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. 2021 Feb 23;4(4):e1350. doi: 10.1002/cnr2.1350

HPV and lung cancer: A systematic review and meta‐analysis

Julia Karnosky 1, Wolfgang Dietmaier 2, Helge Knuettel 3, Viola Freigang 4, Myriam Koch 1, Franziska Koll 1, Florian Zeman 5, Christian Schulz 1,✉
PMCID: PMC8388180  PMID: 33624444

Abstract

Background

Lung cancer has emerged as a global public health problem and is the most common cause of cancer deaths by absolute cases globally. Besides tobacco, smoke infectious diseases such as human papillomavirus (HPV) might be involved in the pathogenesis of lung cancer. However, data are inconsistent due to differences in study design and HPV detection methods.

Aim

A systematic meta‐analysis was performed to examine the presence of HPV‐infection with lung cancer.

Methods and Results

All studies in all languages were considered for the search concepts “lung cancer” and “HPV” if data specific to HPV prevalence in lung cancer tissue were given. This included Journal articles as well as abstracts and conference reports. As detection method, only HPV PCR results from fresh frozen and paraffin‐embedded tissue were included. Five bibliographic databases and three registers of clinical trials including MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched through February 2020. A total 4298 publications were identified, and 78 publications were selected, resulting in 9385 included lung cancer patients. A meta‐analysis of 15 case‐control studies with n = 2504 patients showed a weighted overall prevalence difference of 22% (95% CI: 12%‐33%; P < .001) and a weighted overall 4.7‐fold (95% CI: 2.7‐8.4; P < .001) increase of HPV prevalence in lung cancer patients compared to controls. Overall, HPV prevalence amounted to 13.5% being highest in Asia (16.6%), followed by America (12.8%), and Europe (7.0%). A higher HPV prevalence was found in squamous cell carcinoma (17.9%) compared to adenocarcinoma (P < .01) with significant differences in geographic patterns. HPV genotypes 16 and 18 were the most prevalent high‐risk genotypes identified.

Conclusion

In conclusion, our review provides convincing evidence that HPV infection increases the risk of developing lung cancer.

Keywords: carcinogenesis, HPV, lung cancer, meta‐analysis

Abbreviations

AC

adeno carcinoma

AhR

aryl hydrocarbon receptor

ALK

anaplastic lymphoma kinase

ARI

absolute risk increase

cIAP‐2

baculoviral IAP repeat‐containing protein3

E6

E6 oncoprotein of human papillomavirus

E7

E7 oncoprotein of human papillomavirus

EGFR

epidermal growth factor receptor

Embase

biomedical and pharmacological bibliographic database

EU

European Union

FHIT

fragile histidine triad protein

HER‐2

receptor tyrosine‐protein kinase erbB‐2

HIF‐1α

hypoxia‐inducible factor 1‐alpha

HPV

human papillomavirus

hTERT

human telomerase reverse transcriptase

IL

interleukin

MCL1

induced myeloid leukemia cell differentiation protein

MEDLINE

U.S. National Library of Medicine

NHS

National Health Service

p53

cellular tumor antigen p53

PCR

polymerase chain reaction

PD

prevalence difference

PR

prevalence ratio

pRb

retinoblastoma protein

ROS1

proto‐oncogene tyrosine‐protein kinase ROS

SCC

squamous cell carcinoma

VEGF

vascular endothelial growth factor

WHO

World Health Organization

1. INTRODUCTION

Lung cancer is estimated to be the leading cause of cancer‐related mortality worldwide, with 2.1 million new lung cancer cases and 1.8 million predicted deaths worldwide in 2018.1 Although smoking by far has been identified as the most important risk factor in lung cancer, other interactions with environmental and/or genetic risk factors as well as infectious diseases have been identified to contribute to the pathogenesis of lung cancer as well.

