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Human Papillomavirus Infection and Laryngeal Cancer Risk: A systematic

review and meta-analysis

Xiangwei Li1,#

, Huijun Li2,#

, Jing Gao2, Yu Yang

1, Feng Zhou

1, Cong Gao

1, Mufei Li

1, Qi Jin

1,*,

Lei Gao1,*

1MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese

Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of

Harbin Medical University, Harbin, China

*Correspondence: Prof. Lei Gao and Prof. Qi Jin, Institute of Pathogen Biology, CAMS & PUMC.

Dong Dan San Tiao 9. 100730 Beijing, China. Phone: 86-10-67828550. Fax: 86-10-67828550.

Email: [email protected](LG); [email protected](QJ)

#These two authors contributed to this work equally

Journal of Infectious Diseases Advance Access published November 21, 2012

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ABSTRACT

Background:Numbers of molecular epidemiological studies have been conducted to explore the

association of human papillomavirus (HPV) infection with laryngeal cancer. However, the findings

were heterogeneous.

Methods: We systematically reviewed published studies on HPV infection and laryngeal cancer

until 15 May 2012, and quantitatively summarized the prevalence of HPV infection and its

association with the risk of laryngeal cancer by means of meta-analysis.

Results: In total, 55 eligible studies were included. The overall HPV prevalence in laryngeal cancer

tissues was 28.0% (95% confidence interval [CI], 23.5%-32.9%). There were 26.6% laryngeal

cancer patients were infected with high-risk types only, and HPV-16 was most frequently observed

with a prevalence of 19.8% (95% CI, 15.7%-24.6%). The meta-analysis based on 12 eligible

case-control studies suggests a strong association between HPV infection and laryngeal squamous

cell carcinoma with a summarized odds ratio (OR) of 5.39 (95% CI, 3.25-8.94). Different

magnitude of the association was observed for HPV-16 (OR=6.07, 95% CI: 3.44-10.70) and

HPV-18 (OR=4.16, 95% CI: 0.87-20.04) (p


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INTRODUCTION

Cancer of the larynx accounts for over 3% of all cancers, making it the sixth most common cancer

in worldwide [1]. In 2011, the number of laryngeal cancer related deaths in the world was estimated

to be 3560 [1]. The potential oncogenic role of Human papillomavirus (HPV) infection in the

development of laryngeal cancer has been well recognized over the past decades [2].

HPV infection has been suggested as the source of laryngeal cancer morbidity since the early

twentieth century [3]. As reported, the frequency of HPV infection in laryngeal invasive lesions or

carcinomas varies was between 0% and 79% [4, 5]. Up to now, over 100 different types of HPV

have been identified [6]. About 15 types have been classified as high-risk types (H-R HPV) with

oncogenic potentiality, however, low-risk types (L-R HPV) can also be found in several kinds of

cancers. As in cervical carcinomas, HPV-16 seems to be the most common genotype, being

reported in nearly 34% of the laryngeal cancers [7] and 11% head and neck tumors [8]. However,

the role of H-R HPV in the development of laryngeal cancer has not been clearly defined.

A previous meta-analysis, based on a review of studies published until February 2004, suggested

that HPV infection might increase laryngeal cancer risk with a summarized odds ratio (OR) of 2.0

(95% confidence interval, 1.0-4.2) [9]. In this study, the prevalence of HPV infection was not

addressed, and more detailed analyses were restricted by the limited number of included studies.

Since 1990s, a number of studies have addressed HPV prevalence in various histological types of

laryngeal cancers, mainly in squamous cell carcinoma (SCC). Moreover, a review summarized the

HPV infections in the laryngeal cancer and drew a conclusion that the distribution of HPV



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The present study aims to explore the prevalence of HPV in laryngeal cancer tissues and the

association between HPV infection and laryngeal cancer risk by means of systematic review and

meta-analysis.

