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Editorial |
Address correspondence to Steven I. Hajdu, M.D., 1759 Drumcliff Court, Westlake Village, California 91361-1636; tel 805 496 0691; fax 805 496 0620; e-mail sih15{at}aol.com.
Keywords: papillomavirus, lung carcinoma, HPV infection, history of medicine
Humans have likely carried papillomavirus (HPV) for millennia. Aurelius Celsus (25 BC–AD 50), a Roman physician, named anogenital tubercles "condyloma" and treated them by cautery with a hot iron [1]. It required 2000 years to develop laboratory techniques–ultrastructural, immunohistochemical, and molecular–for the detection of viral particles and HPV-DNA in a wide variety of cutaneous warts, including prosectors’ warts and butchers’ warts [2–4]. An impetus for large scale research came from the discovery of HPVs in squamous cell carcinomas [5,6]. Almost instantaneously, clinical and laboratory efforts became focused primarily on the detection of HPVs in uterine cervical cancers. Twenty-five years later this vast undertaking paid dividends in the realization that HPVs are the etiologic agents of squamous cell carcinoma of the cervix and that infection by HPVs can be prevented by vaccination [7].
It is difficult to comprehend that the success in linking HPVs as causative agents of cervical carcinoma has been heralded by thousands of articles and monographs, while less than two dozen scientific studies have been published–during the same period of time–that have addressed the role of HPVs in the etiology of pulmonary carcinoma.
In 1985, for the first time, an oncogenic HPV, HPV-16, was found by Stremlau et al [8] of Germany in 1 of 24 cases of lung carcinoma. In 1989, Strijänen et al [9] of Finland, in a series of 131 cases of bronchial squamous cell carcinomas, detected 12 (9%) HPV-positive cases by in-situ DNA hybridization [9]. These researchers were the first to point out that HPV infection may play a role in the oncogenesis of squamous cell carcinoma of the lung [9].
In 1990, as precise molecular typing became available, HPV-16 and HPV-18 were identified by Bejui-Thivolet et al [10] of France in 4 (12%) of 33 cases of squamous cell carcinoma of the lung. They proposed that HPV DNA could be a cocarcinogenic factor with chemical or physical carcinogens [10].
In 1992, Yousem et al [11] at Montefiore University Hospital in Pittsburgh, PA, USA, using biotinylated DNA probes to HPV subtypes 6/11, 16/18, and 31/33/35, detected positive reactions in 6 (30%) of 20 pulmonary squamous cell carcinomas and in 1 of 6 cases of large cell undifferentiated carcinoma of the lung. They speculated that HPV may be a cause of lung carcinoma [11].
In 1995, Quingquan et al [12] of China studied 50 lung carcinomas; they detected HPV-16 and HPV-18 DNA sequences in 48% of squamous cell carcinomas; 2 adenocarcinomas and 1 small cell carcinoma also tested positive. Consequently, the authors suggested that primary bronchogenic carcinomas are related to HPV infection [12]. In the same year, Nuorva et al [13] in Finland used PCR amplification to demonstrate HPV DNA in 8 (36%) of 22 bronchioloalveolar carcinomas (BACs) [13]. BACs have been long suspected to have a viral etiology [14].
In 1996, Hirayasu et al [15] of Okinawa compared the sensitivity of PCR amplification and non-isotopic in situ hybridization (NISH) in 43 cases of squamous cell carcinoma; they reported that 70% of the cases were positive for HPV DNA by PCR and 53% by NISH. There was no correlation between the patients’ smoking history and the detection of HPV DNA [15].
In 1998, two papers published from Greece and Japan respectively [16,17] pointed out that the rate of detection of HPVs in lung cancers is influenced by the level of differentiation of the neoplastic cells. Papadopouiou et al [16] observed that 11 (38%) of 29 well-differentiated squamous cell carcinomas tested positive, while only 1 of 6 poorly differentiated carcinomas was positive. In 23 cases of adenosquamous carcinoma, Tsuhako et al [17] found that the squamous component was positive in all but 2 well-differentiated cases; HPV DNA was detected in 78% of the total group. It may be noteworthy that some adenocarcinoma cells adjacent to squamous carcinoma cells were positive for HPV [17]. Both groups of authors suggested that HPV infection might contribute to the development, progression, and differentiation of squamous cell carcinoma of the lung [16,17].
In 2000, Miyagi et al [18] of Okinawa analyzed all surgically resected lung carcinomas between 1986 and 1998. The authors found that although most of the patients were heavy smokers, the incidence of squamous cell carcinoma decreased from 1986 to 1998 and the decrease coincided with a falling rate of HPV-positive cases from >70% to <30%. The authors deduced from these findings that HPV may be involved in the development of squamous cell carcinoma of the lung [18].
In 2003 in Taiwan [19], where <10% of female lung cancer patients are smokers, Cheng et al [19] studied 141 cases of lung cancer and noted that HPV-positive cases were 5 times more common in women than in men. Their data strongly suggest that HPV-16 and HPV-18 infections are associated with lung cancer development in nonsmoking females {19].
Three articles on HPV infection and lung cancer were published recently from Italy [20], Korea [21] and Chile [22]. Ciotti et al [20] found that 8 (21%) of 38 non-small cell lung carcinomas tested positive for HPV-16, HPV-18, or HPV-31, supporting the hypothesis that HPV infection could play a role in bronchogenic carcinogenesis [20]. Park et al [21] studied 112 non-small cell lung carcinomas and concluded that HPV-16, HPV-18, and HPV-33 infections are carcinogenic; smoking status, gender, and histologic type were not statistically different in the presence or absence of HPV DNA. Aguayo et al [22} analyzed 69 lung carcinomas by PCR Southern blot and sequencing. HPV-16 was detected in 46% of the squamous cell carcinomas and 9% of the adenocarcinomas. These authors noted that HPV-positivity depended on the DNA integrated viral load [22].
After all is said, the mounting evidence and global concern about the role of HPVs in pulmonary carcinogenesis cannot be ignored. We believe that the time has come to add HPV to the traditionally accepted carcinogenic agents such as smoking, air pollution, asbestos, and radiation. We find it curious that among the 14 published studies on HPV and lung cancer, only one paper was written by American authors [11]. It is important and timely that an editorial in the October 2007 issue of CANCER, the journal of the American Cancer Society, is subtitled with the question: "An emerging epidemic of human papillomavirus-associated cancers?" [23].
References
This article has been cited by other articles:
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  M. Srinivasan, E. Taioli, and C. C.Ragin Human papillomavirus type 16 and 18 in primary lung cancers--a meta-analysis Carcinogenesis, October 1, 2009; 30(10): 1722 - 1728. [Abstract] [Full Text] [PDF]
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 J. Joh, K. Hopper, K. Van Doorslaer, J. P. Sundberg, A. B. Jenson, and S.-J. Ghim Macaca fascicularis papillomavirus type 1: a non-human primate betapapillomavirus causing rapidly progressive hand and foot papillomatosis J. Gen. Virol., April 1, 2009; 90(4): 987 - 994. [Abstract] [Full Text] [PDF]
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