27
in the United States, primary HPV testing has been recommended only in combina-
tion with cytology in primary screening or for triage of cytologic abnormalities.
Accumulating data support that HPV testing without cytology might be sufficiently
sensitive for primary screening [ 23 ]. However, developing countries face several
challenges in widespread adoption of these tests for screening purposes.
3.5.1 HPV and Cervical Cancer
Cervical cancer, caused by HPV, is the third leading malignancy among women in
the world, after breast cancer and colorectal cancer, with an estimated 527,624 new
cases and 265,653 deaths in 2012. Incidence and mortality rates have been declining
in most areas of the world in the past 30 years, at a worldwide rate of about 1.6%
per year [ 24 ].
Almost every cervical cancer is positive for some HR HPV [ 25 ]. In a worldwidesurvey, HPV16 was the most prevalent type in cervical cancer (61%), followed by
HPV18 (10%), HPV45 (6%), HPV31 (4%), HPV33 (4%), HPV52 (3%), HPV35
(2%), and HPV58 (2%) [ 26 ]. About 90% of cervical cancers are squamous cell
carcinoma (SCC), whereas 10% are adenocarcinoma [ 27 ]. Both types of cancer are
mainly caused by HPV type 16 (62% and 50%, respectively), but adenocarcinoma
is significantly associated more with HPV types 18 (32%) and 45 (12%). Another
study that evaluated HPV infection in 10,575 histologically confirmed cases of inva-
sive cancer from 38 countries in Asia, Europe, Latin America and the Caribbean,
North America, Oceania, and sub-Saharan Africa over a 60-year period found that
85% (n = 8977) of the cases were positive for HPV DNA [ 27 ]. HPV types 16, 18,
and 45 were the three most common types in each histologic form of cervical cancer
(squamous cell, adenocarcinoma, and adenosquamous carcinoma), accounting for
61%, 10%, and 6%, respectively.
Good evidence suggests that HPV infection precedes the development of cervi-cal cancer by decades and that persistent infection with HPV is necessary for the
development and progression of precancerous lesions of the cervix, either to higher
grades of precancerous disease or to cancer. Cervical cancer progresses slowly from
a preinvasive state to invasive cervical cancer, a process that can take 10–30 years.
Although HR-HPV infection may result in cervical low-grade squamous intraepi-
thelial lesion (LSIL) and HPV infections are very common, particularly among
young women, most HR HPV infections resolve in instances of spontaneous regres-
sion without appearance of any clinical manifestations. Only a small proportion
(10–30%) of HR HPV infection that persists for a long time, with a high viral load,
eventually progress to high-grade squamous intraepithelial lesion HSIL and/or inva-
sive cervical cancer [ 28 – 33 ]. A small proportion (~1%) of LSIL and ~12% of HSIL
will progress into invasive cancer, if left untreated [ 34 ]. Progression of precursor
lesions to invasive cancer usually takes place over a period of more than a decade,
allowing time for the identification and treatment. Cervical cancer precursor lesions
progress more quickly in women with HPV16 and/or 18 infections than in women
3 HPV-Related Cancers