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Keywords:

  • sinonasal;
  • human papillomavirus;
  • p16;
  • squamous cell carcinoma;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

BACKGROUND:

The role of human papillomavirus (HPV) in the pathogenesis of squamous cell carcinomas (SCCs) of the sinonasal tract and its clinicopathological implications were evaluated.

METHODS:

All SCCs of the sinonasal tract diagnosed in the Hospital Clinic of Barcelona from 1981 to 2006 were retrospectively evaluated (N = 60). Clinical and pathological data were reviewed. HPV infection was determined and typed by amplification of HPV DNA by polymerase chain reaction using the SPF-10 primers. p16INK4a expression was determined by immunohistochemistry. Overall and progression-free survival for HPV-positive and -negative patients was estimated by Kaplan-Meier analysis and by the use of a multivariate Cox proportional hazards model.

RESULTS:

HPV DNA was detected in tumor tissue of 12 of 60 (20%) patients. HPV16 was identified in 11 tumors and HPV35 in 1. Immunohistochemistry for p16INK4a stained all HPV-positive and no HPV-negative tumors (P < .001). No differences were observed in terms of site and histological grade or stage at presentation between HPV-positive and -negative tumors. However, HPV-positive patients had a significantly better 5-year progression-free survival (62%; 95% confidence interval [CI], 23%-86% vs 20%; 95% CI, 9%-34%; P = .0043, log-rank test) and overall survival (80%; 95% CI, 20%-96% vs 31%; 95% CI, 15%-47%; P = .036, log-rank test) than patients with HPV-negative tumors. In multivariate analysis, HPV-positive tumors were associated with improved progression-free survival (hazard ratio, 0.21; 95% CI, 0.17-0.98; P = .012).

CONCLUSIONS:

A subgroup of sinonasal SCCs is associated with HPV infection. These tumors have a significantly better prognosis. Cancer 2009. © 2009 American Cancer Society.

Infection by sexually transmitted human papillomaviruses (HPVs) is a cause of virtually all cancers of the uterine cervix1, 2 and a significant number of other carcinomas of the anogenital region such as vagina, vulva, anus, and penis.3-6 Over the last few years, both molecular and epidemiological data have provided support implicating HPV as an important agent in a subset of carcinomas of the head and neck region. The evidence is compelling for oropharyngeal carcinomas, particularly for carcinomas of the tonsil.7-9 Furthermore, an increase of the HPV-related carcinomas of the oral and oropharyngeal regions has been stated recently.10 Clear identification of this subset of tumors is of clinical interest, because HPV-positive oropharyngeal carcinomas have better prognosis than HPV-negative tumors of the area.3, 11-15

The evidence of HPV involvement in other carcinomas of the head and neck, such as larynx or sinonasal cavities, is far less conclusive.9, 16 The 2005 International Agency for Research on Cancer evaluation on the carcinogenicity of HPV in humans concluded that there is sufficient evidence for the carcinogenicity of HPV in the oral cavity and oropharynx, limited evidence in the larynx, and inadequate evidence in sinonasal cavities.17 However, some previous reports have suggested a possible implication of HPV in the development of several carcinomas of the sinonasal region.18-20

In this study, we evaluate the possible role of HPVs and their clinical implications in sinonasal squamous cell carcinomas (SCCs), using a large series of tumors treated at a single institution.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Patients

All patients (n = 60) with histologically confirmed SCCs of the sinonasal tract diagnosed in the Department of Pathology and treated at the Hospital Clinic, University of Barcelona during a 25-year period (January 1981-December 2006) were included in the study. Tumors originating in the nasal vestibule were excluded. Demographic data including age at diagnosis, sex, and tobacco consumption were obtained from the medical records. Tumor site and stage were determined from the review of the operative, radiology, and pathology reports. Tumor stage was assigned by using the 2002 American Joint Committee on Cancer staging criteria.21 Primary treatment modality data (including surgery, radiation therapy, chemotherapy) was obtained from the review of the clinical files. All cases were followed up in the Cancer Unit of the Department of Otolaryngology of the Hospital Clinic. Routine follow-up of each patient was conducted at intervals of at least 6 months. The study was approved by the institutional ethical review board.