METHODS

Literature search

Articles addressing HPV and laryngeal cancer until 5 May 2012 were considered and searched in

the database of PubMed (1946- ), MEDLINE (1947- ) and EMBASE (1974- ). Combinations of key

words papillomavirus, human, laryngeal cancer and larynx carcinoma were used for

literature search.

Eligible criteria

The criteria for inclusion in the meta-analyses were as follows: 1) observational studies detected

HPV DNA in laryngeal cancer tissues; 2) explicitly provided the information on the HPV DNA

detection method; 3) articles published in English; 4) necessary data could be directly extracted or

calculated from the original article. If the study was reported in duplication, the one published

earlier in time or provided more detailed information was included. 5) HPV DNA could be tested

by PCR-based methods (using broad-spectrum PCR primers, type-specific PCR primers, or a

combination of both kinds of primers) as well as non-PCR methods.



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Data Extraction

All the potentially relevant literatures were reviewed independently by two investigators and

reached a consensus on all items. For each included study, the following information was extracted:

first author and year of publication, study population and enrollment time, major characteristics of

the study participants (age, sex), sample size, specimen type, HPV DNA source, detection method,

andthe numbers specific to HPV types.

Statistical analysis

The summarized prevalence of HPV infection in laryngeal cancer was carried out using a

random-effects model by Comprehensive Meta-Analysis (V2.0, Biostat, and Englewood, NJ, USA).

The association between HPV infection and laryngeal cancer risk was estimated by means of odds

ratios (ORs) and corresponding 95% confidence intervals (CIs) comparing cases with controls.

Stratified analyses were subsequently performed with respect to the characteristics of the study

population (histological type, localization, clinical stage and histology grade of the cancer, and

geographic areas of the study) and study methods (HPV DNA specimen and detection methods).

Heterogeneity between included studies was assessed by calculating I2 and Q test (p0.05 was

considered indicative of statistically significant publication bias) [2]. Publication bias was assessed

with Begg rank correlation [11] and Egger weighted regression methods [12]. Differences between

the stratified analyses were assessed by chi-square tests.



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were identified and included in this study. Please refer to Table 1for the detailed information of the

included articles. A total of 2559 laryngeal cancer cases were evaluated in the 55 included studies.

The publication date of the studies were performed between 1990 and 2012, and the sample size

varied from 20 to 130 (Table 2). Study populations were from North America (10 studies), Central

and South America (8 studies), Europe (29 studies) and Asia (8 studies). Thirty seven studies

addressed SCC and 16 studies investigated laryngeal verrucous carcinoma/ laryngeal carcinoma.

The prevalence of HPV infection in each study ranged from 0% to 79% (Table 2) with a

summarized estimate of 28.0% (95% CI, 23.5%-32.9%) as shown in Table 3. Twenty HPV

genotypes (H-R HPV: HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68; L-R

HPV: HPV-6,-11,-40,-42,-44,-61,-73) were reported among laryngeal cancer patients across the

included studies. The prevalence of H-R HPV types (26.6%) was found to be much higher than that

of L-R HPV types (3.7%). The most common HPV individualtype was HPV-16 with a summarized

prevalence of 19.8% (95% CI, 15.7%-24.6%). The remaining most frequently identified HPV types

were HPV-18 (6.2%, 95% CI: 4.0%-9.5%), HPV-33 (3.3%, 95% CI: 2.1%-5.1%), HPV-31 (2.4%,

95% CI: 1.3%-4.4%), HPV-6 (4.3%, 95% CI: 2.4%-7.7%) and HPV-11 (2.3%, 95% CI:

1.2%-4.4%).

Seventeen studies provided detailed data on the prevalence of HPV according to gender of the

patients, histological types and location of the cancer (please refer to Supplementary Table 2).

