EBV EA and EBNA-1 recombinant antigens has high sensitivity and acceptable specificity and accuracy in the diagnosis of nasopharyngeal carcinoma. This assay should be useful for early diagnosis and mass screening of patients.

Antibody Responses to Recombinant Epstein-Barr Virus Antigens in Nasopharyngeal Carcinoma Patients: Complementary Test of ZEBRA Protein and Early Antigens p54 and p138.

Dardari R, Hinderer W, Lang D, Benider A, El Gueddari B, Joab I, Benslimane A, Khyatti M.

Institut Pasteur du Maroc, Morocco

J Clin Microbiol 2001 Sep;39(9):3164-70 Abstract quote

Serological tests based on the antibodies directed against the Epstein-Barr virus early antigen (EA) and viral capsid antigen (VCA), which have been recognized as tumor markers for nasopharyngeal carcinoma (NPC), are routinely used to help in the diagnosis of this malignancy. The detection of these antibodies reveals very low titers, found only in a small proportion of young compared with older NPC patients. This is a problem for the diagnosis of NPC, especially among Maghrebians, among whom young people are also affected, and emphasizes the necessity to search for more reliable markers.

The present study reports results of immunoglobulin G (IgG) and IgA responses of NPC patients to recombinant EA antigens p54 (BMRF1) and p138 (BALF2), VCA complex antigens p18 (BFRF3) and p23 (BLRF2), and EBNA antigen p72 (BKRF1).

Our results show that IgA-EA-p54 and -p138 (IgA-EA-p54+138) antibodies have a diagnostic value for detection of NPC (70%), compared with IgA-VCA-p18+23 and IgA-EBNA-p72, which have limited diagnostic value, especially in young patients. It is also noteworthy that IgA-EA-p54+138 can detect a high percentage (64%) of NPC cases negative by immunofluorescence. These results, however, clearly show that a single test cannot achieve the objective of detecting all NPC patients, and it seems advisable to combine different tests for the diagnosis of NPC. The combination of IgG-ZEBRA with IgA-EA-p54+138 improved the sensitivity of detection of NPC to 95% in the overall NPC population.

The use of IgA-EA-p54+138 in combination with IgG-ZEBRA will facilitate detailed studies on the pattern of antibody response, which may result in the development of useful serological markers to guide the treatment of NPC.

Nasopharyngeal carcinoma heterogeneity of DNA content identified on cytologic preparations.

Maohuai C, Chang AR, Lo D.

Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong.

Anal Quant Cytol Histol 2001 Jun;23(3):213-7 Abstract quote

OBJECTIVE: To evaluate tumor heterogeneity of DNA content in nasopharyngeal carcinoma (NPC) performed on cytologic specimens.

STUDY DESIGN: Image cytometric analysis of DNA ploidy status of 40 NPCs was performed on nasopharyngeal brushing smears stained with the Feulgen method after hematoxylin eosin staining. If the DNA distribution pattern from the same tumor exhibited diploid, aneuploid or/and tetraploid peaks or some combination of these patterns, the presence of tumor heterogeneity of DNA content was identified.

RESULTS: Thirty-four cases (85%) had a nondiploid DNA pattern among the 40 NPCs. Twenty-eight cases exhibited tumor heterogeneity of DNA content (70%). Of the 28 tumors, 13 (46%) had a combination of diploid and tetraploid patterns, 10 (37%) had a combination of diploid and aneuploid patterns, 3 cases (11%) had a combination of tetraploid and aneuploid patterns, and 2 cases had two aneuploid stem lines. The relationship between DNA ploidy pattern and tumor histologic and cytologic morphology was also examined.

CONCLUSION: There is a high incidence of DNA content heterogeneity in NPC. The relevance of tumor heterogeneity to the biologic behavior of NPC awaits further study. DNA quantification with image cytometry on destained cytologic preparations is feasible and reliable.

Presence of Epstein-Barr virus latent membrane protein 1 gene in the nasopharyngeal swabs from patients with nasopharyngeal carcinoma.

Lin SY, Tsang NM, Kao SC, Hsieh YL, Chen YP, Tsai CS, Kuo TT, Hao SP, Chen IH, Hong JH.

Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China.

Head Neck 2001 Mar;23(3):194-200 Abstract quote

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy in southeastern China and Taiwan. Early detection of the local disease followed immediately by proper treatment is essential to increase the cure and survival rates. Because every NPC tumor cell carries Epstein-Barr Virus (EBV) genomes, detection of EBV genomic DNA such as latent membrane protein 1 gene (LMP1) might indicate the presence of NPC. We developed a simple and noninvasive technique of nasopharyngeal swabbing to acquire nasopharyngeal cells for detecting the presence of EBV genome. The aim of this study was to investigate the feasibility and reliability of this technique.

METHODS: We collected nasopharyngeal cells by means of a nasopharyngeal swabbing technique and detected the presence of EBV LMP1 with polymerase chain reaction (PCR). Thirty-eight swab specimens were obtained from patients with NPC who were newly diagnosed or were just beginning radiotherapy. Two groups of control subjects were recruited, including 20 patients with other head and neck cancers and eight family members of the NPC patients. An additional group of 65 NPC patients were enrolled in the course of regular follow-up after definitive radiotherapy.

RESULTS: All of the samples yielded sufficient DNA for PCR amplification. Thirty-six of 38 NPC swab samples were positive for EBV LMP1, and all the control subjects had swab sample results negative for EBV. All five patients with suspected local recurrence exhibited positive EBV test results.

CONCLUSIONS: Demonstration of EBV LMP1 in the nasopharyngeal swab specimens detected NPC with a sensitivity of 94.7% and specificity of 100%. This study confirms the reliability and feasibility of nasopharyngeal swab in the predicting and screening of NPC.

Detection of Epstein-Barr virus DNA the peripheral-blood cells of patients with nasopharyngeal carcinoma: relationship to distant metastasis and survival.

Lin JC, Chen KY, Wang WY, Jan JS, Liang WM, Tsai CS, Wei YH.

Institute of Clinical Medicine, College of Medicine, and Department of Biochemistry and Center for Cellular and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan.

J Clin Oncol 2001 May 15;19(10):2607-15 Abstract quote

PURPOSE: Nasopharyngeal carcinoma (NPC) has been proved to be an Epstein-Barr virus (EBV)-associated cancer. By use of nested polymerase chain reactions (PCRs), we examined whether the presence of EBV DNA in the peripheral-blood cells (PBC) can serve as a prognostic indicator for NPC.