Viral infections, such as human papillomavirus (HPV) infections have been reported to be an important risk factor of cervical cancer if genotypes with a high oncogenic risk are found. Since the first identification of human papillomavirus, more than 200 different subtypes have been identified They are classified into high‐risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, and 58) and low‐risk HPV types (6, 11, 42, 43, and 44).2 In some other publications, a differentiation between high‐, intermediate‐, and low‐risk HPV types can be found.3 Although HPV infection has been identified as a potential contributor to the pathogenesis in lung cancer in certain populations, such as never smokers, its role still remains controversial. Numerous tests, such as nucleic acid amplification, HPV DNA‐based in situ hybridization, immunohistochemistry, and cytology are available for HPV‐testing and screening.4, 5 The current study focused on the prevalence of HPV infections in lung cancer patients in which HPV detection was performed by means of PCR from fresh frozen and/or paraffin‐embedded tissue to first minimize differences in HPV prevalence due to methodological bias and second to rely on the method with the highest sensitivity to detect HPV positivity, which has been proven to have the highest sensitivity in earlier studies.4, 5 We conducted and report here a systematic review on the issue above.

2. METHODS

The methods of the systematic review and meta‐analysis were specified in advance and published in a protocol registered with PROSPERO. Reporting of this meta‐analysis was done according to the recommendation of Stroup et al for reporting observational studies.6

2.1. Evidence search and meta‐analysis

The digital databases Embase (via Ovid, 1974‐present), MEDLINE (via Ovid, 1946‐present), Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effect, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, NHS Economic Evaluation Database; from inception to present), and Science Citation Index Expanded (Web of Science, 1965‐present), as well as the search engine Google Scholar (using Anne‐Wil Harzing's “Publish or Perish” program available from https://harzing.com/resources/publish-or-perish), were searched. From Google Scholar, only the first 200 records (initial search on April 25, 2018; no date limit) and the first 100 records (update search on February 6, 2020; date limit years 2018‐2020) were downloaded (default sort order). In addition, WHO's International Clinical Trials Registry Platform, ClinicalTrials.gov, and the EU Clinical Trials Register were searched for completed studies. All searches were last updated on February 6, 2020. We deviated from the protocol; in that, we did not search the German Clinical Trials Register due to its search interface giving erroneous results. An initial, sensitive search strategy for the concepts “lung cancer” AND “HPV” was developed for Embase by a medical librarian in cooperation with subject matter experts and then adapted to the other databases. Controlled terms from the databases' thesauri and a broad range of synonyms were used. No limits such as for study type, publication type, publication date, or language were applied. Search strategies that allow for reproducing the searches are documented in Appendix 1. Database searches were carried out by a medical librarian. The reference lists of included studies and of relevant systematic reviews were screened for additional studies. Records from the database searches were imported into Endnote software for deduplication. Screening by title and abstract and subsequent full‐text assessment were done in Covidence. Titles and abstracts of the publications were analyzed by three independent reviewers (F.K., J.K., and C.S.) for relevance and matching inclusion criteria. Analysis of the publications was done according to prespecified inclusion and exclusion criteria.

All studies reporting HPV prevalence in primary lung cancer cases in adults were included. Case reports were excluded. As detection method, only PCR from fresh frozen and/or paraffin‐embedded tissue were included. All types of tissue sampling method were included. HPV detection in archival tumor tissue was included as well. Only studies that provide data specific to HPV prevalence in lung cancer tissue were included. No exclusions were made based on language. Journal articles as well as abstracts and conference reports were included if they met the inclusion criteria. Journal articles that reported about not only cases of HPV detection in primary lung cancer but, for example, in head and neck cancer as well, were included but only the data of the primary lung cancer group were extracted.

