Non-keratinising Nasopharyngeal Carcinoma Research Articles

Investigation of the feasibility of synthetic MRI in the differential diagnosis of non-keratinising nasopharyngeal carcinoma and benign hyperplasia using different contoured methods for delineation of the region of interest

To assess the feasibility and preliminary diagnostic performances of relaxation times derived from synthetic magnetic resonance imaging (syMRI) for differentiating nasopharyngeal carcinoma from nasopharyngeal benign lymphoid hyperplasia, and to assess the influence of tissue segmentation method on relaxation estimates. Fifty participants with nasopharyngeal carcinoma (NPC) and 40 participants with benign hyperplasia (NPH) who underwent syMRI examination were enrolled prospectively. T1, T2, and proton density (PD) values were obtained from four different regions of interest (ROIs), namely, partial-section, single-section, three-sections, and whole-lesion. The metrics between NPC and NPH or among different ROIs were compared using Student's t-test or one-way ANOVA. The area under curve (AUC) was calculated to assess the performance of metrics obtained from different ROIs to differentiate NPC and NPH. The T1, T2, and PD values for NPH were significantly higher than those for NPC, regardless of the type of ROI used, except for the PD value obtained from the whole-lesion ROI. The T2 values obtained from the single-section ROI showed the highest diagnostic accuracy in distinguishing NPC from NPH, with an AUC of 0.894, sensitivity of 0.900, and specificity of 0.800. Additionally, the T1, T2, and PD values for nasopharyngeal lesions showed no statistical difference among different kinds of ROI, except for the difference in T1 value between partial-section and other methods. Quantitative analysis of syMRI has the potential to distinguish NPC from NPH. Moreover, different types of ROI showed limited influence on the relaxation time estimation for nasopharyngeal lesions.

SSTR2a is constantly expressed in lymphoepithelioma-like carcinoma with squamous differentiation other than that with glandular differentiation

AimsSomatostatin receptor 2a (SSTR2a) is an important diagnostic marker of meningioma and neuroendocrine tumours and is frequently expressed in primary and metastatic non-keratinising nasopharyngeal carcinoma (NK-NPC). Since NK-NPC cases are...

Differential diagnosis of nasopharyngeal carcinoma and nasopharyngeal lymphoma based on DCE-MRI and RESOLVE-DWI

To explore the utility of dynamic contrast-enhanced MRI (DCE-MRI) and readout-segmented diffusion-weighted imaging (RESOLVE-DWI) in the differentiation of nasopharyngeal carcinoma (NPC) and nasopharyngeal lymphoma (NPL). Sixty-two patients with NPC and 39 patients with NPL who underwent DCE-MRI and RESOLVE-DWI examinations were evaluated. The time signal-intensity curve (TIC) types, time to peak (TTP), enhancement peak (EP), maximum contrast enhancement ratio (MCER), washout ratio (WR), apparent diffusion coefficient (ADC), and relative ADC (rADC) values were calculated. Statistical analysis between the two groups was performed to determine the statistical significance of each parameter. Receiver operating characteristic (ROC) curve analysis and binary logistic regression analysis were used to assess the diagnostic ability of single and combined metrics for distinguishing NPC from NPL. The most common TIC curve was type III in patients with NPC (n = 26), while the majority of the curves were types I (n = 14) and II (n = 19) in patients with NPL. TTP, EP, MCER, ADC, and rADC were statistically significantly different between NPCs and NPLs (p < 0.05). Among these factors, ADC revealed the most reliable diagnostic performance, followed by rADC, TTP, MCER, and EP. Moreover, the diagnostic efficiency of the combined DCE-MRI parameters was higher than that of TTP, MCER, and EP each alone. In addition, the combination of all DCE-MRI and DWI parameters together demonstrated the highest diagnostic efficiency (area under the curve = 0.961). However, none of the parameters was significantly different between keratinising NPC and non-keratinising NPC or between NK/T lymphoma and diffuse large B cell lymphoma (all p > 0.05). DCE-MRI and RESOLVE-DWI are effective in differentiating NPC from NPL. • RESOLVE offers high image quality in the head and neck regions. • Dynamic contrast-enhanced MRI and RESOLVE-DWI help clinicians to make the differential diagnosis between NPC and NPL. • The combination of all the DCE-MRI and DWI parameters together demonstrated the highest diagnostic efficiency compared with each parameter alone.