PATIENTS AND METHODS: Peripheral blood from 124 patients with NPC who had no evidence of distant metastasis and 114 healthy volunteers with serologically positive findings for EBV infection was collected prospectively. Plasma and erythrocytes were separated. DNA was extracted from PBCs and analyzed by a nested PCR using primers specific to Epstein-Barr virus nuclear antigen 1 (EBNA-1). All patients were treated by radiotherapy with or without chemotherapy. Clinical parameters and status of EBNA-1 in PBCs were used for survival analysis using the Kaplan-Meier method and the Cox proportional hazards model.

RESULTS: Positive rates of EBNA-1 DNA in PBCs of NPC patients and healthy volunteers are 71% and 14%, respectively (P =.001). No significant difference was observed with regard to the clinical characteristics of patients who were EBNA-1-positive (n = 88) and those who were EBNA-1-negative (n = 36). After a median follow-up period of 38 months (range, 24 to 56 months), 29 of 88 EBNA-1-positive patients and only one of 36 EBNA-1-negative patients developed distant metastases (P =.00015). Kaplan-Meier estimates of overall survival (P =.0010), metastasis-free survival (P =.0004), and progression-free survival (P =.0004) were significantly lower for the patients in the EBNA-1-positive group than for those in the EBNA-1-negative group. Multivariate Cox analysis confirmed the same results.

CONCLUSION: The presence of EBNA-1 DNA in PBCs is a novel, important risk factor for patients with NPC that indicates a significantly higher risk of developing distant metastasis as well as a lower survival rate.


Keratinizing Less association with EBV
Least radiosensitive
Poorest prognosis
Microscopic evidence of keratinization
Non-keratinizing-Differentiated Strong association with EBV
No microscopic evidence of keratinization with cells with well defined margins and cells that interdigitate in a pavement stone pattern
Undifferentiated (Lymphoepithelioma) Strong association with EBV
Poorly differnentiated cells with pleomorphic nuclei growing in a syncytial pattern
Inflammatory cell infiltrate rich in lymphocytes and eosinophils
Regaud, Shmincke, and mixed patterns of growt

Thyroid transcription factor-1 expression in thyroid-like nasopharyngeal papillary adenocarcinoma: report of 2 cases.

Carrizo F, Luna MA.

Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Ann Diagn Pathol. 2005 Aug;9(4):189-92. Abstract quote  

We present the cases of 2 pediatric patients with low-grade nasopharyngeal papillary adenocarcinoma with features suggestive of thyroid origin.

Both cases showed strong nuclear immunoreactivity for thyroid transcription factor-1 protein and positive immunostaining for cytokeratins 7 and 19. After thyroid imaging studies, local excision was performed in both patients.

The patients remain free of disease 2 and 15 years after treatment, with no evidence of lesions in the thyroid or elsewhere.
Salivary gland type nasopharyngeal carcinoma

Am J Surg Pathol 2001;25:80-86

Study of 15 cases
Mucoepidermoid CA most common type
Median age 50 years
Other subtypes:
Adenoid cystic CA
Papillary adenocarcinoma
Composite adenocarcinoma and undifferentiated carcinoma

EBV detected by EBER ISH in 9/15 cases and by PCR of the LMP-1 gene in 10/15 cases

Overall prognosis poor with 6/13 DOD with median survival of 1 year



Sinonasal undifferentiated carcinoma, nasopharyngeal-type undifferentiated carcinoma, and keratinizing and nonkeratinizing squamous cell carcinoma express different cytokeratin patterns.

Franchi A, Moroni M, Massi D, Paglierani M, Santucci M.

Am J Surg Pathol 2002 Dec;26(12):1597-604 Abstract quote

Sinonasal undifferentiated carcinoma (SNUC) is a highly aggressive malignant neoplasm that is often difficult to distinguish from other poorly differentiated carcinomas arising in the sinonasal tract.

To search for a differential cytokeratin (CK) expression that could be useful for diagnostic purposes, we compared the expression of a large panel of CKs in a series of 6 SNUCs, 10 poorly differentiated squamous cell carcinomas (SCCs), 10 nonkeratinizing squamous cell carcinomas (NKSCCs), and 5 nasopharyngeal-type undifferentiated carcinomas (NPTCs). SCC, NKSCC, and NPTC frequently showed immunoreactivity for CK5/CK6, CK8, CK13, and CK19. In addition, SCC and NKSCC expressed CK14, which was not detected in NPTC, and SCC expressed CK7 (60% of cases) and CK4 (30% of cases), which were absent in NKSCC and NPTC. Three NKSCCs were associated with a Schneiderian papilloma, and the results of the immunostaining were similar in the two components, with the exception of CK4 and CK7, which were expressed by the papilloma and not by the carcinoma.

In contrast to other carcinomas, SNUC was characterized by the exclusive expression of CKs of simple epithelia, such as CK8 (100% of cases), CK7 (50% of cases), and CK19 (50% of cases). Thus, there are significant differences in the pattern of CK expression between SNUC, SCC, NKSCC, and NPTC, which could be of diagnostic aid. Moreover, these findings support the hypothesis that SNUC is a separate entity from SCC and NPTC of the sinonasal tract.

P53 overexpression in nasopharyngeal carcinoma.

Agaoglu FY, Dizdar Y, Dogan O, Alatli C, Ayan I, Savci N, Tas S, Dalay N, Altun M.

Istanbul University, Istanbul Medical Faculty, Radiation Oncology Department, Istanbul, Turkey.
In Vivo. 2004 Sep-Oct;18(5):555-60. Abstract quote

Nasopharyngeal carcinoma (NPC) is a characteristic tumor displaying epidemiological, genetic and regional distribution properties and is unique by its natural behavior and therapy. Investigation of the molecular and biological changes, gene amplifications and activations that occur during carcinogenesis and progression can provide new insight into the pathology of the disease and may add biological factors that can be used as new prognostic markers. The p53 tumor suppressor gene is the most frequently mutated gene in human cancer. Although point mutations in the p53 gene are observed in nasopharyngeal cancer, the mutation rate is lower than in other tumors.
Immunohistochemical studies have shown significant p53 overexpression in NPC material.

