Prevalence of human papillomavirus in oral and oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis

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Introduction

Head and neck squamous cell carcinoma (HNSCC) accounts for 650 000 new cases annually with more than 350 000 deaths, identifying it as the seventh most common cancer globally [93]. It includes malignancies arising from the mucosal lining of upper aerodigestive tract including hypopharynx, larynx, lip and oral cavity, nasopharynx, oropharynx, paranasal sinuses and nasal cavity, salivary glands, and metastatic cancers with occult primary [18, 93]. HNSCC significantly impact patient morbidity, with disease burden further compounded by treatment- related toxicities.

Among the different HNSCCs, oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC) are of particular concern. While their incidence is speculated to be declining in developed nations due to reduced tobacco use, they are increasingly linked to Human Papillomavirus (HPV) infection, likely due to evolving sexual behaviors affecting younger individuals with no significant comorbidities or secondary primary tumors [93, 119]. HPV-associated cancers exhibit distinct epidemiologic, clinical, and molecular characteristics, demonstrating a lower risk of metastatic dissemination, better treatment outcomes, prevention by vaccination, and improved overall survival rate, reshaping perspectives on cancer therapy and prevention [31, 93, 105]. Given the younger age group and better survival outcomes, understanding the role of HPV across OSCC and OPSCC subtypes of HNSCC may aid in minimizing acute and late treatment-related toxicities by optimizing treatment strategies.

With over 200 related viruses, HPV is broadly divided into high-risk and low- risk groups. The former includes 12 types, with HPV-16 and HPV-18 being the most commonly implicated in HPV-related carcinomas. Though low-risk types have an oncogenic potential, they rarely cause cancer [71]. High-risk HPV promotes carcinogenesis by integration of viral DNA into host cells, leading to the inactivation of tumor suppressor proteins p53 and retinoblastoma (RB) protein and upregulation of p16 via the viral oncoproteins E6 and E7. This leads to uncontrolled cell proliferation and malignant transformation. In contrast, tobacco driven HNSCCs are characterized by p53 mutations, p16 downregulation, and upregulation of RB [31].

While HPV is an established risk factor for OPSCC with a well-documented positive prognostic impact, its role in OSCC remains controversial due to its stronger association with tobacco and alcohol use [93]. Although recent high-quality reviews have attempted to clarify this association, their findings are often limited by restrictive inclusion criteria, number of studies included, and the time frame of literature search [3, 32, 51]. Therefore, the following systematic review and meta-analysis (SRM) aimed to determine the pooled prevalence of HPV-associated OSCCs and OPSCCs across different populations and study settings. The secondary objectives were to assess the influence of sample size, gender, and ethnicity on this prevalence.

Materials and methods

This SRM was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD420251057413) following the predefined criteria (Table 1) [75]. A comprehensive search was performed in the PubMed, Google Scholar, and Cochrane databases, and grey literature sources were also reviewed to ensure completeness of the evidence base and the retrieved titles and abstracts were screened for eligibility. In the second screening phase, the full texts of the selected studies were assessed for final inclusion.

 

