1 {1, 66}. This classification applies only to carcinomas.

2 A help desk for specific questions about the TNM classification is available at

3 This includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through muscularis mucosae into submucosa.

1 {1, 66}. This classification applies only to carcinomas.

2 A help desk for specific questions about the TNM classification is available at

3 This includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through muscularis mucosae into submucosa.

Tumours of the anal canal

C. Fenger M. Frisch


Tumours that arise from or are predominantly located in the anal canal. The most frequent neoplams of this region are human papilloma virus (HPV-)associ-ated squamous cell carcinomas and adenocarcinomas.

Topographic definition of anal canal and anal margin

The anal canal is defined as the terminal part of the large intestine, beginning at the upper surface of the anorectal ring and passing through the pelvic floor to end at the anus {68}. The most important macroscopic landmark in the mucosa is the dentate (pectinate) line composed of the anal valves and the bases of the anal columns. Histologically, the mucosa can be divided into three zones. The upper part is covered with colorectal type mucosa. The middle part is the anal transitional zone (ATZ), which is covered by a specialized epithelium with varying appearances; it extends from the dentate line and on average 0.5-1.0 cm upwards {490, 1929}. The lower part extends from the dentate line and downwards to the anal verge and has formerly been called the pecten. It is covered by squamous epithelium, which may be partly kera-tinized, particularly in case of mucosal prolapse.

The perianal skin (the anal margin) is defined by the appearance of skin appendages. There exists no generally accepted definition of its outer limit {62, 66, 845}. The term anus refers to the distal external aperture of the alimentary tract. Anal margin tumours are classified according to the WHO histological typing of skin tumours {682}.

Squamous cell carcinoma


Squamous cell carcinoma (SCC) of the anal canal is a malignant epithelial neoplasm that is frequently associated with chronic HPV infection.

ICD-O code 8070/3


SCC of the anal canal and anal margin typically occurs among patients in their 6th or 7th decade of life {540}. However, anal SCCs may occur in young adults, particularly in patients with cellular immune incompetence {1212}. Unselec-ted, population-based studies show an approximate 2:1 female predominance among patients with anal SCC {540, 600, 1213}.

There are few published, histologically verified incidence rates of anal cancer {540, 600, 1213}. Data from most population-based cancer registries worldwide show age standardized incidence rates of anal SCC of between 0.5 and 1.0 per

100,000 in women and between 0.3 and 0.8 per 100,000 in men {1471}. Still a relatively rare disease, anal SCC has shown a remarkable increase in incidence during the past half century {540, 600, 1213}. From being similar in the two sexes until approximately 1960 at 0.2 per 100,000, annual age-adjusted incidence rates in Denmark rose 2.5-fold in men and 5-fold in women during the period 1943-1994. For both men and women, urban populations are at higher risk than rural populations {540, 600, 1213}, and there are considerable racial differences in incidence. In the United States, blacks tend to have higher incidence rates than whites {1213}, while Asians and Pacific Islanders appear to be at very low risk {70}. Homosexual men appear to constitute a group at particular risk {368, 538, 140, 96, 369, 540, 1213, 1690, 730}. In the United States, the incidence of anal SCC in homosexual men has been estimated to be 11 to 34 times higher than in the general male population and approximately as high as the incidence of cervical cancer before the introduction of cervical cytology screening {369, 1447}. HIV infected homosexual men appear to be at particularly risk {1212, 1449, 598}. Other sexual factors strongly associated with anal SCC include number of sexual partner, receptive anal intercourse, and co-existence of sexually transmitted diseases {368, 538, 730, 733}.


Sexually transmittable human papillo-maviruses (HPVs) are detected by PCR in the majority of anal SCC {355, 367, 538, 704, 732, 1448}. One large study showed that SCCs involving the anal canal are more often high-risk HPV positive (92%) than lesions confined to the perianal skin (64%) {536}, suggesting that HPV-unrelated pathways may apply particularly to cancers of the perianal skin. A strong association with tobacco smoking has been established in women, but the role of smoking in men is less clear {367, 539, 730, 733}. States of cellular immunosuppression are associated

Fig. 7.01 Anatomy of the anal canal. Printed with permission from ref 490.
Fig. 7.02 Normal histology of the anal transition zone.

with increased risk of anal squamous cell carcinoma. This has been observed for renal transplant recipients {150, 1494} and for patients with HIV infection and AIDS {1212}.

