Section 5 -

Anal Neoplasia Claus Fenger Department of Pathology Odense University Hospital , Denmark

History 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 [1]. 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 [1, 2]. 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 [3, 4, 5] Natural History 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. [1, 6, 7]. Clinical Appearance 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 [4]. High resolution anoscopy is recommended but cannot distinguish reliably between AIN I-II and AIN III [8]. Cytology 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 [8, 9]. Histology AIN is graded in the same way as CIN and VIN. Also here the reproducibility is rather poor [8]. 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. Differential Diagnosis 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 [10]. 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 depth. 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 [11]. 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 [12]. Treatment is mainly non-surgical, and the extent of radiotherapy can be guided by the sentinel lymph node procedure [13]. Selected References Fenger C. The anal transitional zone. Thesis. Acta Pathol microbiol immunol Scand sect A. 1987:95. Suppl. 289: 1-42. Fenger C, Frisch M, Marti MC, Parc R. Tumours of the anal canal. In: Hamilton SR, Aaltonen LA, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press, 2000; 146-55. Frisch M, Fenger C, van den Brule AJC, Sorensen P, Meijer CJLM, Walboomers JMM, Adami HO, Melbye M, Glimelius B. Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses. Cancer Research 1999;59:753-57. Kreuter A, Brockmeyer NH, Hochdorfer B et al. Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol 2005;52:603-8. Zbar AP, Fenger C, Efron J, Wexner SD, Beer-Gabel M. The pathology and molecular biology of anal intraepithelial neoplasia: comparisons with cervical and vulvar intraepithelial carcinoma. Int J Colorectal Dis 2002:17:203-15. Scholefield JH, Castle MT, Watson NFS. Malignant transformation of high-grade anal intraepithelial neoplasia. Br J Surg 2005;92:1133-1136. Chang GJ, Berry JM, Jay N, Palefsky JM, Welton ML. Surgical treatment of high-grade anal squamous intraepithelial lesions. A prospective study. Dis Colon Rectum 2002;45:453-458. Mathews WC, Sitapati A, Caperna JC et al. Measurement characteristics of anal cytology, histopathology, and high-resolution anoscopic visual impression in an anal dysplasia screening program. J Acquir Immune Defic Syndr 2004;37:1610-1615. Arain A, Walts AE, Thomas P, Bose S. The anal Pap smear: cytomorphology of squamous intraepithelial lesions. CytoJournal 2005;2:4. Fox PA. Human papillomavirus and anal intraepithelial neoplasia. Review. Curr Opin Infect Dis 2006;19:62-66. Fenger C, Frisch M, Jass JJ, Williams GT, Hilden J. Anal cancer subtype reproducibility study. Virchows Arch 2000;436:229-233. Fenger C. Prognostic factors in anal carcinoma. Pathology 2002:34:573-8. Damin DC, Rosito MA, Schwartzmann G. Sentinel lymph node in carcinoma of the anal canal: A review. EJSO 2006;32:247-252.