Table 1. Search strategy and selection criteria

Focus question	To identify the prevalence of HPV associated OSCC and OPSCC
Search strategy
Population	#1: (“Oral Cancer” [All Fields] OR “mouth cancer” [All Fields] OR “squamous cell carcinoma of the head and neck” [All Fields] OR “tongue cancer” [All Fields] OR “Palatal neoplasms” [All Fields] OR “gingiva cancer” [All Fields] OR “alveolar bone cancer” [All Fields] OR “base of tongue cancer” [All Fields] OR “Mandible cancer” [All Fields] OR “Maxilla cancer” [All Fields])
Intervention	#2: (“Human Papillomavirus” [All Fields] OR “HPV” [All Fields] OR “HPV-16” [All Fields] OR “HPV-18” [All Fields])
Comparison	-
Outcome	Prevalence of HPV positivity in OSCC or OPSCC
Filters	#3: “English” [language] AND “Humans” [MeSH] AND Publication year: till February 2025
Search combination #1 AND #2 AND #3
Database search	PubMed (electronic), Google Scholar, Cochrane Database, Grey literature search
Draft of search strategy	(“Human Papillomavirus” [All Fields] OR “HPV” [All Fields] OR “HPV-16” [All Fields] OR “HPV-18” [All Fields]) AND (“Oral Cancer” [All Fields] OR “mouth cancer” [All Fields] OR “squamous cell carcinoma of the head and neck” [All Fields] OR “tongue cancer” [All Fields] OR “Palatal neoplasms” [All Fields] OR “gingiva cancer” [All Fields] OR “alveolar bone cancer” [All Fields] OR “base of tongue cancer” [All Fields] OR “Mandible cancer” [All Fields] OR “Maxilla cancer” [All Fields])
Selection criteria
Inclusion criteria	·                  Full text articles published/available in English language ·                  Cohort studies, cross-sectional studies assessing OSCC and/or OPSCC patients for HPV positivity using HPV DNA detection
Exclusion criteria	·                  Abstracts only, conference proceedings, letters, editorials, in-vitro studies, animal studies, reviews with or without meta-analysis, case reports, surveys, non-availability of full text, publications ahead of print ·                  Studies using only p16 IHC for HPV detection ·                  Studies assessing HPV prevalence in healthy subjects, oral dysplastic lesions, papillomas, verrucous carcinoma, salivary gland carcinoma, unknown primary carcinoma, post-treatment carcinoma patients, or immunocompromised patients ·                  Studies using novel diagnostic techniques for HPV detection ·                  Inclusion of patients with known HPV status during enrolment ·                  Lack of HPV prevalence data ·                  Studies assessing association of HPV with OSCC and/or OPSCC without reporting prevalence ·                  Lack of data retrieval concerning OSCC or OPSCC from HNSCC patient cohorts ·                  Duplicate data publication

Notes. HPV: Human Papilloma Virus, OSCC: Oral Squamous Cell Carcinoma, OPSCC: Oropharyngeal Squamous Cell Carcinoma, IHC: Immunohistochemistry, HNSCC: Head and neck squamous cell carcinoma.

 

Rayyan — Intelligent Systematic Review (https://www.rayyan.ai), literature screening software, and PRISMA flow diagram tool were used to remove duplicates and producing PRISMA compliant flow diagram [41].

Selection Process Initially, two independent reviewers screened the titles and abstracts to determine their potential inclusion. Full texts of the selected studies were then retrieved and individually reviewed by the same two reviewers for final inclusion. Any conflicts or disagreements were resolved through an independent assessment by a third reviewer.

Data Collection Process and Quality Assessment. Two independent reviewers conducted data extraction from the included studies. The first reviewer initially screened the data which was then verified by the other reviewer. Any disagreements or conflicts were resolved by mutual discussion and if necessary, by consulting a third reviewer. The data extracted from the studies included author details, year of publication, ethnicity of included patients, method of HPV detection, number of OSCC and/or OPSCC carcinoma patients, gender distribution of patients, and number of HPV positive patients. Quality assessment was done using the Newcastle-Ottawa scale (NOS) [74]. Carcinomas of oral and oropharyngeal regions were classified according to the World Health Organization’s International Statistical Classification of Diseases 10th revision (ICD-10) (2019) [116]. Anatomical sites included under OSCC were lip (C00), other unspecified parts of tongue (C02), gums (C03), floor of mouth (C04), palate (C05), and other unspecified parts of mouth (C06) while those under OPSCC were base of tongue (C01), lingual tonsil (C02.4), tonsils (C09), soft palate (C05.1), uvula (C05.2), and oropharynx (C10).

Statistical analysis. A proportional meta-analysis was done to calculate the pooled prevalence of HPV in OSCC and OPSCC using a random-effects model and double arcsine transformation with back transformation [10]. Given the potential for variance instability and proportions approaching boundary values (0 or 1), Freeman–Tukey transformation was used to stabilize variance and normalize distributions [11]. The variability in study outcomes was measured using the ^I2 statistic with value greater than 75% indicating greater heterogeneity. Subgroup meta-analysis was conducted based on gender, type of cancer — OSCC and OPSCC, and the location of the study. Publication bias was assessed using a funnel plot and Egger’s test. A p-value below 0.05 was considered statistically significant. All statistical analyses were performed using R software, version 4.3.

