7
Microbiology, inflammation, and Viral infections
Fig. 7.48 Herpes zoster.
(A) Note the basophilic intranuclear inclusion. (B) Higher power showing the texture and details of the inclusions. Vaginopancervical
smear (Papanicolaou (A) x MP, (B) x OI).
A smear from the base of the lesion often reveals numer-
ous multinucleated giant cells with little intercellular mold-
ing. Numerous infected single cells may occur. Intranuclear
inclusions may be basophilic, large, and inseparable from the
markedly thickened inner nuclear membrane. Infected paraba-
sal-type cells may show some cytoplasmic degenerative changes.
Intracytoplasmic vacuolation and hyalinization may be present
(Fig. 7.48).
Human Papillomavirus (HPV)
HPVs belong to the family
Papovaviridae,
which includes dou-
ble-stranded DNA members, papillomaviruses, and polyoma-
viruses. The papillomavirus genome is approximately 8000 base
pairs in length. It has three functioning areas, including genes
for early viral function, the late region containing genes for viral
structural proteins, and a noncoding regulatory region. The viral
capsid has two proteins and polypeptides. Papillomavirus has
been isolated from more than 60 animal species, including
mammals, reptiles, and amphibians. The vast majorities of these
viruses infect epithelial surfaces of either the skin or mucosa
and cause self-limiting warty growth. The papillomaviruses are
species-specific and generally do not cross-infect.
In humans, using molecular hybridization restriction enzyme
analyses and polymerase chain reaction (PCR), greater than 100
distinct HPV types have been identified. These different HPV
types tend to be site-specific. Approximately 40 different HPV
types affect the anogenital tract. HPV types are generally sepa-
rated into two major groups, low and high risk, depending on
their risk for the development of cervical cancer. Low-risk types
of HPV (most commonly types 6 and 11) have essentially no risk
association for invasive cervical carcinoma, but tend to cause
condyloma acuminatum, flat condyloma, and some low-grade
squamous dysplasia (cervical intraepithelial neoplasia [CIN]
I).71 The high-risk or "oncogenic" HPV types (16, 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82) are often found in
high-grade cervical dysplasia (CIN II and III), cervical carcinoma
in situ, and invasive squamous cell carcinoma and adenocar-
cinoma and its precursors. High-risk HPV types are also com-
monly seen in CIN I lesions72'1 72b (Table 7.7).
HPV replicates in the nuclei of squamous epithelial cells. In
the superficial squamous epithelium, the virus reaches full matu-
rity as a permissive infection and undergoes koilocytic changes
Table 7.7
Common human papillomavirus lesions (over 100 types)
HPV type
Lesion
1,2, 3, 4, 10, 28
Common warts
6, 11,31,42
Anogenital condyloma, low-risk
(CIN grade I) lesions
16, 18, 31,33, 35, 39, 45, 51,52, 56,
58, 59, 66, 68, 73, 82
High-risk (CIN grade II and III)
lesions—anogenital, laryngeal,
esophageal, lung cancer
(possibly)
26, 27
Warts, immune deficiency, renal
transplant
with HPV virions filling the nucleus and upon cell death, capa-
ble of reinfecting other cells. In the basal layers of squamous
and glandular epithelium, the virus is latent and its DNA can
only be detected by molecular techniques.73 In many low-grade
precancerous lesions, HPV DNA is usually retained intact in an
episomal form. In contrast, in invasive cancers and some high-
grade precancers, viral DNA is integrated into the host DNA,
and retains only genes associated with oncogenesis.73
Papillomavirus and Cancer
The virus is believed to enter the
body through small, inconspicuous cuts or abrasions on the skin
or mucous membrane. It stimulates the growth of the prickle
cell layer. The growth is by clonal expansion and, as suggested
by Broker and Butcher,74 it pushes aside the normal epithelium
to form benign warts. In these low-grade processes virus replica-
tion occurs episomally in the nucleus.
In addition to the numerous benign, self-limiting warty
growths, papillomaviruses are associated with a number of
neoplasms occurring in animals, such as rabbits and cattle. The
most convincing evidence for the association of HPV with cer-
vical cancer comes from the studies by Bosch et al.75 and Wal-
boomers et al.,76 who elegantly demonstrated the presence of
HPV DNA in 99.7% of cervical cancers (932 cervical cancer cases
from 32 hospitals in 22 countries). HPV DNA and RNA has also
been demonstrated in at least 80% of all cervical, vulvar, and
penile squamous cell carcinomas, in a similar proportion of pre-
malignant CIN lesions, and in 95% of genital condylomas.77,78
HPV types 6 and 11 predominate in benign warty lesions,
whereas types 16 and 18 occur in 60-70% of all cervical tumors
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