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7/23/2019 J Infect Dis.-2012-Li-infdis-jis698.pdf
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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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cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet
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20. Morshed K. Association between human papillomavirus infection and laryngeal squamous cell
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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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