2.2. Statistical analysis

The total number of cases, as well as the number of positive and negative HPV detections, was collected from the selected records, and HPV prevalences were calculated by means of the extracted patient data. The Chi‐squared‐test of independence was used to analyze whether prevalence rates differ between continents. Furthermore, a meta‐analysis was performed on a small subset of case‐control studies regarding HPV prevalence. Prevalence difference (PD) and prevalence ratio (PR) both accompanied with the corresponding 95% confidence intervals were estimated for each study. To estimate PR in studies with no HPV positive cases, 0.5 was added to each cell of the 2 × 2 table as usually recommended. Random‐effect models were used to determine the weighted averages of PD and PR while allowing for heterogeneity of effects. The Q‐statistic as a measurement for between‐study heterogeneity and I2‐statistic for quantification of the proportion of total variation due to heterogeneity were calculated. Analyses were performed using R version 4.0.3 (The R Foundation for Statistical Computing), the meta‐analysis by using the metafor package. For all comparisons, a P value <.05 was considered as statistically significant.

3. RESULTS

3.1. Evidence Search

The database searches were last updated on February 6, 2020 and yielded a total of 4525 records. Following deduplication, 3135 publications were evaluated on relevance for the research question. A total of 2754 of the titles and abstracts did not relate to the current research and were excluded. In summary, 381 publications were entered into the full text review. Full texts of three possibly relevant publications could not be obtained despite some efforts and therefore were not available7, 8, 9 for further analyses. The remaining 378 full‐texts were assessed for eligibility. After applying the inclusion and exclusion criteria, 78 publications were included in this systematic review. Reasons for exclusion were as follows: No PCR data were reported (n = 80). HPV detection method was not detailed (n = 2). Duplication of the data (n = 22). Case reports (n = 9). Corrections and/or comments on screened publications (n = 15). Systematic reviews and meta‐analysis (n = 29). Overview articles (n = 29). HPV detection was not done in lung biopsies (n = 32). HPV prevalence analyzed in cancers other than lung cancer or on metastasis (n = 6). Missing data on HPV prevalence (n = 40). Same patients in separate publications (n = 7). Same information in different languages (n = 4). Abstract published in a different journal than the full text (n = 12). HPV prevalence in lung cancer in special patient groups, for example, patients after lung transplantation, immunocompromised patients, butchers, and respiratory papillomatosis (n = 7). Unfinished studies (n = 4). No data on sampling method were provided (n = 2). This review process was performed according to the PRISMA statement. Figure 1 depicts the flow of citations reviewed for the meta‐analysis.

FIGURE 1.

FIGURE 1

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PRISMA flowchart of selected and analyzed studies

A total of 15 publications were case‐control studies, in which normal lung tissue was used as a control (see Table 1).

TABLE 1.

Included case‐control studies

Author Year No. of cases No. of positive cases HPV prevalence cases [%] No. of controls No. of positive controls HPV prevalence controls [%]
Carpagnano et al10 2011 89 12 13.5 68 0 0.0
Cheng et al11 2004 141 54 38.3 60 1 1.7
Cheng et al12 2001 141 77 54.6 60 16 26.7
Eberlein‐Gonska et al13 1992 55 3 5.5 15 0 0.0
Fan et al14 2015 262 22 8.4 19 0 0.0
Galvan et al15 2012 85 0 0 100 0 0.0
Gatta et al16 2012 50 2 4.0 23 2 8.7
Li et al17 1995 50 16 32.0 22 0 0.0
Lu et al18 2016 72 33 45.8 54 2 3.7
Nadji et al19 2007 129 33 25.6 89 8 9.0
Robinson et al20 2016 70 9 12.9 10 1 10.0
Wang et al21 2008 313 138 44.1 96 4 4.2
Wang et al22 2010 45 19 42.2 16 0 0
Yu et al23 2015 180 100 55.6 110 7 6.4
Zhang24 2009 68 30 44.1 12 1 8.3
Total 1750 548 31.3 754 42 5.6
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The studies were stratified according to the geographical region in which the patients lived. There were 36 studies on patients from Asia, 25 studies on European patients, and 17 studies carried out on the American continent. The countries most represented were Japan (n = 11), China (n = 11), United States (n = 9), and Italy (n = 5). Three studies from Germany met the inclusion criteria. Six studies were done in multiple countries with the information summarized in one publication. Most of the publications were written in English (n = 73). The other publications were published in Chinese (n = 3), French (n = 1), and German (n = 1). In order to get information on as many cases as possible not only journal articles but every type of available study was included. Of the 78 included publications, 67 were journal articles. Of the remaining publications, six were abstracts, three were poster presentations, and two were meeting abstracts.

