MRI of benign hyperplasia in the nasopharynx: is there an association with Epstein-Barr virus?

AIM: To evaluate whether there is an association between persistently positive plasma Epstein-Barr virus (EBV) DNA and the presence and the change in benign hyperplasia. MATERIALS AND METHODS: One hundred and seventeen participants with positive-plasma EBV-DNA, but without NPC from previous nasopharyngeal carcinoma (NPC) screening, underwent follow-up magnetic resonance imaging (MRI) and plasma EBV-DNA after 2 years. Logistic regression was used to analyse associations between MRI (benign hyperplasia on the follow-up MRI and change from 2 years earlier), and plasma EBV-DNA, smoking, and age. RESULTS: At follow-up, EBV-DNA positivity and smoking were independent parameters for the presence of benign hyperplasia (p=0.027 and 0.023 respectively). Compared with participants in whom EBV-DNA became negative (n=44/117 37.6%), those in whom EBV-DNA remained positive (n=73/117 62.4%) had a greater risk of benign hyperplasia developing (previous MRI normal), being stable or processing (52/73 71.2% versus 18/44 40.9%; p=0.001). CONCLUSION: These results suggest a potential link between benign hyperplasia on MRI and the EBV. As EBV contributes to NPC oncogenesis, future MRI research is warranted to determine if persistent benign hyperplasia is a risk marker for development of NPC.

Early Detection of Cancer: Evaluation of MR Imaging Grading Systems in Patients with Suspected Nasopharyngeal Carcinoma.

BACKGROUND AND PURPOSE: We evaluated modifications to our contrast-enhanced MR imaging grading system for symptomatic patients with suspected nasopharyngeal carcinoma, aimed at improving discrimination of early-stage cancer and benign hyperplasia. We evaluated a second non-contrast-enhanced MR imaging grading system for asymptomatic patients from nasopharyngeal carcinoma plasma screening programs. MATERIALS AND METHODS: Dedicated nasopharyngeal MR imaging before (plain scan system) and after intravenous contrast administration (current and modified systems) was reviewed in patients from a nasopharyngeal carcinoma-endemic region, comprising 383 patients with suspected disease without nasopharyngeal carcinoma and 383 patients with nasopharyngeal carcinoma. The modified and plain scan systems refined primary tumor criteria, added a nodal assessment, and expanded the system from 4 to 5 grades. The overall combined sensitivity and specificity of the 3 systems were compared using the extended McNemar test (a χ2 value [Formula: see text]> 5.99 indicates significance). RESULTS: The current, modified, and plain scan MR imaging systems yielded sensitivities of 99.74%, 97.91%, and 97.65%, respectively, and specificities of 63.45%, 89.56% and 86.42%, respectively. The modified system yielded significantly better performance than the current ([Formula: see text] = 122) and plain scan ([Formula: see text] = 6.1) systems. The percentages of patients with nasopharyngeal carcinoma in grades 1-2, grade 3, and grades 4-5 for the modified and plain scan MR imaging systems were 0.42% and 0.44%; 6.31% and 6.96%; and 90.36% and 87.79%, respectively. No additional cancers were detected after contrast administration in cases of a plain scan graded 1-2. CONCLUSIONS: We propose a modified MR imaging grading system that improves diagnostic performance for nasopharyngeal carcinoma detection. Contrast was not valuable for low MR imaging grades, and the plain scan shows potential for use in screening programs.

Complementary roles of MRI and endoscopic examination in the early detection of nasopharyngeal carcinoma.

