Cervical cancer used to be the leading cause of cancer death for women. Human Papillomavirus (HPV) infection is responsible for more than 90% cervical cancer. About 6.6% of women in Indian population are estimated to harbor cervical HPV infection. HPV 16 and 18 are accounting most prevalent type in cervical adenocarcinomas. In HPV life cycle, high-level amplification of the viral genome move outer layers of the epithelium are released to re-initiate infection, persistent infection leads to precancerous lesion. The numbers of cervical cancer cases and deaths have decreased significantly over the period with efficient diagnostic technique like Pap smear test. Development of sensitive technique for early detection of HPV infection and vaccination further reduce the incidence of cervical cancer.
Keywords: Cervical cancer; Human Papillomavirus infection; Pap smear test
Abbrevations: HPV: Human Papillomavirus; LCR: Long Control Region; SCC: Squamous Cell Carcinoma; LSIL: Low Grade Squamous Intraepithelial Lesion; HSIL: High Grade Intraepithelial Lesion; TLR: Toll Like Receptors; NK: Natural Killer
Globally cervical cancer is the fourth most common cancer in women. Cervical cancer occurs due to neoplastic transformation of cells in the cervix i.e. lower part of the uterus. The worldwide incidence of cervical cancer, 5,10,000 new cases diagnosed every year and approximately 2,88,000 deaths . In India, 1,32,000 new cases diagnosed and 74,000 death every year. The incidence is more common in women above the age of 30 years. Cervical
cancer is almost always caused by Human Papilloma Virus (HPV)
infection . HPV infection is responsible for more than 90% cervical cancer causes and the other less important factors include smoking, weak immune system, birth control pills, and unsafe sex (contraceptives) . 90% of cervical cancer cases are squamous cell carcinomas and 10% are adenocarcinoma. About 6.6% of women in Indian population are estimated to harbor cervical HPV infection.
HPV are small (50 nm) double-stranded DNA viruses
composed of a genome of 8kilobase pair, enclosed inside a nonenveloped
capsid protein. The genome consists of three sets: (a)
early genes (E1, E2, E4, E5, E6, E7) which regulate the vegetative
and productive phase of viral life cycle: (b) late genes (L1, L2)
which encode the capsid protein and (c) a non-coding regulatory
region called Long Control Region (LCR) control the regulation of
viral replication and transcription  (Figure 1).
Approximately 200 different HPV types have been characterized,
and the two most frequent high-risk HPV genotypes, HPV-
16 and HPV-18, according for 70% of cases. HPV6 and HPV11 are
common causes of genital warts and precancerous lesions . The
HPVs can be broadly grouped into cutaneous types and mucosal
types based on tissue tropism. The cutaneous types are found in
the general population and cause common warts with individuals
are immunosuppressed. The mucosal HPVs are further classified
into high-risk and low-risk types, based on their respective degree
of association with cervical cancer. The most common lowrisk
types are HPV 6 and 11, detected most often in benign genital
warts. HPV 16, 18, 31, and 45 are predominant types found in cervical
Squamous Cell Carcinoma (SCC), accounting for more than
90% of cases, with HPV 16 alone accounting for about half the
cases worldwide . HPV 18 is the most prevalent type in cervical
adenocarcinomas (55%), followed by HPV 16 (32%) and HPV 45
(10%). Epidemiological evidence suggests that infection with HPV
is the greatest risk factor . Its, role in the progression of the precursor
lesions to cervical cancer is well established .
HPV infection normally does not integrate its DNA to host
DNA. In high-risk HPV, DNA is often integrated into the human
genome in cervical squamous cell carcinoma. It has been
proposed that integration can be an early event associated with
Low Grade Squamous Intraepithelial Lesion (LSIL) to High Grade
Intraepithelial Lesion (HSIL) progression . HPV can infect cells
through damaged tissue. In the immune response, keratinocytes
play an important role which can express Toll Like Receptors (TLR),
participate in the innate immune response and recognize both
endogenous and exogenous. In this process, TLRs are activated
and can synthesize and release a variety of cytokines involved in
immune regulation like IL-1, IL-6, IL-8, IL-10, TNF-α and IFN-β to
activate Natural Killer (NK) cells . The NK-activating receptors
affect the cytolytic functionality. It elicits a proinflammatory
expression profile which promotes innate immunity. The initial
inflammatory response leads to infiltration of immune cells such
as neutrophils, macrophages and lymphocytes.
HPVs are exclusively epitheliotropic, and their replication is
intimately linked to the differentiation process of the host cells.
Normal squamous epithelial cells grow as stratified epithelium,
with those in the basal layers dividing as stem cells of transient
amplifying cells. After division, one of the daughter cells migrates
upward and begins to undergo terminal differentiation while the
other remains in the basal layer as a slow-cycling, self-renewing
population. Productive papillomavirus infection begins when
infectious daughter cells of the basal layer, probably through
micro-wounds. The viral genome is maintained in these cells as a
stable episome at low copy number, and that generate productive
wart. The early HPV genes E1 and E2 support viral DNA replication
and its segregation such that the infected cells can be maintained
in the lesion for a long period. As infected daughter cells migrate
towards the epithelial surface, viral late gene products are
produced to initiate the vegetative phase of the HPV life cycle,
resulting in the high-level amplification of the viral genome. In
the outer layers of the epithelium, viral DNA is packaged into
capsids and progeny virions are released to re-initiate infection,
persistent infection rather than clearance of the virus linked to
the development of precancerous lesion followed for invasion and
The important methods to diagnose HPV infection are
• Pap smear test-It is a screening test first describe
by Papanicolaou and Traut. Apart from premalignant and
malignant changes, viral infections like HPV infection and
Herpes can also be detected. Positive test requires further
confirmatory tests like colposcopy, cervical biopsy, and DNA
tests like PCR.
• Colposcopy and acetic acid test- Colposcopy is the
examination of the cervix, vagina, and in some instances the
vulva after the application of acetic acid solution.
• Biopsy- Colposcopy allows tissue sampling (biopsy)
that is targeted to the abnormal areas.
• DNA test (PCR, Southern Blot Hybridization, In Situ
Hybridization) - Initial methods of HPV detection used were
direct probe hybridization such as dot blot and Southern blot.
The two novel and highly efficacious prevention methods
are prophylactic HPV vaccination to control the early peak of
infections and sensitive HPV-based screening to detect and treat
the secondary peak of precancerous [12,13].
This review has described the mechanism of HPV mediated
carcinogenesis in human cells. A future challenge to this end
is defining the research agenda for deciding on the optimal
technology and intensity of screening to make cervical cancer a
very rare disease while minimizing the possible harms.