3.2. Patients characteristics

A total of 9385 lung cancer patients were included into this systematic review. Twenty‐eight studies provided data on the patients' age. The average age of all studies ranged from 51.6 to 70 years. Information on patients' gender was available in 52 out of the 78 studies. Those studies included 6326 patients. Of them, 62.8% were male and 37.2% were female, respectively. The percentage of male patients ranged from 0.0% to 91%. Smoking behavior was detailed in 31 of the studies. There were 3577 current or former smokers, 1958 never smokers, and in 3850 cases, no information on smoking status was available. The rate of smokers was 64.6% and ranged from 0% to 100%.

3.3. Meta‐analysis of 15 case‐control studies

A total of 1750 lung cancer cases and 754 controls were analyzed, which were derived from 15 case‐control studies (Table 1). One of them is from America, 10 are from Asia, and four from Europe. The overall HPV prevalence was detected to be 31.3% (548/1750) in the lung cancer group and 5.5% (42/754) in the control group (P < .001). Figure 2 shows the HPV prevalence derived from case‐control studies as well as divided by different continents. Comparing HPV prevalence of patients with lung cancer and controls in a meta‐analysis, using the 15 case‐control studies with a total of 2504 patients, a higher prevalence could be found for the lung cancer patients for prevalence difference (PD = 0.22; 95%‐CI, 0.12‐0.33; P < .001) as well as prevalence ratio (PR = 4.7; 95% CI, 2.7‐8.4; P < .001). A forest plot summarizing the data and the effect estimates is shown in Figure 3. Due to the large confidence intervals of the PRs, only PDs are presented graphically. According to the Q‐statistic, a significant difference in between‐study heterogeneity could be identified [PD: Q(df = 14) = 344.4, I 2 = 95.94%, P < .001; PR: Q(df = 14) = 33.0, I 2 = 57.6% (PR), P = .003].

FIGURE 2.

FIGURE 2

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Overall HPV prevalence in case‐control studies as well as divided by different continents. There was a significant difference between the HPV prevalence in cases and controls overall as well as in Europe and Asia (P < .01)

FIGURE 3.

FIGURE 3

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Forest plot demonstrating prevalence difference and prevalence ratio of HPV detection in lung cancer patients compared to control patients without lung cancer. PR of studies with no HPV positive cases in one of the groups was calculated by adding 0.5 to each cell of the 2 × 2 table. Random effect models were used to calculate summary statistics

3.4. HPV prevalence

Of all included patients with lung cancer (n = 9385), HPV was detected to be positive in 1268 cases. The overall HPV prevalence was calculated to be 13.5%. The highest HPV prevalence was detected in Asia with 16.6% (P < .01 vs America and Europe), followed by The Americas (12.8%; P < .01 vs Europe) and Europe (7.0%). The highest HPV 16 prevalence was detected in The Americas (9.4%), followed by Asia (7.5%), and Europe (3.5%). Overall, the HPV 16 prevalence was calculated to be 6.1%. The highest HPV 18 prevalence was found in Asia (4.8%) followed by the Americas (2.3%) and finally Europe (0.7%). Overall, the HPV 18 prevalence was 3.1%. On all three continents, the calculated prevalence of HPV 16 was higher than for HPV 18 (P < .01). Figure 4 depicts the calculated overall HPV prevalence as well as divided by regions and HPV‐genotypes. Tables 2, 3, 4 show the selected studies from Europe, Asia, and America.

FIGURE 4.

