Vulva, Vagina, and Anus
Fig. 11.20 Histopathology of anal intraepithelial neoplasia. (A) Histology of AIN-1 with koilocytotic cells present at the surface of the anal epithelium;
(B) AIN-3. Dysplastic parabasal cells showing enlarged nuclei and hyperchromasia (H&E xLP).
among men with HIV infection.85 Anal SCC affects both men
and women, but it is the only cancer with a greater prevalence
among men who have sex with men (MSM) than in the gen-
eral population. About 35 in every 100,000 MSM develop anal
cancer, compared to less than 1 in every 100,000 heterosexual
men. The risk for anal cancer in HIV-positive men is twice as high
as that for HIV-negative MSM. The American Cancer Society esti-
mates that in 2007 there will be 4,650 new cases of anal cancer in
the United States, and about 690 people will die of the disease.
Anal cancer is found mainly in adults older than age 35. The
exact pathogenesis of anal SCC remains unknown, although it
probably arises and behaves in the same way as cervicovaginal
lesions do in women. Anal SCC has comparable histologic fea-
tures with cervical SCC which also has a strong association with
HPV.86-91 The increased incidence of HPV-associated neoplasia
in immune-compromised individuals suggests a role of the host
immune system in the elimination of the virus, which is not yet
understood in full detail. A large and growing number of patients
are living longer with HIV infection as a result of the administra-
tion of highly active antiretroviral therapy, and these men and
women are at high risk for HPV-mediated anal cancer. The past
two decades have witnessed a doubling in anal cancer incidence
among those living with HIV infection. The incidence of anal SCC
and its precursor anal intraepithelial neoplasia (AIN) in women
is not known. It has been suggested that AIN is more often seen
in those women with cervicovaginal and vulva squamous dyspla-
sia.92 A recent study found that approximately 30% of women
with cervicovaginal and vulvar dysplasia also had AIN.93
AIN arises at the ATZ that lies between colorectal columnar
epithelium and squamous epithelium. Apparently, the ATZ site
is susceptible to transformation by HPVs in a manner similar to
the transformation zone of the cervix uteri. Based on morpho-
logic features, AIN can be divided into two subtypes: basoloid
and warty types. Histopathologically, AIN resembles the classic
or bowenoid type of VIN (Figs. 11.20A, 11.20B).
Anorectal Cytology and Salient Features
Cytology has been proposed as a potential screening tool in
the evaluation of anorectal specimens for anorectal squamous
neoplasias because of the morphologic similarities of anal and
cervical SCC and intraepithelial neoplasia,94 and because of its
Recently, the 2001 Bethesda system for cervical cytology
included an appendix for anal cytology.101 The terminology used
to describe the epithelial changes observed with HPV-associated
anal disease are very similar to those used for cervical cytology.
Anal cytologies are read as either normal or abnormal. In the
abnormal group there are three possible subgroups: atypical
squamous cells of undetermined significance (ASC-US), low-
grade squamous intraepithelial lesions (LSIL), and high-grade
squamous intraepithelial lesions (HSIL). LSIL and ASC-US fre-
quently regress, while HSIL regresses less and is considered a
pre-cancerous lesion. In one study of MSMs, 62% of LSIL lesions
in HIV-positive men progressed to HSIL compared to 36% in
HIV negative men.102
lesions usually had eosinophilic or orangeophilic
cytoplasm with enlarged round to ovoid nuclei, greater than two
times the size of an intermediate nucleus. The nuclei were hyper-
chromatic and had evenly distributed granular chromatin and
irregular nuclear membranes (Fig. 11.21). Typical koilocytes were
much less frequently observed in anal LSIL smears than in cervi-
cal smears.103,104
lesions contain cells reminiscent of
metaplastic squamous cells with basophilic and/or eosinophilic
cytoplasm. The nuclei are hyperchromatic with unevenly dis-
tributed, coarsely granular chromatin and irregular nuclear
contours. The nuclear-to-cytoplasmic (N/C) ratios are high, and
nucleoli are usually not appreciated (Fig. 11.22). In HSIL, high-
grade squamous cells are usually small, found as single cells or
small clusters admixed with mildly dysplastic cells and atypical
parakeratotic cells.
Anal SCC
contained sheets and single pleo-
morphic tumor cells with variable amounts of basophilic and/
or eosinophilic cytoplasm. Hyperchromatic nuclei were round,
oval, and varied in shape, and they contained coarsely granular,
unevenly distributed chromatin and irregular nuclear contours.
Nucleoli also were present in some cells. Tumor diathesis can be
seen in some of the cases.104
The presence of
atypical keratinized squamous cells
is a com-
mon finding and is unique to anorectal cytology.104-106 Atypical
keratinized cells are usually associated with a high suspicion
for an abnormal keratinized lesion or SCC in cervicovaginal
specimens. However, in anal specimens, such cells should be
interpreted with care. The appearance of these keratinized cells
can vary from benign to markedly atypical and a false-positive
diagnosis of SCC can easily be made. In a study with correlation of
anorectal cytology to histologic diagnoses, atypical parakeratotic
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