Table 4 shows the stratified analyses with respect to the above factors. The HPV prevalence was

found to be higher in the South America (35.6%, 95% CI: 26.1%-46.3%) as compared to the other

three regions (p=0.00): Asia (25.6%, 95% CI: 15.9%-38.5%), North America (26.4%, 95% CI:



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(27.7%, 95% CI: 20.7%-36.1%). Stratified analysis by localization of cancer showed that laryngeal

cancers in glottis region have the highest HPV prevalence (35.2%, 95% CI: 28.2%-42.8%), and

followed by the supraglottic (30.5%, 95% CI: 24.0%-37.8%) and subglottic region (27.5%, 95% CI:

17.5%-4.04%). With respect to HPV DNA detection methods, the estimation based on PCR-based

methods (29.5%, 95% CI: 24.5%-35.0%) was observed to be higher than that on non-PCR methods

(20.4%, 95% CI: 11.8%-32.9%) (p < 0.01).

To estimate the association of HPV infection and laryngeal cancer risk, 12 case-control studies

providing necessary data were included in the meta-analysis with a total of 638 patients and 419

controls. Detailed information about the included studies please refers to Supplementary Table 3.

Most of the studies collected the control specimens from normal laryngeal mucosa of the laryngeal

cancer patients, but one study from the tissues of cadavers [13]. As shown in Table 5, a summarized

OR of 5.39 (95% CI, 3.25-8.94) suggested a significant increased laryngeal SCC risk related to

HPV infection, which is higher than that of breast cancer (OR=3.63, 95% CI: 1.429.27) [14],

oropharynx cancer (OR=4.3, 95% CI: 2.18.9) and oral cancer (OR=2.0, 95% CI: 1.23.4) [9].

When restrict the analysis to HR-HPV, the association was found to be 5.74 (95% CI: 3.05-10.80).

The ORs of individual types indicated different magnitude of the association for HPV-16 (6.07,

95% CI: 3.44-10.70) and HPV-18 (4.16, 95% CI: 0.87-20.04) (p=0.00). For HPV-6 and HPV-11,

the summarized ORs were not statistically significant (data not shown). The HPV DNA detection

based on fixed tissue showed a significant higher association as compared to specimen from fresh

tissue with an OR of 8.43 (95% CI, 4.03-17.61) and 3.23 (95% CI, 1.69-6.18) (p = 0.01),

respectively.



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DISCUSSION

In this meta-analysis addressing HPV prevalence and its association with laryngeal cancer, a total of

55 studies were included and summarized. The overall HPV prevalence in laryngeal cancer was

found to be 28.0% (95% CI, 23.5%-32.9%). HPV-16 was the most frequently observed subtype

with a prevalence of 19.8% (95% CI, 15.7%-24.6%). Significant association was found between

HPV infection and laryngeal SCC risk with a summarized OR of 5.39 (95% CI, 3.25-8.94).

HPV infection has been suggested to play an important role in both benign and malignant pathology

of the larynx [15]. Our results indicate that the association between HPV infection and laryngeal

cancer risk is strong with an OR of 5.39 (95% CI, 3.32-8.73) which is higher than that of breast

cancer (OR=3.63, 95% CI: 1.429.27) [14], oropharynx cancer (OR=4.3, 95% CI: 2.18.9) and oral

cancer (OR=2.0, 95% CI: 1.23.4) [9]. By means of Meta-analysis, the relation between HPV

infection and laryngeal cancer has been assessed previously in 2006 [9]. However, the results

(OR=2.0, 95% CI: 1.04.2) were obscure because it included relatively few publications (8 studies).

The published studies have indicated the virus is epithelium-tropic [16] and might cause cancers in

multiple sites. But in the previous meta-analysis, three included studies only detected HPV in the

plasma and serum specimens but not cancer tissues. Moreover, this meta-analysis did not assess the

prevalence of HPV infection in the laryngeal cancer. Our present update meta-analysis not only

estimated the impact of HPV infection on laryngeal cancer risk based on much more newly

published data but also provided a summary of HPV prevalence in the laryngeal cancer.

Considering HPV prevalence in cancers might vary with respect to the study population, detection



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stratified by HPV type, the prevalence of H-R HPV was higher than that of L-R HPV and therefore

was associated with a higher risk of the laryngeal cancer. Various HPV prevalences in laryngeal

cancers were observed in different geographical regions (25.6%35.6%). Studies from the South

America reported higher HPV infection rate, which might be explained by the different genetic

background and other ethnic and cultural differences, as well as other unknown sources.