FIGURE 4

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Overall HPV, HPV 16, and HPV 18 prevalence in all analyzed lung cancer cases and between analyzed continents. The highest HPV prevalence was detected in Asia followed by The Americas and Europe. Overall and on all three continents the prevalence of HPV 16 was significantly higher than for HPV 18. The highest HPV 16 prevalence was detected in The Americas followed by Asia and Europe. The highest HPV 18 prevalence was found in Asia followed by The Americas and finally Europe

TABLE 2.

Included studies from Europe

Reference Country No. of cases Year HPV prevalence [%] Specimen type used Histological subtypes HPV types detected
Anantharaman et al25 Multiple countries 290 2014 9.7 FFPE, fresh frozen SCC/AC/others 11, 16, 51, and 58
Argyri et al26 Greece 67 2017 3.0 SCC/AC/others 16 and 53
Carpagnano et al10 Italy 89 2011 16.4 FFPE SCC/AC/others 16, 30, 31, and 39
Ciotti et al27 Italy 38 2006 8.0 FFPE, fresh SCC/AC/others 16 and 18
Coissard et al28 France 218 2005 1.8 Fresh frozen SCC/AC/others 16
Eberlein‐Gonska et al13 Germany 55 1992 5.5 Fresh SCC/AC/others 16
Galvan et al15 Italy, United Kingdom 100 2012 0 Fresh frozen SCC/AC/others None
Gatta et al16 Italy 50 2012 4.0 FFPE SCC
Guliani et al29 Italy 78 2007 12.8 Fresh frozen SCC/AC/others 16, 18, 31, and 53
Hennig et al30 Norway 22 1999 13.6 FFPE SCC/AC/others 6
Miasko et al31 Poland 94 2004 12.7 SCC/AC/others
Miasko et al32 Poland 40 2001 10.0 FFPE SCC/AC/others
Jaworek et al33 Czech Republic 80 2020 0 FFPE SCC/AC/others None
Papadopoulou et al34 Greece 52 1998 40.0 Fresh frozen, FFPE SCC 6, 11, 16, and 18
Podsiadlo et al35 Poland 33 2012 3.0 Fresh NSCLC/SCLC 120
Ramqvist, et al36 Sweden 87 2019 0 FFPE AC/others None
Sagerup et al37 Norway 334 2014 3.9 Fresh frozen SCC/AC/others 11, 16, 33, and 66
Sarchianaki et al38 Greece 100 2014 19.0 FFPE SCC/AC/others 6, 11, 16, 18, 31, 33, and 59
Shamanin et al39 Germany 85 1994 0 Fresh frozen SCC/AC/others None
Spandidos et al40 Greece 99 1996 15.0 FFPE SCC/AC/others 11, 16, 18, and 33
Syrjanen et al41 Finland 77 2012 5.2 FFPE, archival tissue SCC/AC/others 6 and 16
Van Boerdonk et al42 Netherlands 211 2013 0 FFPE, archival tissue SCC/AC/others None
Thomas et al43 France 31 1995 16.0 Fresh frozen SCC/AC/others 6, 11
Welt et al44 Germany 38 1997 0 FFPE SCC/SCLC None
Zafer et al45 Turkey 40 2004 5.0 Fresh frozen SCC/AC/others 18
Total 2393
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TABLE 3.

