Fig. 7.09 Squamous cell carcinoma of anus. A Combination of basaloid features and keratinization. B Large cells, poorly differentiated.

conservative treatment. In contrast to an ordinary condyloma, it is characterized by a combination of exophytic and endophytic growth. Histologically, it shows acanthosis and papillomatosis with orderly arrangement of the epithelial layers and an intact but often irregular base with blunt downward projections and keratin-filled cysts. The endophytic growth is accompanied by destruction of the underlying tissues. Cytologically, the epithelial cells appear benign. Large nuclei with prominent nucleoli may be present, but dysplasia is usually minimal and mitoses are restricted to the basal layers {162}.

Some verrucous carcinomas contain HPV, the most common types being 6 and 11. They are regarded as an intermediate state between the ordinary condyloma and SCC, and the clinical course is typically that of local destructive invasion without metastases. Among

33 published anorectal cases, 42 per cent have shown malignant transformation {133}. The presence of severe cyto-logical changes, unequivocal invasion or metastases should lead to the diagnosis of SCC and to the appropriate therapy.


Poor prognosis has been related to poor differentiation {165}, especially if this was defined only by the degree of dissociation of tumour cells {599}. However, such differences may be related to tumour stage in multivariate analysis {1734}. Grading on biopsies is not recommended, as these may not be representative for the tumour as a whole.

Precursor lesions and benign tumours

Chronic HPV infection

Warts in the perianal skin and lower anal canal (condyloma acuminatum) show the same histology as their genital counter parts. Flat koilocytic lesions also occur. They should always be totally embedded and examined histologically for possible presence of intraepithelial neoplasia.

Intraepithelial neoplasia

Precancerous anal intraepithelial neoplasia (AIN) in the anal transition zone (ATZ) and the squamous zone, has also been termed dysplasia, carcinoma in-situ and anal squamous intraepithelial lesion (ASIL) {494, 1449}. The corresponding lesions in the perianal skin are commonly referred to as Bowen disease. This terminology is complicated by the fact that the precancerous changes are not always restricted to one area. Leukoplakia is a clinical term and should not be used as a histological diagnosis. Anal intraepithelial neoplasia (squamous cell dysplasia in the anal canal). Most cases of AIN are incidental findings in minor surgical specimens for benign conditions. When macroscopically detected, AIN may present as an eczematoid or papillomatous area, or as papules or plaques. The latter may be irregular raised, scaly, white, pigmented or erythe-matous and occasionally fissured. Induration or ulceration may indicate invasion. Histologically, AIN is characterized by varying degrees of loss of stratification and nuclear polarity, nuclear pleomor-phism and hyperchromatism, and increased mitotic activity with presence of mitoses high in the epithelium. The surface may or may not be keratinized, and koilocytic changes may be present. AIN has been graded into I, II or III, or into mild, moderate and severe dysplasia {494}. Reproducibility studies have shown considerable observer variation {254}. A two grade system (low- and high-grade) may be more appropriate. Squamous dysplasia at the anal margin -Bowen disease. Clinically, this presents as a white or red area in the perianal skin that may be in continuity with dysplastic lesions in the anal canal. HPV DNA is sometimes identified, including types 16 and 18, among others. Histologically it shows full thickness dysplasia of the squamous and sometimes the piloseba-ceous epithelium, with disorderly maturation, mitoses at all levels and dyskeratosis. Occasionally, atypical keratinocytes may resemble Paget cells, but are negative for low molecular weight CKs and for mucin. In pigmented Bowen disease the neoplastic cells are invariably negative y ^ .- jfl wwTiC - ■

Fig. 7.10 Mucinous carcinoma of anus. Tumour extends to anal sphincter.

Fig. 7.11 Giant condyloma.

for S-100 protein and HMB-45. Bowen disease has a strong tendency to recurrence after local treatment but only a few percent will progress to SCC. It is often associated with genital neoplasia but not with internal malignancies {1161, 1668}.

Bowenoid papulosis. This condition presents as multiple 2-10 mm reddish brown papules or plaques, most commonly in sexually active young adults. Aetiologically it is related to HPV infection, usually HPV 16. Bowenoid papulo-sis is similar histologically to Bowen disease, and the distinction is made on a combination of clinical and pathological observations. Bowenoid papulosis tends to resolve spontaneously, but can recur {635}. It does not progress to carcinoma.

Genetic susceptibility

Human leukocyte antigens (HLAs) are involved in the presentation of viral antigens to the immune system. Since the aetiology of most anal SCCs involves HPV infection {536}, susceptibility to cancer development might be HLA type dependent. However, no study has addressed the association between specific HLA class I or II alleles and the risk, and attempts to identify other genetic susceptibility markers for anal SCC have so far been unsuccessful {286, 287}.


HPV DNA is detectable in most anal SCCs; in a large population-based series of anal SCCs in Denmark and Sweden, 84% contained HPV DNA, with higher proportions of HPV-DNA positive cancers among women and homosexual men than among non-homosexual men {536}.