Tumor Specimens

All tissues had been routinely fixed in 4% buffered neutral formalin and embedded in paraffin. Review of hematoxylin and eosin–stained slides of tumor specimens was performed independently by 3 pathologists who did not know either the results of HPV testing or the tumor staging and clinical outcome. Tumors were classified and graded according to the 2005 World Health Organization classification.22 Diagnostic categories included keratinizing (K-SCC), nonkeratinizing (NK-SCC), papillary (P-SCC), and basaloid squamous cell carcinoma (B-SCC). The coexistence of an inverted papilloma was evaluated in each case.22 When differences between the 3 independent evaluations were detected, a new evaluation was conducted, and a consensus diagnosis was reached.

In all cases, a representative block of the invasive carcinoma was selected for immunohistochemical and molecular analyses.

DNA Extraction

Ten-micrometer-thick sections of formalin-fixed, paraffin-embedded tissues were cut using the sandwich technique, which implies that the first and last sections are stained with hematoxylin-eosin and used to confirm the adequacy of the sample, whereas the central sections are used for DNA extraction. The microtome blade was replaced after each case. A vacuum cleaner was used to avoid cross-contamination between paraffin blocks. The tissue sections were digested with proteinase K in a volume of 250 μL at 56°C overnight. Proteinase K was heat inactivated at 95°C for 10 minutes. A 1/10 dilution of the sample was used for polymerase chain reaction (PCR) (10 μL).

HPV Detection and Typing

Broad-spectrum HPV DNA amplification was performed using the short PCR fragment (SPF10) primer set6 (Innogenetics Diagnostica, Barcelona, Spain). The SPF10 primers amplify a 65-bp fragment from the L1 region of the HPV genome. For HPV amplification, a 9-minute denaturation step at 94°C was followed by 40 cycles of amplification using 1.5 IU DNA polymerase (Amplitaq Gold DNA polymerase, Applied Biosystems, Foster City, Calif) with a thermocycler (GeneAmp 9700, Applied Biosystems). These cycles included denaturation at 94°C for 30 seconds, primer annealing at 52°C for 45 seconds, and chain elongation at 72°C for 45 seconds. The final elongation step was prolonged by 7 minutes.

Amplification products were first tested for the presence of HPV DNA by DNA enzyme-immunoassay (DEIA), which consists of hybridization with conserved probes in a microtiter-plate assay format (Universal DNA ELISA kit, Labo Bio-medical Products, BV, Rijswijk, Netherlands). SPF10 amplimers from DEIA-HPV–positive samples were subsequently analyzed by reverse hybridization in an HPV line-probe assay LiPA25 system version 1 (Labo Bio-medical Products) at high stringency, generating a type-specific hybridization pattern. In this assay, 10 μL of denatured HPV PCR product was hybridized to the genotype-specific probes immobilized as parallel lines on a nitrocellulose strip. After the washing step, the products of hybridization were detected by a color reaction with alkaline-phosphatase-streptavidin conjugate and substrate (5-bromo-4-chloro-3-indolyl phosphate and nitroblue tetrazolium), which results in a purple precipitate. The results of the hybridization were assessed visually by comparing to the standard grid. The HPV LiPA25 version 1 permits specific detection of 25 HPV types: HPV6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 70, 73, and 74. These assays were automatically performed using the AutoLipa (Innogenetics Diagnostica) system for 48 strips.

To confirm DNA amplification, a second PCR using primers for β-globin was conducted with primers β-globin-PCO3 and β-globin-PCO5.

Immunohistochemistry

Immunohistochemical studies for p16INK4a, p53, and LMP-1 were done with the automated immunohistochemical system TechMate 500 (Dako Co, Carpinteria, Calif), using the EnVision system (Dako), following previously reported protocols.6 p16INK4a was detected using a monoclonal antibody (clone JC8, Biocare Medical, Walnut Creek, Calif; dilution 1:100, antigen retrieval with pressure cooker and 1 mM ethylenediaminetetraacetic acid, pH 8.0, 2 minutes). p53 was detected with the monoclonal antibody BP53-12 (Novocastra, Newcastle upon Tyne, UK; dilution 1:50, antigen retrieval with pressure cooker and 10 mM sodium citrate, pH 6.0, 5 minutes). Epstein-Barr virus (EBV) antigen LMP-1 was detected using a monoclonal antibody (clone CS 1-4, Dako; dilution 1:100, antigen retrieval with pressure cooker and 10 mM sodium citrate at pH 6.0, 2 minutes).