Included studies from Asia

Reference Country No. of cases Year HPV prevalence [%] Specimen type used Histologic subtypes HPV types detected
Aguayo et al46 Pakistan, China 60 2010 13.0 FFPE SCC/AC/others 16
Baba et al47 Japan 57 2010 19.3 FFPE SCC/AC 6, 16, 18, and 33
Cheng et al11 Taiwan 141 2004 38.3 SCC/AC 6 and 11
Cheng et al12 Taiwan 141 2001 54.6 FFPE, fresh frozen SCC/AC 16 and 18
Fan et al14 China 262 2015 8.4 FFPE SCC/AC 16, 18, 31, and 58
Goto et al48 Multiple countries 304 2011 7.9 FFPE SCC/AC 6, 11, 16, and 18
Halimi et al49 Iran 30 2011 10.0 FFPE SCC
Hartley et al50 Lebanon 20 2015 0 FFPE SCLC none
He et al51 China 140 2019 9.3 Fresh frozen SCC/AC/others 16 and 18
Hirayasu et al52 Japan 73 1996 60.3 FFPE SCC 6, 16, and 18
Hiroshima et al53 Japan 22 1999 4.5 FFPE AC 16
Ilahi et al54 Pakistan 9 2016 11.1 FFPE SCC/AC/others 16
Isa et al55 Japan 96 2015 1.0 FFPE SCC/AC/others 6
Ito et al56 Japan 901 2014 0.9 SCC/AC/others
Iwakawa et al57 Japan 297 2010 0 Fresh frozen AC none
Jafari et al58 Iran 50 2013 18.0 FFPE SCC/AC/others 6 and 18
Jain et al59 India 40 2005 5.0 Fresh frozen SCC/AC/others 18
Kato et al60 Japan 42 2012 16.7 FFPE SCC/AC/others 16 and 58
Kawaguchi et al61 Japan 876 2016 0.3 FFPE SCC/AC 16, 62, and 66
Kinoshita et al62 Japan 36 1995 8.0 FFPE, fresh frozen SCC/AC 18
Lee et al63 Korea 233 2016 0 FFPE SCC/AC none
Li et al17 China 50 1995 32.0 FFPE, fresh frozen SCC/AC/others 16 and 18
Lin et al64 Taiwan 57 2005 50.9 FFPE SCC/AC 16 and 18
Lu et al18 China 72 2016 45.8 FFPE SCC/AC 16 and 18
Miyagi et al65 Japan 121 2001 33.9 FFPE SCC/AC 6, 16, and 18
Nadji et al19 Iran 129 2007 25.6 FFPE SCC/AC/others 6, 11, 26, 31, 16, and 18
Ogura et al66 Japan 29 1993 10.3 Fresh frozen SCC 16 and 18
Park et al67 Korea 112 2007 53.6 AC/NSCLC 16, 18, and 33
Wang et al68 Taiwan 153 2006 45.1 Fresh SCC/AC 16 and 18
Wang et al21 China 313 2008 44.1 Fresh frozen SCC/AC 16 and 18
Wang et al22 China 45 2010 42.2 Fresh frozen SCC 16 and 18
Xing et al69 China 49 1993 14.2 FFPE SCC 6, 11, and 16
Yang et al70 China 50 1998 26.0 FFPE SCC 16
Yu et al23 China 180 2015 55.6 FFPE SCC/AC/SCLC 16 and 18
Zhang et al24 China 68 2009 44.1 Fresh frozen SCC, AC 16 and 18
Zhang et al71 China 104 2010 17.3 FFPE SCC/AC/others 16
Total 5362
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TABLE 4.

Included studies from The Americas

Reference Country No. of cases Year HPV prevalence [%] Specimen type used Histologícal subtypes HPV types detected
Aguayo et al72 Chile 69 2007 29.0 FFPE SCC/AC/others 6, 16, 18, 31, and 45
Badillo‐Almaraz et al73 Mexico 39 2013 41.0 SCC/AC 16 and 18
Bohlmeyer et al74 USA 34 1998 5.9 FFPE SCC 18
Cardona et al75 Multiple South American countries 132 2013 39.4 FFPE AC 16
Carlson et al76 USA 12 2007 0 FFPE SCLC None
Castillo et al77 Peru/Colombia/Mexico 36 2006 28.0 FFPE SCC/AC/others 16, 18, and 33
de Oliveira et al78 Brazil 63 2018 52,4 FFPE SCC/AC/others 16 and 18
Garcia Falcone et al79 Argentina 40 2017 25.0 FFPE SCC 16 and 18
Joh et al80 USA 30 2010 16.7 FFPE SCC/AC/others 11, 16, and other
Koshiol et al81 USA 399 2011 0 FFPE, ethanol fixed SCC/AC none
Mehra et al82 USA 36 2013 11.0 SCC/AC 16 and 18
Pillai et al83 USA 208 2013 14.9 FFPE NSCLC 16 and 18
Rezazadeh et al84 USA 16 2008 25.0 FFPE NSCLC 11 and 16
Robinson et al20 USA 70 2016 42.9 Fresh frozen SCC/AC 16, 18, 39, 44, 51, 52, and 68
Silva et al85 Brazil 62 2019 0 FFPE SCC/AC/others None
Suh et al86 USA 48 2010 2.0 FFPE SCC No data
Yanagawa et al87 Canada 336 2013 1.5 FFPE SCC/AC 16
Total 1630
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3.5. Histology and HPV prevalence

