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198
Fig. 8.4 Anal condyloma
acuminata in the region of
the corrugator cutis
M.D. Inkster et al.
Although examination is focused on the anus, the presence of condyloma in the
oropharynx, skin, and genitalia is noted. Anal examination includes inspection and
palpation of the perianal skin, circumferential palpation of the anal canal and rectal
vault, and anoscopy. We routinely obtain specimens for anal HPV serotyping and
anal cytology at the fi rst visit. A typical example of perianal condyloma is shown
in Fig. 8.4 .
8.6.1 Human Papillomavirus Serotyping
Anal HPV serotyping is done using the digene HC2 High-Risk HPV DNA test,
Qiagen™. The HC2 High-Risk HPV DNA test is an in vitro nucleic acid hybridization assay for the qualitative detection of thirteen high-risk types of human papillomavirus (HPV) DNA. The HPV types detected by the assay are the high-risk HPV
types 16/18/31/33/35/39/45/51/52/56/58/59/68. The test does not determine the
specifi c HPV type present [
59 ].
8.6.2 Anal Cytology/Pap Smear
Anal cytology is interpreted according to the terminology proposed by the Bethesda
system [ 60 ]. In 1997, Palefsky et al. [ 61 ] examined a total of 2958 anal examina-
tions assessing anal cytology as a screening tool for anal SIL. The authors found
8 Anal Condyloma Acuminata and Anal Dysplasia
199
that the grade of disease on anal cytology did not always correspond to the histologic grade and concluded that anal cytology should be used in conjunction with
histopathologic confi rmation. A report by Scholefi eld et al. in 1998 [ 62 ] supported
the use of anal cytology for diagnosis and follow-up of at risk individuals. In 2003,
Friedlander et al. [ 63 ] blindly reviewed anorectal cytology specimens from 51
patients. Of these, 32 patients had anoscopic evaluation and 30 had histologic correlation. A 2005 report by Arain et al. [ 64 ] reported the cytomorphological features
of 200 consecutive anal smears collected in liquid medium. Findings were correlated with results of surgical biopsies and/or repeat smears. The authors found that
anal smears had a high sensitivity (98 %) for anal squamous intraepithelial lesions
but a low specifi city (50 %) for predicting the severity of the abnormality in a subsequent biopsy. A review of anorectal cytology by Bean and Chhieng in 2009 [ 65 ]
found that sensitivity and specifi city of a single anal–rectal cytology specimen are
comparable with that of a single cervical cytology test, but that cytological interpretations do not always correlate with lesion severity.
8.6.3 Treatment of External Condyloma Acuminata
According to the 2010 Sexually Transmitted Diseases Treatment Guidelines [ 66 ],
treatment is directed to the macroscopic (i.e., genital warts) or pathologic (i.e., precancerous) lesions caused by infection. As shown in Table 8.5 , choice of therapy is
based on lesion characteristics, patient preference, cost, convenience, adverse
effects, and clinician experience [ 67 ].
8.6.3.1 Podophyllotoxin
Podophyllotoxin , also known as podofi lox , is a natural product extracted from the
rhizomes of Podophyllum plants [ 68 ]. The medication is self-applied twice a day for
3 days followed by 4 days without treatment. This be repeated for up to four cycles.
Table 8.5 CDC Recommended regimens for external genital warts
Patient applied
Podofi lox 0.5 % solution or gel
Imiquimod 5 % cream
Sinecatechins 15 % ointment
Provider applied
Cryotherapy with liquid nitrogen or cryoprobe
Repeat applications every 1–2 weeks
Podophyllin resin 10–25 % in a compound tincture of benzoin
Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) 80–90 %
Surgical removal either by tangential scissor excision, tangential shave excision, curettage,
or electrosurgery
Centers for Disease Control and Prevention, Atlanta [
ment/2010/genital-warts.htm
71 ]. Genital warts. www.cdc.gov/std/treat-
200
M.D. Inkster et al.
8.6.3.2 Imiquimod
Imiquimod is an imidazoquinoline that possesses immunomodulating and antiviral
activity [ 69 ]. Typically, imiquimod is applied once daily at bedtime, three times a
week for up to 16 weeks [ 70 ]. The treatment area should be washed with soap and
water 6–10 h after application [ 71 ].
8.6.3.3 Sinecatechins
Topical sinecatechins , extracted from green tea, have been used to treat external
anogenital warts. In a randomized, double blind trial involving 502 patients,
patients applied sinecatechins ointment three times daily for a maximum of
16 weeks [ 72 ].