Geographical variation of the HPV infection in other cancers has also been observed . The

worldwide prevalence of cervical HPV infection showed a higher rate in Africa and East Asia and a

lower prevalence in North America and Europe [19]. Stratified analysis by localization of the tumor

showed that HPV prevalence in cancer at glottis was higher as compared to the other locations. The

microenvironment of glottis might favor HPV infection because the squamocolumnar junction

exists in the ventricle which is just like the transitional zone of the uterine cervix.

Targeted HPV types tested in different studies might be different due to different study design and

various sensitivity and specificity of the used methods. We observed that the estimation based on

PCR-based studies was higher than that on non-PCR based studies, which suggested that PCR

methods might be more sensitive as compared to non-PCR methods. This finding is consistent with

the reports which used both PCR and non-PCR methods in the same study [20]. Furthermore, the

different consensus primers (i.e. MY09-11, GP5+/GP6+) used in the detection methods might be

another potential factor for heterogeneity between studies. However, corresponding stratified

analyses were restricted by the limited number of study providing necessary information. It is well

known that significant DNA degradation might occur with paraffin-embedded tissue [21]. However,

our results did not found statistically significant different HPV DNA positivity between studies



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It is necessary to consider the limitations of the present meta-analysis while interpreting the results.

First, potential bias could not be excluded completely because the estimates of HPV infection

largely depends on the sensitivity and accuracy of HPV DNA detection method and HPV types

covered by the method. Second, potential language bias might exist because our literature search

only considered articles published in English. Third, evident heterogeneity was observed between

the included studies. As suggested by our subgroup analyses, it might be explained, at least in part,

by various study populations and study design (such as characteristics of the patients and HPV

DNA detection methods). Fourth, the crude division of study population by geographic regions

makes the analyses be prone to bias. Further studies providing detailed information on different

populations are warranted to verify current findings.

In conclusion, our meta-analysis suggested a significant increased risk of SCC associated with HPV

infection. HPV-16 was the most frequently observed subtype in the tissues of laryngeal cancer and

showed a strong association with the development of cancer. However, the association between

HPV infection and laryngeal cancer risk has not been substantial influenced by factors that might

influence the estimate of HPV prevalence, such as geographic regions, clinical stages and locations

of the cancer, and HPV DNA detection methods. Further studies are needed to verify the relation of

HPV infection with laryngeal cancer and to explore the underlying mechanisms.



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References:

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socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-36

2. Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W and zur HH. A new type of

papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical

cancer. EMBO J 1984;3:1151-7

3. Ullmann, EV. On the aetiology of the laryngeal papilloma. Acta Oto-laryngol 1923; 5:317-334.

Duray A, Descamps G, Arafa M, et al. High incidence of high-risk HPV in benign and malignant

lesions of the larynx. International Journal of Oncology 2011;39:51-59

5. Gallo A, Degener AM, Pagliuca G, et al. Detection of human papillomavirus and adenovirus in

benign and malignant lesions of the larynx. Otolaryngology - Head and Neck Surgery

2009;141:276-281

6. de Villiers EM, Fauquet C, Broker TR, Bernard HU and zur HH. Classification of

papillomaviruses. Virology 2004;324:17-27

7. Stephen JK, Chen KM, Shah V, et al. Human Papillomavirus Outcomes in an Access-to-Care

Laryngeal Cancer Cohort. Otolaryngol Head Neck Surg 2012;146:730-738

8. Major T, Szarka K, Sziklai I, Gergely L and Czegledy J. The characteristics of human

papillomavirus DNA in head and neck cancers and papillomas. J Clin Pathol 2005;58:51-5