Only the information on primary squamous cell carcinoma (SCC) and primary adeno carcinoma (AC) of the lung was collected. In the remaining cases, it was neither one of them or the histological subtype was not detailed. There were 2750 cases of SCC and 2887 cases of AC. In total, 29.3% of the included cases were squamous cell carcinomas and 30.8% were adenocarcinomas.

The overall HPV prevalence in SCC (n = 492) was calculated to be 17.9%. The highest prevalence was calculated in Asia (28.8%), followed by The Americas (10.0%), and Europe (5.1%).

The overall HPV prevalence in adenocarcinomas (n = 265) was calculated to be 9.2%. In contrast, the highest HPV prevalence in AC was calculated in the Americas (11.1%), followed by Asia (10.4%), and Europe (6.0%).

When the HPV prevalences of SCC and AC are compared, the difference is statistically highly significant (P < .01), which is due to a significantly higher HPV prevalence in SCC (P < .01) in Asia, whereas no differences in prevalence were found in The Americas and Europe based on histological subtypes of lung cancer. Figure 5 shows the calculated HPV prevalences.

FIGURE 5.

FIGURE 5

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HPV prevalence in SCC vs AC. There was no statistically significant difference between the HPV prevalence in SCC and AC in the studies from America (P = .78). Statistically significant differences were found in studies from Asia (P < .01) and Europe (P < .01). On a global observation HPV prevalence in SCC was significantly higher (P < .01) when compared to AC

4. DISCUSSION

Growing evidence supports the association between HPV‐infection and lung cancer but the relationship is still debatable. The aim of the present study was to conduct a systematic database and literature review by means of a molecular biology based clear definition of HPV positivity and lung cancer. Selection was restricted to studies with lung tissue analysis and PCR‐based confirmation of HPV‐positivity to take advantage of the high specificity and sensitivity of the diagnostic approach. Data of over 9000 lung cancer patients were analyzed, which underlines the robustness of the dataset generated.

The included case‐control studies demonstrated an absolute risk increase of 22% (95% CI: 12%‐33%) in lung cancer patients of being HPV positive, which resulted in a 4.7‐fold (95% CI: 2.7%‐8.4%) increase in the likelihood to detect HPV in patients diagnosed with lung cancer compared to healthy controls regardless of histology or stage of tumor disease.

The meta‐analysis shows that the average HPV infection rate of lung cancer in the world is 13.5% based on PCR‐based assays only. PCR was permitted as the sole method to minimize differences in prevalence related to significant disparities in methodological sensitivity and specificity. Significant regional differences in HPV prevalence in lung cancer patients were found being highest in Asia with 16.6% and lowest in Europe with 7.0%. In addition, the data demonstrate a higher overall HPV prevalence in lung cancer with squamous cell histology, which is mainly due to a significantly higher HPV prevalence in squamous cell carcinoma in Asian regions since this difference was not found in squamous cell carcinoma and adenocarcinoma diagnosed in Europe and America. Most likely, the intriguing different geographic patterns of HPV prevalence in lung cancer are related to the regional differences of the HPV infection itself.

