DISCUSSION
Inverted papilloma is a rare benign sinonasal tumour known for its local aggressiveness, high recurrence rate and the propensity for malignant transformation. It’s pathogenesis still remains to be elucidated though these characteristics however potentially implicate an infectious aetiology. Numerous studies have been conducted, and the role of HPV infection still remains debatable. The recurrence and malignant transformation of nasal inverted papilloma is related to HPV infection, and the higher infection rate of high risk HPV subtype is one of the reasons for malignant transformation.9
A meta-analysis of 20 studies found that 131 IPs were positive for HPV from a total of 341 IPs, (38%).11 Another meta-analysis study, a total of 1,041 IPs and IPsSCC were analysed and HPV DNA was detected in 347 (33.3%) of cases.12 In our study, we found that the overall detection rate of HPV in IPs was 34.1% (15/44). This correlates with the detection rate as seen in other studies.
Sham et al found that the detection rate of HPV in benign IP was 31.7% (13/41) which is higher than the average of 26%.13The most prevalent type of HPV detected in our samples was Type 11 which accounted for 18% (18 of 44) followed by 11% (5 of 44) who had HPV Type 6. Study by Zhou et al showed that the commonest type of HPV detected was Type 11.14 In the current study, we found that 12 patients had at least one type of the low risk group of HPV (Type 6 and 11) and four patients had at least one type from the high risk group (Type 16 and 18). This results correlates with other studies that also showed that HPV subtypes 6 and 11 were the most frequently identified HPV subtypes in sinonasal papilloma.10
All the patients who had the low risk type of HPV belonged to the benign IP group. Out of the four patients who were positive for the high risk group of HPV, two had IP with SCC and two others belonged to the benign group. Studies have shown that the high risk types are usually more commonly associated with concomitant malignancy. This further raises the question of whether the benign group which are positive for HPV type 16 or 18 may potentially progress to premalignancy and malignancy. Histological analysis has suggested that IP tumorigenesis may occur through a series of discrete events. HPV high risk subtypes infection, can occur in benign inverted papilloma as an early event during the multistep tumorigenesis of these lesions. Cumulative genetic defects may be required to progress from benign to dysplastic inverted papilloma and to carcinoma.15
Inverted papilloma has the propensity to convert to squamous cell carcinoma in 5–9% of cases. Malignant alteration is found to be caused by the specific viral genes E6 and E7 of high risk HPV types 16 and 18 and their respective proteins, causing cell immortalisation with increased efficiency when they are expressed together.7 In cervical cancers, it is well established that the malignancy originate in the transformation zone, where the columnar cells of the endocervix form a junction with the stratified squamous epithelium of the vagina, giving rise to squamous metaplasia. Cells at this junction will undergo rapid turnover and are vulnerable to the effects of carcinogens.16 This theory may also be true for sinonasal epithelium, and may explain how HPV is responsible for the potential malignant transformation of IPs to malignancy.17
Barnes et al reported that of all carcinomas that were associated with IPs, 61% were synchronous and 39% were metachronous. There were 6.8% of patients (3 of 44) who had IP with malignant transformation. All the three patients had synchronous SCC and there were no patients with metachronous tumour.11 There was evidence of HPV integration into inverted papilloma causing malignant transformation to squamous cell carcinoma which involved two out of three tumours in their study (66.7%). HPV type 16 was the predominant genotype found in those studies, followed by HPV types 18 and 11.17 HPV was detected in 54% (12/22) of benign IP and 70% (7/10) of IP with SCC. By contrast, the rate of HPV detection in sinonasal SCC that are unrelated to IP is lower (22.3%, 95% CI 15.9–28.6).18 HPV was detected in 21 out of 36 (58.3%) of inverted papilloma, and in 11 of 16 (68.8%) cases of inverted papilloma with squamous cell carcinoma.19 In our study, we also found a high detection rate of high risk HPV infection (66.7%) in patients with IP with SCC as compared to 31.7% (13/41) in benign IP. This further supports that HPV infection plays an important role in malignant transformation of inverted papilloma.
Inverted papilloma is known for its high recurrence rate of about 16-60%. Most surgeons agree that recurrence is due to either incomplete removal of tumour or disease developing from predisposed mucosa, both of which occur more often with limited resections. However, studies have shown a high incidence of recurrence rate despite complete surgical removal. Many studies have shown correlation of HPV infection with recurrence. Study by Syrjanen et al found that all the four recurrent cases were HPV positive (three had HPV 11, one had HPV 16).20 There was recurrence in 13 out of 15 HPV positive IP patients and in none of the 10 HPV negative patients.18 In this study, we found that the recurrence rate was 15.9% (7/44). The detection rate of HPV infection in IP with recurrence was 28.6% (2/7). The detection rate seen in our study is lower than that reported in other studies.
There have been many theories as to why there is such a discrepancy in detection rates of HPV infection. The lower number of specimens testing positive for HPV may be attributable to several factors. DNA extraction from frozen specimens would be the most reliable source. Tissue banking would therefore serve as an ideal method to preserve tissue for optimal HPV detection. A few technical factors have been found to account for the observed striking variations in HPV detection rates.21 PCR technique of HPV detection has been found to be sensitive to false positive results from a variety of sources. This may be due to errors in result interpretation or, from true HPV negative specimens which may have been contaminated with HPV DNA. The current study focused on Malaysian population of multi-ethnicities (Malays, Chinese and Indians) while most other studies have detected higher detection rate of HPV IP in North American and European populations.
Lack of the expression of HPV DNA in the remaining samples may also be due to HPV subtypes other than that investigated. For instance, Xiang et al demonstrated a possible role for HPV subtype 57 in the pathogenesis of nasal inverted papilloma.22 In this study, we only examined specimens for only four HPV types (6, 11, 16, 18). The number of patients that were enrolled in this study was small due to the rarity of this disease. Patients who have been found positive for HPV infection should be closely followed up in view of potential recurrence and malignant transformation. Regular screening of upper aerodigestive tract for SCC related malignancy should also be performed in this group of patients.