9. Hobbs CG, Sterne JA, Bailey M, Heyderman RS, Birchall MA and Thomas SJ. Human

papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol

2006;31:259-66

10. Torrente MC, Rodrigo JP, Haigentz MJ, et al. Human papillomavirus infections in laryngeal



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graphical test. BMJ 1997;315:629-34

13. Guvenc MG, Midilli K, Ozdogan A, et al. Detection of HHV-8 and HPV in laryngeal carcinoma.

Auris Nasus Larynx 2008;35:357-62

14. Li N, Bi X, Zhang Y, Zhao P, Zheng T and Dai M. Human papillomavirus infection and

sporadic breast carcinoma risk: a meta-analysis. Breast Cancer Res Treat 2011;126:515-20

15. Torrente MC, Ojeda JM. Exploring the relation between human papilloma virus and larynx

cancer. Acta Otolaryngol 2007;127:900-6

16. Geneva. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human

papillomaviruses.IARC Monogr Eval Carcinog Risks Hum 90, 2007

17. Termine N, Panzarella V, Falaschini S, et al. HPV in oral squamous cell carcinoma vs head and

neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). Ann Oncol 2008;19:1681-90

18. Clifford GM, Smith JS, Plummer M, Munoz N and Franceschi S. Human papillomavirus types

in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003;88:63-73

19. de Sanjose S, Diaz M, Castellsague X, et al. Worldwide prevalence and genotype distribution of

cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet

Infect Dis 2007;7:453-9

20. Morshed K. Association between human papillomavirus infection and laryngeal squamous cell

carcinoma. J Med Virol 2010;82:1017-23

21. Srinivasan M, Taioli E, Ragin CC. Human papillomavirus type 16 and 18 in primary lung

cancers--a meta-analysis. Carcinogenesis 2009;30:1722-8

Competing interests: The authors declare that they have no competing interests.



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Funding:

The work was supported by National Natural Sciences Foundation of China (Grant No: 81001272).

Acknowledgments

We thank Dr. Theresa Redaniel, at University of Bristol, for her kind assistance and comments

which lead to important improvements of this manuscript on English writing.

Authors' contributions:

XWL carried out the literature search and data extraction, drafted the manuscript. HJL carried out

the literature search and performed the statistical analysis. JG, YY, CG, MFL, FZ participated in the

data extraction and quality control. YY participated in the design of the study. QJ and LG conceived

of the study, and participated in its design and coordination and helped to draft the manuscript. All

authors read and approved the final manuscript.



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Figure legend:

Figure 1. Flow diagram of study search and identification.



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Table 1. Characteristics of the included studies (Part 2/2)

Abbreviation: SCC, squamous cell carcinoma; NA, not available; SD, Standard Deviation; ISH, in situ hybridization; LVC, laryngeal verrucous carcinoma

*, male; #: female;&, adult; , children;, Immunohistochemisty

First Author

Period of

diagnosis Country Study base

Percentage of

males (%)

Mean age

(SD)/(Range) Histological type

Detection

method HPV DNA specimen

Analle D,2011 2001.1-2007.12 Belgium retrospectively 97.1 57 SCC PCR Fixed tissue

Jiang HR,2010 1995.12-2008.11 China retrospectively 69.7 36-78 SCC PCR Fixed tissue

Liu B,2010 2000-2008 China retrospectively 72.6 38-74 SCC PCR Fixed tissue

Kamal M,2010 1999-2002 Poland retrospectively 86.15 58.6 SCC PCR Fixed tissue

Yudira S,1998 NA Cuba retrospectively NA 34-58 SCC PCR Fixed tissue

Gary LC,2012 1989.6- United States retrospectively NA 30-81 SCC PCR Fixed tissue

Dan M F,1994 1967-1989 United States retrospectively 96.57 59 LVC PCR Fixed tissue

Vassilis G,1994 NA Athens retrospectively NA NA SCC ISH Fixed tissue

Jan L K,1994 1975-1984 United States retrospectively 95 58.05 LVC PCR Fixed tissue