The role of Epstein-Barr virus in epithelial malignancies.

The close association of Epstein–Barr virus (EBV) infection with non-keratinizing nasopharyngeal carcinomas and a subset of gastric carcinomas suggests that EBV infection is a crucial event in these cancers. The difficulties encountered in infecting and transforming primary epithelial cells in experimental systems suggest that the role of EBV in epithelial malignancies is complex and multifactorial in nature. Genetic alterations in the premalignant epithelium may support the establishment of latent EBV infection, which is believed to be an initiation event. Oncogenic properties have been reported in multiple EBV latent genes. The BamH1 A rightwards transcripts (BARTs) and the BART-encoded microRNAs (miR-BARTs) are highly expressed in EBV-associated epithelial malignancies and may induce malignant transformation. However, enhanced proliferation may not be the crucial function of EBV infection in epithelial malignancies, at least in the early stages of cancer development. EBV-encoded gene products may confer anti-apoptotic properties and promote the survival of infected premalignant epithelial cells harbouring genetic alterations. Multiple EBV-encoded microRNAs have been reported to have immune evasion functions. Genetic alterations in host cells, as well as inflammatory stroma, could modulate the expression of EBV genes and alter the growth properties of infected premalignant epithelial cells, encouraging their selection during carcinogenesis.

Das visionäre Konzept des „Lymphoepithelioms“ 1921 und A. Schmincke

In 1921 Alexander Schmincke established the visionary concept of a clinically and histomorphologically defined carcinoma entity of different lymphoepithelial organs that he named "lymphoepithelioma". This nowadays mainly comprises non-keratinizing oropharyngeal carcinomas frequently associated with human papillomavirus (HPV) and non-keratinizing nasopharyngeal carcinomas mostly associated with Epstein-Barr virus (EBV). The term lymphoepithelioma was originally defined by A. Schmincke and J. Ewing as a combined clinical and histological tumor entity of lymphoepithelial organs. The main reason for the longstanding terminological confusion regarding the term lymphoepithelioma is based on the fact that lateron a pure histological interpretation (lymphoepithelial differentiation) caused an artificial and nonreproducible exclusion of tumors with transitional and basaloid differentiation. For the forthcoming new WHO classification it has been suggested that squamous cell carcinoma of the head and neck should no longer be classified according to the heterogeneous histological differentiation but according to etiopathogenetic criteria (e.g. HPV-related, EBV-related, nicotine and alcohol-related). This proposed classification corresponds much better to the prognosis and therapy and would represent a late acknowledgement of Schmincke's visionary concept of a clinically and histomorphologically defined tumor entity. In addition, the ongoing terminological confusion over the heterogeneous and prognostically weak spectrum of histological differentiation would subside.

A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma

To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m(2) day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m(2)/day for 5 days of weeks 1, 4 and 7. 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5-98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6-96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.

Prolonged Remission in a Patient With Nasopharyngeal Carcinoma With a Solitary Bone Metastasis

