Epidemiology, Etiology, Genetics, and Cytogenetic Abnormalities

Cancers of the anal region account for 1% to 2% of all large bowel cancers and 4% of all anorectal carcinomas. The majority of these patients (75% to 80%) have squamous cell carcinomas.¹ Approximately 15% have adenocarcinomas.

In 2007, a total of 4650 cases of cancers of the anal region were reported in the United States, including 1900 men and 2750 women.² It is estimated that there will be 690 deaths per year. Anal cancers, although still uncommon, have increased substantially in incidence during the last 30 years. This increase may be due to sexual transmission of human papilloma virus (HPV), especially HPV-16 and HPV-18.³ It is postulated that, as in cervical carcinoma, with which HPV is strongly associated and may be a necessary factor for development of the disease, high-grade squamous intraepithelial lesions (HSIL) are the immediate precursors to anal cancer.^4,5

Whereas anal squamous intraepithelial lesions are rare in heterosexual men, the incidence is 5% to 30% in HIV-negative men who have sex with men (MSM). These changes are rare among HIV-negative women, yet common in women with immunosuppression and HPV-related dysplasia of the lower genital tract.⁶ Anal squamous intraepithelial lesions are linked to HPV and are common in MSM and immunosuppressed patients, especially those who are HIV-positive.^7,8 The prevalence of HSIL in HIV-positive MSM reaches 52%.⁹

There is a clear association between HIV and anal canal cancer. Cross-referencing U.S. databases for AIDS with those for cancer, the relative risk of anal cancer in homosexual men at the time of or after AIDS diagnosis was 84.1.¹⁰ The relative risk of anal cancer for up to five years before AIDS diagnosis was 13.9. In a series of 3595 patients undergoing a solid organ transplant the incidence of anal cancer was 0.11%, corresponding to a relative risk of approximately 110.¹¹

Mutations in or aberrant expression of genes in key cellular pathways have been implicated in anal cancer. Overexpression of p53 protein has been studied in patients receiving radiation and chemotherapy (combined modality therapy [CMT]). In an analysis involving approximately 20% of patients entered on both arms of the Radiation Therapy Oncology Group (RTOG) protocol 87-04 there was a trend towards adverse outcome (decreased local control and survival) in patients overexpressing p53.¹² In one study of 55 patients, MIB-1 murine monoclonal antibody measuring KI-67 failed to predict outcome for patients treated with radiation with or without chemotherapy.¹³ Patel et al. proposed that activation of AKT, possibly through the PI3K-AKT pathway, is a component of the development of squamous cell cancers.¹⁴ This latter finding may be of interest now that PI3K-AKT pathway inhibitors are entering early clinical trials.

Anatomy

Cancers of the anus can occur in three regions; the perianal skin, the anal canal, and the lower rectum (Fig. 42-1). The anal canal is 3 to 4 cm long and extends from the anal verge to the pelvic floor.¹⁵ A clear anatomic distinction between the anal canal and the anal margin is needed, because of the different natural histories of cancers that arise in these two anatomic areas. There is considerable confusion when comparing series in the literature because of the use of different definitions of the anal canal and the anal margin.

FIGURE 42-1 • Anatomy of the anal region.

(From Nigro ND: Neoplasms of the anus and anal canal. In Zuidema GD, ed. Shackelford’s Surgery of the Alimentary Tract, ed 2, Philadelphia, 1991, WB Saunders, p 319.)

To clarify this issue, the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) formed a consensus that the anal canal extends from the anorectal ring (dentate line) to the anal verge.^16,17 This is an important distinction, since these two governing bodies agree that anal margin tumors behave in a similar fashion to skin cancers and therefore are to be classified as skin tumors and treated as such. However, if there is any involvement of the anal verge by tumor then it should be treated as an anal canal cancer.

An alternative and clinically oriented classification includes intra-anal, perianal, and skin.¹⁸ Intra-anal lesions cannot be visualized or are incompletely visualized when traction is applied to the buttocks. Perianal lesions are visible and are located within 5 cm of the anal opening when traction is applied to the buttocks. Skin lesions are located outside this 5 cm radius and are treated, as stated above, as skin cancers.

The anal region has an extensive lymphatic system, and there are many connections between the various levels (Fig. 42-2). The three main pathways include (1) superiorly from the rectum along the superior hemorrhoidal vessels to the inferior mesenteric lymph nodes, (2) from the upper anal canal and superior to the dentate line along the inferior and middle hemorrhoid vessels to the hypogastric lymph nodes, and (3) inferior from the anal margin and anal canal to the superficial inguinal lymph nodes.

FIGURE 42-2 • Lymphatic drainage of the anal region.

(From Pemberton JH: Anatomy and physiology of the anus and rectum. In Zuidema GD, ed. Shackelford’s Surgery of the Alimentary Tract, ed 2, Philadelphia, 1991, WB Saunders, p 253.)

Pathology

There are a variety of histologic cell types which are present in the anal area (Table 42-1).¹⁹ The most common is squamous cell carcinoma. Since the mucosal epithelium over the rectal columns is cuboidal, transitional (cloacogenic) carcinomas can arise. Most investigators agree that prognosis is more dependent on stage than histologic subtype. By contrast, using a multivariate analysis, Das and associates from the M.D. Anderson Cancer Center reported a higher distant metastasis rate for patients with basaloid histologies.²⁰ Adenocarcinomas can arise from anal crypts and should be treated as a rectal cancer though with a higher risk of inguinal node spread, given their location and lymphatic flow compared with rectal adenocarcinomas.²¹ In this chapter, squamous cell and cloacogenic histologies are collectively defined as anal canal cancers. Other rare histologic entities can arise, such as small cell neuroendocrine carcinomas,²² lymphoma, and melanomas.^23,24

Table 42-1 Histologic Types of Anal Cancer

Modified from Peters PK, Mack TM: Patterns of anal carcinoma by gender and marital status in Los Angeles County, Br J Cancer 48:629, 1983.