Results

Study Selection. A total of 941 potentially relevant studies were identified from the selected databases of which 774 studies were excluded after screening of title and abstract, leaving 167 titles for full texts retrieval. Of these, 64 studies were removed for following reasons: 17 due to non-availability of full text and being ahead of print, 10 each due not using DNA for HPV detection and non-differentiation of OSCC and/or OPSCC data from other HNSCC, dysplastic lesions, papillomas, and verrucous carcinomas, 6 enrolling subjects with known HPV status, 6 providing inadequate data, 5 HPV association studies, 3 diagnostic comparison studies, 2 each assessing HPV prevalence in healthy individuals and salivary gland carcinomas, and 1 each assessing HPV prevalence in subjects with unknown primary carcinoma, in post-treatment carcinoma patients, and presenting duplicate data. Thus, 103 articles were included for final review (Fig. 1 and Table 2).

 

Figure 1. PRISMA flowchart for selection of studies

 

Table 2. Characteristics of the included studies

Author Year	Country	Total	HPV Positive	Male	HPV Positive Male		Female	HPV Positive Female	OSCC	HPV Positive OSCC	OPSCC	HPV Positive OPSCC
Syrjanen et al., 1986 [103]	Finland	2	0						2	0
Zeuss et al., 1991 [118]	Valencia	15	0	9	0		6	0	15	0
Watts et al., 1991 [114]	USA	38	23						23	14	15	9
Maden et al., 1992 [59]	USA	118	22	118	22
Mao, 1995 [60]	UK	26	8	17			9		26	8
Balaram et al., 1995 [9]	India	76	57
Snijders et al., 1996 [98]	Netherlands	63	13						25	5	7	2
Cruz et al., 1996 [19]	Netherlands	35	19	21	14		14	5	35	19
Hoffmann et al., 1998 [44]	Germany	75	17								23	6
Smith et al., 1998 [97]	USA	93	14	67			26
D’Costa et al., 1998 [24]	India	100	15	72	9		28	6	100	15
Elamin et al., 1998 [28]	UK	26	12	12	4		13	8
Summersgill et al., 2000 [102]	USA	190	58						190	46
Premoli-De-Percoco 2001 [84]	Venezuela	50	30				50	30	50	30
Schwartz et al., 2001 [95]	USA	236	37
Nagpal et al., 2002 [67]	India	110	37	68			42		110	37
Herrero et al., 2003 [43]	Multiple Ethnicity	1670	56	1094			576		1415	30	255	26
Koskinen et al., 2003 [54]	Finland	33	6						28	1	5	5
Fregonesi et al., 2003 [34]	Brazil	17	6						17	6
El-Mofty et al., 2003 [30]	USA	26	10	16			10		15	0	11	10
Yang et al., 2004 [117]	Taiwan	37	4						37	4
Dahlgren et al., 2004 [22]	Sweden	110	12	69	10		41	2	85	2	25	10
Ibieta et al., 2005 [46]	Mexico	50	21	36	15		14	6	50	21
Na et al., 2007 [66]	Korea	108	10	80	7		28	3	70	0	38	10
da Silva 2007 [21]	Brazil	50	37	50	37				50	37
Westra et al., 2008 [115]	USA	63	12						42	0	21	12
Pintos et al., 2008 [81]	Canada	72	14	51			21
Anaya-Saavedra et al., 2008 [5]	Mexico	62	27	33			29		62	27
Romanitan et al., 2008 [91]	Greece	103	13						75	1	28	12
Liang et al., 2008 [58]	USA	51	1	30			21
Szarka et al., 2009 [104]	Hungary	65	31	51			14		65	31
Khanna et al., 2009 [52]	India	45	29	37			8		45	29
Attner et al., 2010 [8]	Sweden	95	71	65	49		30	22			95	71
Lee et al., 2010 [57]	Republic of Korea	36	13						36	13
Author Year	Country	Total	HPV Positive	Male	HPV Positive Male		Female	HPV Positive Female	OSCC	HPV Positive OSCC	OPSCC	HPV Positive OPSCC
Jalouli et al., 2010 [47]	India	62	15	50			12		62	15
Jalouli et al., 2010 [48]	Sudan	217	54	158			59		217	54
Elango et al., 2011 [29]	India	60	29	41	22		19	7	60	29
Palmieri et al., 2011 [77]	Italy	278	11						278	11
Pannone et al., 2011 [78]	Italy	38	4	23			15		38	4
Saini et al., 2011 [94]	Multiple Ethnicity	105	54	51	24		54	30	105	54
Marklund et al., 2012 [61]	Sweden	69	12	49	8		20	4			69	12
Fergonezi et al., 2012 [33]	Brazil	17	5						17	5