The evaluation of the p16INK4a immunostained slides was performed on 3 different staining patterns: negative, focal, and diffuse staining. Negative staining was defined as nonimmunoreactive. Focal staining was defined as noncontinuous staining of isolated cells or small cell clusters. Diffuse staining was defined as a continuous staining of cells of the basal and parabasal layers, independently of the positive or negative staining in the center of the tumor nests. p16INK4a expression was nuclear, as well as cytoplasmic. Only cases with diffuse staining were considered as positive for analytical purposes.23 Immunostaining for p53, which was always only nuclear, was considered positive when >25% of the neoplastic cells showed reactivity.

EBV In Situ Hybridization

Detection of mRNA of EBER genes 1 and 2 of EBV was done on tissue sections by in situ hybridization (InformEBER, Ventana Medical Systems, Tucson, Ariz) on an automated platform (BenchMark XT, Ventana Medical Systems). Nuclear red was used as a counterstain. In all cases, a EBV-positive classical Hodgkin lymphoma was used as a positive control. In negative cases, a control probe was used to assess mRNA preservation (Ventana Medical Systems).

Statistical Analysis

Data was analyzed with the program STATA (Version 8.0, StataCorp 2003, College Station, Tex). Chi-square analysis or Fisher exact test was used for comparisons between qualitative variables, and Student t test and analysis of variance were applied for quantitative variables according to application conditions.

Overall survival was defined as the time from the date of registration to the date of death or to the last date of follow-up. Progression-free survival was defined as the time from registration to local recurrence or metastasis. Death without documented progression was censored at the date of death. Survival data were analyzed by the Kaplan-Meier method, and survival curves were compared by use of the log-rank test in univariate analysis. In multivariate analyses, a Cox proportional hazards model was used. All statistical tests were 2-sided, and a P value of ≤.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

HPV DNA Detection and Histological and Immunohistochemical Characteristics of Tumors

Of all tumors, 12 of 60 (20.0%) were HPV SPF10/DEIA–positive, whereas the remaining 48 tumors (80.0%) were negative. In 11 of 12 (91.7%) positive tumors, a HPV type 16 was detected. One tumor (8.3%) harbored a HPV type 35. On histological analysis, 42 tumors were classified as K-SCCs (70.0%), 11 as NK-SCCs (18.4%), 5 as B-SCCs (8.3%), and 2 as P-SCCs (3.3%). Two of 12 (16.7%) of the HPV-positive carcinomas and 40 of 48 (83.3%) HPV-negative tumors were K-SCCs (P<.001). The histological typing and the immunohistochemical expression of p16INK4a and p53 in HPV-positive and -negative tumors are shown in Table 1.

Table 1. Relation Between Histological Types, Immunohistochemical Expression of p16INK4a and p53, and Human Papillomavirus (HPV) DNA Detection
 HPV+, n=12, No. (%)HPV−, n=48, No. (%)P
  1. HPV indicates human papillomavirus.

Histological type  <.001
 Keratinizing, n=422 (16.7)40 (83.3) 
 Nonkeratinizing, n=116 (50.0)5 (10.4) 
 Basaloid, n=52 (16.7)3 (6.3) 
 Papillary, n=22 (16.7)0 (0) 
Immunohistochemistry   
 p16INK4a positive12 (100)0 (0)<.001
 p53 positive4 (33.4)32 (66.6).05

p16INK4a had a 100% sensitivity and specificity for the detection of HPV-positive tumors. Figure 1 shows the histological characteristics, the p16INK4a immunohistochemical staining, and the PCR test in 4 HPV-positive tumors (K-SCC, NK-SCC, B-SCC, and P-SCC types). Figure 2 shows the histological characteristics, the p16INK4a immunohistochemical staining, and the PCR test in 3 HPV-negative tumors (K-SCC, NK-SCC, and B-SCC types).

thumbnail image

Figure 1. Human papillomavirus (HPV)-positive sinonasal squamous cell carcinomas are shown: (A) keratinizing (H & E, original magnification, ×100), (B) nonkeratinizing (H & E, original magnification, ×100), (C) basaloid (H & E, original magnification, ×100), and (D) papillary (H & E, original magnification, ×100). A', B', C', and D' show p16INK4a immunohistochemical expression of the same cases (p16, original magnification, ×100). A'', B'', C'', and D'' show HPV identification and typing with SPF10 of each case.