In this study, p53 protein immunoreactivity was investigated in paraffin sections of primary nasopharyngeal tumors and metastatic cervical lymph nodes and association with clinical and histopathological characteristics was evaluated. Ninety-seven paraffin sections from 81 patients with NPC treated from 1990 to 1996 were examined by immunohistochemistry and were correlated with clinical features and treatment outcome. Among a total of 97 samples, positive staining for p53 protein was observed in 83 (85.5%) samples while no staining was found in 14 (14.5%) cases. Immunoreactivity was observed in 62 (81.5%) of the primary nasopharyngeal biopsy specimens. The correlation between p53 expression and histological type, stage, age and sex distributions was tested. After statistical analysis according to Chi-square test and Yates' correction, no significant difference was demonstrated (p>0.05). There was no statistically significant correlation with p53 immunoreactivity and overall and disease-free survival.

Although the association between NPC and p53 is not clear, our study confirms that p53 overexpression is present in a considerable subset of patients with NPC.


General In the non-keratinizing and undifferentiated types, the pathologist is often faced with a differential diagnosis of other poorly differentiated tumors that may histologically mimic this tumor. In particular, a Hodgkin's and non-Hodgkin's lymphoma and a melanoma should be excluded by appropriate studies including immunoperoxidase stains.
Sinonasal undifferentiated carcinoma  

Bizarre Epithelial Atypia of the Sinonasal Tract After Chemotherapy

William H. Westra, etal.

Am J Surg Pathol 2001;25:652-656 Abstract quote

Certain chemotherapeutic agents can induce bizarre epithelial atypia. The lower respiratory tract is a frequently targeted site, but similar changes have not been described adequately in the sinonasal tract. Unfamiliarity with these changes could potentially cause confusion with an infectious or neoplastic process.

All biopsies of the sinonasal tract at The Johns Hopkins Hospital were reviewed prospectively over a 54-month period. Eleven cases with bizarre atypia of the respiratory epithelium formed the basis of this study. The medical records of these patients were reviewed. The specimens were from 11 patients who had previously undergone chemotherapy and bone marrow transplantation for acute myelocytic leukemia (n = 5), multiple myeloma (n = 3), acute lymphocytic leukemia (n = 2), and chronic myelocytic leukemia (n = 1). Although the chemotherapy regimens were highly variable, all included one or more of the alkylating agents (cyclophosphamide, n = 11; busulfan, n = 5; melphalan, n = 1). In all 11 patients, biopsies were acquired to rule out invasive fungal sinusitis. The atypical epithelial changes included striking nuclear enlargement, hyperchromasia, and pleomorphism. Sometimes these changes were full thickness and were associated with squamous metaplasia. Two of eight cases evaluated by frozen section were misinterpreted initially as high-grade epithelial dysplasia.

Certain chemotherapeutic agents can induce striking epithelial atypia in the sinonasal tract. These changes should not be interpreted as neoplastic in nature, a potential pitfall in the frozen section evaluation of a destructive nasal process in oncology patients.

Sinonasal Undifferentiated Carcinoma and Nasopharyngeal-Type Undifferentiated Carcinoma
Two Clinically, Biologically, and Histopathologically Distinct Entities

Yung-Ming Jeng, M.D.; Ming-Tse Sung, M.D.; Chia-Lang Fang, M.D., M.S.; Hsuan-Ying Huang, M.D.; Tsui-Lien Mao, M.D., M.S.; Wei Cheng, M.D., M.S.; Cheng-Hsiang Hsiao, M.D.

From the Department of Pathology (Y.-M.J., T.-L.M., W.C., C.-H.H.), National Taiwan University Hospital, Taipei, the Department of Pathology (M.-T.S., H.-Y.H.), Chang-Gung Memorial Hospital, Koahsiung, and the Department of Pathology (C.-L.F.), Taipei Medical University-affiliated Taipei Wan Fang Hospital, Taipei, Taiwan.


Am J Surg Pathol 2002;26:371-376 Abstract quote

Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive neoplasm arising in the nasal cavity and paranasal sinuses. Primary sinonasal nasopharyngeal-type undifferentiated carcinoma (PSNPC) is an even rarer tumor that has not been adequately reported. Both tumors have been reported to be associated with Epstein–Barr virus (EBV).

We studied the clinicopathologic features and EBV status of 36 SNUC and 13 PSNPC patients from Taiwan, an EBV endemic area.

The median age of SNUC patients was 53 years (range 20–76 years), with a male/female ratio of approximately 2:1. Five patients had histories of previous nasopharyngeal carcinoma treated with irradiation 6–26 years earlier. The most common locations were nasal cavity and ethmoid sinus. Orbital and intracranial invasion and distant metastasis were frequent findings. The median survival was 10 months. All 36 tumors were negative for EBER-1 by in situ hybridization.

The median age of PSNPC patients was 58 years (range 36–75 years), with a male/female ratio of approximately 2:1. The most common location is nasal cavity. Eight patients achieved disease-free survival. Eight tumors had the morphology of lymphoepithelioma, whereas significant inflammatory infiltrate was not detected in the other five tumors. All 13 tumors were positive for EBER-1 by in situ hybridization.

Because of the difference in the relation with EBV, prognosis, and response to radiotherapy, SNUC and PSNPC should be considered as two entirely different entities. The most important criteria for PSNPC are vesicular nuclei, syncytial pattern, spindle cells, and absence of necrosis.


The diagnosis of Thornwaldt's cyst.

Boucher RM, Hendrix RA, Guttenplan MD.

Department of Otorhinolaryngology and Human Communication, Hospital of the University of Pennsylvania, Philadelphia.

Trans Pa Acad Ophthalmol Otolaryngol 1990;42:1026-30 Abstract quote

Thornwaldt's cyst is an uncommon nasopharyngeal lesion which develops from the remnant of the primitive notochord. A case report of a patient with a Thornwaldt's cyst and cervical adenitis is presented.

Though computed tomography of the head and neck was unremarkable, magnetic resonance imaging of the nasopharynx revealed the Thornwaldt's cyst, suggesting that this modality may be more sensitive in detecting and evaluating cystic lesions of the nasopharynx. The differential diagnosis of cystic nasopharyngeal masses is discussed.


Prognostic significance of parapharyngeal space venous plexus and marrow involvement: Potential landmarks of dissemination for stage I-III nasopharyngeal carcinoma.

Cheng SH, Tsai SY, Yen KL, Jian JJ, Feng AC, Chan KY, Hong CF, Chu NM, Lin YC, Lin CY, Tan TD, Hsieh CY, Chong V, Huang AT.

Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.
Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):456-65. Abstract quote

PURPOSE: To determine whether the parapharyngeal space venous plexus and marrow of the skull base bones are anatomic landmarks of the potential routes for the spread of disease for Stage I-III (American Joint Commission on Cancer 1997 staging system) nasopharyngeal carcinoma (NPC).

