HPV-related cancers: oropharyngeal is most common

 Background:

-- chronic HPV infection is associated with six different anatomical regions: five are in the genital area (penis, cervix, anus, vagina, and vulva) and the sixth is in the oropharynx

-- of note, there has been an increase in HPV-related cancers over time, with oropharyngeal cancer being the single most common HPV-related cancer in the US

-- the CDC reported in  2019 (https://www.cdc.gov/mmwr/volumes/68/wr/pdfs/mm6833a3-H.pdf) that  there were an average of 43,999 potential HPV-associated cancers (12.2/100K) annually, with 79% (34,800) attributable to HPV:

    -- oropharynx: 19,000 cases, 4.9/100K people, with 12,600 from the 9 serotypes covered by the vaccine, 900 from other HPV serotypes, and 5,500 that were HPV-negative

    -- cervix: 12,015 cases, 7.2/100K people, with 9,700 from the 9 serotypes covered by the vaccine, 1200 from other HPV serotypes, and 1,100 that were HPV-negative

        – the 9vHPV vaccine covers the following HPV types: 6,11,16,18,31,33,45,52, and 58 (types 6 and 11 cause genital warts)

-- this is a graph from the article below:

-- most HPV cases are asymptomatic and clear spontaneously within 1-2 year, though persistent infections with high risk serotypes are associated with cancer in the above sites

-- one caveat here: most cancers are not tested for HPV in most cancer registries, so some of these estimates are from assessing the site of the cancer where HPV is frequently found, especially in the labial musosa and palate  (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405797/pdf/12105_2019_Article_1003.pdf )

-- the reasons why oropharyngeal carcinoma now exceeds cervical cancer are basically that cervical cancer  is routinely accessible by cervical screening (which largely includes HPV screening), those that are found to be of concern by cytology or are HPV-positive are followed closely with repeated exams and potential excision, vaccination is very effective, and cervical cancer screening is integrated into clinical care.

-- the reasons that oropharyngeal cancer is increasing is the opposite: there are no easy early detection methods routinely available, the sites of cancer growth are often not apparent on routine mouth exam, vaccination is suboptimal and less frequent in males vs females at 34.6% vs 42.9%  as well as in children who have Medicaid coverage (37%) and those without insurance (20.7%), per data from the CDC in 2022 (https://www.cdc.gov/nchs/data/databriefs/db495.pdf, and assessing for oropharyngeal cancer is not part of routine clinical care. 

-- this graph reflects those getting at least one vaccination against HPV, which is quite effective by itself (lowest predicted effectiveness of a single shot is about 85%:https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(23)00180-9/fulltext, and more likely in the 90+% range, though this still a bit lower than the multi-dose regimen).

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--a recent article reviewed human malignancies associated with persistent HPV infection (see hpv oropharyg ca most common Oncologist2024 in dropbox, or doi.org/10.1093/oncolo/oyae071)

Details (I will summarize relevant points; see article for more of the pretty extensive discussions on HPV virology):

-- about 5% of human cancers worldwide are associated with HPV

-- the high-risk oncogenic HPV types promote cellular proliferation and genomic instability, and in particular affect cells that are in the transitional regions between different types of epithelia (esp in the anus, cervix, and oropharynx)

    -- these transitional zones render these sites more vulnerable to HPV-related oncogenesis, related to access to the basal cells and easier oncogenesis

    -- the transitional zones are apparent in the cervix and anus, but are also present in the tonsillar crypts of the oropharynx; and, HPV-positive tumors typically arise in the tonsillar crypts, whereas HPV-negative tumors tend to arise in the surface epithelium of the oropharynx.