Loss of functional tumour suppressor protein p53 appears to be centrally involved in the development of anal and anogenital SCCs {355, 356, 704, 1040}. Inactivation of p53 may occur at the gene level through point mutations leading to the production of inactive p53 or, less frequently, by means of deletions in the relevant area of chromosome 17p {704}. More typically, p53 inactivation occurs at the protein level through formation of a complex between the viral protein E6 (expressed by 'high-risk' HPV types) and a cellular protein, the E6-associated protein, which when bound to p53 leads to rapid proteolytic degradation of p53 {2092}. The level of p53 expression does not correlate with HPV status {704}. The E7 protein of 'high risk' HPV types binds to the retinoblastoma protein, pRb {440}, disrupting signals that normally restrict proliferation to the basal epithelial layer. The resulting increased proliferation increases the risk of malignant transformation on exposure to DNA damaging stimuli. The combination of increased cell proliferation (pRb inactivation) and impaired ability to induce cell cycle arrest or apoptosis following DNA damage (p53 inactivation) are two central mechanisms through which 'high risk' types of HPV increase the risk of anogenital cancer. Additional gene alterations appear to be involved in malignant progression and invasion. In one study, the c-myc gene

Fig. 7.12 High-grade intraepithelial neoplasia adjacent to normal rectal epithelium.

ICD-O code

Fig. 7.13 In situ hybridisation (black stain) for HPV 6/11 in an anal condyloma.

Fig. 7.14 Carcinoma of anal canal. Small neoplastic glands simulate anal glands.

was found to be amplified in 30% of anal SCCs {355}, while other cellular oncogenes, including ras and cyclin D, do not seem to be centrally involved {708, 1737}. Several chromosomal aberrations have been observed in anal SCCs {704, 1294}. Using comparative genomic hybridization, one study identified consistent gains in chromosomes 3q, 17, and 19 as well as losses in chromosomes 4p, 11q, 13q, and 18q {704}.

Prognosis and predictive factors

The most important prognostic factors in recent larger series of anal canal SCC are tumour stage and nodal status {530, 1483, 1734}. SCC of the anal margin has a slightly better prognosis, which depends only on inguinal node involvement {1484}. DNA ploidy status has only been shown to be of independent prognostic significance in one of three larger series {599, 1702, 1734}. Expression of p53, cathepsin D, c-erb B2 and retino-blastoma gene protein are not predictive factors {169, 731, 784, 1901}.

Adenocarcinoma Definition

Anal canal adenocarcinoma is an adeno-carcinoma arising in the anal canal epithelium, including the mucosal surface, the anal glands and the lining of fis-tulous tracts.

ICD-O code


Fig. 7.13 In situ hybridisation (black stain) for HPV 6/11 in an anal condyloma.

Clinical features

The clinical features of anal adenocarci-noma of colorectal type do not differ from those of anal SCC. Perianal adenocarci-nomas may present as submucosal tumours, sometimes in combination with fistulas. Occasionally, there may be

Fig. 7.17 A, B Inflammatory cloacogenic polyp. Dilated elongated hyperplastic glands showing regenerative atypia. Surface erosion is a constant feature.

Fig. 7.15 Low-grade squamous intraepithelial neo-plasia with koilocytosis.

Fig. 7.16 High-grade squamous intraepithelial neo-plasia with hyperkeratosis.

Fig. 7.17 A, B Inflammatory cloacogenic polyp. Dilated elongated hyperplastic glands showing regenerative atypia. Surface erosion is a constant feature.

associated Paget disease of the anus (see below). Tumour spread and staging largely correspond to anal SCC.


Adenocarcinoma arising in anal mucosa

Most adenocarcinomas found in the anal canal represent downward spread from an adenocarcinoma in the rectum or arise in colorectal type mucosa above the dentate line. Macroscopically and histologically, they are indistinguishable

Fig. 7.18 Adenocarcinoma arising in a fistula.

from ordinary colorectal type adenocar-cinoma, and do not seem to represent a special entity except for their low location. Adenocarcinoma in the anal transitional zone (ATZ) may develop after restorative proctocolectomy for ulcera-tive colitis {1711}.

Extramucosal (perianal) adenocarcinoma

Approximately two hundred cases of extramucosal adenocarcinoma have been reported, the largest series unfortunately with insufficient histological data {9}. A minimum criterion for the diagnosis is an overlying non-neoplastic mucosa, which may be ulcerated. Recent reports indicate that about two thirds of these tumours manifest in men with a mean age about 60 years. Reliable data for the prognosis for such patients have not been identified. Difficulties in establishing the correct diagnosis may delay proper treatment.

Extramucosal adenocarcinoma seem to fall into two groups, based on their association with either fistulae or remnants of anal glands. At present, no laboratory methods can distinguish between these two.

The epithelium of persistent anal fistulae is most often of the same type as found in the anal glands and ATZ {1117}, and the epithelium in these two locations show the same profile with regard to mucin composition {491} and keratin expression {2113}.

Adenocarcinoma within anorectal fistula.

These tumours develop in pre-existing anal sinuses or in fistulae {74}. Some are associated with Crohn disease {992}. Others may contain epithelioid granulomas, often related to foci of inflammation or extravasated mucin but without other signs of inflammatory bowel disease {863}.