A 24-year-old man presented with a 2-month history of a painlessleftnecklump.Clinicalexaminationrevealeddiffusethickeningof the left neck without a discernable mass and a single right-sided 1.5-cm jugulodigastric node, but no abnormalities elsewhere. Nasendoscopy demonstrated an ulcerated tumor involving bilateral posterior nasopharyngeal walls and roof, blocking the left Eustachian cushion and abutting the right Eustachian cushion. Biopsy of the primary confirmed the diagnosis of nonkeratinising nasopharyngeal carcinoma(NPC),WHOgrade2.Thepatientdeniedanyothersymptomsonfurtherquestioning.HewasofChinese-Malaysianoriginand had lived in Australia from the age of 8 years. He had no significant past medical history, was on no medications, and had no family historyofNPC.Computedtomography(CT)oftheneckconfirmeda nasopharyngeal lesion involving the left torus tuberous, multiple leftsided necrotic lymph nodes and a solitary posterior right triangle lymph node. Chest and abdominal CT did not demonstrate disease elsewhere. He was initially staged as T2 N2 WHO grade 2 NPC. To complete his staging, fused positron emission tomography (PET)/CT was organized, which revealed metabolic avidity in the primary nasopharyngeal lesion (Fig 1A, baseline fused PET/CT axial image of nasopharynx),bilateralcervicalnecknodesasdescribed(Fig1B,baseline

HPV‐positive/p16‐positive/EBV‐negative nasopharyngeal carcinoma in white North Americans

Human papillomavirus (HPV) has been detected in keratinizing nasopharyngeal carcinomas (NPCs); however, the relationship between HPV and Epstein-Barr virus (EBV) among whites with nonkeratinizing NPCs remains unclear. The HPV, p16, and EBV status was examined in current University of Michigan patients with NPC. From 2003 to 2007, 89 patients, 84 with oropharyngeal cancer (OPC) and 5 with NPC, were enrolled in an organ-sparing trial. Biopsy tissues from all 89 patients were evaluated for HPV and p16 expression. A separate HPV analysis of the 84 OPC patients is in progress. Among the patients with NPC, tumor tissue was also analyzed for EBV-encoded RNA (EBER). Five of 89 patients (5.6%) had NPC, all with nonkeratinizing histology. The 4 white patients with NPC were HPV(+) (subtype-16, subtype-18 [2 patients], and subtype-59)/p16(+)/EBER(-). One Asian patient with NPC had an HPV(-)/p16(-)/EBER(+) NPC tumor that developed distant metastases. We postulate that HPV may be the etiologic factor in some EBV-negative, nonkeratinizing NPCs among whites.

P63 Expression in Olfactory Neuroblastoma and Other Small Cell Tumors of the Sinonasal Tract

Olfactory neuroblastoma (ONB) is a rare neoplasm of the head and neck region that is included in the differential diagnosis of other sinonasal tract malignancies. We studied the usefulness of using p63 as an aid in the diagnosis of ONB and other tumors of the sinonasal region. The specimens were 14 ONBs; 4 nasopharyngeal carcinomas (NPCs), nonkeratinizing subtype; 2 NPCs, undifferentiated subtype; 10 sinonasal undifferentiated carcinomas (SNUCs); 7 malignant melanomas; and 2 extranodal natural killer (NK)/T-cell lymphomas. We observed p63 expression in 5 ONBs (36%), 4 nonkeratinizing NPCs (100%), 1 undifferentiated NPC (50%), 2 SNUCs (20%); 0 malignant melanomas (0%); and 1 extranodal NK/T-cell lymphoma (50%). While all cases of NPC with positive staining for p63 showed strong and diffuse immunoreactivity, the ONB, SNUC, and lymphoma cases with positive immunoreactivity showed only focal staining for p63. No p63 expression was observed in malignant melanoma. We think p63 is a useful marker to help distinguish nonkeratinizing or undifferentiated NPC subtypes from various sinonasal tract malignancies. In particular, p63 helps distinguish nonkeratinizing and undifferentiated NPC subtypes from SNUC.

Epstein-Barr-virus-encoded LMP2A induces primary epithelial cell migration and invasion: possible role in nasopharyngeal carcinoma metastasis.

