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Human Papillomaviruses: Their Clinical Significance in the Management of Cervical Carcinoma

Human Papillomaviruses: Their Clinical Significance in the Management of Cervical Carcinoma

ABSTRACT: Studies have shown a strong association between certain human papillomaviruses and the development of cervical carcinoma and its precursor lesions. The oncogenic potential of papillomaviruses has been clearly demonstrated in both laboratory animals and cultured cells. Recent advances in our understanding of viral pathogenesis have provided insights into the natural history of papillomavirus infection and subsequent development of neoplasia. A more thorough understanding of the molecular mechanisms responsible for viral oncogenesis will facilitate the development of novel preventive and therapeutic strategies to prevent and treat papillomavirus-associated cervical neoplasias. Strategies under current investigation are focusing on the induction of effective humoral and cell-mediated immunity, the expression of HPV gene products, and cofactors that interact with HPV gene products to affect cell transformation. As a result of these investigative efforts, prophylactic HPV capsid vaccines and other gene therapies may soon become clinically available. [ONCOLOGY 9(4):279-291, 1995]

Introduction

Papillomaviruses are ubiquitous in a wide variety of vertebrate
species, including humans. They infect and cause proliferative
lesions of cutaneous and mucosal squamous epithelium [1]. More
than 60 types of human papillomaviruses (HPVs) have been described
(Table 1) [2,3], each of which shows a particular predilection
for tissue sites and has defined oncogenicities. Particular interest
has focused on HPVs as-sociated with anogenital tract disease.
There is a well-established association between HPV infection,
cervical dysplasia, and cervical carcinoma [4-6].

In 1994, 15,000 new cases of invasive cervical cancer and 4,600
deaths attributable to cervical cancer are projected in the United
States.7 Statistics on cervical cancer worldwide are much more
staggering, with 500,000 deaths per year caused by this cancer
[8]. These figures highlight the public health significance of
controlling cervical cancer and its precursor lesions.

Recent advances in immunology and molecular biology have broadened
our understanding of the biology of HPV. In particular, insights
into the molecular mechanisms of HPV-mediated tumorigenesis may
be the basis for new preventive and therapeutic strategies for
HPV-associated disease (Figure 1).

Characteristics of Human Papillomavirus

The viral etiology of warts was first described by Licht in the
late 19th century [8]. In 1933, Shope and Hurst described the
first DNA tumor virus isolated from the papillomavirus of cottontail
rabbits [9]. Condyloma acuminata, long recognized to be sexually
transmitted, were linked to a viral etiology when virus particles
were detected in genital warts by electron microscopy in the 1970s
[10,11].

Papillomaviruses have been classified into the papovavirus group
because of similarities among papillomavirus, polyoma virus, and
the vacuolating virus of monkeys [12]. The structure and genetic
organization of all the papilloma- viruses are strikingly similar.
Papillomaviruses consist of a 55-nm, nonenveloped, icosahedral-shaped
virion whose genome is organized as closed, circular, double-stranded
DNA of approximately 8,000 base pairs in length [13] (Figure 2).

The papillomavirus genome can be divided into three functional
regions (Table 2) [14]: The "early" region contains
eight open reading frames, or genes, whose products are responsible
for viral DNA replication, transcriptional control, and cellular
transformation. The "late" region encodes the two structural
capsid proteins, L1 and L2, of the virion. The "long control
region" contains the origin of DNA replication, promoter
elements, and transcriptional enhancer sequences.

The true prevalence of HPV infection in the general population
is unknown. This is due to a number of variables, including coital
activity, host response to infection, and the diagnostic modality
used to detect HPV infection. Cutaneotropic HPVs cause verruca
plana, which is common among young children, and verruca vulgaris,
which is common among adolescent children [15]. Mucosotropic HPVs
produce a variety of lesions of the conjunctiva, oropharynx, and
larynx, in addition to anogenital tract lesions.