Haemorrhoids and fissures, fistulae and abscesses in the anal region were long considered predisposing factors {192, 198, 1618}. However, three case-control studies {368, 537, 733} and two cohort studies {541, 1074} failed to support the association. Crohn's disease of long duration, which has been implicated in the aetiology of anal SCC based on case reports {992, 1765}, was not associated with risk in the only controlled study addressing the issue {537}. Oestrogen and androgen receptors have been found in the anal mucosa and its supportive tissue {1396}, suggesting a physiological role of sex hormones in their maintenance. Women who reach menarche late and women with short fertile periods may be at elevated risk of anal SCC {539}.

Clinical features

Symptoms and signs

Anal intraepithelial neoplasia is often an unexpected finding in minor surgical specimens. Clinical manifestations of anal cancer are often late and non-spe-

Fig. 7.03 In situ hybridisation for HPV 16/18 is positive in this anal carcinoma.

cific and are mainly related to tumour size and extent of infiltration. They include anal pruritus, discomfort in sitting position, sensation of a pelvic mass, pain, change in bowel habit, incontinence due to sphincter infiltration, discharge, bleeding, fissure, or fistula. The initial non-specificity of clinical features explains why diagnosis can be delayed {855, 1621, 1719, 1835}.

The clinical diagnosis of an anal tumour should always be confirmed by histological examination. A forceps or needle biopsy is usually sufficient to establish the diagnosis. The biopsy should be accompanied by an exact description of location and appearance of the biopsy site. An excisional biopsy is inadvisable, because wound healing delay would postpone optimal chemo-radiotherapy treatment. Enlarged lymph nodes may be excised or biopsied with needle aspiration under radiological control.


Computerised tomography (CT) scan, magnetic resonance imaging (MRI), and needle aspiration are used to detect inguinal and pararectal node involvement. Endoanal ultrasonography (EUS) enables assessment of spread in terms of proximal and circumferential extension and infiltration of deep layers. Furthermore, EUS enables the follow-up of irradiated carcinomas {703}. CT scan and MRI allow detection of involved lymph nodes and distant metastases {1835}.

Exfoliative cytology

In patients with increased risk such as individuals with HIV or women with genital tract SCC, the use of anal smears taken with a cytology brush from the area below the dentate line is recommended {1689}.


The tumour may present as a small ulceration or fissure with slightly exophytic and indurated margins, and irregular thickening of the anoderm and anal margin with chronic dermatitis. The lesion may have a different colour from the surrounding tissue.

If ulceration and infiltration develop, the lesion becomes fixed to the underlying structures and may bleed. In advanced stages, the sphincteric muscles are deeply infiltrated although there may be little mucosal ulceration.

Fig. 7.04 Ulcerating nodular squamous cell carcinoma of anus.

Tumour spread and staging

Anal SCC should be staged according to the TNM system {66}. Treatment for anal SCC has now changed from surgery alone to sphincter preserving procedures including radiation and chemotherapy sometimes in combination with local excision. Large surgical specimens are therefore rare. The examination should include resection lines in all directions and a careful search for lymph nodes. Clinical results of the combined treatment regimes are comparable or even better than those for surgery alone, but detection of residual disease can be more difficult by imaging techniques due to local fibrosis. In such cases a transanal full thickness tru-cut needle biopsy may be helpful {785}. Identification of residual

Fig. 7.05 Squamous cell carcinoma arising at dentate line.
Fig. 7.06 Well differentiated squamous cell carcinoma composed of large cells showing keratiniza-tion.

tumour cells may be facilitated by immunostaining for high molecular weight cytokeratins (CKs).

In 15-20% of cases, the lesion may infiltrate the lower rectum and the neighbouring organs including the rectovagi-nal septum, bladder, prostate and posterior urethra, sometimes with suppuration and fistulas. The vulva is usually spared. Lymphatic spread occurs in up to 40 percent of cases {165, 1174, 1621, 1719, 2033}. Tumours proximal to the pectinate line drain into the pelvis along the middle rectal vessels to the pelvic side walls and internal iliac chains and superiorly via the superior rectal vessels to the periaortic nodes. Tumours distal to the dentate line drain along cutaneous pathways to the inguinal and the femoral nodal chains. Inguinal nodes are involved in about 10-20% of cases {230, 575, 1174, 1650, 1692}. Inguinal lymph nodes can be involved bilaterally in a small number of cases at time of presentation. Retrograde lymphatic drainage occurs in advanced cases when the lymphatics are obstructed by malignant spread {1621, 1719}.


