Study On The Correlation Between Human Papillomavirus And World Health Organization Type ? Nasopharyngeal Carcinoma,and Role Of Surgery In The Treatment Of Osteoradionecrosis And Its Complications After Radiotherapy For Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma(NPC)is unique among other head and neck malignancies with regard to its epidemiology,pathology,and treatment outcome.It is endemic in southern China,including Hong Kong,with a reported annual incidence of up to 50 cases per 100,000 population(incident rate of 0.05%).Nearly all tumors are undifferentiated,nonkeratinizing carcinoma,corresponding to the World Health Organization(WHO)type ?.This is in contrast with nonendemic areas such as North America,where the incidence of WHO tumors of types ?,?,and ? is 25%,12%,and 63%,respectively.It is well recognized that NPC in endemic areas is almost universally associated with Epstein-Barr virus(EBV).Conversely,there has been an increasing incidence of human papillomavirus(HPV)-associated oropharyngeal carcinoma in European and American populations.With the corresponding differences in the demographics and treatment results in this group of patients,questions have been raised regarding the role of this epitheliotropic virus in NPC.However,to the best of our knowledge,studies to date have investigated NPC tumor tissues from nonendemic regions,and data from Southern China,where to our knowledge NPC is most endemic in the world,are lacking.The objective of the current study was to investigate the prevalence of HPV and NPC using tumor tissues from multiple centers in Southern China,where the disease is endemic.Additionally,with a 5-year local control rate of up to 91%after chemoradiation,it is not uncommon that long-term survivors have the long-term morbidities of radiotherapy despite that they are cured from the original cancer.The purpose of thecurrent study was to investigate the characteristics of patients with osteoradionecrosis(ORN)after radiotherapy for NPC and the results of surgical treatment.OBJECTIVE:In present study,we aimed to detectthe prevalence of HPVandEBVusing tumor tissues from multiple centers in Southern Chinain the first part,investigate the association of HPV with NPC and the corresponding treatment outcome in the second part and further investigate the characteristics of patients with ORN after radiotherapy for NPC and the results of surgical treatment.METHODS:1.We identified 1328 consecutive patients who were diagnosed and treated for NPC in 3 major institutes in HongKong and Guangdong Province between 2000 and 2015.All patients had histologically confirmed undifferentiated,nonkeratinizing carcinoma of the nasopharynx,and had tumor samples available for investigation.All patientsunderwent clinical examinations,including endoscopic assessment and biopsy for histological confirmation,contrastenhancedmagnetic resonance imaging for staging purposes,and plasma EBV DNA for baseline assessment.In situ hybridization was performed for EBV-encoded RNA(EBER)using the fluorescein-conjugated EBV peptidenucleic acid(PNA)probe.All specimens were screened with RNA probes that detected 13 high-risk HPV types(types 16,18,31,33,35,39,45,51,52,56,58,59,and 68)and,low-risk types(types 6,11,42,43,and 44).What's more,tumor specimens were tested for p16 immunohistochemistry.2.Prospective clinical data were collected,including:a.age,sex,smoking status;b.Tumor staging:T classification and AJCC staging;c.treatment methods:radiotherapy,concurrent chemoradiotherapy;d.Tumor recurrence and local recurrence;e.Survival:5-year disease-free survival(DFS),5-year overall survival(OS).Patients were grouped according to viral infection status and clinical indicators were compared between groups.3.Additionally,Between 2000 and 2016,we identified 162 patients with skull base ORN,among which 58 patients required surgery.A retrospective medical chart review was performed and the indications and results of surgical interventions were recorded.RESULTS:1.The prevalence of HPV and EBV in WHO type III NPC tumor tissues:Between 2000 and 2015,a total of 1328 patients with NPC were treated in 3 study institutes in Hong Kong and Foshan City in Guangdong Province,China.All tumors were undifferentiated,nonkeratinizing carcinoma,of which 91.9%were positive for the Epstein-Barr virus(EBV+)and 7.7%were positive for HPV/p16(HPV+).Although coinfection with both viruses occurred only in 8 patients(0.6%),94 patients had tumors that were EBV negative(EBV-)and HPV+.2.The association of HPV with NPC and the corresponding treatment outcome:All patients were treated with intensity-modulated radiotherapy alone for American Joint Committee on Cancer stage I and II disease,and concurrent chemoradiotherapy for stage III and IV disease.With a median follow-up of 72.8 months,we found that the local recurrence rate was significantly lower for patients with tumors that were EBV-/HPV+compared with patients with tumors that were EBV+/HPV-(6.4%vs 13.8%;P=0.03).Similar trends were observed for the 5-year disease-free survival rate(89.8%vs 70.8%;P=0.03)and 5-year overall survival rate(86%vs 72%;P=0.03).3.Role of surgery in the treatment of osteoradionecrosis and its complications after radiotherapy for NPC:All surgeries were performed for the treatment of secondary complications of ORN,including central nervous system(CNS)infection(48.4%),blowout bleed-ing(24.1%),and severe pain(17.2%).Endoscopic debridement was done in 12 patients,whereas the rest required either maxillary swing or mandibulotomy,depend-ing on the location of the necrosis.The majority of the patients required free vastus lateralis flap(72.5%)for reconstruction.Surgery was effective in the control of infec-tion,bleeding,and pain.Multivariate analysis identified reirradiation and bone exposure on MRI as the significant independent risk factors predicting the future need of surgery.CONCLUSIONS:In regions that are endemic for NPC,the prevalence of EBV and HPV coinfection in patients with NPC is extremely low.Conversely,patients with EBV-/HPV+NPC demonstrate significantly better local tumor control and survival after radiotherapy.What's more,surgery is effective in the treatment of secondary complications of skull base ORN after previous radiotherapy for NPC.Patients with skull base ORN after radiotherapy for NPC should be followed up closely and treated aggressively,particularly for the high-risk group of patients with a history of reirradiation for recurrence and evidence of bone exposure on MRI.Early surgical debridement and reconstruction are effective to prevent secondary complications that are debilitating and potentially fatal.