METHODS AND MATERIALS: A total of 364 patients with NPC were enrolled in this study. The selection criteria were Stage I-III disease and primary radiotherapy at our hospital between 1990 and 2001. All patients had undergone MRI to evaluate the head-and-neck tumors. Patients who had undergone inadequate radiotherapy at a dose of <60 Gy and/or preradiotherapy chemotherapy before the imaging evaluation were excluded from the study.

RESULTS: Of the 364 patients treated between 1990 and 2001, 163 (44.8%) had low-risk Stage I-III NPC (without parapharyngeal space extension or T3 disease). The 5-year distant metastasis-free survival rate, with and without adjuvant chemotherapy, was 97% and 96%, respectively. The remaining 201 patients had Stage II-III with parapharyngeal space extension or T3 disease. Their 5-year recurrence-free survival rate, with and without adjuvant chemotherapy, was 76.8% and 53.2% (p = 0.01), respectively.

CONCLUSION: Our findings suggest that the risk of distant metastasis in Stage I-III NPC patients without parapharyngeal space extension or T3 disease is extremely low. Invasion into the parapharyngeal space venous plexus and marrow of the skull base bones is associated with distant metastasis, and involvement of these anatomic sites is considered a potential route for hematogenous disease spread in patients with Stage I-III NPC.

Retrospective comparison of the AJCC 5th edition classification for nasopharyngeal carcinoma with the AJCC 4th edition: an experience in Taiwan.

Chien CR, Chen SW, Hsieh CY, Liang JA, Yang SN, Huang CY, Lin FJ.

Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.

Jpn J Clin Oncol 2001 Aug;31(8):363-9 Abstract quote

OBJECTIVE: The aim of this study was to compare the new AJCC 5th edition classification system for nasopharyngeal carcinoma (NPC) with the AJCC 4th edition by re-evaluating the staging of patients treated in Taiwan.

METHODS: From 1992 through 1996, 117 NPC patients without distant metastasis were treated using complete courses of radiotherapy. All patients had complete CT examinations of the nasopharynx and neck. Each patient was re-staged according to the 5th edition of the AJCC classification system. Their overall survival (OS), loco-regional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) were compared between the two staging systems, using the Kaplan-Meier method, log-rank test, Wilcoxon test and Cox proportional hazard model.

RESULTS: After a median follow-up of 58.3 months, the 5-year OS for stage I, II, III and IV was 88, 86, 61 and 48%, respectively, according to the new staging. A more even distribution of patients was noted among the patients classified according to the AJCC 5th edition than the 4th edition. The distribution of stages I, II, III and IV was 13.7, 37.6, 15.4 and 33.3%, respectively, using the new staging system, whereas it was 0.8, 14.5, 20.5 and 64.2%, respectively, using the old staging system. More statistically significant differences among 5th edition stages and T classifications than the 4th edition were also noted.

CONCLUSIONS: The 5th edition of the AJCC staging system appears to have a more even distribution of patients and more statistically significant differences in predicting prognosis than the 4th edition, mostly in stages and T classification.

Roles of DNA cytometry and detection of EBERs in predicting a diagnosis of nasopharyngeal carcinoma.

Maohuai C, Chang AR, Shikyuen L.

Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong.

Anal Quant Cytol Histol 2001 Jun;23(3):207-12 Abstract quote

OBJECTIVE: To analyze the suitability of DNA cytometry and detection of Epstein-Barr virus (EBV)-encoded RNAs (EBERs) on nasopharyngeal brushings for predicting a diagnosis of nasopharyngeal carcinoma (NPC).

STUDY DESIGN: Cytologic preparations in 66 cases suspicious for NPC were evaluated for NPC diagnosis in comparison with the histologic diagnosis. Based on cytologic examination, 38 cases containing cytologically proven cancer and 8 cases interpreted as cytologically negative for cancer with adequate cellularity in the smear specimens were analyzed for DNA ploidy with an image analyzer and for EBER expression by in situ hybridization (ISH).

RESULTS: Based on the cytologic diagnosis, DNA aneuploidy analysis, DNA nondiploidy analysis and EBER detection demonstrated a sensitivity of 50%, 84% and 92%, respectively, with the same specificity, 100%, for predicting a diagnosis of cancer. Their negative predictive values were 30%, 57% and 73%, respectively. There was a significant difference between DNA aneuploidy analysis and EBER analysis in sensitivity (P < .001) and in negative predictive value (P < .05) but not between DNA nondiploidy analysis and EBER analysis even though EBER analysis showed a slightly higher value in both parameters (P > .1 and P > .5, respectively).

CONCLUSION: ISH for EBERs in cytologic smears showed a role superior to that of DNA aneuploidy analysis in the diagnosis of NPC. Considering its advantages of simple experimental conditions and lower cost as compared with DNA measurement, EBER detection can play a practical and important diagnostic role in patients suspected of having primary NPC.

Prognostic features and treatment outcome in patients with nasopharyngeal carcinoma: an experience of 20 years.

Tombolini V, De Sanctis V, Donato V, Osti MF, Raffetto N, Santarelli M, Domenico V, De Nicolo M, Enrici RM.

Cattedra di Radioterapia, Universita degli Studi di L'Aquila, via Vetoio no. 67, Coppito, L'Aquila, Roma, Italy

Anticancer Res 2001 Mar-Apr;21(2B):1413-8 Abstract quote

BACKGROUND: The best treatment of Nasopharyngeal Carcinoma (NPC) is still an open question. The purpose of this retrospective study was to determine risk factors that affect locoregional control and treatment outcome of NPC patients after radiotherapy, with or without chemotherapy.

METHODS: Between January 1976 and December 1996, 66 consecutive patients (stage I = 0; stage II = 13; stage III = 32; stage IV = 21) were given definitive radiotherapy at a single Institution. Concurrent or adjuvant chemotherapy was also given to 14 of them (21%). Multivariate analysis was performed to evaluate age, T stage, N stage, radiotherapy dose, histology, chemotherapy bone of skull erosions or cranial nerve palsies and base of skull involvement as prognostic factors of locoregional control and overall survival.

RESULTS: By the end of January 2000, after a median follow-up of 66 months and a minimal follow-up of 36 months, the event-free overall survival rate of 5 years was 48% and the overall survival 54%. Risk factor analysis revealed that radiotherapy dose, age and stage were the most important factors for overall survival of these patients. The 5 year overall survival was 89% for stage II and 49% for stage III-IV (p = 0.004), 62% for dose higher than 60 Gy and 20% for dose below 60 Gy (p = 0.007), 62% for age below 65 years and 36% for age higher than 65 years (p = 0.027). The concurrent or adjuvant chemotherapy did not have prognostic significance.