BACKGROUND: Early-stage nasopharyngeal carcinoma (NPC) evades detection when the primary tumor is hidden from view on endoscopic examination. Therefore, in a prospective study of subjects being screened for NPC using plasma Epstein-Barr virus (EBV) DNA, we conducted a study to investigate whether magnetic resonance imaging (MRI) could detect endoscopically occult NPC. PATIENTS AND METHODS: Participants with persistently positive EBV DNA underwent endoscopic examination and biopsy when suspicious for NPC, followed by MRI blinded to the endoscopic findings. Participants with a negative endoscopic examination and positive MRI were recalled for biopsy or surveillance. Diagnostic performance was assessed by calculating sensitivity, specificity and accuracy, based on the histologic confirmation of NPC in the initial study or in a follow-up period of at least two years. RESULTS: Endoscopic examination and MRI were performed on 275 participants, 34 had NPC, 2 had other cancers and 239 without cancer were followed-up for a median of 36 months (24-60 months). Sensitivity, specificity and accuracy were 76.5%, 97.5% and 94.9%, respectively, for endoscopic examination and 91.2%, 97.5% and 96.7%, respectively, for MRI. NPC was detected only by endoscopic examination in 1/34 (2.9%) participants (a participant with stage I disease), and only by MRI in 6/34 (17.6%) participants (stage I = 4, II = 1, III = 1), two of whom had stage I disease and follow-up showing slow growth on MRI but no change on endoscopic examination for 36 months. CONCLUSION: MRI has a complementary role to play in NPC detection and can enable the earlier detection of endoscopically occult NPC.

MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia.

BACKGROUND AND PURPOSE: MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia. MATERIALS AND METHODS: MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the χ2 test. RESULTS: The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas. CONCLUSIONS: MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases.

Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors (HDIs) are promising anticancer therapies and have been clinically used for the treatment of hematological malignancy. However, their efficacy in solid tumors is marginal and drug resistance hampers their further clinical utility. To develop novel strategies for the HDI-based anticancer therapeutics in non-small cell lung cancer (NSCLC), in the present study, we investigated the mechanisms underlying resistance to HDI treatment in NSCLC cells. We show the STAT3-mediated IGF2/IGF-1R signaling cascade as a key modulator for both acquired and primary HDI resistance. The treatment with HDI upregulated IGF2 transcription in NSCLC cells carrying intrinsic or acquired drug resistance via direct binding of STAT3 in IGF2 P3 and P4 promoters. Acetylated STAT3 emerged upon HDAC inhibition was protected from the proteasome-mediated degradation of STAT3 and functioned as a direct transcription factor for IGF2 expression. Genomic or pharmacological strategies targeting STAT3 diminished the HDI-induced IGF2 mRNA expression and overcame the resistance to HDI treatment in HDI-resistant NSCLC- or patient-derived tumor xenograft models. These findings provide new insights into the role of acetylated STAT3-mediated activation of IGF2 transcription in HDI resistance, suggesting IGF2 or STAT3 as novel targets to overcome HDI resistance in NSCLC.

Detection of Nasopharyngeal Carcinoma by MR Imaging: Diagnostic Accuracy of MRI Compared with Endoscopy and Endoscopic Biopsy Based on Long-Term Follow-Up.