Rarely, the tumours may be related to fis-tulae lined by normal rectal mucosa including muscularis mucosae, most likely representing adenocarcinomas arising in congenital duplications {863}. Histologically, carcinomas arising in fistulae usually are of the mucinous type, but tubular adenocarcinomas and squamous neoplasia can also be found {992, 2173}. Adenocarcinoma of anal glands. Only a few cases have been reported in which convincing evidence for origin in an anal gland has been demonstrated by continuity between anal gland epithelium and tumour {118, 650, 1472, 2087, 2131}. With a single exception {650}, these patients have had no history of previous or concomitant fistula. The tumours were all characterized by a combination of ductular and mucinous areas. Pagetoid spread was present in at least one case {2131}.


Anal adenocarcinomas are graded as colorectal adenocarcinomas.

Precursor lesions

Anal adenocarcinomas are thought to arise from glandular intraepithelial neoplasia, which can be graded as in the colorectum.

Prognosis and predictive factors

The prognosis for anal adenocarcinoma seems to be related only to the stage at diagnosis and is poorer than that for SCC {118, 930, 1305}.

Basal cell carcinoma of the anal margin

Basal cell carcinoma, the most common skin cancer, is primarily found on sun-exposed areas, and only a few more than a hundred cases have been reported in the anal area. {1353}. The aetiology is unknown and there is no evidence of HPV infection {1332}. The tumour commonly presents as an indurated area with raised edges and central ulceration, located in the perianal skin but occasionally involving the squamous zone below the dentate line. Histologically, it can show the same variability in morphology as basal cell carcinoma elsewhere, most reported cases having had a solid or adenoid pattern.

Basal cell carcinoma is sufficiently treated by local excision and metastases are extremely rare. It is therefore important to distinguish it from squamous carcinoma, and this may be particularly difficult on small biopsies. Both tumours can be found in the squamous zone, and both can show a combination of basaloid, squamous and adenoid features and an inflammatory infiltrate in the stroma {50}. Numerous and even atypical mitoses may be present in basal cell carcinomas {1538}. However, basaloid areas in squa-

Fig. 7.19 Paget disease of the anal canal.

mous carcinoma usually show less conspicuous peripheral palisading, more cellular pleomorphism, and often large, eosinophilic necrotic areas. Immunohisto-chemistry may be helpful in establishing the diagnosis. Basal cell carcinoma is positive for Ber-EP4 and negative for CKs 13, 19 and 22, and for CEA, EMA, AE 1 and UEA 1, while basaloid variants of squamous cell carcinoma usually show the opposite pattern {50, 1061}.

Paget Disease

Extramammary Paget disease usually affects sites with a high density of apoc-rine glands, such as the anogenital region, where it presents as a slowly spreading, erythematous eczematoid plaque that may extend up to the dentate line {1667}. Histologically, the basal part or whole thickness of the squamous epithelium is infiltrated by large cells with abundant pale cytoplasm and large nuclei. Occasional cells have the appearance of signet-rings. Paget cells invariably react positively for mucin stains and nearly always for CK 7, but Merkel cells and Toker cells may also be positive for the latter {120, 1112}. Paget disease of the anus appears to represent two entities. About half of the cases are associated with a synchronous or metachronous malignancy, most often a colorectal adenocarcinoma. Such cases can be regarded as a pagetoid extension of the tumour. They usually react positively for CK 20 and negatively for gross cystic disease fluid protein-15, a marker for apocrine cells. This is in contrast to the other half, which are not associated with internal malignancies but have a high local recurrence rate and may become invasive {1162}. Only this latter entity can be regarded as a true epidermotrophic apocrine neoplasm {85, 120, 595, 1374}.

Other lesions

Squamous cell papilloma of the anal canal

Rarely, papillomatous processes covered by normal, more or less keratinized squamous epithelium can be found in the anus. Such lesions should be tested for the presence of HPV. Negative cases are commonly regarded as 'burned-out' condylomas.

Fig. 7.20 Paget disease of the anal canal. Large Paget cells are distributed throughout the nonneoplastic squamous epithelium.

Papillary hidradenoma

This rare tumour arises in the perianal apocrine glands, typically in middle aged women and only exceedingly rarely in men {1082}. It presents as a circumscribed nodule approximately 1 cm in diameter and may resemble a haemor-rhoid.

Histologically, it consists of a papillary mass with a cyst-like capsule. The papillae are lined by a double layer of epithelial cells, the outer layer being composed of cells containing mucin. The tumour does not express the eccrine marker IKH-4, but it must be remembered that adenocarcinoma metastases also are negative {811}. Convincing examples of anal apocrine adenocarcinoma have not been published.


There are a few reports on keratoacan-thoma arising in the perianal skin {454}.

Neuroendocrine tumours

Neuroendocrine tumours may arise in the anus {493, 744}. They are, however, conventionally classified as rectal. An immunohistochemical study of 17 rectal neuroendocrine tumours showed that most were of L-cell type {294}. For details, see in chapter 5 the section on endocrine tumours of the colon and rectum.

Fig. 7.19 Paget disease of the anal canal.

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