CONCLUSIONS: We confirm the need to determine the risk factors in patients with NPC. The choice of treatment, whether radiotherapy alone, at dose > 60 Gy, or radiotherapy plus chemotherapy, should be made after identification of patients with high risk disease, suitable for the combined modality.

Expression of multidrug resistance 1 and glutathione-S-transferase- protein in nasopharyngeal carcinoma

Chi-Long Chen, MD, PhD
Tzung-Shiahn Sheen, MD, PhD
Ia-Uen Lou, MS
Ai-Chun Huang, MS

Hum Pathol 2001;32:1240-1244. Abstract quote

Radiotherapy is the modality of choice for the treatment of nasopharyngeal carcinoma (NPC). However, systemic chemotherapy has recently been found to play an increasing role in the treatment of advanced or metastatic disease. The status of drug resistance gene expression that has crucial impact on chemotherapy has not been fully addressed for patients with NPC.

In this study, we examined the expression of multidrug resistance 1 (MDR-1) and glutathione-S-transferase- (GST-) in primary, recurrent, and metastatic NPC using results of immunohistochemical examinations. The results were correlated with the expression of Epstein-Barr virus (EBV) latent protein, latent membrane protein 1 (LMP1), and clinicopathologic features, including stage, histopathologic types, and survival rates. MDR-1 protein expression was detected in 18 (12.6%) of 143 patients with primary NPC, 14 (32.6%) of 43 with recurrent NPC, and O (0%) of 20 with metastatic NPC, whereas 83 (58%) of 143 patients with primary NPC, 30 (69.8%) of 43 with recurrent NPC, and 13 (65%) of 20 with metastatic NPC expressed GST-. EBV-LMP1 was expressed in 59 (41.3%) of 143 patients with primary NPC, 23 (53.5%) of 43 with recurrent NPC, and 9 (45%) of 20 with metastatic NPC. Simultaneous expression of MDR1 and GST- was observed in 13 (72.2%) of 18 patients with primary NPC and 12 (85.7%) of 14 with recurrent NPC. The expression of LMP1 was detected in only 6 of the 13 patients with primary NPC and 6 of the 12 with recurrent NPC.

We concluded that the expression of GST- was more frequent in NPC tumor tissues than the expression of MDR-1. The expression of MDR-1 correlated with clinicopathologic features of primary NPC, including the histopathologic types and survival rates, but not with disease stage. The expression of GST- did not correlate with clinicopathologic features. The expression of MDR-1 and GST- did not correlate with expression of EBV-LMP1 for patients with NPC.

Absence of caspase 3 activation in neoplastic cells of nasopharyngeal carcinoma biopsies predicts rapid fatal outcome.

Oudejans JJ, Harijadi A, Cillessen SA, Busson P, Tan IB, Dukers DF, Vos W, Hariwiyanto B, Middeldorp J, Meijer CJ.

1Department of Pathology, VU Medical Center, Amsterdam, The Netherlands.

Mod Pathol. 2005 Jul;18(7):877-85. Abstract quote  

Poor prognosis in nasopharyngeal carcinoma patients may result from resistance to the apoptosis-inducing effect of radio- and/or chemotherapy. Apoptosis depends on proper activation of caspase 3, resulting in cleavage of key proteins like PARP-1.

To investigate whether disruption of the apoptosis pathway results in therapy-resistant tumour cells, we investigated whether absence of caspase 3 activation in tumour biopsies of nasopharyngeal carcinoma patients is related to poor clinical outcome. Moreover, we investigated whether absence of caspase 3 activation is related to loss of procaspase 3 expression or expression of the apoptosis regulators p53, bcl-2 and XIAP.

We studied 36 Indonesian nasopharyngeal carcinoma patients without evidence of distant metastases who were treated with curative intent by radiotherapy only. Activation of caspase 3 and expression of the different markers were determined using specific antibodies. Levels of caspase 3 activation were determined by quantifying positively staining tumour cells. Nasopharyngeal carcinoma-derived C15 and C17 tumour cells were used as control. Absence of caspase 3 activation was strongly related to a poor clinical response to radiotherapy and to a higher T and N stage, resulting in a particularly poor clinical outcome with regard to progression-free (P<0.0001) and overall survival time (P<0.0001). Absence of caspase 3 activation was significantly correlated to loss of expression of procaspase 3 (P=0.04).

In nasopharyngeal carcinoma patients treated with curative intent, absence of active caspase 3-positive neoplastic cells predicts rapid fatal outcome, and is associated with poor response to radiotherapy and high T and N stage at time of presentation.

Expression of HER2 and C-KIT in nasopharyngeal carcinoma: implications for a new therapeutic approach.

Bar-Sela G, Kuten A, Ben-Eliezer S, Gov-Ari E, Ben-Izhak O.

Departments of Oncology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Mod Pathol. 2003 Oct;16(10):1035-40 Abstract quote.  

We sought to determine the expression and prognostic significance of HER2 and c-KIT proteins in nasopharyngeal carcinoma (NPC). In this retrospective study, immunohistochemical stains for HER2 and c-KIT were performed on formalin-fixed paraffin-embedded sections from 49 patients with NPC who were treated at our hospital from 1971 to 2000.

The clinical and immunohistochemical data were correlated, including gender, ethnic origin, age, histological type, EBV status (EBER in situ hybridization), stage, and overall survival. HER2 expression was not found in the tested samples. C-KIT overexpression was found in 33% (16/49) of the patients. Nine of the 16 samples (56%) were strongly positive for c-KIT protein (staining of >50% of the tumor cells). C-KIT expression was associated with younger age. C-KIT was not found in patients with squamous carcinoma or in those with negative EBV status, although these two groups consisted of only five patients each. Although c-KIT-positive cases tended to be associated with slightly better survival, this was not statistically significant. C-KIT protein was expressed in one third of the NPC patients in this study, only in EBV-positive, undifferentiated, or nonkeratinizing carcinoma patients.

Further study is needed to check whether c-KIT expression is correlated with c-KIT DNA mutations and to test the possibility of treatment with imatinib mesylate (Gleevec). HER2 protein was negative in the same tested specimens.

Expression of interleukin-8 receptor a predicts poor outcome in patients with nasopharyngeal carcinoma.

Horikawa T, Kaizaki Y, Kato H, Furukawa M, Yoshizaki T.