Hajime O,1993 1981-1991 Japan prospective NA 36-82 SCC PCR Fresh tissue

Tomohide H,1990 1965-1988 Japan retrospectively 88.2 64 SCC PCR Fixed tissue

Atula S,1999 NAGerman

United Statesretrospectively 81.5 NA Laryngeal carcinoma PCR Fixed tissue

Sajini E J,2002 NA India retrospectively NA NA Laryngeal carcinoma PCR Fixed tissue

Markus F,2003 NA German prospective NA NA SCC PCR Fresh tissue

Britta K,2004 NA German retrospectively NA 36-83 SCC PCR Fixed tissue

Azzimonti B,2004 NA Italy retrospectively NA 45-87 SCC PCR Fixed tissue

Glanna B,2007 NA Italy prospective NA NA Laryngeal carcinoma PCR Fresh and fixed tissue

Carole F,2008 NA United States prospective NA NA SCC ISH Fixed tissue

Dirk R,2011 2000-2009 German retrospectively NA NA SCC ISH Fixed tissue

Lee SY,2010 1995-2005 Korea retrospectively NA 62 Glottis cancer RT-PCR Fixed tissue

Josena K S,2012 NA United States prospective 76.3 NA SCC PCR Fresh tissue

Marcela K,2012 1995-2004 Brazil retrospectively 73.0 NA SCC PCR Fixed tissue

Garca M R,1998 NA Cuba prospective 37&/8 27-70c/5-16d SCC PCR Fresh tissue

Nishioka S,1999 1990-1993 Japan prospective NA NA SCC PCR Fresh tissue

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Table 2. HPV infection in Laryngeal Cancer in the included studies (Part 1/2)

Any Type Oncogenic type Individual typeFirst Author Total

Positive Negative H-R HPV H-L HPV Mixed HPV-6 HPV-11 HPV-16 HPV-18 HPV-31 HPV-33

FJ B,2009 30 12 18 12 0 0 NA NA NA NA NA NA

Andrea G,2009 40 0 40 0 0 0 0 0 0 0 0 0

Jessica B,2009 38 6 32 6 0 0 NA NA 2 0 1 0

Kamal M,2008 93 33 60 33 0 0 0 0 28 6 0 5

Melih G,G 2008 * 3 2 1 1 1 0 NA NA NA NA NA NA

Melih G,G 2008 # 47 5 42 3 2 0 NA NA NA NA NA NA

Jan L,2008 24 14 10 14 NA NA NA NA 14 0 NA NA

Walter J K,2007 69 3 66 NA NA NA NA NA 1 NA NA NA

Gungor A,2007 95 7 88 0 6 1 2 3 1 0 NA NA

Deilson O,2006 110 41 69 NA NA NA NA NA 15 18 NA NA

Markus H,2005 19 5 14 NA NA NA 0 0 5 NA NA NA

Major T,2005 18 8 8 NA NA NA 2 3 2 NA NA NA

Kamal M,2005 40 6 35 NA NA NA NA NA NA NA NA NA

Mariela C,2005 31 10 21 10 0 0 0 0 3 0 0 0

Adriana B,2004 52 24 28 24 0 0 NA NA 24 NA NA NARekha V,2004 42 4 38 4 NA NA NA NA 4 NA NA NA

Giovanni A,2001 42 15 28 15 0 0 0 0 7 9 NA NA

Kaya H,2001 21 10 11 2 4 4 6 6 2 2 3 3

Hugo B,2000 32 4 28 NA NA NA NA NA NA NA NA NA

Elaine M S,2000 39 5 34 5 0 0 0 0 4 0 1 0

Aldo V,2000 25 13 12 8 5 0 5 0 7 0 0 0

Vassilis, G,2000 91 19 72 16 1 2 3 0 13 3 0 3

Henning L,2000 30 1 29 NA NA NA NA NA NA NA NA NA

Javier P,2000 52 8 44 NA NA NA NA NA NA NA NA NA

Paola C,1998 75 22 53 NA NA NA 0 0 10 9 0 1

Rolando M,1998 33 16 17 15 1 0 1 0 15 1 0 0

Ma X L,1998 102 60 42 33 7 20 25 2 30 22 0 1

Benjamin P,1997 28 1 27 NA NA NA NA NA NA NA NA NA

Almadori G,1996 45 9 36 7 0 2 2 0 9 0 NA NA



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Table 2. HPV infection in Laryngeal Cancer in the included studies (Part 2/2)