BACKGROUND AND PURPOSE: Our previous nasopharyngeal carcinoma detection study, comparing MR imaging, endoscopy, and endoscopic biopsy, showed that MR imaging is a highly sensitive test that identifies nasopharyngeal carcinomas missed by endoscopy. However, at the close of that study, patients without biopsy-proved nasopharyngeal carcinoma nevertheless had shown suspicious abnormalities on endoscopy and/or MR imaging. The aim of this study was to determine whether there were any patients with undiagnosed nasopharyngeal carcinoma by obtaining long-term follow-up and to use these data to re-evaluate the diagnostic performance of MR imaging. MATERIALS AND METHODS: In the previous study, 246 patients referred to a hospital ear, nose, and throat clinic with suspected nasopharyngeal carcinoma, based on a wide range of clinical indications, had undergone MR imaging, endoscopy, and endoscopic biopsy, and 77 had biopsy-proved nasopharyngeal carcinoma. One hundred twenty-six of 169 patients without biopsy-proved nasopharyngeal carcinoma underwent re-examination of the nasopharynx after a minimum of 3 years, including 17 patients in whom a previous examination (MR imaging = 11; endoscopy = 7) had been positive for nasopharyngeal carcinoma, but the biopsy had been negative for it. Patients with nasopharyngeal carcinoma were identified by biopsy obtained in the previous and this follow-up study; patients without nasopharyngeal carcinoma were identified by the absence of a tumor on re-examination of the nasopharynx. The sensitivity and specificity of the previous investigations were updated and compared by using the Fisher exact test. RESULTS: One patient with a previous positive MR imaging finding was subsequently proved to have nasopharyngeal carcinoma. Nasopharyngeal carcinomas were not found in the remaining 125 patients at follow-up, and the previous positive findings for nasopharyngeal carcinoma on MR imaging and endoscopy were attributed to benign lymphoid hyperplasia. The diagnostic performances for the previous MR imaging, endoscopy, and endoscopic biopsy were 100%, 88%, and 94%, respectively, for sensitivity, and 92%, 94%, and 100%, respectively, for specificity; the differences between MR imaging and endoscopy were significant for sensitivity (P = .003) but not specificity (P = .617). CONCLUSIONS: MR imaging detected the 12% of nasopharyngeal carcinomas that were endoscopically invisible, including 1 cancer that remained endoscopically occult for several years. Lymphoid hyperplasia reduced the specificity of MR imaging.

Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway.

Although the hyper-glycosylated transmembrane protein Mucin 1 (MUC1) is aberrantly overexpressed in human breast carcinoma, the biological significance of MUC1 overexpression is unclear. This study showed that MUC1 expression promoted the synthesis and secretion of vascular endothelial growth factor (VEGF) through the AKT signaling pathway. Increase VEGF production through MUC1 expression had a number of effect. First, MUC1 transfection increased expression of VEGF in breast cancer cells. Second, MUC1-mediated VEGF induction was attenuated by a chemical inhibitor of AKT or MUC1 knock-down by MUC1 siRNA. Third, MUC1 expression led to the activation of insulin-like growth factor-1 receptor, which correlated with VEGF expression. In addition, when MDA-MB-231 human breast cancer cells were directly injected into NOD/SCID mice, MUC1 expression accelerated xenograft tumor growth in vivo. Finally, MUC1 expression enhanced tumor growth and angiogenesis in a PyMT-MMTV/hMUC1 transgenic mouse model. Concurrent with these results, analysis of a human tissue microarray identified a high correlation between MUC1 and VEGF expression in human breast carcinoma. The current report is the first to demonstrate that MUC1 expression promotes angiogenesis in human breast cancer in vivo and in vitro.

Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated disease with high prevalence in Southern Chinese. Using multiparametric flow cytometry, we identified significant expansions of circulating naïve and memory CD4+CD25(high) T cells in 56 NPC patients compared with healthy age- and sex-matched controls. These were regulatory T cells (Treg), as they overexpressed Foxp3 and GITR, and demonstrated enhanced suppressive activities against autologous CD4+CD25- T-cell proliferation in functional studies on five patients. Abundant intraepithelial infiltrations of Treg with very high levels of Foxp3 expression and absence of CCR7 expression were also detected in five primary tumours. Our current study is the first to demonstrate an expansion of functional Treg in the circulation of NPC patients and the presence of infiltrating Treg in the tumour microenvironment. As Treg may play an important role in suppressing antitumour immunity, our findings provide critical insights for clinical management of NPC.

c-Myc alters the DNA damage-induced G2/M arrest in human mammary epithelial cells.