Nonkeratinizing nasopharyngeal carcinomas (NPC) are >95% associated with the expression of the Epstein-Barr virus (EBV) LMP2A latent protein. However, the role of EBV, in particular, LMP2A, in tumor progression is not well understood. Using Affymetrix chips and a pattern-matching computational technique (neighborhood analysis), we show that the level of LMP2A expression in NPC biopsy samples correlates with that of a cellular protein, integrin-alpha-6 (ITGalpha6), that is associated with cellular migration in vitro and metastasis in vivo. We have recently developed a primary epithelial model from tonsil tissue to study EBV infection in epithelial cells. Here we report that LMP2A expression in primary tonsil epithelial cells causes them to become migratory and invasive, that ITGalpha6 RNA levels are up-regulated in epithelial cells expressing LMP2, and that ITGalpha6 protein levels are increased in the migrating cells. Blocking antibodies against ITGalpha6 abrogated LMP2-induced invasion through Matrigel by primary epithelial cells. Our results provide a link between LMP2A expression, ITGalpha6 expression, epithelial cell migration, and NPC metastasis and suggest that EBV infection may contribute to the high incidence of metastasis in NPC progression.

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

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. J. Med. Virol. 65:105–113, 2001. © 2001 Wiley-Liss, Inc.

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

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.

Epstein-Barr virus expression within keratinizing nasopharyngeal carcinoma.

Three stages of maturation can be seen in keratinizing nasopharyngeal carcinomas. These stages are similar morphologically to basal cells, intermediate and superficial squamous cells seen in normal squamous epithelium. Taking advantage of such a diverse tumour cell population, 10 keratinizing nasopharyngeal carcinoma (NPC) were examined by in situ hybridization for the presence of latent Epstein-Barr Virus (EBV) using EBV encoded RNAs (EBERs) and by immunohistology for the presence of EBV early antigen-diffuse (EA-D) and the 350/220 kd membrane glycoprotein of the EBV. The basal cell-like tumour cells are mainly infected latently with the virus; viral replication was found in isolated intermediate squamous cells, whilst superficial squamous cells are largely depleted of all the viral markers. We used a control series of nonkeratinizing nasopharyngeal carcinomas composed of undifferentiated and poorly differentiated tumour cells and EBV latency was present in these tumours. Viral replication was detected by RT-PCR, in the undifferentiated tumours but viral replication was not seen by immunohistology. The possible relationship between EBV life cycle in these tumours and tumour cell differentiation is discussed in the light of these findings.

MDM-2 protein expression in nasopharyngeal carcinomas. Comparative study with p53 protein expression

Aims-To investigate the immunohistochemical expression of MDM-2 protein in comparison with that of p53 protein in nasopharyngeal carcinomas.Methods-Formalin fixed, paraffin wax embedded tissue from 59 cases of nasopharyngeal carcinoma was stained by immunohistochemistry for MDM-2 and p53 proteins.Results-The tumours were divided histologically into seven cases of keratinising nasopharyngeal carcinoma (KNPC), 14 cases of non-keratinising nasopharyngeal carcinoma (NKNPC), and 38 cases of undifferentiated nasopharyngeal carcinoma (UNPC). MDM-2 nuclear expression was observed in 0/7 KNPC, 1/14 NKNPC, and 11/38 UNPC. p53 nuclear expression was observed in 1/7 KNPC, 2/14 NKNPC, and 15/38 UNPC. Parallel MDM-2 and p53 expression was found in 12 cases (11 UNPC and one NKNPC). Discordant MDM-2-/p53 + expression was found in six cases (four UNPC, one NKNPC, and one KNPC), and absence of expression of both proteins in the remaining 41 cases.Conclusions-Expression of MDM-2 and p53 proteins may be associated with the level of tumour cell differentiation in nasopharyngeal carcinoma. Simultaneous expression of MDM-2/p53 in a proportion of UNPC suggests that MDM-2 protein may be responsible for stabilisation of p53 protein in these cases, in view of the previous demonstration of the p53 gene in germ line configuration. This could be important in the pathogenesis of these cases, since MDM-2 may deregulate the p53 dependent growth suppressive pathway. Discordant MDM-2-/p53 + expression in a few cases of nasopharyngeal carcinoma may reflect stabilisation of p53 protein by other proteins, or p53 mutations unable to activate MDM-2.