Clinical Presentation

The most common presenting symptoms are bleeding and anal pain. Other less common symptoms include pruritus and a palpable mass. It is common for patients and their physicians to attribute such symptoms to hemorrhoids for many months preceding the diagnosis, underscoring the importance of performing a simple anorectal examination for patients with such symptoms.

Routes of Spread

The primary routes of spread of anal canal cancer are direct extension into soft tissues and lymphatic pathways (see Fig. 42-2). Hematogenous spread is less common. At the time of presentation, pelvic lymph node metastases occur in 30% of patients and inguinal lymph node metastases in 15% to 35%.²⁵ The incidence of metachronous inguinal node metastasis in patients who initially present with clinically negative nodes and are not treated to the inguinal nodes is T1:10%; T2:8%; T3:16%; and T4:11%.²⁶ Most inguinal lymph node metastases are unilateral.

Involvement of para-aortic lymph nodes constitutes M1 or metastatic spread. Only 10% of patients present with extrapelvic visceral metastasis. These metastases occur most commonly in the liver and lungs.

Diagnostic and Staging Studies

Required as well as optional diagnostic and staging studies for anal cancer are shown in Table 42-2. Transanal ultrasound may help identify the depth of tumor penetration, but this has not been validated as a staging tool.²⁷ Abdominal/pelvic computed tomographic (CT) scan or magnetic resonance imaging (MRI) is the preferred imaging study. In a series of 41 patients, fluorodeoxyglucose-positron emission tomography (FDG-PET) detected 91% of nonexcised primaries compared with 59% using CT alone.²⁸ In addition, 17% of inguinal nodes negative by CT and physical examination were positive by PET. In a separate trial by Nguyen and colleagues, FDG-PET upstaged 17% of patients with CT-staged N0 disease to N+.²⁹ However, PET, like sentinel node mapping,³⁰ remains investigational. At present, there are no reliable serum tumor markers.

Table 42-2 Workup for Anal Canal Cancer

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, ed 7, 2010, published by Springer Science and Business Media, LLC, www.springerlink.com.

Surgery for the initial diagnosis and staging of anal canal tumors should be limited to a biopsy of the primary tumor and evaluation of the inguinal lymph nodes. Clinically enlarged inguinal lymph nodes should be aspirated. If the cytology is nondiagnostic or demonstrates only benign disease, an open excisional biopsy of 1 or 2 lymph nodes is recommended. Under no circumstances should a formal lymph node dissection be performed for the initial evaluation of suspicious nodes, as it can increase the morbidity of radiation and has no therapeutic value.

Staging

In 1997, the American Joint Commission on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) developed a common staging system. This staging system takes into account the fact that anal canal carcinoma is treated primarily by CMT or, in selected cases, by radiation alone. Abdominoperineal resection (APR) is reserved for patients failing initial treatment. Thus, the TNM classification for anal canal cancers is clinical. The primary tumor is assessed for size and, for T4 tumors, invasion of local structures such as the vagina, urethra, or bladder. The sixth edition of the AJCC staging system is shown in Table 42-3.³¹ Additional descriptors, although they do not affect the stage grouping, indicate cases needing separate analysis.

Standard Therapeutic Approaches

Techniques of Radiation Therapy

Pelvic Field

A prone three-field technique (posteroanterior [PA] plus opposed laterals) is recommended. Examples are seen in Figs. 42-3 and 42-4. This arrangement results in the lowest dose to the anterior structures such as the genitalia and bladder. The underdosed inguinal nodes are then treated concurrently with electrons to bring the dose up to 100% of the prescription dose. An alternative method is to use an AP/PA technique. Although this technique treats the pelvic and inguinal nodes in the same field it results in the highest dose to the anterior pelvic structures and skin thereby increasing toxicity. An electron boost for the perineum is not recommended since there will be overlap between the electron and photon fields. The portion of the perineum that needs to be treated should be included in the photon fields. The whole pelvis receives 30.6 Gy followed by a 14.4 Gy cone-down to the true pelvis, for a total dose of 45 Gy. Dosimetry from a representative conventional three-field plan is shown in Fig. 42-5.

FIGURE 42-3 • Idealized treatment fields for a clinical T2N0M0 squamous cell carcinoma of the anal canal. The inguinal nodes are included in the posterior-anterior field and are supplemented with electrons.

FIGURE 42-4 • Example illustrating the position of the wire on the Foley catheter outlining the anal verge (arrow). The open arrows identify a separate wire outlining the perineum.

FIGURE 42-5 • Dosimetry of a three-field plan for anal canal cancer. In this case, because of the patient’s large body habitus, the inguinal nodes are 4 cm below the anterior skin surface. They receive 35% of 18 Gy from the posterior-anterior field. Therefore, an additional 65% (1.17 Gy) needs to be delivered with 12 MeV electrons prescribed to 90%. The arrows indicate the prescription point located 1.5 cm inside the edge of the field. Since the volume inside this point should receive at least 100% of the dose, the dose is prescribed to the 99% isodose line.

It is interesting to note that in the retrospective analysis of 167 patients reported by Das et al, all 5 of the pelvic recurrences occurred at the bottom of the sacroiliac joints (SJ) joints. This is the superior border of the true pelvic field and superior border of the boost field that begins at 30.6 Gy.²⁰