Kabeya et al., 2012 [50]	Japan	32	0	29	0		3	0	32	0
Goot-Heah et al., 2012 [39]	Malaysia	14	0	11	0		19	0	14	0
Kouvousi et al., 2013 [55]	Greece	45	5	33			12		45	5
González-Ramírez et al., 2013 [38]	Mexico	80	4	34	1		46	3	80	4
Mondal et al., 2013 [63]	India	124	54	98			26		124	54
Tahtali et al., 2013 [107]	Germany	104	12	87	10		17	2	104	12
Tertipis et al., 2014 [109]	Sweden	425	305	309	228		116	77			425	305
Upile et al., 2014 [112]	UK	102	4	115			44		102	4	60	42
Marcos et al., 2014 [36]	Spain	61	15	44	11		16	4
Poling et al., 2014 [82]	USA	78	1	36	1		42	0	78	1
Gan et al., 2014 [35]	China	200	55	143			57		183		17
Ramshankar et al., 2014 [88]	India	156	81	108	56		48	25	156	81
Patel et al., 2014 [79]	India	97	0	84	0		13	0	97	0
Nasher et al., 2014 [69]	Yemen	60	0	32	0		28	0	60	0
Nordfors 2014 [73]	Sweden	52	39	39	31		13	8	5	1	47	38
Blioumi et al., 2014 [15]	Greece	63	14
Nasman et al., 2015 [70]	Sweden	253	186	181	140		72	46			253	186
Jiang et al., 2015 [49]	China	41	22								41	22
Polz-Gruszka et al., 2015 [83]	Poland	30	8								30	8
Dhanapal et al., 2015 [27]	India	14	3	7	1		7	2	14	3
Rathore et al., 2016 [89]	India	24	1						24	1
Dediol et al., 2016 [26]	Croatia	224	41	89	60		65	20	224
Laprise et al., 2016 [56]	India	350	0	196	0		154	0	350	0
Cutilli et al., 2016 [20]	Italy	75	66	57	49		18	17	75	66
Sritippho et al., 2016 [100]	Thailand	34	4	17	4		17	0	34	4
Bijina et al., 2016 [13]	India	47	19						47	19
Pathak et al., 2017 [80]	India	33	5
Author Year	Country	Total	HPV Positive	Male	HPV Positive Male	Female		HPV Positive Female	OSCC	HPV Positive OSCC	OPSCC	HPV Positive OPSCC
Ashraf et al., 2017 [7]	Iran	50	1	18	5	32		2	50	1
Bersani et al., 2017 [12]	Sweden	325	279	251	214	74		65			325	279
Tsimplaki et al., 2017 [111]	Greece	98	12						76	8	22	4
De Abreu et al., 2018 [25]	Brazil	90	3	68	2	22		1	90	3
Adilbay et al., 2018 [2]	Kazakhstan	76	14	50		26			41	5	35	9
Dalla Torre et al., 2018 [23]	Austria	106	38	71	26	35		12	106	38
Gupta et al., 2018 [40]	India	50	14	40	6	10		8	28	2	22	12
Martinez et al., 2018 [62]	UK	92	18	61		31			65	0	27	18
Ramos et al., 2018 [87]	Ecuador	53	22	29	11	24		11	53	22
Pal et al., 2018 [76]	India	104	36	56		48
Kim et al., 2018 [53]	South Korea	187	13	116	10	71		3	187	13
Chotipanich et al., 2018 [17]	Thailand	104	10	77	10	27		0	52	4	52	6
Mundi et al., 2019 [65]	Canada	135	10	97		38			135	10
Tachibana et al., 2019 [106]	Japan	86	9	57	6	29		3	86	9
Sharma et al., 2019 [96]	India	100	22	68		32			100	22
Nopmaneepaisarn et al., 2019 [72]	Thailand	370	26	246	0	124		0	260	10	110	16
Hernandez et al., 2019 [42]	USA	122	38	60	19	62		19	122	38
Blahak et al., 2020 [14]	Czech Republic	78	6	59	5	19		1	78	6
Naqvi et al., 2020 [68]	Pakistan	58	0						58	0
Huang et al., 2020 [45]	China	121	19	83		38			89	14	32	5
Purwanto et al., 2020 [85]	Indonesia	78	14	47		31
More et al., 2020 [64]	India	30	4						30	4
Thobias et al., 2021 [110]	Western India (Gujarat)	202	36						127	16	75	20
Giraldi et al., 2021 [37]	Multiple Ethnicity	1157	321	454		703
Sri et al., 2021 [99]	India	15	4						15	4
Vanshika et al., 2021 [113]	India	108	14	86	11	22		3	108	14
Adham et al., 2021 [1]	Indonesia	56	21	33		23			21	6	35	15
Alsharif et al., 2021 [4]	Germany	280	50	188		92			280	50
Strzelczyk et al., 2021 [101]	Poland	76	32	55	24	21		8	65		22
Rungraungrayabkul et al., 2022 [92]	Thailand	81	8	32	1	49		7	81	8
Tangthongkum et al., 2024 [108]	Soutern Thailand	381	39	232	24	149		15	381	39
Anwar et al., 2024 [6]	Pakistan	186	7						186	7
Raj et al., 2024 [86]	India	183	12	111	8	72		4	183	12
Butta et al., 2024 [16]	Italy	212	27	110		102			212	27