Pathogenesis of HPV Infection

Sexual transmission of anogenital warts is supported by data confirming
the presence of similar HPV types on cervical and penile lesions
of sexual partners [16]. Several factors affect the rate of transmission
of mucosotropic HPVs. These include coitus with multiple sexual
partners, immunodeficient states, and pregnancy.

These highly infectious viruses have a relatively long incubation
period following inoculation. Lesions caused by mucosotropic HPV
types usually appear within 4 to 6 weeks in humans. The same incubation
time is observed with mucosotropic viruses that infect keratinocytes
in the athymic nude mouse
model [11,17].

The host response to infection is similar for all HPV types. All
three types of squamous epithelia (cutaneous-keratinized, mucosal-nonkeratinized,
and metaplastic) are susceptible to HPV infection. While infection
may manifest itself differently for different HPV types, infection
begins in the basal layer of squamous epithelia. Presumably, virus
from infected cells is released into epithelial breaks of the
susceptible host [18].

Human papillomaviruses demonstrate specific tissue tropism to
anatomic sites. Equally important is the fact that HPVs can only
synthesize structural proteins that encapsidate the genome and
form virions in the most differentiated keratinocytes.

Three Sequelae of Infection

Following infection with HPV, three sequelae are possible:

First, the HPV genome can stabilize as a nonintegrated episome
and remain latent in the host without producing clinical or morphologic
changes in the squamous epithelium.

Second, active infection can be established with vegetative replication
of HPVs, which induces the proliferation of squamous epithelia
into benign tumors (warts, papillomas).

Third, the HPV genome can become integrated into the host genome,
which interrupts its control of oncoproteins of highly oncogenic
viruses.

Expression of early and late viral gene products accounts for
the morphologic changes seen in affected epithelia. Early gene
expression causes cellular proliferation, which results in acanthosis.
Late gene expression results in production of viral capsid proteins,
which are evident (by electron microscopy and immunocytochemistry)
only within nuclei of terminally differentiated, superficial epithelial
cells (keratinocytes). In latently infected cells and benign tumors,
the HPV genome is present in nonintegrated, episomal form. Viral
capsid assembly in productively infected, terminally differentiated
keratinocytes causes degenerative changes in the nuclei and cytoplasm,
which are recognized histologically as koilocytosis [19].

Latent infections with no pathologically identifiable lesions
comprise a large reservoir of virus that may be reactivated for
transmission and autoinfection. It is believed that 10% of sexually
active individuals harbor latent HPV infections [20]. Active infections
occur in up to 5% of sexually active women, and appear as flat
or exophytic condylomas of the cervix, vagina, or vulva. Condyloma
acuminata are usually associated with HPV types 6 and 11.

Association with Dysplasia and Malignancy

Infection with certain HPV types has a high probability of being
associated with dysplasias (types 6 and 11) or with malignancies
(types 16 and 18). Squamous intraepithelial lesions show characteristic
disorderly, undifferentiated, proliferating basaloid and parabasaloid
cells that occupy different portions of the epithelium, from the
lower third in mild cervical intraepithelial neoplasia to full
epithelial involvement in carcinoma in situ. Conversely, invasive
cervical carcinomas extend beyond the basement membrane.

The HPV genome in malignancies is usually not episomal, but rather,
is integrated into the host genome in at least 80% of cervical
cancer cases. The viral E2 gene serves as the most significant
site of integration into the host genome. With integration, normal
regulatory function of E2 is interrupted. This event appears to
be critical for tumorigenesis. Loss of regulation results in overexpression
of viral E6 and E7 oncoproteins, which are known to inactivate
the cellular tumor-suppressor gene products, p53 and pRb, respectively
[21].

It is not known which stage of HPV genome integration correlates
with the change from dysplasia to malignancy. Integration of the
viral genome is not always required for tumorigenesis. In some
HPV-16 and other HPV-associated carcinomas, viral DNA exists in
an extrachromosomal state [22].