Effects of c-Myc overexpression on the DNA damage-induced G2/M checkpoint were studied in finite lifespan, normal human mammary epithelial cells (HMECs). Previously, we showed that c-Myc attenuates G1/S arrest and leads to an inappropriate entry of cells with damaged DNA into the S phase, following treatment with ionising radiation (IR). Here we show that, in striking contrast to control cells, c-Myc-overexpressing HMECs demonstrate a significant attenuation of the G2/M arrest, following IR, and enter into inappropriate mitoses. At the molecular level, ectopic overexpression of c-Myc leads to an unusually high level of expression of cyclin B1, and the elevated levels of cyclin B1 were maintained, after gamma-irradiation. Introduction of DNA damage in c-Myc-overexpressing, normal mammary epithelial cells eventually induces apoptosis, indicating a dramatic sensitisation by c-Myc of DNA damage-induced apoptosis. These two remarkable phenotypes, checkpoint attenuation and sensitisation to apoptosis, resulting from a deregulation of the protooncogene c-myc, may produce a unique pattern of alternating cycles, consisting first of amplification of DNA damage, followed by apoptosis-assisted selective pressure. The result of this alternating pattern of damage apoptosis could facilitate the selection of certain genomic alterations required for cellular survival and cellular transformation.

Cytomegalovirus infection of the nasopharynx.

This report describes a case of cytomegalovirus (CMV) infection of the nasopharynx. A 47 year old man presented with a nasopharyngeal mass of one month's duration. The patient had a history of pneumonia one month previously. Sinus computed tomography incidentally picked up a nasopharyngeal mass. The initial biopsy showed lymphoid hyperplasia. Repeated nasopharyngoscopy showed a prominent central nasopharyngeal mass without ulceration. Histology of the nasopharyngeal biopsy revealed several enlarged epithelial cells with characteristic CMV cytopathic changes. An immunohistochemical study, using a monoclonal IgG antibody against a CMV antigen, confirmed CMV infection. The patient's nasopharyngeal mass decreased in size gradually on follow up. To the best of our knowledge, this is the first reported case of CMV infection of the nasopharynx in the English literature. This disease entity should be considered in those patients presenting with nasopharyngeal mass, biopsy negative for malignancy, and no underlying immunosuppression or immunodeficiency.

Management of ingested foreign bodies: a retrospective review of 5240 patients.

This review was carried out to assess the effectiveness of our protocol designed for the management of ingested foreign bodies. It was a retrospective review of 5240 patients with ingested foreign bodies admitted over a five-year period to the Ear Nose and Throat Unit. These patients were managed according to a standardized protocol which was adopted and modified from our previous study. Under his management protocol, the mean hospital stay was 1.6 days. Flexible oesophagoscopy under local anaesthesia, and rigid oesophagoscopy under general anaesthesia, were performed in 1.5 per cent and 7.7 per cent of cases respectively. Major complications including oesophageal perforation and deep neck abscesses occurred in 0.19 per cent of patients. There was no mortality. This management protocol for ingested foreign bodies was both safe and cost-effective when compared to similar studies reported in the literature.

Compartmentalized maxillary sinus mucocele.

A rare case of compartmentalized maxillary sinus mucocele 12 years after a Caldwell-Luc operation is reported. The two separate mucoceles were drained intranasally by endoscopic sinus surgery. The clinical features of this mucocele are presented and the incidence, presentation and theories on formation of post-operative mucoceles are reviewed.

Endoscopic resection of inverted papilloma of the nose and paranasal sinuses.

The results of a retrospective study of 22 patients with inverted papillomas resected by the endoscopic approach are presented with a follow-up of 33 to 96 months. Twenty-one patients had unilateral disease and one patient had bilateral involvement. None of the patients had orbital or cranial extension. One patient had synchronous carcinoma in situ. Eight patients had undergone previous surgical procedures. Following endoscopic surgery, six patients had residual disease requiring further revisions. Three of these six patients eventually required excision via limited external approaches. No patient required lateral rhinotomy or mid-facial degloving procedures. No complication occurred in any of the patients. The advantages of endoscopic surgery include precise determination of tumour extent, preservation of normal mucosa and bony structures and avoidance of external scars. Close endoscopic follow-up is mandatory to ensure early recognition and treatment of recurrent disease. Although the endoscopic approach is gaining popularity for the treatment of inverted papilloma, indiscriminate application may result in a high recurrence rate. The endoscopic approach should be performed by experienced surgeons and restricted to carefully selected patients with nasal, ethmoidal and limited maxillary disease. More extensive disease should be managed by radical external approaches or by combining endoscopic with limited external approaches.