        -- in the oropharynx, there is a "stratified epithelium interspersed with patches of reticulated epithelium specialized to transport antigens from the tonsil to the underlying lymphoid tissue"

-- mathematical modeling: if each country achieved a 90% vaccine uptake, 70% performed high-performance screening and 90% had treatment of precancerous lesions or cancers in females by 2030, 62 million lives would be saved by 2120

-- oropharyngeal cancer is typically associated with HPV infection (about 85% of all oropharyngeal cancers) or alcohol and tobacco use (in the rest)

-- HPV has evolved to establish a persistent reservoir by evading the host immune system: the virus persists in the outermost layer of the epithelium, and ultimately in the more superficial dead cells (cornified envelopes, which are full of HPV particles and pretty much inaccessible to the immune system) and are shed from the surface of the epithelium and able to infect others:

    -- HPVs interact with and manipulate several immunological pathways in the host by hiding in these soon-to-be desquamated epithelial cells: they can exploit the cell cycle, cell division, differentiation, the DNA damage response, innate immunity , the cornified envelope integrity, etc; all of this allows HPV to establish a reservoir of persistent infection in dividing basal cells and to avoid host immune-mediated elimination of infected cells

    -- the oncogenic HPVs in particular manipulate the host cell to make them very susceptible to genetic instability, in areas where the cells are undifferentiated and continue to divide without normal cell cycle checkpoints

    -- the immune system's humoral response is not strong enough after a natural infection in those with persistent infection, especially in those with immunodeficiencies (eg by HIV; more aggressive HPV screening for cervical cancer is recommended and throughout a woman's life: https://www.nature.com/articles/s41591-023-02601-3)

-- there are potentially a few ways that people might develop long-term infections: 

    -- latency: there may be latency of HPV virus leading to no detectable virus, but later reactivation (similar to what happens with HSV, though a site of the latency for HPV has not been identified). older women "often experience recurrence of HPV infections many years after apparent clinical clearance:"

        -- there have been cases of reactivation of latent HPV infections after immunosuppression post-organ transplant

    -- waning immunity leading to resurgence of virus that had been under immunological control

    -- reinfection, "possibly by auto-inoculation from different lesions"

Commentary:

-- HPV is a huge global issue: approximately 12% of women worldwide have detectable HPV infections; 1 in 3 men are infected with at least one genital HPV type and one in 5 men over 15yo have one or more high-risk HPV types  (https://www.sciencedirect.com/science/article/pii/S2214109X23003054 ); these rates were highest  in men aged 25-29 and did vary by the area of the world (the highest reported number was in Sub-Saharan Africa, followed closely by Europe and Northern America)

-- 25% of sexually active women in Costa Rica are infected with oncogenic HPV (though still about 90% resolved within a couple of years, confirming that the immune system is often robust enough to eliminate these oncogenic HPVs in the vast majority of people)

-- HPV vaccination is remarkably successful in decreasing the oncogenic HPV strains and decreasing cervical cancer

    -- a very recent Danish study found that 3867 women receiving at least one dose of HPV vaccine by age 15 had a 35% lower risk of CIN 3+, more advanced cervical dysplasia (and only 14% lower risk if vaccinated by age 15-20, and no clear benefit if vaccinated >20y, presumably because the younger group were less exposed to HPV prior to vaccination), and therefore likely a lower risk of cervical cancer after 28 months of followup (there were only 20 cases: 15 women who were unvaccinated vs  5 who were, and all 5 cancers were in women vaccinated after age 20): https://www.ajog.org/action/showPdf?pii=S0002-9378%2823%2902035-5

-- in terms of vaccinations:

    -- there is fortunately some evidence of herd immunity in unvaccinated men by vaccinating women: https://gmodestmedblogs.blogspot.com/2019/10/hpv-vaccine-and-herd-immunity-in-men.html .  But,but,but it still is really important to vaccinate both males and females. And the message needs to be publicized through public health channels and individual relationships by clinicians with their patients that oropharyngeal cancer is likely preventable (and transmission of HPV from men to women would be reduced), oropharyngeal cancer has significant mortality (though, it turns out that it is typically more amenable to treatments than non-HPV oropharyngeal cancers), and we need to close the gap in vaccination rates for boys vs girls (oropharyngeal cancer is much  more common in males than females)

    – the standard in the US is to give 2 doses of HPV vaccine to girls and boys 9-14yo, since they seem to have a particularly robust response to the vaccine

        -- but, as noted above, it seems that one dose is also pretty effective. should we be using one dose and allow the second dose to be available in countries that do not have HPV vaccines available?