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thumbnail image

Figure 2. Human papillomavirus (HPV)-negative sinonasal squamous cell carcinomas are shown: (A) keratinizing (H & E, original magnification, ×100), (B) nonkeratinizing (H & E, original magnification, ×100), and (C) basaloid (H & E, original magnification, ×100). A', B', and C' show p16INK4a immunohistochemical expression of the same cases (p16, original magnification, ×100). A'', B'', and C'' show HPV identification and typing with SPF10 of each case.

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In 12 cases, the carcinoma developed on a sinonasal inverted papilloma that coexisted in 11 cases and had been previously excised in 1 case. Only 1 of the carcinomas arising on a sinonasal inverted papilloma tested positive for HPV16.

Clinical Characteristics of the Patients at Diagnosis and Survival Analysis

Table 2 shows the age and sex characteristics, percentage of smokers at the time of diagnosis, cigarettes smoked in pack/years, presence of inverted papilloma, site of origin, and stage of tumors at diagnosis by HPV status.

Table 2. Age, Gender, Smoking History, Association With Inverted Papilloma, Site of Origin and Stage of Tumors at Diagnosis in Human Papillomavirus–Negative and –Positive Patients
 HPV Positive, n=12HPV Negative, n=48P
  1. HPV indicates human papillomavirus.

Age   
 Median age, y [range]69 [49-87]62 [42-93].206
Sex, No. (%)  .456
 Men8 (66.7)37 (77.1) 
 Women4 (33.3)11 (22.9) 
Smoking history, No. (%)  .659
 Never2 (16.7)11 (22.9) 
 Yes9 (75.0)34 (70.8) 
 Unknown1 (8.3)3 (6.3) 
Cigarettes smoked, pack years, No. (%)  .010
 <205 (55.6)5 (14.7) 
 ≥204 (44.4)29 (85.3) 
Previous/coincident inverted papilloma1 (8.3)11 (22.9).431
Site  .050
 Nasal cavity4 (33.4)5 (10.4) 
 Paranasal sinuses1 (8.3)18 (37.5) 
 Nasal cavity and paranasal sinuses7 (58.3)25 (52.1) 
Stage  .977
 I1 (8.4)5 (10.4) 
 II4 (33.3)13 (27.1) 
 III4 (33.3)17 (35.4) 
 IV3 (25.0)13 (27.1) 

Median follow-up time for the entire study population was 24 months (range, 5-254 months). Five patients were lost to follow-up (1 HPV-positive, 4 HPV-negative). All patients received primary surgery and local radiotherapy as standard treatment, with the exception of 6 stage I tumors that did not receive radiotherapy. Chemotherapy was administered to all 16 patients with stage IV tumors and to 6 additional patients that developed metastases during follow-up.

Three of 11 (27.3%) HPV-positive and 35 of 44 (79.5%) HPV-negative patients developed local recurrences (P = .002). One of 11 (9.1%) HPV-positive and 9 of 44 (20.5%) HPV-negative patients developed lymph node metastases (P = .66). There were 30 deaths from disease in the overall group. Three of 11 (27.3%) patients with HPV-positive and 27 of 44 (61.4%) patients with HPV-negative tumors died from the disease (P = .08).

Median disease-free and overall survival in the HPV-positive group were 36 months (range, 8-90 months) and 53 months (range, 8-254 months), respectively. Median disease-free and overall survival in the HPV-negative group were 14 months (range, 0.5-14 months) and 20.5 months (range, 8-90 months), respectively.

On the basis of Kaplan-Meier estimates, HPV-positive tumors statistically had a significantly better progression-free survival than patients with HPV-negative tumors (P = .0043, log-rank test, Fig. 3A). The estimated 1-, 2-, and 5-year progression-free survival for HPV-positive patients was 100%, 100%, and 62% (95% confidence interval [CI], 23%-86%). In contrast, the estimated 1-, 2-, and 5-year progression-free survival for HPV-negative patients was 57% (95% CI, 40%-70%), 34% (95% CI, 20%-48%), and 20% (95% CI, 9%-34%).

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Figure 3. Kaplan-Meier curves are shown for progression-free survival (A) and overall survival (B) stratified by human papillomavirus status. HPV indicates human papillomavirus.