Determination of nonendemic nasopharyngeal carcinoma by in situ hybridization for Epstein-Barr virus EBER1 RNA: sensitivity and specificity in cervical node metastases.

After time-consuming and costly investigations, patients with neck metastases from an occult primary often receive unnecessarily large radiation volumes to treat a possible origin in the nasopharynx. In this study a colorimetric antisense Epstein-Barr early ribonucleoprotein 1 (EBER1) oligonucleotide probe specific for Epstein-Barr virus RNA was hybridized in situ to metastatic tissue obtained from 18 nasopharyngeal, 54 oral and pharyngeal, and 12 occult carcinomas derived from an unselected population. All 16 nonkeratinizing nasopharyngeal carcinomas (NPCs) were positive for EBER1. Both cases of keratinizing NPC and all 54 other metastases were negative. A single positive case of occult carcinoma indicated its origin from NPC. In retrospect, 7 patients with occult carcinoma had received unnecessary treatment with irradiation to the nasopharynx. Nasopharyngeal carcinoma appears to be a less common origin of occult carcinoma than previously considered. In the proper clinicopathologic context EBER1 in situ hybridization (EBER1-ISH) allows exclusion of NPC with a high degree of accuracy. Thus unnecessarily large radiation volumes and their adverse sequelae may be reduced in the treatment of occult carcinoma. Conversely, a positive result of ISH allows exclusion of further extensive diagnostic procedures.

Human papillomavirus types 11 and 16 detected in nasopharyngeal carcinomas by the polymerase chain reaction.

Most nasopharyngeal carcinomas (NPCs) are of the nonkeratinizing or undifferentiated types, which are consistently associated with Epstein-Barr virus (EBV). The smaller group of highly differentiated, keratinizing NPCs seems to be only infrequently associated with EBV. In order to examine whether these rare tumors were related to another oncogenic virus, the authors used the polymerase chain reaction to examine paraffin-embedded sections of 15 keratinizing NPCs for human papillomavirus (HPV) types 6, 11, 16, and 18 genomic sequences. HPV DNA was found in 4 tumors (1 HPV-11-positive, and 3 HPV-16-positive tumors). None of 23 undifferentiated or nonkeratinizing NPCs harbored HPV DNA. The putatively oncogenic HPV type 16 may thus be involved in the carcinogenesis of some EBV-negative keratinizing squamous cell nasopharyngeal carcinomas.

Metastatic lobular carcinoma.

Immunocytochemical stains for three epithelial cell markers--keratin, epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA)--have been examined on paraffin-embedded material from 14 patients with nasopharyngeal carcinoma (NPC). Tumour cells staining positively for keratin were found in all cases and for EMA in eight; two tumours contained CEA-positive cells. Seven cases of Hodgkin9s disease and 24 non-Hodgkin9s lymphomas were uniformly negative. Keratin is the most reliable epithelial marker for identifying NPC and excluding lymphoma. The regular finding of stainable keratin in non-keratinising and anaplastic NPC supports the view that NPC is a homogeneous group exhibiting variable degrees of squamous differentiation.

Epithelial markers in the diagnosis of nasopharyngeal carcinoma: an immunocytochemical study.

Immunocytochemical stains for three epithelial cell markers--keratin, epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA)--have been examined on paraffin-embedded material from 14 patients with nasopharyngeal carcinoma (NPC). Tumour cells staining positively for keratin were found in all cases and for EMA in eight; two tumours contained CEA-positive cells. Seven cases of Hodgkin's disease and 24 non-Hodgkin's lymphomas were uniformly negative. Keratin is the most reliable epithelial marker for identifying NPC and excluding lymphoma. The regular finding of stainable keratin in non-keratinising and anaplastic NPC supports the view that NPC is a homogeneous group exhibiting variable degrees of squamous differentiation.