    -- maybe we should be extending the interval for vaccination to age 45yo, as suggested by the FDA (https://gmodestmedblogs.blogspot.com/2018/10/vaccine-approved-to-age-45-tdap-best.html ).  perhaps later vaccination might prevent the unknown extent of HPV reactivation in those with waning immunity??? of course, the older folks also have likely been exposed to many of the HPV types, but may get protection if they have not been exposed to the high-risk types???

    -- and we need to directly confront the current increase in anti-vaccination rhetoric proffered by 2 likely candidates in the upcoming election: kennedy (a long-outspoken anti-vaxxer), and trump (a current opportunist antivaxxer: https://www.sciencedirect.com/science/article/abs/pii/S0022103119302628 , both of whom have promoted an anti-vaccination agenda

so,

-- there are 2 basic issues that urgently need to be addressed:

    -- prevention: we need to dramatically increase the access and popular acceptance to HPV vaccine, which  means:

        -- aggressively confronting the vaccine hesitancy that increased dramatically in the past few years and is being politicized/weaponized by Trump and RFK Jr misinformation

        -- aggressively increasing access to vaccine throughout the US, including in areas with extreme poverty and inadequate health insurance and health care systems
        -- aggressively promoting vaccine for males

        -- aggressively improving access to the HPV vaccines globally, with dramatic increases in vaccine production (there is not even close to enough vaccine produced) and appropriate distribution to even the poorest countries (the WHO needs to aggressively take on this task. their most recent position is quite underwhelming: it only addresses the need for vaccination for females, commenting that "vaccination of secondary targets such as boys" is recommended where feasible and affordable, though males get much more oropharyngeal cancer than females). the WHO has no concrete plans even for expanding vaccination globally (and including boys), and no comment that drug companies need to increase vaccine production (without further comment on how this will be funded): https://www.who.int/news/item/20-12-2022-WHO-updates-recommendations-on-HPV-vaccination-schedule

    -- treatment: it is painful that there is no treatment for HPV infection, in light of its huge frequency globally and huge burden of severe/fatal diseases

        -- when searching around for HPV treatments globally, there is essentially no funding of direct treatments for the virus (as we now have with hepatitis C, for example).  the WHO only seems to comment on the need for funding vaccination and treatments to eliminate cervical cancer: https://www.who.int/news/item/05-03-2024-wave-of-new-commitments-marks-historic-step-towards-the-elimination-of-cervical-cancer. i am told by some basic virology researchers who have been working on direct HPV treatments for many decades that funding the needed basic science has largely dried up and the WHO statements belie this fact and do not promote the necessary research (and neither does the US). And this is at a time when the technology for virologic research in other areas has made great leaps forward and HPV treatment could potentially be closer than in the past.

        -- the focus on cervical cancer is likely because it is easily ascertained through direct HPV testing, has general acceptance of its importance, and has clear algorithms for treatment that do decrease mortality dramatically

        -- however, oropharyngeal cancer does not have this easy an assessment/treatment. Per the article above, "HPV-positive tumors arise from the tonsillar crypt whereas HPV-negative tumors tend to originate from the surface epithelium of the oropharynx". But, there are studies finding that oral swabs for HPV have good specificity (92%) but moderate sensitivity (72%) for those with HPV-positive cancers (https://www.sciencedirect.com/science/article/abs/pii/S1368837517303974?via%3Dihub ). it seems to me that this could be operationalized....

        -- and it is a bit concerning that we have known that oropharyngeal cancer has been increasing so much since a 2018 CDC report: https://gmodestmedblogs.blogspot.com/2018/12/hpv-self-testing-and-hpv-prevalence.html

geoff

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