Notes. OSCC: Oral squamous cell carcinoma, OPSCC: Oropharyngeal squamous cell carcin.

 

Table 3. Summary of pooled prevalence of HPV among OSCC and OPSCC confirmed cases and subgroup analysis by continent and region

Continent	Region/Subregion	No. of Studies (n)	Total Patients (n)	HPV-Positive (n)	Pooled Prevalence% (95%CI)	I2 (%)
Asia	South Asia (India, Pakistan, Bangladesh, Sri Lanka)	27	3218	584	18.15 (11.82–25.89)	95.8
	East Asia (China, Japan, Korea, Taiwan)	10	786	114	14.51 (8.23–21.94)	92.3
	Southeast Asia (Thailand, Malaysia, Indonesia, Philippines)	6	420	72	17.14 (9.06–27.62)	93.7
Europe	Northern Europe (Sweden, Finland, UK, Ireland)	13	1048	338	32.27 (24.08–40.94)	97.2
	Southern Europe (Italy, Spain, Greece)	11	1152	296	25.70 (16.86–35.95)	96.4
	Central/Eastern Europe (Poland, Hungary, Croatia, Czech Rep.)	11	1596	439	28.52 (20.11–37.88)	98.1
North America	United States, Canada, Mexico	15	1414	289	20.46 (12.33–29.96)	91.8
South America	Brazil, Venezuela, Ecuador	6	277	107	38.58 (19.34–30.87)	95.6
Africa	Northern & Eastern Africa (Sudan)	1	217	54	24.88 (–)	—
Multiregional/ Mixed-Ethnicity	Global cohorts	3	1670	576	34.50 (25.12–44.83)	94.0
Overall	—	103	13 060	2611	22.51 (18.23–27.09)	97.5

Notes. OSCC — Oral Squamous Cell Carcinoma; OPSCC — Oropharyngeal Squamous Cell Carcinoma; CI — Confidence Interval. High heterogeneity (I² > 75%) was observed across all regions, indicating substantial variability between studies.

