Diagnostic Cytology
Fig. 8.47
Changes consistent with a
herpes simplex type 2 virus.
Multinucleated giant cell with nuclear enlargement and dense opaque
nuclear chromatin (Papanicolaou x OI).
It may be difficult to decide whether the epithelial abnormality
is a nonspecific response to the inflammatory stimulus or a true
preneoplastic intraepithelial lesion. The cytologic report should
clearly state the diagnostic dilemma, and recommendation for
a repeat examination after a follow-up interval should be part
of the report.
This minimal-to-mild atypia may eventually be followed
by the appearance of cellular changes consistent with mild
dysplasia. Smears showing signs of atypia related to inflamma-
tion should therefore be repeated after 1 year.21
either due to
caused by medication conveys a significant risk for infections
with herpes simplex virus type 2 and human papillomavirus
(HPV) and for developing neoplastic conditions (Fig. 8.47).34,35
Patients at risk are those receiving immunosuppressive drugs
because of transplants or for various other conditions, patients
with Hodgkin's disease, and patients with cancer following treat-
ment with cytostatics.27,36,37 The reported significantly increased
risk for cervical cancer with the number of pregnancies is an
interesting association in view of the fact that pregnancy is con-
sidered a transient state of immunodepression.30,38
Intrauterine Contraceptive Devices
The most severe reactive changes, those that most closely
mimic intraepithelial neoplasia, both of squamous and of
glandular type, are associated with the presence of an IUD.39,40
Composing cells may show severe cellular and nuclear poly-
morphism, an increased nucleocytoplasmic ratio, prominent
nucleoli, and cytoplasmic vacuolization. Severely atypical cells
arranged in clusters are often present. There is usually a marked
inflammatory reaction. The cells may be extremely difficult to
differentiate from those derived from an adenocarcinoma,
but the cytopathologist can avoid this erroneous diagnosis
because these IUD-related changes usually are found in rel-
atively young women who are using an IUD. This, however,
emphasizes the importance of correct and complete clinical
information accompanying the request for a cytologic exami-
nation. It may sometimes be necessary to remove the device
and to repeat the cytologic examination after an interval of
4 to 6 weeks. The epithelial abnormalities usually will have
disappeared by then.
Human Papillomavirus and Cervical Cancer
In the late 1970s epidemiological studies suggested that trans-
fer of a sexually transmitted factor could explain the occurrence
of cervical cancer in women.41,42 Already in 1973, zur Hausen
pointed out the possible etiological role of HPV in cervical car-
cinoma.43 Two decades earlier, Koss introduced the term "koilo-
cytotic atypia" for abnormal squamous epithelial cells in smears
from patients with CIN or cervical cancer.44 Koilocytotic cells
exhibit vacuolization of the cytoplasm with condensation of the
chromatin and slight atypia of the nuclei (Fig. 8.48). Not until
the introduction of high-resolution imaging by electron micro-
scopy could viral particles be demonstrated in koilocytotic cells
of CIN lesions.45 After the introduction of molecular techniques
as southern blot hybridization and polymerase chain reaction
(PCR), many epidemiological and clinicopathological studies
demonstrated that HPV is associated with the development of
CIN and cervical cancer.46-51
To date, more than 100 different genotypes of HPV have
been identified thus far. Two large groups of HPVs can be
distinguished based on the site of infection: cutaneous and
genital (mucosal/cervical). Most cutaneous HPV types (HPVs
1, 2, 3, 4, 10, 28, 29, and 38) cause benign lesions of the skin
such as verruca plantaris, verruca vulgaris, and verruca plana.
The group of genital HPVs is further subdivided based on the
behavior of the resulting cervical lesions. Low-risk cervical HPV
types (HPVs 6, 11, 40, and 42-44) are predominantly present
in condyloma acuminatum, ASCUS, and CIN1 lesions. Eight-
een out of more than 35 genotypes (HPVs 16, 18, 26, 31, 33,
35, 39, 45, 51-53, 56, 58, 59, 66, 68, 73, and 82) that infect
the mucosal types of epithelium are considered high-risk HPV
since they have been detected in the cervix of patients with cer-
vical carcinoma. Infections with HPV 16, 18, and 31 together
account for almost 80% of all squamous cell carcinomas of
the cervix.52
The effects of HPV on the infected cervical cell are described
in more detail in chapter 7. In short, in low-grade cervical lesions
the double-stranded circular HPV DNA genome of approximately
8000 base pairs is in an episomal state. With progression of the
cervical lesion, the HPV DNA becomes disrupted and integrates
in the host genome. In cervical carcinoma, HPV is always in an
integrated state. Not until integration of HPV in the genome of
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