Prognostic impact of p16 and HPV discordance in cancer of unknown primary: a systematic review and meta-analysis

Clara H Pinborg; Amanda-Louise F Carlander; Joachim Hansen; Christian Grønhøj; Kathrine K Jakobsen; Christian von Buchwald

doi:10.1080/00016489.2025.2509655

Prognostic impact of p16 and HPV discordance in cancer of unknown primary: a systematic review and meta-analysis

Clara H Pinborg^*, Amanda-Louise F Carlander, Joachim Hansen, Christian Grønhøj, Kathrine K Jakobsen, Christian von Buchwald

^*Corresponding author for this work

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology

Abstract

BACKGROUND: Discordance between human papillomavirus (HPV) and its surrogate marker, p16INK4a (p16), raises concerns about the reliability of p16 as a sole prognostic marker.

OBJECTIVES: To investigate the impact of HPV, p16, and discordant HPV/p16 status on survival in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN).

MATERIALS AND METHODS: PubMed and EMBASE were searched for relevant studies that used a strict definition of SCCUPHN and reported survival outcomes stratified by HPV/p16 status. A meta-analysis assessed the prevalence and overall survival (OS).

RESULTS: Twelve studies (n = 864) were included. The pooled prevalence rates were: 23% HPV+/p16+ SCCUPHN (95% CI: 14-33%); 50% HPV-/p16- (95% CI: 32-67%); 13% HPV-/p16+ (95% CI: 6-19%); and 6% HPV+/p16- (95% CI: 1-10%). OS hazard ratios were: 0.37 (95% CI: 0.17-0.78) for p16+ vs. p16-, 0.35 (95% CI: 0.19-0.64) for HPV+ vs. HPV-, and 0.24 (95% CI: 0.12-0.50) for HPV+/p16+ vs. HPV-/p16-. Only one study (n = 103) compared survival in the four HPV/p16 subgroups individually.

CONCLUSIONS: HPV and p16 are individual positive prognostic markers in SCCUPHN. Although significant discordance exists, the current literature does not provide sufficient evidence to support risk stratifying SCCUPHN patients into four distinct HPV/p16 subgroups.

Original language	English
Journal	Acta Oto-Laryngologica
Pages (from-to)	1-9
Number of pages	9
ISSN	0001-6489
DOIs	https://doi.org/10.1080/00016489.2025.2509655
Publication status	E-pub ahead of print - 31 May 2025

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@article{52e70e92003947a29f12ab6cdbdc922c,

title = "Prognostic impact of p16 and HPV discordance in cancer of unknown primary: a systematic review and meta-analysis",

abstract = "BACKGROUND: Discordance between human papillomavirus (HPV) and its surrogate marker, p16INK4a (p16), raises concerns about the reliability of p16 as a sole prognostic marker.OBJECTIVES: To investigate the impact of HPV, p16, and discordant HPV/p16 status on survival in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN).MATERIALS AND METHODS: PubMed and EMBASE were searched for relevant studies that used a strict definition of SCCUPHN and reported survival outcomes stratified by HPV/p16 status. A meta-analysis assessed the prevalence and overall survival (OS).RESULTS: Twelve studies (n = 864) were included. The pooled prevalence rates were: 23% HPV+/p16+ SCCUPHN (95% CI: 14-33%); 50% HPV-/p16- (95% CI: 32-67%); 13% HPV-/p16+ (95% CI: 6-19%); and 6% HPV+/p16- (95% CI: 1-10%). OS hazard ratios were: 0.37 (95% CI: 0.17-0.78) for p16+ vs. p16-, 0.35 (95% CI: 0.19-0.64) for HPV+ vs. HPV-, and 0.24 (95% CI: 0.12-0.50) for HPV+/p16+ vs. HPV-/p16-. Only one study (n = 103) compared survival in the four HPV/p16 subgroups individually.CONCLUSIONS: HPV and p16 are individual positive prognostic markers in SCCUPHN. Although significant discordance exists, the current literature does not provide sufficient evidence to support risk stratifying SCCUPHN patients into four distinct HPV/p16 subgroups.",

author = "Pinborg, {Clara H} and Carlander, {Amanda-Louise F} and Joachim Hansen and Christian Gr{\o}nh{\o}j and Jakobsen, {Kathrine K} and {von Buchwald}, Christian",