Auditory brainstem responses after radiotherapy for nasopharyngeal carcinoma.

The effect of irradiation for nasopharyngeal carcinoma on auditory brainstem responses and hearing was investigated in 19 otologically normal patients undergoing standard fractionated megavoltage radiotherapy. Auditory brainstem responses and pure tone audiometry were performed before radiotherapy, and at 3 and 12 months after completion of radiotherapy. There were no significant changes in the wave I-III and III-V interpeak intervals, or in sensorineural hearing thresholds (bone conduction at 4 kHz and average of bone conduction at 0.5, 1, 2 and 4 kHz), after radiotherapy. In contrast to previous studies, we found no evoked potential evidence of subclinical brainstem damage arising from irradiation for nasopharyngeal carcinoma.

Congenital laryngeal cysts: current approach to management.

Congenital laryngeal cysts are a rare cause of neonatal upper airway obstruction which may lead to serious morbidity and mortality if diagnosis and treatment are delayed. We reviewed our experience with nine patients over a six-year period. The annual incidence of this condition was 1.82 per 100,000 live births. The diagnosis can be confirmed safely by flexible laryngoscopy before definitive surgery is contemplated. Contrary to other studies, we found that endoscopic removal of cysts can achieve an effective cure without recurrence. Endoscopic deroofing is as effective as endoscopic excision but is technically simpler and thus is recommended as the treatment of choice.

Hypermethylation of the p16 gene in nasopharyngeal carcinoma.

We have recently reported that inactivation of the p16 gene by mutation and deletion is common in nasopharyngeal carcinoma (NPC). The present study demonstrates that hypermethylation of the 5' CpG island can serve as an alternative mechanism for inactivation of the p16 gene in this tumor. Using Southern blotting analysis and multiplex PCR, aberrant methylation of the 5' CpG island of the p16 gene was found in a NPC xenograft (xeno-666) and 6 (22%) of 27 primary tumors, but not in normal tissues of the nasopharynx. In the NPC xenograft (xeno-666) and its newly derived cell line (cell-666), both showing hypermethylation of the p16 gene, no p16 gene expression was found. After treatment with 5-aza-2'-deoxycytidine, reexpression of the p16 gene was detected in the cell line cell-666. These findings suggest that aberrant methylation of the 5' CpG island may participate in the transcriptional inactivation of the p16 gene in NPC. The present results further support that the p16 gene is the critical target on chromosome 9p21 for inactivation during the development of this disease.

Preliminary results of photodynamic therapy for recurrent nasopharyngeal carcinoma.

Photodynamic therapy (PDT) is a promising new modality in the treatment of cancer. In Hong Kong where nasopharyngeal carcinoma (NPC) is endemic, radiotherapy has been the primary treatment of choice. For recurrent disease after radiotherapy, there is no effective treatment. This latter report summarizes our initial experience in using PDT for these patients. Twelve patients (three females and nine males) with ages ranging from 33 to 65 years were treated with an infusion of hematoporphyrin derivative (5 mg/kg) 48-72 h before exposure to 200 J/cm2 light (wavelength, 630 nm) delivered from a gold vapor laser. All 12 patients showed a dramatic response as judged by computed tomography or magnetic resonance imaging at 6 months post-PDT. Of the eight patients in whom cure was aimed for, three remained disease-free at 9-12 months after a single treatment. Three of the remaining four patients achieved useful palliation. Skin hypersensitivity occurred in two patients and was the only significant complication encountered. This experience indicates that PDT can be an encouraging palliative or definitive management for recurrent superficial NPC.