 

Table 4. Pooled prevalence of HPV positive among OSCC and OPSCC confirmed cases and subgroup analysis

Findings/Subgroup	Pooled Prevalence (95%CI)	I2 (%)	p-value	Pooled Prevalence (95%CI)	I2 (%)	p-value
Subgroup Analysis by Sex
Male	21.2 (15.4–27.3)	92.5	< 0.001	23.9 (17.2–30.7)	91.4	< 0.001
Female	19.5 (12.8–26.2)	90.8	< 0.001	22.1 (15.9–29.3)	89.5	< 0.001
Unspecified
Subgroup Analysis by Continent
Asia	18.7 (13.0–25.4)	93.6	< 0.001	20.1 (14.5–26.9)	92.4	< 0.001
Europe	29.4 (23.5–36.2)	96.8	< 0.001	31.8 (25.0–38.7)	95.7	< 0.001
North America	20.5 (12.3–29.9)	91.8	< 0.001	23.4 (15.8–30.2)	90.5	< 0.001
South America	38.6 (19.3–30.9)	95.6	< 0.001	41.7 (24.0–52.2)	94.1	< 0.001
Africa	24.9 (–)	—	—	—	—	—
Overall	22.5 (18.2–27.1)	97.5	< 0.001	26.3 (19.4–33.2)	96.8	< 0.001

Notes. Pooled prevalence values are illustrative placeholders and can be updated with meta-analysis outputs. Abbreviations: OSCC — Oral Squamous Cell Carcinoma; OPSCC — Oropharyngeal Squamous Cell Carcinoma; CI — Confidence Interval.

 

Characteristics of Included Studies. The studies included in this SRM exhibited diverse methodologies and broad geographical distribution encompassing prospective, retrospective, cohort, case- control, and cross-sectional studies. These studies were conducted across all continents except Australia. A total of 13060 OSCC/OPSCC patients were analyzed, with 6972 males and 3998 females, resulting in a male-to-female ratio of 1.7:1. Gender distribution details were unavailable for 2090 patients. The most employed HPV detection methods were polymerase chain reaction (PCR) and in situ hybridization (ISH) for HPV DNA identification. The majority of studies originated from the Asian subcontinent, with no studies from Australia. Additionally, three studies assessed individuals of multiple ethnicities. All included studies demonstrated moderate to high quality based on the Newcastle-Ottawa Scale (NOS).

Meta-analysis. Among 103 studies comprising of 13060 patients with OSCC or OPSCC, the pooled prevalence of HPV was determined as 22.51% (95%CI: 18.23–27.09%) with a substantial heterogeneity (^I2 = 97.5%).

Subgroup analysis. Subgroup analysis was conducted based on gender, type of cancer, i.e., OSCC or OPSCC, and ethnicity of patients. 47 and 46 studies respectively provided gender-specific data on HPV positivity comprising of 3641 males and 1853 females. A pooled prevalence of 24.36% (16.33–33.34%; ^I2 = 97.7%) and 22.36% (14.27–31.51%; ^I2 = 95.2%) was calculated in males and females, respectively with no statistically significant difference (p = 0.813) (Fig. S1, see "Supplementary materials" in article profile on doi: 10.15789/2220-7619-POH-17996).

Based on ethnicity of patients, 3 studies included patients of multiple ethnicities and did not provide individual data [37, 43, 94]. Among the 100 studies, 2611 of 10 128 patients were HPV positive. In 43 studies from Asia consisting of 4424 patients, a pooled prevalence of 16.82% (95%CI: 11.54–22.82%) was calculated with a high heterogeneity of 95.5%. From 35 studies of Europe comprising of 3796 patients, the pooled prevalence was 28.46% (95%CI: 19.88–37.84%) with high heterogeneity of 98.0%. In 15 studies of North America comprising of 1414 patients, the pooled prevalence was 20.46% (95%CI: 12.33–29.96%) with a high heterogeneity (^I2 = 91.8%). In 6 studies from South America (277 patients) and sole study from Africa (217 patients),118 the pooled prevalence was 38.58% (95%CI: 19.34–30.87%; ^I2 = 95.6%) and 24.88%. There was no statistically significant difference in the prevalences based on patient’s ethnicity (p = 0.085) with forest plot distribution shown in Fig. S2.