Furthermore, if HPV infection was found, high‐risk genotypes with oncogenic potential were prevalently identified as well. With focus on the most common high‐risk genotypes, overall HPV genotype 16 was the most frequent genotype reported with a twofold higher prevalence compared to HPV genotype 18. With some minor modification, similar findings were reported in all different continents analyzed. These findings additionally support the hypothesis that HPV infections with high‐risk oncogenic potential significantly increase the risk of lung cancer and provide new possibilities in the future in the prevention of lung cancer by means of prophylactic vaccines for the carcinogenic HPV‐16/18 infections.88

The pathogenesis of HPV infection in thoracic visceral lungs is still incompletely understood. Blood based transmission through cervical lesion to the lung, high‐risk sexual behavior, and airborne transmission to the lungs have been discussed.89 HPV oncogenes (eg, HPV E6 and HPV E7) are known to regulate the expression of multiple target genes and proteins such as p53, pRb, HIF‐1α, VEGF, IL‐6, IL‐10, Mcl‐1, Bcl‐2, cIAP‐2, EGFR, FHIT, hTERT, HER‐ 2, ROS1, and AhR, which can facilitate lung cell proliferation, angiogenesis, and cell immortalization by means of various signaling pathways.89

The data of the present study provide evidence for a possible relationship between lung cancer and HPV infection, but the study fails to show a high causal interference since no longitudinal data derived from cohort studies or nested case‐control studies are given. In addition, cofounders of possible importance such as smoking status, gender, age, immunosuppressive co‐medications, oncogenic driver mutations, and estrogenic signaling pathways have not been taken into considerations, which limit the value of the results reported. Furthermore, not all HPV subtypes were assessed due to missing specification in many studies, and no transcriptional activity of the HPV genotypes found was included in the meta‐analysis. Since only PCR was included as HPV detection method but this not being the only way to detect HPV, which can potentially bias the study's results further.

In conclusion, our systematic review provides evidence that HPV infection might increase the risk of developing lung cancer. Whereby relevant regional differences with respect to prevalence and histological subtypes were found with a predominance of squamous cell carcinoma. Consistently, our results support the assumption that the high‐risk genotypes HPV 16 and 18 are risk factors for lung cancer. If the understanding of the process of HPV‐related carcinogenesis in lung cancer could be further elucidated by larger prospective studies, this would facilitate the development of efficient HPV‐targeted prevention strategies.

CONFLICT OF INTEREST

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

AUTHOR CONTRIBUTIONS

J.K., H.K., M.K., and C.S. provided substantial contributions to the conceptualization of the study. J.K., H.K., W.D., F.Z., and C.S. designed the methodology and were involved in data curation. J.K., W.D., V.F., M.K., F.K., and C.S. wrote the inital draft of the manuscript. All authors critically reviewed the manuscript, and approved the final version for publication.

ETHICAL STATEMENT

Not applicable.

Supporting information

Appendix 1: Search strategies.

Click here for additional data file. (16.1KB, docx)

Karnosky J, Dietmaier W, Knuettel H, et al. HPV and lung cancer: A systematic review and meta‐analysis. Cancer Reports. 2021;4:e1350. 10.1002/cnr2.1350

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available in the digital databases Embase (via Ovid, 1974–present), MEDLINE (via Ovid, 1946–present), Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effect, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, NHS Economic Evaluation Database; from inception to present) and Science Citation Index Expanded (Web of Science, 1965–present) as well as the search engine Google Scholar (using Anne‐Wil Harzing's “Publish or Perish” program available from https://harzing.com/resources/publish‐or‐perish).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix 1: Search strategies.

Click here for additional data file. (16.1KB, docx)

Data Availability Statement

The data that support the findings of this study are available in the digital databases Embase (via Ovid, 1974–present), MEDLINE (via Ovid, 1946–present), Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effect, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, NHS Economic Evaluation Database; from inception to present) and Science Citation Index Expanded (Web of Science, 1965–present) as well as the search engine Google Scholar (using Anne‐Wil Harzing's “Publish or Perish” program available from https://harzing.com/resources/publish‐or‐perish).

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