Microbiology, inflammation, and Viral infections
Fig. 7.50 Human papillomavirus (HPV) infection.
This slide has been
processed for
in situ
hybridization using an S35-labeled HPV-16 probe. The
radiolabeled granules are distinctly seen on the surface of the infected nuclei.
Vaginopancervical smear (autoradiograph with hematoxylin x HP).
The worldwide understanding of the role of HPV as a neces-
sary, but not sufficient, cause of invasive cervical cancer, coupled
with the development of liquid cytology providing residual
cervical sample for testing and molecular techniques, has led
to multiple changes in cervical cancer screening and triage algo-
rithms over the past decade. The NCI-sponsored multicenter
randomized ASC-US LSIL Triage Study (ALTS) demonstrated the
clinical utility of "reflex" HPV high-risk (HPV HR) testing for the
cytologic diagnosis of atypical squamous cells of undetermined
significance (ASC-US). HPV HR testing for ASC-US was found
to have greater sensitivity (96%) to detect CIN III or worse
lesions and similar specificity as compared to a repeat cytol-
ogy specimen.104 The strong scientific evidence led to changes in
the Bethesda System (TBS) classification and terminology and
the American Society for Colposcopy and Cervical Pathology
(ASCCP) and the American Cancer Society (ACS) management
guidelines for abnormal cervical cytology.103-105 ASC-US high-
risk (HR) HPV positive cases are recommended to be referred
to colposcopy and biopsy, while negative HR HPV ASC-US cases
can return to annual screening.107 It is estimated that 80% of
ASC-US cases are now triaged using HPV HR testing.105
HPV HR testing can also be used as an adjunct to cervical
cancer screening with cytology in women aged 30 and older. The
FDA approved this use in 2003 for assessment of overall cervical
cancer risk due to the 99.2% negative predictive value for devel-
oping CIN III or invasive cervical cancer in the next three years
if both tests are negative. The ACS and the American College
of Obstetrics and Gynecology (ACOG) have defined this dual
screening method as an option. Women who have a negative
Pap cytology and negative HPV HR test are at a very low risk for
developing cervical cancer in the next 3-5 years (0.8%) and can
increase their screening interval safely to 3 years.77,84 The com-
bined cytology and HPV testing is not appropriate for women
under age 30, since they frequently test positive for HPV, which in
this age group is most frequently a transient and/or clinically
insignificant infection.
The more recent development of the HPV vaccine and its
implementation will most likely impact upon cervical cancer
screening cytology volume and protocols in the future. Impor-
tantly, despite the development of molecular techniques to detect
Fig. 7.51 Typical koilocytic cells.
Vaginopancervical smear
(Papanicolaou x MP).
HPV and changes to cervical cancer screening algorithms, the
molecular tests do not substitute or replace cytologic morphol-
ogy and diagnosis. Cytomorphology corroborates molecular
changes as illustrated by the high incidence of HR HPV in low-
grade squamous intraepithelial lesion (LSIL) and worse lesions,
making HPV HR testing in these diagnoses unnecessary.107,1073 In
addition, HPV HR infection is very common, but only a minor-
ity of women will develop precancerous changes detectable by
cytology, and even a smaller number will develop invasive carci-
noma. It is estimated that the lifetime risk of becoming infected
with one or more of the sexually transmitted HPV types is 50-
79% of all women who have had sexual intercourse as com-
pared to the 1.3% lifetime risk of developing invasive cancer.71
Currently, cytomorphologic examination for diagnosis remains
as important as ever.
Cytomorphologic identification of cellular
changes is currently the most convenient, rapid, and economi-
cal, procedure for detection of HPV infection in the genital
tract. As discussed previously, HPV infection generally mani-
fests as verrucous or flat-surface epithelial lesions. Both lesions
have the same basic pathognomonic features; additionally, the
papilliferous lesions reveal surface hyper- and parakeratosis and
HPV, being a DNA virus, affects both the nucleus and the cyto-
plasm of the infected cells. It is generally believed that the virus
gains entrance into the susceptible cell through the plasma mem-
brane. The cytoplasmic changes of the infected cells—dyskerato-
sis—are a prominent feature of HPV infection. HPV DNA may
occur within the epithelial cell nucleus as either unintegrated/
episomal or integrated forms. Consequently, nuclear changes
are commonly seen with HPV infection. These, however, tend
to be more pronounced in cases of HPV DNA integration with
the epithelial cell nuclear DNA. Such lesions typically appear as
dysplastic and atypical. Chromosome and ploidy alteration, a
hallmark of CIN or dysplastic change, may occur in these cases.
The classic manifestation of HPV infection is the presence of
the koilocyte, so named by Koss and Durfee,87 *
also been called
nearo-carcinoma by Ayre89 and balloon cells by Meisels and
Typical koilocytes are squamous epithelial cells (Fig. 7.51).
Most commonly intermediate cells and sometimes metaplastic-
type koilocytic cells may occur. The latter may be indistinguish-
able from parabasal cells.
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