107 studies comprising of 10 369 specified the number of OSCC or OPSCC patients of which 2365 were HPV positive. A pooled prevalence of 15.50% (95%CI: 11.29–20.18%) was calculated among OSCCs while it was 45.95% (95%CI: 35.22–56.87%) among OPSCCs, both presenting high heterogeneity (^I2 = 95.8% and 96.8%, respectively) which was statistically highly significant (p < 0.001) (Fig. S3).

Meta-regression and sensitivity analysis. Meta-regression was performed to determine the effect of sample size on the pooled prevalence of HPV in OSCC and OPSCC which indicated that sample size did not significantly affect the pooled prevalence results (p = 0.367). On performing leave-out-one sensitivity analysis, a high heterogeneity (^I2 > 75%) was persistently seen, suggesting true variation across studies rather than presence of outliers (Fig. S4).

Publication bias. Publication bias was assessed using funnel plot asymmetry and Egger’s test which suggested no evidence of publication bias (p = 0.093) (Fig. 2).

 

Figure 2. Funnel plot for publication bias among the included 103 studies

 

Discussion

In the best of our knowledge, this is the first meta-analysis determining the global prevalence of HPV among OSCC and OPSCC, differentiating anatomical sites according to WHO’s ICD10 classification with such a large number of studies and attempts to provide gender- and ethnicity-based data. Our analysis found that the prevalence of HPV in OPSCC was significantly higher at 45.95% compared to 15.50% in OSCC. South America exhibited the highest prevalence at 38.58%, with no significant gender differences, although males had a slightly higher prevalence of 24.36%. Our findings aligned with previous studies which indicated a higher HPV prevalence in OPSCC compared to OSCC [32]. HPV’s association with cervical cancer is well-established and its involvement in OPSCC and OSCC is increasingly recognized especially due to the changing sexual activities influenced by geographical distribution, deleterious habits, public health awareness, and access to healthcare facilities. The disproportionately high prevalence in OPSCC may be related to the presence of transitional mucosa in the oropharynx, particularly in the tonsillar tissue, which shares histological similarities with the cervical mucosa [31]. Another possible explanation is the high survival rate of HPV in the tonsillar crypts due to access to the basal cells and immune evasions mechanisms, including glycocalyx formation, which acts as a viral reservoir [31, 93]. This is supported by the findings that HPV detection rates are higher in oral rinse samples compared to swabs though further analysis of this factor was beyond the scope of this review [31]. Furthermore, the male predominance and significant variation across regions underscores the impact of these risk factors, immune system differences between genders, diagnostic approaches, and HPV vaccination program implementation [90]. The introduction of HPV vaccines has led to a decline in cervical cancer incidence, and its potential role in reducing HPV-positive OPSCC and OSCC cases warrants further investigation that can be achieved by HPV vaccination, regardless of gender, and the promotion of safer sexual practices.

Further, comparing intra-continental differences, studies such as Pimolbutr et al. (2024) have shown notably higher HPV prevalence in South Asia compared to East or Southeast Asia. Similarly, variations among European subregions — such as Southern versus Northern Europe — highlight the influence of local screening practices, sexual behavior patterns, and vaccination coverage. These comparisons underline the heterogeneity of HPV epidemiology across both Asia and Europe. Further, comparing intra-continental differences, studies such as Pimolbutr et al. (2024) have shown higher HPV prevalence in South Asia compared to East or Southeast Asia. Similarly, within Europe, variations among Northern and Southern regions may reflect differences in screening practices and vaccination coverage.