year = "2025",

month = may,

day = "31",

doi = "10.1080/00016489.2025.2509655",

language = "English",

pages = "1--9",

journal = "Acta Oto-Laryngologica",

issn = "0001-6489",

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TY - JOUR

T1 - Prognostic impact of p16 and HPV discordance in cancer of unknown primary

T2 - a systematic review and meta-analysis

AU - Pinborg, Clara H

AU - Carlander, Amanda-Louise F

AU - Hansen, Joachim

AU - Grønhøj, Christian

AU - Jakobsen, Kathrine K

AU - von Buchwald, Christian

PY - 2025/5/31

Y1 - 2025/5/31

N2 - BACKGROUND: Discordance between human papillomavirus (HPV) and its surrogate marker, p16INK4a (p16), raises concerns about the reliability of p16 as a sole prognostic marker.OBJECTIVES: To investigate the impact of HPV, p16, and discordant HPV/p16 status on survival in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN).MATERIALS AND METHODS: PubMed and EMBASE were searched for relevant studies that used a strict definition of SCCUPHN and reported survival outcomes stratified by HPV/p16 status. A meta-analysis assessed the prevalence and overall survival (OS).RESULTS: Twelve studies (n = 864) were included. The pooled prevalence rates were: 23% HPV+/p16+ SCCUPHN (95% CI: 14-33%); 50% HPV-/p16- (95% CI: 32-67%); 13% HPV-/p16+ (95% CI: 6-19%); and 6% HPV+/p16- (95% CI: 1-10%). OS hazard ratios were: 0.37 (95% CI: 0.17-0.78) for p16+ vs. p16-, 0.35 (95% CI: 0.19-0.64) for HPV+ vs. HPV-, and 0.24 (95% CI: 0.12-0.50) for HPV+/p16+ vs. HPV-/p16-. Only one study (n = 103) compared survival in the four HPV/p16 subgroups individually.CONCLUSIONS: HPV and p16 are individual positive prognostic markers in SCCUPHN. Although significant discordance exists, the current literature does not provide sufficient evidence to support risk stratifying SCCUPHN patients into four distinct HPV/p16 subgroups.

AB - BACKGROUND: Discordance between human papillomavirus (HPV) and its surrogate marker, p16INK4a (p16), raises concerns about the reliability of p16 as a sole prognostic marker.OBJECTIVES: To investigate the impact of HPV, p16, and discordant HPV/p16 status on survival in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN).MATERIALS AND METHODS: PubMed and EMBASE were searched for relevant studies that used a strict definition of SCCUPHN and reported survival outcomes stratified by HPV/p16 status. A meta-analysis assessed the prevalence and overall survival (OS).RESULTS: Twelve studies (n = 864) were included. The pooled prevalence rates were: 23% HPV+/p16+ SCCUPHN (95% CI: 14-33%); 50% HPV-/p16- (95% CI: 32-67%); 13% HPV-/p16+ (95% CI: 6-19%); and 6% HPV+/p16- (95% CI: 1-10%). OS hazard ratios were: 0.37 (95% CI: 0.17-0.78) for p16+ vs. p16-, 0.35 (95% CI: 0.19-0.64) for HPV+ vs. HPV-, and 0.24 (95% CI: 0.12-0.50) for HPV+/p16+ vs. HPV-/p16-. Only one study (n = 103) compared survival in the four HPV/p16 subgroups individually.CONCLUSIONS: HPV and p16 are individual positive prognostic markers in SCCUPHN. Although significant discordance exists, the current literature does not provide sufficient evidence to support risk stratifying SCCUPHN patients into four distinct HPV/p16 subgroups.

UR - http://www.scopus.com/inward/record.url?scp=105007153563&partnerID=8YFLogxK

U2 - 10.1080/00016489.2025.2509655

DO - 10.1080/00016489.2025.2509655

M3 - Review

C2 - 40448922

SN - 0001-6489

SP - 1

EP - 9

JO - Acta Oto-Laryngologica

JF - Acta Oto-Laryngologica

ER -

Prognostic impact of p16 and HPV discordance in cancer of unknown primary: a systematic review and meta-analysis

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