Department of Otolaryngology, Fukui Saiseikai Hospital, Fukui, Japan.
Laryngoscope. 2005 Jan;115(1):62-7. Abstract quote

OBJECTIVES/HYPOTHESIS: The authors recently demonstrated that interleukin-8 (IL-8) is induced by Epstein-Barr virus encoding latent membrane protein 1 and that IL-8 is overexpressed in tumor cells and correlates significantly with angiogenesis in nasopharyngeal carcinoma. The present objective was to investigate the expressions and the roles of IL-8 receptors in nasopharyngeal carcinoma.

STUDY DESIGN: Retrospective patient file review and immunohistochemical study of tissues of patients with nasopharyngeal carcinoma.

METHODS: The authors examined the expressions of two high-affinity IL-8 receptors, IL-8 receptor A (IL8RA) and IL-8 receptor B (IL8RB), in 30 patients with nasopharyngeal carcinoma by immunohistochemical analysis.

RESULTS: As expected, both IL-8 receptors were expressed on microvessels in tumor nests and surrounding stroma. Interestingly, they were also abundantly expressed on tumor cells. The expressions of IL8RA and IL8RB had no associations with gender, metastasis, or clinical stage. However, the expression of IL8RA in tumors significantly correlated with a shorter overall survival rate (P = .0045). Although the estimated 5-year overall survival rate for IL8RA-negative patients was 68.2%, that in IL8RA-positive patients was only 33.3%.

CONCLUSION: The study results suggest that the expression of IL8RA in tumor cells becomes an important indicator of poor prognosis in nasopharyngeal carcinoma.

Recurrent nasopharyngeal carcinoma: the puzzles of long latency.

Lee AW, Foo W, Law SC, Poon YF, Sze WM, O SK, Tung SY, Chappell R, Lau WH, Ho JH.

Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong.

Int J Radiat Oncol Biol Phys 1999 Apr 1;44(1):149-56 Abstract quote

PURPOSE: To study the peculiar characteristics of relapses with long latency following radical treatment for nasopharyngeal carcinoma.

METHODS AND MATERIALS: 847 patients with nasopharyngeal recurrence were retrospectively studied, focusing on the independent effects of latency on different outcome aspects and its relationship with other prognostic factors.

RESULTS: The proportion of recurrence with latency <2 years (Group A), 2-<5 years (Group B), and 25 years (Group C) were 52%, 39%, and 9%, respectively. A higher proportion of Group C originated from patients with node-negative early primary, but fewer of them were still confined within the nasopharynx at detection of recurrence. There was no significant difference in the choice of salvage modality, but among those reirradiated, more of Group C were treated with external beams to a higher dose. The difference in local salvage rate was not statistically significant, but the 5-year distant failure-free rates of the 3 groups were 57%, 67%, and 83%, respectively; and the corresponding disease-specific survival (DSS) were 14%, 20%, and 35%. Multivariate analysis confirmed the independent significance of latency in predicting distant failure (hazard ratio = 0.81 per year, p < 0.01) and cancer deaths (hazard ratio = 0.90 per year, p < 0.01).

CONCLUSIONS: Nasopharyngeal recurrence with long latency showed different natural behavior: the prognosis was significantly better due to lower risk of distant failure.

Long-Term Survival After Cisplatin-Based Induction Chemotherapy and Radiotherapy for Nasopharyngeal Carcinoma: A Pooled Data Analysis of Two Phase III Trials.

Chua DT, Ma J, Sham JS, Mai HQ, Choy DT, Hong MH, Lu TX, Min HQ.

Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR; and Department of Radiation Oncology & Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University, Guangzhou, China.
J Clin Oncol. 2005 Jan 18; [Epub ahead of print] Abstract quote

PURPOSE: To evaluate the long-term outcome in patients with nasopharyngeal carcinoma (NPC) treated with induction chemotherapy and radiotherapy (CRT) versus radiotherapy alone (RT).

PATIENTS AND METHODS: The data from two phase III studies comparing CRT with RT in NPC were updated and pooled together for analysis. A total of 784 patients were included for analysis, with an equal number of patients in both arms. Induction chemotherapy consisted of two to three cycles of cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin. RT was given to the nasopharynx and neck using megavoltage radiation (median dose, 70 Gy). The median follow-up time for surviving patients was 67 months. Analysis was based on intention to treat.

RESULTS: The addition of induction chemotherapy to RT was associated with a decrease in relapse by 14.3% and cancer-related deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = .014), and the 5-year disease-specific survival rate was 63.5% and 58.1% in the CRT and RT arm, respectively (P = .029). The 5-year overall survival rate was 61.9% and 58.1% in CRT and RT arm, respectively (P = .092). The incidence of locoregional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively, with induction chemotherapy. There was no significant difference in the treatment failure patterns between the two arms.

CONCLUSION: The addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in relapse and improvement in disease-specific survival in advanced-stage NPC. However, there was no improvement in overall survival.
Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience.

Kam MK, Teo PM, Chau RM, Cheung KY, Choi PH, Kwan WH, Leung SF, Zee B, Chan AT.

Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
Int J Radiat Oncol Biol Phys. 2004 Dec 1;60(5):1440-50. Abstract quote

PURPOSE: To evaluate the efficacy of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC), including the role of dose escalation above 66 Gy level.

METHODS AND MATERIALS: Between July 2000 and September 2002, 63 newly diagnosed NPC patients were treated with IMRT. The disease was Stage I in 9 (14%), Stage II in 18 (29%), Stage III in 22 (35%), and Stage IV in 14 (22%). The prescribed dose was 66 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the planning target volume (PTV), and 54-60 Gy to the clinically negative neck. All 20 (100%) patients with T1-2a tumors received intracavitary brachytherapy (ICB) boost, and 15/42 (36%) patients with T2b-T4 tumors received conformal boost (8 Gy/4 fractions). Nineteen patients with advanced stage disease also received either neoadjuvant or concurrent chemotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method.

RESULTS: With a median follow-up of 29 months (range 8-45 months), 4 patients developed local in-field failure, 1 patient developed regional relapse, and 13 patients developed distant metastases. All 4 patients with local failure had either T3 or T4 disease before primary treatment and did not have ICB or conformal boost. The 3-year actuarial LRFS, NRFS, DMFS, and OS were 92%, 98%, 79%, and 90%, respectively. Multivariate analysis showed that dose escalation above 66 Gy was significantly associated with better PFS and DMFS, whereas GTV size was a significant adverse factor for OS. The worst acute mucositis was Grade 1 or 2 in 36 (59%), and Grade 3 in 25 (41%) patients. Acute dysphagia requiring tube feeding occurred in 5 (8%) patients. The proportion of patients with Grade 2-3 xerostomia was 57% at 3 months, and 23% at 2 years after IMRT. Within the subset of patients with a mean parotid dose of <31 Gy, the proportions with Grade 2-3 xerostomia were 30% and 17% at 3 months and 2 years, respectively.