8.6.3.4 Cryotherapy
Cryotherapy destroys warts by freezing. The procedure is usually done in the offi ce
setting using liquid nitrogen. Repeat applications may be done every 1–2 weeks.
The technique has the advantage of being applicable to the treatment of warts in the
pregnant female [ 73 ].
8.6.3.5 Trichloroacetic Acid
Trichloroacetic acid (TCA) is a strong acid [ 74 ] that precipitates protein. Topical
application of TCA to genital warts can result in wart ablation [ 75 ].
8.6.3.6 Topical 5-FU
5- Fluorouracil is a pyrimidine analog that cases irreversible inhibition of thymidylate synthetase. It has been used topically to treat squamous cell carcinoma in situ
(Bowen’s disease) [ 76 – 78 ].
8.6.3.7 Side Effects
All treatment methods can cause pain, erythema, ulceration, and scarring. Sitz baths
and anti-infl ammatory analgesic medications are benefi cial during the postoperative
period. None of the above treatments are so effective that any one supercedes all
others.
8.6.4 Surgical Ablation
Lesion identifi cation and destruction has been achieved with a variety of methods.
As shown in Figs. 8.5a–c , large lesions that are visible with the naked eye are most
easily removed by excision.
Small lesions are detected either with magnifi cation or by blind biopsy. In 1936,
Hinselmann examined cervical tumors with magnifi cation using a technique he
named “Kolposcopie” [ 79 ]. In 1979, Strauss and Fazio [ 80 ] described the technique
of “anal mapping” to determine the extent of Bowen’s disease of the anal and perianal area. In 1989, Scholefi eld et al. [ 45 ] prospectively studied the use of an
8 Anal Condyloma Acuminata and Anal Dysplasia
201
Fig. 8.5 ( a ) Large perianal condyloma. ( b ) Perianal skin following condyloma excision. The
lesion is excised down to the dermis. Residual minute condyloma was ablated by electrocautery in
this case. ( c ) Perianal condyloma following excision. ( d ) Low power views show a papillary squa-
mous proliferation characterized by hyperplastic squamous epithelium with prominent fi brovascular cores ( arrow ) (H–E; original magnifi cation ×10); ( e ) At high power, the surface epithelium
shows areas of parakeratosis as well as a superfi cial layer of koilocytes ( arrow ; squamous cells
with nuclear enlargement, hyperchromasia, irregular nuclear contours, and occasional binucleated
forms) (H–E, original magnifi cation ×200). The overall morphology is diagnostic of a
condyloma
202
M.D. Inkster et al.
Fig. 8.6 High-resolution anoscopy: the anoderm is inspected with magnifi cation using an operating colposcope through an anoscope with white light and green light following anoderm preparation with acetic acid and Lugol’s iodine
“endoscope” (colposcope) to examine the anal canal for the detection of premalignant lesions. In 1997, Jay et al. [ 81 ] used a colposcope in conjunction with an ano-
scope to describe the appearance of anal squamous intraepithelial lesions and their
relationship to histopathology. Anal colposcopy/high-resolution anoscopy (HRA)
now is used widely for the detection of precancerous anal lesions (Fig.
8.6 ).
Figure 8.7 shows multiple raised lesions in the anal canal of a renal transplant
patient. In Fig. 8.8a , a serpiginous lesion is seen with green light after anoderm
treatment with dilute acetic acid and Lugol’s iodine in an HIV-positive male. Lesion
destruction by electrocautery is shown in Fig. 8.8b . Pathology showed HSIL (Fig.
8.8c, d ). Figure 8.9 shows an ulcerated squamous cell carcinoma. Alternate energy
sources used for lesion ablation include cryotherapy, infrared coagulation (IRC),
and laser [ 82 – 84 ].