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Overall survival for patients with HPV-positive tumors was improved to a statistically significant extent compared with that of patients with HPV-negative tumors (P = .0364, log-rank test; Fig. 3B). The estimated 1-, 2-, and 5-year overall survival for HPV-positive patients was 100%, 100%, and 80% (95% CI, 20%-96%), whereas the estimated 1-, 2-, and 5-year progression-free survival for HPV-negative patients was 78% (95% CI, 62%-88%), 54% (95% CI, 37%-68%), and 31% (95% CI, 15%-47%).

On univariate analysis, HPV status, tumor location, and stage were associated with progression-free survival outcomes, whereas HPV status and tumor grade were associated with overall survival (Table 3). On multivariate analysis, HPV status retained statistical significance for progression-free survival (P = .012).

Table 3. Univariate and Multivariate Analysis for Overall and Progression-free Survival
CharacteristicUnivariateMultivariate
HR95% CIPHR95% CIP
  1. HR indicates hazard risk; CI, confidence interval; HPV, human papillomavirus.

Progression-free survival      
 Age (≥60 y vs <60 y)0.710.38-1.35.297   
 Sex (women vs men)0.990.48-2.04.974   
 HPV status (positive vs negative)0.210.07-0.70.0110.210.06-0.71.012
 P53 (negative vs positive)0.530.26-1.07.078   
 Previous papilloma (yes vs no)0.660.29-1.47.3100.410.17-0.98.045
 Tumor grade (2, 3 vs 1)0.340.11-1.05.149   
 Smoking (yes vs never)0.740.34-1.60.241   
 Tumor location (sinusal vs nasal)3.911.13-13.53.0313.751.07-13.17.111
 Stage (I+II vs III+IV)2.101.04-4.22.038   
Overall survival     
 Age (≥60 y vs <60 y)0.760.36-1.59.461   
 Sex (women vs men)0.670.27-1.66.3830.090.01-0.68.020
 HPV status (positive vs negative)0.200.05-0.83.0270.170.04-0.81.065
 P53 (negative vs positive)0.710.32-1.56.394   
 Previous papilloma (yes vs no)0.720.27-1.89.5010.400.14-1.17.095
 Tumor grade (2, 3 vs 1)0.220.07-0.71.0260.220.06-0.85.028
 Smoking (yes vs never)0.690.28-1.65.238   
 Tumor location (sinusal vs nasal)3.880.87-17.38.1644.440.88-2.34.071
 Stage (I+II vs III+IV)1.910.87-4.17.105   

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Our study suggests that HPV infection could be the cause of a subgroup of sinonasal tumors, with HPV16 involved in 91.7% of the tumors. All HPV-positive tumors harbored sequences of oncogenic HPV, and had also a strong immunohistochemical overexpression of p16INK4a, which is highly specific for premalignant and malignant lesions associated with HPV infection.3, 6, 24

SCCs of the head and neck represent the 6th most prevalent cancer in the Western world.25 However, sinonasal SCCs are rare, accounting for <3% of all malignancies of the region.26-28 Most SCCs developing in the head and neck are known to be associated with smoking and alcohol abuse.29 However, in recent years both molecular and epidemiological data have provided support implicating HPV as an important agent in a subset of these tumors, particularly for those located in the oropharynx.3, 7 Currently, sinonasal carcinomas are not considered HPV-related tumors.17 However, scarce previous studies have suggested a possible implication of HPV in the development of several carcinomas of the sinonasal region, with a percentage of HPV-associated tumors (20%-23.1%) similar to the percentage observed in our series.18-20 Our study confirms that sinonasal SCCs should be included in the list of neoplasms related to HPV infection, with a rate of HPV-positive tumors of 20%.

In our study, HPV16 was identified in 91.7% of HPV-positive sinonasal tumors. These results are in agreement with evidence indicating that HPV16 alone accounts for >90% of HPV-positive carcinomas of the head and neck.8, 9, 18-20, 30 Our results indicate that currently developed vaccines may prevent the large majority of head and neck carcinomas associated with HPV infection.