CONCLUSION: Our experience of using IMRT in the primary treatment of NPC showed a very high rate of locoregional control and favorable toxicity profile. Furthermore, we found that dose escalation above 66 Gy of IMRT-based therapy was a significant determinant of progression-free survival and distant metastasis-free survival for advanced T-stage tumors. Distant metastases represent the predominant mode of treatment failure.

Neoadjuvant chemotherapy plus conventional radiotherapy or accelerated hyperfractionation in stage III and IV nasopharyngeal carcinoma--a phase II study.

El-Weshi A, Khafaga Y, Allam A, Mosseri V, Ibrahim E, El-Serafi M, El-Badawi S.

Department of Medical Oncology, National Cancer Institute of Cairo, Egypt.

Acta Oncol 2001;40(5):574-81 Abstract quote

A prospective phase II trial was initiated in previously untreated patients with locally advanced nasopharyngeal carcinoma (NPC). The goal was to achieve improvement in locoregional control, disease-free interval and overall survival using induction chemotherapy and to compare conventional fractionation (CF) with an accelerated hyperfractionation (AHF) regimen.

Fifty patients were treated (5 AJCC Stage III, 45 Stage IV) with induction chemotherapy consisting of two cycles of cisplatin and 5-fluorouracil. Patients were then randomized between CF and AHF therapy.

A clinical response to induction chemotherapy was reported in 86% of patients prior to radiotherapy (44% complete response, 42% partial response). Patients with complete or major partial responses to induction chemotherapy had a significantly better 5-year overall survival (60%) and disease-free interval (59%) than those with no response or minor partial response (15% and 18% p = 0.009 and 0.0009). Acute radiation reactions were more pronounced in the AHF group (p = 0.0002), and the incidence of late normal tissue injury was more frequent (p = 0.08).

At 5 years, the locoregional control rate was higher in the AHF arm (76%) than in the CF group (54%), but the difference was not significant (HR, 0.52; 95%, Cl, 0.15-2.83; p = 0.186). With a median follow-up period of 55 months (range 4-120), the 5-year disease-free interval and overall survival rates were more favorable in the AHF group than in the CF group, but the differences were not significant (59% and 54% vs. 34% and 36%, respectively, HR for disease-free interval = 0.71; 95% CI, 0.27-1.88; p=0.198 and HR for overall survival = 0.81; 95% CI, 0.37-1.78; p=0.433). The overall treatment failure rate was 48%. Locoregional failures occurred in 12 patients (24%) and the incidence of distant metastases reached 30%.

Response to induction chemotherapy is strongly predictive for locoregional control, disease-free interval and overall survival. Accelerated hyperfractionation was associated with high incidence of acute and late toxicity without significant improvement in locoregional control rate. The optimal chemotherapy dose and sequencing with radiotherapy needs to be investigated in future studies. Distant metastases remain the main cause of treatment failure in NPC.

Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma.

Chua D, Huang J, Zheng B, Lau SY, Luk W, Kwong DL, Sham JS, Moss D, Yuen KY, Im SW, Ng MH.

Department of Radiation Oncology, University of Hong Kong, Pokfulam Road, Hong Kong SAR, People's Republic of China.

Int J Cancer 2001 Oct 1;94(1):73-80 Abstract quote

Tumor cells from NPC patients are regularly and latently infected with EBV.

To examine whether the virus serves as target for immune intervention of the cancer, we determined levels of EBV-specific CTLp in peripheral blood from NPC patients, long-term survivors of the cancer and healthy subjects.

CTLp levels of test subjects varied between 3- 3,000/10(6) PBMCs. The plasma EBV burden increased when the CTLp level fell below 150, whereas the EBV burden of PBMCs was not correlated with CTLp level. Compared with healthy carriers, CTLp levels of patients were lower and varied over a wider range, between 3-1,500/10(6) PBMCs. The quantitative immune deficit was probably attributed to the tumor because, first, CTLp in survivors was restored to levels similar to those in healthy carriers after the tumor had been successfully treated. Second, the CTLp level changed as disease progressed, being lower in local disease, increased in locoregional disease and decreased again when the tumor metastasized. Based on these findings, 4 patients with advanced disease were infused with 5 x 10(7)-3 x 10(8) autologous EBV CTLs. The treatment was safe and unaccompanied by inflammatory or other complications, but whether it improved tumor control could not be discerned from the large tumor bulk. Nevertheless, the treatment regularly increased CTLp levels of patients, maintained it at higher levels for protracted periods and, in 3 patients, restored host surveillance of EBV replication, reducing the plasma EBV burden.

Taken together, these results provided a rationale to further explore EBV as a target of immune intervention of NPC.

Fractionated stereotactic radiosurgery for 50 patients with recurrent or residual nasopharyngeal carcinoma.

Xiao J, Xu G, Miao Y.

Department of Radiation Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Int J Radiat Oncol Biol Phys 2001 Sep 1;51(1):164-70 Abstract quote

PURPOSE: This study was conducted to evaluate the clinical value of fractionated stereotactic radiosurgery (FSRS) as a boost treatment in 44 patients with residual or recurrent nasopharyngeal carcinoma after conventional radiotherapy (70-80 Gy) or a second course of radiotherapy (50 Gy) or as salvage treatment in 6 patients with recurrent nasopharyngeal carcinoma after a first or second course of radiotherapy at the primary site.

METHODS AND MATERIALS: From September 20, 1995 to December 30, 1998, 50 patients were treated with FSRS with 6 MV of photons. The total FSRS dose was 14-35 Gy (median dose 24) prescribed at 1-4 centers on the 60-90% isodose curves normalized to the isocenter by multiple fractions of 6-8, 12, or 15 Gy, with interfraction intervals of 4-6 days.

RESULTS: Thirty-eight patients (76%) had a complete tumor response, 9 (18%) had a partial response, and 3 (6%) were not assessable. The overall rate of survival was 83.6% at 1 year, 65.0% at 2 years, and 59.6% at 3 years. The overall disease-free survival rate among patients with residual tumor was 89.94% at 1 year, 73.97% at 2 years, and 73.97% at 3 years. Patients who were treated for recurrent lesions or who received FSRS as salvage therapy had a 46.53% rate of disease-free survival at both 1 and 2 years after therapy.

