The prevalence of HPV DNA in lung cancer patients varies significantly by geographical region. In the literature, the prevalence of HPV infection in lung carcinomas varies from 0% to 79%.12,15-17
Hirayasu et al. reported that the prevalence of HPV 16 and 18 infections in Okinawa, a subtropical island of southern Japan, was high (58.1% and 58.1%, respectively), but in Niigata, the mainland of Japan, was lower (6.7% and 23.3%, respectively).12
However, Taiwan, the nearest neighbor to Okinawa, had a high prevalence of HPV 16 and 18 infections (35.5% and 41.1%, respectively) in lung carcinomas.8
Our study of 112 NSCLC patients resulted in the detection rates of HPV DNA 16, 18, and 33 in 12 (10.7%), 11 (9.8%), and 35 (31.3%) patients, respectively. This is the first study of HPV DNA prevalence in lung cancer patients from Korea, where the prevalence rate was lower than that of other Asian countries. The overall prevalence of HPV 16 and 18 infections of the cervix was 12.6% (389/3091) and was calculated at 15.5% when standardized in a Korean study of healthy women.18
This value was similar to the 18.2% (4/22) of women in this study.
The geographic variability is associated with sexual behavior and environmental factors.19
Okinawa was considered a HPV high prevalence region, but recent improvements in hygiene (water supply, toilets, and sewage disposal) after Okinawa reverted to Japan have greatly reduced the incidence of HPV infection.20
This change was followed by a decrease in the incidence of squamous cell carcinoma, especially well-differentiated cases. In Taiwan, non-smoking females with adenocarcinomas had a high prevalence of HPV 16 and 18 infections in lung carcinomas.8,9
In our study, gender, smoking status, tumor differentiation, and histologic cell types were not associated with HPV 16, 18, and 33 infections among patients with lung cancer. These discrepancies might result, in part, from the different detection systems, sample conditions, and geographic sexual activity and behavior. Furthermore, a decreasing trend in the prevalence of HPV in lung squamous cell carcinomas, especially the well-differentiated, is related to a decline in HPV infection.21
In our study, co-infection of HPV 16 and 18 occurred in only one case (0.9%), while co-infection with HPV types 16 and 33, and HPV types 18 and 33 occurred in five cases each (3.6%). In a Taiwanese study, a higher prevalence of co-infection with multiple HPV types had a higher risk of lung cancer compared to patients with only one type of HPV infection.8
However, Japanese patients22
and Korean patients in our study demonstrated a lower prevalence of co-infection, and had a lower risk of lung cancer (). These findings suggest that HPV infection might be type-specific and have a synergistic effect on lung carcinogenesis through multiple steps and modeling.
Literature Review of Asian Studies for HPV 16 and 18 Infections in Lung Carcinomas
HPV 33 infections had previously been considered less important than HPV 16 and 18 in lung cancer. However, our study showed a high prevalence of HPV 33 infections in Korean lung cancer patients. We reviewed the literature and compared the prevalence of HPV 33 infections in several countries (). Other Asian and Western countries had an HPV prevalence of 0% to less than 10% in all except one study.11,12,16,23-27
This implied that HPV 33 might be specific and play an important role in Korean lung carcinogenesis. However, one limitation of our study was not enrolled normal lung tissues from non-cancer subjects, which may have yielded a lower frequency of HPV 33 infection.
Literature Review of Asian and Western Studies for HPV 33 Infections in Lung Carcinomas
The observation of certain types of HPV in association with cervical and oral squamous cell carcinoma raises the possibility of sexual transmission of HPV from the cervix to the oral cavity, with subsequent transmission to the larynx, and then to the lung.28
It is likely that the transmission of viral infection to non-genital sites occurs as a consequence of certain sexual behaviors, such as oral-genital contact, or by autoinoculation from a genital infection and, therefore, is acquired by standard sexual behavior measures. Sexual characteristics known to be associated with HPV exposure include a high number of lifetime sexual partners, young age at first intercourse, and a history of sexually transmitted disease.29
Another transmission pathway of HPV infection to the lung is blood circulation. A recent study showed that HPV E6 mRNA was detected in the peripheral blood of advanced cervical cancer patients. This observation seems to reflect the possibility that HPV infection in lung tissues may originate in the cervix, and would then be mediated by blood circulation.30
Several head and neck squamous cell carcinoma patients carrying HPV positive sera were found to develop distant metastasis.31
Since younger patients have a higher sexual activity, they also have a higher risk of HPV infection.18
In our study, the presence of HPV 16 had a four-fold higher prevalence in NSCLC patients under 50 years old and HPV 18 had a 3.9-fold higher prevalence in NSCLC patients with a tumor stage of III & IV after adjusting for other factors (). These results were similar with that of Taiwanese studies.8,9,32
One reason may be that HPV 18 may play a role in the development of rapidly progressive tumors. Kurman et al. suggested that the deficit of HPV 18 in intraepithelial neoplasia, as compared with invasive carcinoma, could represent a rapid transit time through the precursor stage of cervix cancer.33
Walker et al. also suggested that HPV 18-containing tumors might progress to invasion without a prolonged preinvasive stage.34
Alternatively, Barbosa et al. further demonstrated that the rate of phosphorylation of Rb by HPV 16 and 18 E7 varies, with HPV 18 E7 being phosphorylated 2-fold faster than HPV 16 E7 which in turn is 2-fold faster than HPV 6 E7.35
This can explain why these three viruses differ in their relative efficiency in carcinogenesis, while they all possess E7 proteins. The association of HPV 18 with advanced stage lung cancer may be explained by the apparently higher oncogenic potential of this virus. Furthermore, cellular receptors with a specific potential for binding with each of the HPV types may exist.36
Viral copy number is another important factor in the distribution of HPV viral particles and metastasis. Recently, E5 protein of HPV 16 was found to be expressed in the early stages of neoplastic transformation; HPV vaccines, targeting E5, are being developed.37
Further studies are required to monitor the viral copy number in blood and association those levels with various clinical parameters. The presence of HPV 16, 18 and 33 infections was not associated with the survival times of NSCLC patients (). In a literature review, high Langerhans cell infiltration22
and p53 protein accumulation38
with HPV infection was associated with the prognosis of lung cancer. In the present study, Langerhans cell infiltration was not frequently observed in pathologic samples, and p53 protein regulation was not examined.
The sensitivities of the HPV DNA detection systems have varied between reports (). Standardization of the detection system is needed, including the primers and probes used. The age and handling of samples needs to be standardized. When old samples were used, the detection rate of HPV DNA decreased with sample age. Fresh samples obtained immediately after surgery without fixation, or at most one or two months after surgery, yielded better results.
In conclusion, our study showed that the prevalence of HPV 16 and 18 infections in lung cancer tissue was low, suggesting HPV 16 and 18 infections played a limited role in lung carcinogenesis of Koreans. However, the higher prevalence of HPV 33 infection may be important for Korean lung cancer patients, and warrants further investigation.