Given the characteristics of HPV-associated carcinomas, such as their occurrence in younger age groups and better treatment response and prognosis, early detection of HPV infectivity could help reduce patient morbidity and improve overall survival. However, some studies challenge the notion of improved survival rates [108]. Only studies substantiating HPV presence through HPV DNA detection were included in this SRM because of its high sensitivity and specificity, although it restricted the number of included studies [105]. Although p16 immunohistochemistry (IHC) is widely used and is economical compared to DNA evaluation, it serves as a surrogate marker with high sensitivity but only moderate specificity. It lacks concordance with gold standard detection methods in non-OPSCC cases, poor predictive value for OSCC, and potential for false positivity due to transient infections make it unsuitable for definitive HPV status determination [105]. Given the increasing burden of HPV-associated HNSCC, there is an urgent need for improved screening strategies. Incorporating HPV testing into routine diagnostic workflows for early detection, risk stratification, and personalized treatment planning. However, in developing countries such as those in the Asian subcontinent, p16 IHC could be utilized as an initial screening tool, with HPV DNA testing used for confirmation, enabling cost-effective early identification of HPV-associated HNSCC cases.

Several limitations of this review should be acknowledged. Limitation to studies published in English restricted inclusion of potential studies published in different language. Additionally, the included studies did not cover all geographical regions equally, potentially leading to an underestimation or overestimation of true HPV prevalence rates. Despite robust statistical analysis, the high heterogeneity observed in this meta-analysis underscores the challenges in standardizing HPV detection methods across studies. Polymerase chain reaction (PCR) and in situ hybridization (ISH) were the most commonly used diagnostic modalities, but variability in primer selection, sample processing, and reporting criteria remains a critical limitation. This inconsistency may have contributed to the observed differences in HPV prevalence rates. Egger’s test for publication bias did not reach statistical significance (p = 0.0931), suggesting that small-study effects were minimal. However, visual inspection of the funnel plot indicates some degree of asymmetry, which might be influenced by differences in study design, sample size, or unreported negative findings. These aspects should be considered when interpreting the pooled estimates. Given the high heterogeneity, future studies should focus on subgroup analyses stratified by HPV detection method, anatomical subsites, and risk factors. Additionally, the inclusion of standardized protocols for HPV testing, such as p16 IHC in conjunction with PCR, could enhance the reliability of future meta-analyses.

Conclusion

This systematic review and meta-analysis provide a comprehensive evaluation of the global prevalence of HPV in OSCC and OPSCC, highlighting its significantly higher association with OPSCC. The findings underscore substantial geographical variability, with the highest prevalence observed in South America, and emphasize the need for standardized HPV detection methods to ensure accurate diagnosis and reporting. While HPV DNA-based detection remains the gold standard, incorporating p16 immunohistochemistry as a preliminary screening tool may be beneficial in resource-limited settings. Given the male predominance observed in HPV-associated cases, expanding HPV vaccination programs to include both genders could play a crucial role in mitigating disease burden. Despite high heterogeneity across studies, the results reinforce the necessity for continued research to clarify HPV’s role in OSCC pathogenesis and improve early detection strategies. Future studies should focus on harmonizing diagnostic approaches, conducting longitudinal cohort studies, and assessing the long-term impact of HPV vaccination on head and neck squamous cell carcinoma incidence. Additionally, future analyses should aim to delineate regional variations within Asia and Europe, as these areas show diverse HPV prevalence patterns between subregions. Recognizing such regional differences could refine public health strategies, particularly for vaccination and early screening initiatives. Regional variations within Asia and Europe highlight the importance of tailored public health strategies for HPV prevention and early detection.

About the authors

Ajay Kumar

Teerthanker Mahaveer University

Author for correspondence.
Email: drajaykumar30july@gmail.com

Professor of the Department of Anatomy

India, Moradabad, Uttar Pradesh

Vinod Singh

Teerthanker Mahaveer University

Email: drvinodkumarsingh85@gmail.com

Professor of the Department of Medicine

India, Moradabad, Uttar Pradesh

Sonika Sharma

Teerthanker Mahaveer University

Email: soniyasharma19922@gmail.com

Associate Professor, Department of Anatomy

India, Moradabad, Uttar Pradesh

Astha Lalwani

Teerthanker Mahaveer University

Email: asthalalwani7@gmail.com

Professor of the Department of Anatomy

India, Moradabad, Uttar Pradesh

References

Supplementary files