8.6.5 Photodynamic Therapy
Photodynamic therapy (PDT) is a two-step process involving the topical or systemic
application of a photosensitizer followed by illumination of the treatment area with
a nonthermal laser or non-laser light of a specifi c wavelength. The interaction of
light with the drug results in the generation of singlet oxygen which leads to a local
8 Anal Condyloma Acuminata and Anal Dysplasia
Fig. 8.7 ( a ) HRA: Multiple raised lesions seen under green light after treatment with acetic acid
and iodine in a renal transplant recipient. Targeted biopsy of the 5 o’clock ( arrow ) lesion showed
HSIL. ( b ) Biopsies of the left posterior anus show fragments of anal squamous mucosa with sig-
nifi cant atypia involving the full thickness of the epithelium (H–E, original magnifi cation ×40). ( c )
At higher power, there is overall loss of nuclear polarity (i.e., nuclei oriented in different directions) and signifi cant nuclear atypia characterized by nuclear enlargement, hyperchromasia, and
pleomorphism (H–E, original magnifi cation ×200)
203
cytotoxic effect [ 85 , 86 ]. Aminolevulinic acid is metabolized to protoporphyrin IX
(PpIX) which tends to accumulate in malignant and premalignant cells [ 87 ]. The
application of photodynamic therapy to treat anal dysplasia has been reported by
Hamdan et al. [ 88 ].
8.6.6 Vaccines
A prerequisite for making vaccines is to know the structure of the molecule that is
involved with immunity, that is, which epitopes can provoke the production of antibodies. There have been binding sites determined for the neutralizing antibody sites
for HPV 6, 11, 16, 31, and 52. To date, the virus can be extracted from native tissue,
but the whole virus has not been grown in tissue culture. Frazer and Zhou [ 89 ]
developed an entity called VLPs-these are virus-like particles that are produced in
plasmids and are able to self-assemble into a structure that is similar to native virion.
The VLPs are composed of 72 pentamers of the L1 protein in association with 12 or
204
M.D. Inkster et al.
Fig. 8.8 ( a ) Raised anal lesion seen by HRA ( arrow ). ( b ) Lesion ablation with electrocautery. ( c )
The right lateral anal biopsies show fragments of anorectal mucosa ( black arrow denotes adjacent
colonic epithelium) with areas of parakeratosis along the superfi cial aspect of anal squamous
mucosa (H–E, original magnifi cation ×40); ( d ) HSIL. There is signifi cant atypia along the basal
aspects of the anal squamous mucosa, and several suprabasal mitotic fi gures are seen ( black
arrow ). There does appear to be partial squamous maturation towards the surface, and scattered
koilocytes are identifi ed ( blue arrow ) (H–E, original magnifi cation ×200)
more copies of the L2 protein. They can bind to conformation-dependent monoclonal antibodies. The VLPs also contain a minority population of unknown viral or
cellular proteins/factors such as molecular chaperones and karyopherins that may
infl uence the fi nal structure. Papilloma-based gene transfer vectors are called pseudovirions (PsV) and these are self-assembled within transfected cells allowing the
production of several billion units of virus per milliliter. Native virions are produced
only in stratifi ed and differentiated epithelia and are synthesized only during a natural infection or in a type of culture system called organotypic. The organotypic
culture process uses “rafts” which allow for completion of the HPV life cycle. PsVs,
8 Anal Condyloma Acuminata and Anal Dysplasia
205
Fig. 8.9 ( a ) Gross appearance of the squamous cell carcinoma. ( b ) Low power view shows a
polypoid squamous proliferation. At the arrow, there is an irregular, infi ltrative appearing nest of
squamous epithelium within the core of the biopsy (H–E, original magnifi cation ×20). ( c ) At
higher power, the infi ltrative appearing area shows nests of squamous epithelium with prominent
eosinophilia and an overall “glassy appearance,” characteristic of the “paradoxical maturation”
seen within areas of well-differentiated squamous cell carcinoma (H–E, original magnifi cation
×200)
therefore, bypass the need for differentiating host tissue for viral assembly. A major
problem in defi ning the structure of the virion was that insuffi cient virus was produced in organotypic culture; however, polymerase chain reaction and purifi cation
have made it possible to examine the viral life cycle.
VLPs are noninfectious and non-oncogenic, making them ideal candidates for
use in HPV vaccine production. Suzich in 1995 [ 90 ] reported success with a canine
model for L1 canine oral papillomavirus (COPV) grown in Sf9 insect cells in developing protection that was resistant to experimental challenge with COPV. The
canine model showed that VLPs not only produced protection but that the IgG fraction of serum transferred this immunity to another animal. A vaccine called Gardasil
developed by Merck was later approved by the Food and Drug Administration for
use in women ages 9 to 26-this was the fi rst vaccine designed to prevent cervical
cancer. Cervarix was later produced by GlaxoSmithKline. These are now considered part of the routine vaccinations that are administered to women in the age
group 9 to 26 and also to young men in the same age group.
206
M.D. Inkster et al.
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