CONCLUSION: FSRS is strongly indicated for recurrent or residual nasopharyngeal carcinoma at the primary site.

Management of nasopharyngeal salivary gland malignancy.

Schramm VL Jr, Imola MJ.

Center for Craniofacial-Skull Base Surgery, Denver, Colorado, USA.

Laryngoscope 2001 Sep;111(9):1533-44 Abstract quote

OBJECTIVE: The objective of this study was to evaluate the oncological outcome and complication rate following surgical treatment of nasopharyngeal salivary gland malignancy.

STUDY DESIGN: Retrospective case review at tertiary care skull base center.

METHODS: Pertinent medical records were reviewed from 23 patients presenting with minor salivary gland malignancy. Clinical presentation, prior treatment, histological type and grade, clinical stage, details of surgical treatment, and postoperative adjuvant radiation therapy were studied. Survival and recurrence data were analyzed using the Kaplan-Meier and Cox proportional hazards methods.

RESULTS: Histological types included 11 adenoid cystic carcinomas, 8 mucoepidermoid carcinomas, and 4 cases of adenocarcinoma not otherwise specified. All patients underwent primary surgical resection, and the lateral infratemporal middle fossa approach was used in 20 patients. Prior radiation therapy had been administered in 6 patients who presented for treatment of recurrent disease, and the remaining 17 patients underwent planned postoperative radiation therapy. Elective neck dissection was undertaken in 15 patients, and occult neck disease was present in 47%. Disease specific survival was 67% at 5 years and 48% at 10 years. High-grade tumors had a significantly poorer outcome (P =.035) with a relative risk of 4.6 compared with low-grade disease. Local control was seen to be 77% at 5 years.

CONCLUSIONS: Planned combined surgery and radiation therapy achieves survival outcomes and recurrence rates in nasopharyngeal salivary gland malignancy comparable to results reported using the same treatment for minor salivary gland tumors cancer originating elsewhere in the head and neck. Because of the high rate of occult neck metastases, we recommend elective neck dissection as part of the surgical treatment with this disease entity. The lateral infratemporal middle fossa approach provides safe and adequate access to resect the vast majority of these tumors with acceptable complication rates. A reliable form of vascularized reconstruction is necessary to prevent serious postoperative complications, and we currently prefer the gastro-omental free flap.

Feasibility and long-term results of autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal carcinoma.

Airoldi M, De Crescenzo A, Pedani F, Marchionatti S, Gabriele AM, Succo G, Rosti G, Bumma C.

Department of Medical Oncology, San Giovanni Antica Sede Hospital, Via Cavour 31, 10123 Torino, Italy.

Neck 2001 Sep;23(9):799-803 Abstract quote

BACKGROUND: Recurrent undifferentiated nasopharyngeal carcinoma (UNPC) is a chemosensitive illness. Here we report long-term results of high-dose chemotherapy (HDC) as late intensification, with autologous peripheral blood stem cell (PBSC) support.

METHODS: Six patients (5 men, 1 woman; median age 41years; median ECOG PS = 0) with recurrent UNPC (local, 2; local + nodal, 2; bone metastasis, 2) have been enrolled. All patients had been previously treated with neoadjuvant chemotherapy and radiotherapy; 3 of 4 local relapses had received a re-irradiation. Every patient received three courses of cisplatin + epirubicin and 1 cycle of epirubicin followed by PBSC collection. A median of 7.2 x 10(6)/kg (range, 4.5-18) CD34+ cells were reinfused. HDC was according ICE scheme: ifosfamide, 2.5 g/m(2)/d, + carboplatin, 300 mg/m(2)/d, + VP-16, 300 mg/m(2)/d days 1 through 4.

RESULTS: After conventional chemotherapy, we had 1 CR (16%), 3 PR (50%), and 2 NC (34%). After HDC, we had 4 CR (66%),1 PR (17%), and 1 MR (17%). Toxicity was manageable. After a median follow-up of 30 months (range, 14-50), two patients are alive without disease (34%), one is alive with bone disease (16%), and three (50%) died of disease at 16, 18, and 24 months.

CONCLUSIONS: HDC has an acceptable toxicity, can convert PR in CR, and seems effective, with long-lasting CRs.

Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma.

Weinrib L, Li JH, Donovan J, Huang D, Liu FF.

Department of Experimental Therapeutics, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

Cancer Gene Ther 2001 May;8(5):352-60 Abstract quote

We have previously shown that the introduction of human recombinant wild-type p53 mediated by an adenoviral vector (Ad5CMV-p53), either alone or delivered in combination with ionizing radiation, was cytotoxic to two nasopharyngeal carcinoma (NPC) cell lines.

To further explore the potential therapeutic role for gene therapy, the combination of Ad5CMV-p53 and cisplatin was examined in two NPC cell lines, CNE-1 and C666-1. The C666-1 cells are particularly relevant because they express Epstein-Barr virus latent gene products analogous to human NPC in situ. Cells were infected with 5 pfu/cell of Ad5CMV-p53 or Ad5CMV-beta-gal, followed by exposure to increasing doses of cisplatin. Clonogenic and MTT assays were used to assess the sensitivity of cells to these treatments, and apoptosis was also quantified. The combination of Ad5CMV-p53 and cisplatin resulted in approximately 25% greater cytotoxicity compared to that observed with cisplatin alone in either cell line. Apoptosis was induced in approximately 50% of cells following administration of both Ad5CMV-p53 and cisplatin, but was induced in considerably fewer cells following either treatment alone. The two modalities appeared to interact in an additive manner. Ad5CMV-p53 gene therapy resulted in the expression of biologically active p53 protein, shown by induction of p21(WAF1/CIP1). Cisplatin treatment showed little effect on either p53 or p21(WAF1/CIP1) expression.

Therefore, both p53 gene therapy and cisplatin chemotherapy demonstrated cytotoxicity mediated by apoptosis despite the presence of EBV gene products in the C666-1 cells, but it appears that the two modalities induce cytotoxicity by independent pathways.

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Molecular Biology


Regaud Type-Well defined aggregates of epithelial cells surrounded by fibrous tissue and lymphoid cells

Schmincke Type-Neoplastic epithelial cells grow diffusely and closely intermingled with inflammatory cells.

Sinonasal Undifferentiated Carcinoma

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