An intense and diffuse p16INK4a expression was observed in all HPV-positive and no HPV-negative sinonasal SCCs. p16INK4a overexpression has been proposed as a biomarker that would allow unambiguous identification of truly dysplastic and neoplastic cells in the uterine cervix.24 In addition, p16INK4a overexpression could help in the identification of the subset of tumors related to HPV infection in a variety of genital and extragenital areas such as the vulva,6 penis,5 anus,4 and tonsil.3, 8, 30 The results of our series of sinonasal SCCs confirm that p16INK4a staining can be considered as almost fully equivalent to HPV detection, as has been shown in the vulva or oropharynx.3, 6

SCCs of the head and neck region associated with HPV infection have been shown to be predominantly nonkeratinizing, papillary, or basaloid.3, 30 In our series, although HPV-positive tumors were indeed predominantly nonkeratinizing, basaloid, or papillary, there was some overlap between the histological types and the association with HPV. Thus, 16.7% of HPV-negative tumors had nonkeratinizing or basaloid features, and 16.7% of HPV-positive SCCs were of the keratinizing type. This indicates that the current histological classification of sinonasal SCCs has limited reliability in identifying HPV-related tumors, and confirms that, as previously shown in the vulva, histological analysis alone results in the misplacement of some tumors in terms of their HPV relationship.6

p53 immunohistochemical overexpression was significantly more frequent in HPV-negative than in HPV-positive SCCs. Inactivation of p53 protein through mutation of its gene is a frequent event in a large number of SCCs of the head and neck related to smoking and alcohol abuse.31, 32 This results in a nondegradable protein that accumulates in the nuclei of malignant cells and is easily detected in immunohistochemical studies.31, 32 It has been shown that the frequency of p53 mutations in head and neck tumors is inversely proportional to the presence of HPV.33-35 Interestingly, unlike other sites like the vulva,6 several HPV-positive cases (33.3%) showed p53 immunohistochemical overexpression. Some authors have found a subgroup of head and neck SCCs associated with HPV showing overexpression of p53 protein because of mutations of p53.34, 35

Finally, in contrast with other studies,36, 37 our results indicate that most HPV-positive SCCs arise de novo in the sinonasal tract and have no relationship to inverted papillomas. Conversely, this relationship was more common in HPV-negative cases. A proportion of papillomas have been reported to be associated with HPV infection, mainly by low risk types such as 6 and 11.38, 39 In our series, 12 SCCs developed on a sinonasal inverted papilloma that coexisted in 11 cases and had been previously excised in 1 case. Only 1 of the carcinomas developing on a sinonasal inverted papilloma tested positive for HPV16 and no HPV types 6 or 11 were detected. Interestingly, HPV-positive carcinomas had a tendency to occur in the nasal cavities, in contrast to HPV-negative tumors, which arose more frequently in the paranasal sinuses (P = .05). The tumor location was associated with progression-free survival outcomes on univariate analysis, but this association did not retain significance on multivariate analysis (Table 3). In the nasal cavities coexist 2 different epithelia (columnar cells and stratified squamous epithelium), and squamocolumnar junctions are thought to facilitate the HPV oncogenesis in this region.40 Although the cervical, anogenital and oropharyngeal HPV-positive SCCs have been considered sexually transmitted diseases, the mechanisms explaining the HPV-infection in the sinonasal region remain unclear.

The analysis of the clinical and follow-up data provided remarkable results. The tumors affected predominantly men by a proportion of approximately 3:1; no significant differences in sex and age were found between HPV-positive and-negative groups. There were no significant differences in tumor stage at presentation. Despite the similar clinical characteristics and staging at presentation, patients with HPV-positive tumors had a significantly better prognosis than those with HPV-negative neoplasms. This better survival rate of HPV-positive tumors has been previously reported in oropharyngeal tumors.3, 11-15 However, to our knowledge, this is the first evidence of the better survival of HPV-positive tumors in sinonasal SCCs. HPV status retained a statistically significant correlation with progression-free survival in our study on multivariate analysis. The improved survival in HPV-positive oropharyngeal tumors has been related to a better response to chemo- and radiotherapy.13-15

In conclusion, HPV infection is associated with a subgroup of sinonasal tumors that are easily identifiable with p16INK4a immunostaining and have a significantly better prognosis. The predominant or almost exclusive role of HPV16 suggests that vaccination could result in a substantial reduction of sinonasal as well as other head and neck carcinomas associated with HPV infection.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

We thank Dr. Silvia de Sanjosé for her interesting suggestions and Ms. Kate Johnson for the English revision of the article.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

This work was supported in part by a grant from the Asociación Española Contra el Cáncer, Catalunya Contra el Càncer (Junta de Barcelona, 2006).

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References