Any Type Carcinogenesis Type Individual typeFirst Author Total

Positive Negative H-R HPV H-L HPV Mixed HPV-6 HPV-11 HPV-16 HPV-18 HPV-31 HPV-33

Mahmoud S,1995 36 8 28 NA NA NA 3 1 2 NA NA NA

Analle D,2011 59 47 12 44 3 0 NA NA NA NA NA NA

Jiang HR,2010 99 36 63 36 NA NA NA NA 36 NA NA NA

Liu B,2010 84 35 49 35 0 0 NA NA 29 6 NA NA

Kamal M,2010 130 36 94 NA NA NA NA NA NA NA NA NA

Yudira S,1998 40 20 20 20 NA NA NA NA 20 NA NA NA

Gary LC,2012 54 23 31 NA NA NA NA NA NA NA NA NA

Dan M F,1994 29 13 16 13 0 0 0 0 10 10 NA NA

Vassilis G,1994 40 11 29 11 0 0 0 0 9 2 0 0

Jan L K,1994 20 17 3 NA NA NA NA NA NA NA NA NA

Hajime O,1993 31 6 25 6 NA NA NA NA 5 1 NA NA

Tomohide H,1990 34 7 27 7 0 0 1 NA 6 NA NA NA

Atula S,1999 27 7 20 7 NA NA NA NA 7 NA NA NA

Sajini E J,2002 44 15 29 15 0 0 0 0 15 0 0 0

Markus F,2003 34 13 21 NA NA NA NA NA NA NA NA NABritta K,2004 38 6 32 NA NA NA NA NA NA NA NA NA

Azzimonti B,2004 25 14 11 NA NA NA NA NA NA NA NA NA

Glanna B,2007 30 4 26 3 1 0 1 0 3 0 0 0

Carole F,2008 34 0 34 NA NA NA NA NA NA NA NA NA

Dirk R,2011 20 4 16 NA NA NA NA NA NA NA NA NA

Lee SY,2010 95 7 88 4 3 0 NA NA 4 NA NA NA

Josena K S,2012& 46 16 30 16 NA NA NA NA 16 NA NA NA

Josena K S,2012

31 5 26 5 NA NA NA NA 5 NA NA NA

Marcela K,2012 53 7 46 5 1 1 3 0 2 2 2 1

Garca M R,1998 33 16 17 15 1 0 1 0 15 1 NA NA

Nishioka S,1999 27 5 22 NA NA NA NA NA 5 1 NA NA

Abbreviation: NA, not available; H-R HPV, HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68; L-R HPV, HPV-6,-11,-40,-42,-44,-61,-73; Mix, both H-R HPV and H-L HPV ;

*, laryngeal verrucous carcinoma;#, squamous cell carcinoma; &,Caucasian ;, African



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Table 3. Prevalence of Overall and Individual Human Papillomavirus (HPV) Types in Laryngeal Cancer

Heterogeneity testNo. of studies No. of cases No. of HPV positive HPV prevalence (95% CI)

p for Q test I-square (%)