Squamous cell carcinoma of anal canal

Anal SCC may show a single predominant line of differentiation, but most exhibit a mixture of areas with different histological features. One pattern is that of large, pale eosinophilic cells and kera-tinization of either lamellar or single cell type. Another is that of small cells with palisading of the nuclei in the periphery of tumour cell islands. The latter often contain necrotic eosinophilic centres. Intermediate stages between these two extremes are often present. Differentiation into tubular or spindle cell configuration may be found. The invasive margin can vary from well circumscribed to irreg ular, and a lymphocytic infiltrate may be pronounced or absent. None of these features have been shown to have any prognostic significance, but poor keratiniza-tion, prominent basaloid features and small tumour cell size are related to infection with 'high risk' HPV {536}. The keratin profile of anal SCC is complex and variable {2112, 2113}. The usual immunoexpression pattern is shown in Table 7.01. The second edition of the WHO classification of SCC in the anal canal included the large-cell keratinizing subtype, the large-cell non-keratinizing subtype, and the basaloid subtype {845}. The value of this classification of anal SCC has been questioned in recent years. Many tumours show more than one subtype. Thus in a study of 100 cases of anal carcinomas, 99 showed some features of squamous differentiation (keratinisation, stratification and prickles), 65 showed basaloid features (small cell change, palisading, retraction artefact and central eosinophilic necrosis) and 26 showed focal evidence of ductal proliferation and occasionally positive staining for PAS after diastase digestion {2111}. Furthermore, the diagnostic reproducibility of these subtypes is low {492}. This is probably the reason that the proportion of basaloid carcinoma in larger series has varied from 10 to almost 70 %, and that no significant correlation between histo-logical subtype and prognosis has been established. In addition, the histological diagnosis is nowadays nearly always performed on small biopsies, that may not be representative for the whole tumour {492}. Therefore, it is recommended that the generic term 'squamous carcinoma' be used for these tumours, accompanied by a comment describing those histopatho-logical features that may possibly affect the prognosis or reflect different aetiolo-

Fig. 7.07 Squamous cell carcinoma composed of basaloid cells. Central necrosis (N) of tumour nests is typical.

gies, i.e. size of predominant neoplastic cell, basaloid features, degree of keratin-isation, adjacent squamous intraepithe-lial neoplasia, or presence of mucinous microcysts.

Apart from the verrucous carcinoma mentioned below, only two rare histolog-ical subtypes seem to have a different biological course, both having a less favourable prognosis {1734}. One is characterized by areas with well formed acinar or cystic spaces containing mucin that reacts with Alcian dyes or PAS after diastase digestion. This is termed squa-mous cell carcinoma with mucinous microcysts. The other is characterized by a rather uniform pattern of small tumour cells with nuclear moulding, high mitotic rate, extensive apoptosis and diffuse infiltration in the surrounding stro-ma. This has been called small cell (anaplastic) carcinoma, but should not be confused with small cell carcinoma (poorly differentiated neuroendocrine carcinoma).

Fig. 7.08 Squamous cell carcinoma showing a combination of basaloid and squamous features.

Fig. 7.07 Squamous cell carcinoma composed of basaloid cells. Central necrosis (N) of tumour nests is typical.

Fig. 7.08 Squamous cell carcinoma showing a combination of basaloid and squamous features.

Squamous cell carcinoma of anal margin

The distinction between anal canal and anal margin SCC may be difficult, as tumours often involve both areas at the time of diagnosis. This may account for the varying data on prognosis, but this is generally better for anal margin SCC than for anal canal SCC, in particular if local resection is possible {392, 530, 1484}. Anal margin SCC is often of the large cell variant {536, 1484}.

Verrucous carcinoma

In the anogenital area, this tumour is also called giant (malignant) condyloma or Buschke-Lowenstein tumour. It has a cauliflower-like appearance, is larger than the usual condyloma with a diameter up to 12 cm, and fails to respond to y-Ji ÍJCr.£KK

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