Management of Early Cancer of the Gastrointestinal Tract
Moderators: Robert H. Riddell and Elizabeth Montgomery
Section 5 -
Department of Pathology
Odense University Hospital , Denmark
The normal mucosal lining of the anal canal was described in the second half of the 19th
century and precancerous changes by Gordon in 1966. The relation to vulvar dysplasia was pointed out by
Strauss and Fazio in 1979 and HPV as an etiological factor by Croxson et al in 1984. The first
systematic studies on the occurrence in minor surgical specimens, in cases of anal carcinomas and on the
relation to genital neoplasia and infection were performed in 1981-1986 .
Definitions and Nomenclature
According to WHO the anal canal extends from the upper border of the anorectal ring to the anus. The
epithelial lining is colorectal and ATZ-epithelium above the dentate line (DL), and non-keratinized
squamous epithelium below. At the anus is the transition to keratinized epithelium with skin appendages.
Precancerous changes can occur in all epithelial types. Those in the ATZ- and the squamous epithelium
are referred to as anal intraepithelial neoplasia (AIN) and graded I-III. Other terms are anal squamous
intraepithelial lesion (ASIL) or anal squamous dysplasia. Perianal lesions are sometimes named Bowen's
disease, but most authors do not distinguish between anal canal and perianal lesions as these are often
seen in combination
Epidemiology and Etiology
The prevalence of AIN in the general population is unknown but probably low. The incidence of AIN and
squamous cell carcinoma (SCC) is high among men who have sex with men (MSM), in particular HIV-positive
and those who have a history of receptive anal intercourse, but also among women with CIN and VIN,
patients with a history of condylomas and among transplant recipients. High-risk human papillomavirus
(Hr-HPV} is found in most cases of AIN and SCC
The concept that AIN is the precursor for SCC is based on the observations that AIN is present in the
proximity of most SCC, and that AIN III is characterized by angiogenesis, increased proliferation,
decreased apoptosis and occasionally show mutation of p53 and foci of microinvasion. While AIN I-II may
regress, a considerable portion of AIN III will recur or progress to SCC. The exact risk is unknown but
apparently higher among immunoincompetent patients.
AIN may be located just above as well as below the DL and present as one or more leukoplakic,
erythroplakic, bowenoid or verrucous lesions of which the latter seems to carry the highest risk .
High resolution anoscopy is recommended but cannot distinguish reliably between AIN I-II and AIN III .
Anal cytology is easy to perform and covers a large area. The liquid based technique is advised by
some. Grading is performed according to the Bethesda Guidelines but has a considerable interobserver
variation and a poor specificity. The finding of atypical squamous cells of undetermined significance
(ASCUS} should therefore always lead to biopsy
AIN is graded in the same way as CIN and VIN. Also here the reproducibility is rather poor .
Immunohistochemical investigation for Ki67 (MIB-1), p53 and p16 as well as HPV-typing may be useful. As
AIN may be an unsuspected finding, it is recommended that all specimens from the anus are examined,
preferably by longitudinal sections in order to determine the mucosal area involved. Biopsies from
suspected areas should be cut at several levels.
These include normal variants of ATZ-epithelium, viral changes, reactive changes due to e.g.
prolapse, Paget disease, clear cells and atypical melanocytic hyperplasia.
Treatment and Follow-up
Cases of AIN I-II can probably best be treated conservative and expectantly with anoscopy and cytology
as many regress. Follow-up should include examination of the whole anogenital area. Treatment of AIN
III can be surgical or non-surgical . Of importance for the histological evaluation is that the
assessment of resection line can be difficult in cases treated with i.e. laser vaporization, and that AIN
can persist in skin appendages so that tissue ablation or destruction should involve more than 2 mm in
Squamous Cell Carcinoma
Anal SCC comprises several histological variants and these are often present in the same tumor. A
corresponding variation in the appearance of AIN has not been documented. Subtyping of anal SCC has now
been abandoned because the only material often is a small and not representative biopsy, because it has
no therapeutical or prognostic significance and because the reproducibility is poor. A biological
difference may however exist, as SCC with basaloid features more often are HPV-positive . Various
attempts to find markers that give reliable advice with regard to treatment and prognosis of individual
cases of AIN and SCC have so far failed . Treatment is mainly non-surgical, and the extent of
radiotherapy can be guided by the sentinel lymph node procedure .
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