Total 55 2559 741 28.0% (23.5%-32.9%) 0.00 82.39

HPV Type

High-risk 35 1668 450 26.6% (21.4%-32.5%) 0.00 80.82

Low-risk 27 1328 36 3.7% (2.4%-5.7%) 0.02 39.60

Mix 27 1328 30 2.1% (1.1%-4.0%) 0.00 63.50

Presence of individual type

H-R HPV

HPV-16 38 1226 385 19.8% (15.7%-24.6%) 0.00 78.83

HPV-18 25 1140 93 6.2% (4.0%-9.5%) 0.00 68.53

HPV-33 15 755 14 3.3 %( 2.1%-5.1%) 0.45 0.00

HPV-31 15 755 7 2.4 %( 1.3%-4.4%) 0.36 8.31

L-R HPVHPV-6 23 1068 55 4.3% (2.4%-7.7%) 0.00 70.53

HPV-11 22 1034 15 2.3% (1.2%-4.4%) 0.00 52.00

Abbreviation: CI, confidence interval; H-R HPV, High-Risk HPV; H-L HPV, Low-Risk HPV;



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Table 4. Stratified analysis of Human Papillomavirus (HPV) Prevalence in Laryngeal Cancer

Heterogeneity testNumber of

studies

Summarized Rate

(95% CI) p for Q test I-square (%)

Total 55 28.0% (23.5%-32.9%) 0.00 82.39

Stratified by Region

Asia 9 25.6 % (15.9%-38.5%) 0.00 88.19

North America 9 26.4 % (14.8%-42.6%) 0.00 82.89

Europe 28 26.8 % (20.5%-34.2%) 0.00 82.60

South America 8 35.6 % (26.1%-46.3%) 0.00 73.64

Stratified by Histological type

SCC 38 27.8 % (22.8%-33.4%) 0.00 82.86

Other 17 28.8 % (19.5%-40.2%) 0.00 82.12

HPV DNA specimen

Fixed tissue 34 29.0 % (23.3%-35.5%) 0.00 85.42

Fresh tissue 18 27.7 % (20.7%-36.1%) 0.00 73.93

Stratified by Sex

Male 10 31.9 % (24.0%-41.0%) 0.00 71.97

Female 8 35.2 % (26.5%-45.1%) 0.38 6.34

Stratified by Localization

Supraglottic 14 30.5 % (24.0%-37.8%) 0.04 43.94

Glottic 15 35.2 % (28.2%-42.8%) 0.01 54.62

Subglottic 9 27.5 % (17.5%-40.4%) 0.80 0.00

Stratified by Histology Grade

G1 10 29.7 % (23.6%-36.6%) 0.90 0.00

G2 10 32.1 % (24.8%-40.4%) 0.06 45.27G3 10 31.8 % (22.5%-42.9%) 0.31 14.88

Detection Method

PCR-based 46 29.5 % (24.5%-35.0%) 0.00 82.43

Type-specific primers 12 31.9% (25.2%, 39.5%) 0.00 62.00

Broad-Spectrum primers 12 29.1% (17.5%, 44.4%) 0.00 89.72

Combination of both primers 22 28.2% (21.3%, 36.2%) 0.00 82.41

NonPCR-based 9 20.4% (11.8%, 32.9%) 0.00 81.78

Abbreviation: SCC, squamous cell carcinoma; CI, confidence interval



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Table 5. Meta-analysis of the association between Human Papillomavirus (HPV) Infection and laryngeal Cancer risk

Heterogeneity testNo. of studies OR (95% CI)

p for Q test I-square (%)

Total 12 5.39 (3.32-8.73) 0.43 1.97

Stratified by Histological type

SCC 8 5.39 (3.25-8.94) 0.54 0.00

Other 4 6.43 (0.99-41.70) 0.16 42.23

Stratified by HPV oncogenic type

High-risk 10 5.74 (3.05-10.80) 0.68 0.00

Low-risk 6 1.39 (0.45-4.32) 0.52 0.00

Stratified by Effect of individual type

HPV-16 9 6.07 (3.44-10.70) 0.64 0.00

HPV-18 4 4.16 (0.87-20.04) 0.89 0.00

Stratified by Region

Asia 4 6.11 (2.47-15.09) 0.80 0.00Europe 6 6.21 (1.93-20.00) 0.07 50.52

South America 2 4.94 (2.02-12.12) 1.00 0.00

Abbreviation: SCC, squamous cell carcinoma; CI, confidence interval; OR, odds ratio


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