In vitro biologic assays have enabled investigators to study the
transforming activity of cloned human papillomavirus DNA on primary
and immortalized cells, and thereby evaluate the role of viral
genes in tumorigenesis. Assays of infected and transfected murine
and human cells have been important in determining whether continually
expressed E6 and E7 are necessary and sufficient for in vitro
transformation [23]. Some cell lines produced by these assays
are tumorigenic in nude mice alone; others require cooperation
with the expressed ras oncogene to become tumorigenic.
Tumorigenicity in these instances is dependent upon HPV type [24].

Host Immune Responses

Immunologic response to HPV infection is an important aspect of
host response. Persistence or spontaneous regression of lesions
is related to cell-mediated immunity. Patients with altered cellular
immunity (immunosuppression, immunodeficient states, pregnancy)
have a higher incidence of warts and condylomas [25]. Patients
with the congenitally acquired disease of impaired cellular immunity,
epidermodysplasia verruciformis, have skin warts and increased
rates of detection of HPV types 5 and 8. These warts have a high
likelihood of transforming into squamous or basal cell carcinomas
[26].

Finally, HPV-associated primary, metastatic, and recurrent cervical
cancers frequently exhibit a reduction in or total loss of allelic
expression of critical major histocompatibility complex class
I molecules, which are involved in antigen presentation at the
cell surface and in antigen recognition. Downregulation of these
molecules may enable cervical cancers to escape cell-mediated
immune surveillance [27].

Humoral immune responses to HPV infection have been incompletely
quantified. Sera from animals and humans with a history of infection
generally react positively to enzyme-linked immunosorbent assays
with denatured papillo- mavirus capsid proteins [28-30]. Antibodies
are detected in rabbits and mice inoculated with intact HPV virions
[28,31]. Humoral immunity appears to protect the host against
HPV infection and its transmission.

Recent advances in molecular biology have enabled investigators
to synthesize recombinant virus-like particles and capsid proteins
of papillomaviruses that react with conformational-dependent,
neutralizing antibodies [32-35]. This development will allow for
the investiga-
tion of the role of humoral immunity in the natural history of
papillomavirus infection.

Oncogenic Potential of HPV Types

In an epidemiologic study of 2,627 women, Lorincz et al examined
the prevalence of anogenital HPV infection among normal women
and women with premalignant and invasive lesions using southern
hybridization. The oncogenic potential of 15 anogenital HPV types
was defined. Low-risk HPV types (6, 11, 42, 43, and 44) were found
in 20% of low-grade squamous intraepithelial lesions, and were
absent in all cancers. Intermediate-risk HPV types (31, 33, 35,
51, 52, and 58) were detected in 23% of high-grade squamous intraepithelial
lesions and in 10% of cancers. High-risk HPV types (16, 18, 45,
and 56) were detected in 53% of high-grade squamous intraepithelial
lesions and in 74% of cancers. Adenocarcinomas of the cervix were
usually caused by HPV type 16 or 18.

Continuum of Disease Progression

Studies have documented a continuum of disease progression from
squamous intraepithelial lesions to invasive carcinomas. If left
untreated, 16% of cases of mild dysplasia will progress to carcinoma
within 84 to 96 months, two-thirds will regress, and 22% will
persist as mild dysplasia [36]. The majority of high-grade lesions
will persist or progress. Two-thirds of cervical intraepithelial
stage III lesions will progress to invasive cancer within a mean
of 10 years [37].

Finally, human papillomavirus DNA has been detected, via sensitive
polymerase chain reaction assays, in more than 95% of squamous
and adenocarcinomas of the cervix [38]. This finding, combined
with data showing odds ratios for highly oncogenic HPV types ranging
from 31 to 296 for the occurrence of cervical cancer, supports
the association of certain HPV infections with cervical neoplasia
[3]. Clearly, other factors are probably operative in the development
of cervical cancer (ie, tobacco, oncogenes), but HPV is necessary
although perhaps not sufficient. Eradication or protection against
HPV infection would decrease the number of cervical cancers, perhaps
by as much as 95%.

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