Malignant Tumors of the Anal Canal
Gerald A. Isenberg
While there are several chronic diseases more destructive to life than cancer, none is more feared.
—CHARLES H. MAYO
Carcinomas of the anal canal and perianal skin are uncommon clinical entities, accounting for only 2% or fewer of all colorectal carcinomas. At the Memorial Sloan-Kettering Cancer Center in New York between 1929 and 1974, approximately 400 uncommon neoplasms were found in this area, as compared with almost 10,000 adenocarcinomas of the rectum.126 This is an incidence of 4% in a specialized referral center. The National Cancer Institute (NCI) estimated 5,820 new cases of anal cancer with 770 deaths in 2011.100
Anal canal cancer is almost three times more common than carcinoma of the anal margin.96 If the dentate line is taken as the distal limit of the anal canal, approximately 70% of all anal tumors will occur in the anal canal.37 However, if the anal canal is assumed to extend from the anorectal ring to the anal verge (the junction of modified squamous epithelium with the hair-bearing, keratinized perianal skin), 85% of anal tumors will arise in the anal canal.37 Anal canal tumors are more frequently seen in women (3:2), whereas carcinoma of the anal margin is more common in men (4:1). Morson and Pang noted the same median age for both genders at presentation (57 years).96
▶ ANATOMY AND HISTOLOGY
There is some controversy about the anatomic limits of the anal canal, although it is generally agreed that the proximal extent corresponds to the anorectal ring.58 The distal end has been variously proposed to be the dentate line, Hilton’s line, and the anal verge.56,58 My interpretation of the anal canal is that portion of the distal segment of the intestinal tract that lies between the termination of the rectal mucosa above and the beginning of the perianal skin below (i.e., the mucocutaneous junction; Figure 25-1). It is divided into a proximal transitional zone encompassing the columns and sinuses of Morgagni and a distal zone lined by squamous epithelium (Figure 25-2). The transition zone is derived from the embryonic cloaca and separates the rectal mucosa from the squamous epithelium of the distal anal canal. The anal glands and ducts arise from this area and are lined by stratified columnar epithelium (Figure 25-3). The median number of anal glands is six, with 80% extending to the submucosa, 8% to the circular internal sphincter, 8% to the longitudinal internal sphincter, 2% to the intersphincteric space, and only 1% penetrating the external anal sphincter.140 The implications of the depth of penetration of the anal glands concerning the etiology of fistula-in-ano are discussed in Chapter 14. The anal glands have definite secretory activity and are presumed to be responsible for lubricating the anal canal.
The transitional zone contains epithelium resembling that found in the urethra, but much variability exists in the region. Patches of squamous epithelium are frequently present, especially over the crests of the columns of Morgagni. The junction between the transitional zone and squamous mucosa lies at the inferior limit of the columns of Morgagni and has been referred to as the dentate or pectinate line.
However, some authors place the dentate line at the proximal limit of the anal canal, at the junction between the rectal mucosa and transitional zone.60,78 The more distal zone of the anal canal is lined by stratified squamous epithelium and can be differentiated histologically from perianal skin by the absence of the epidermal appendages found in the skin. Thus, a finger examining the anal canal first passes the perianal skin, the squamous epithelium of the distal anal canal, the transition zone, and finally reaches the rectal mucosa. Separating tumors that arise in the anal canal from those of the perianal skin is important because their biologic behavior and, consequently, the treatments are distinctly different.
However, some authors place the dentate line at the proximal limit of the anal canal, at the junction between the rectal mucosa and transitional zone.60,78 The more distal zone of the anal canal is lined by stratified squamous epithelium and can be differentiated histologically from perianal skin by the absence of the epidermal appendages found in the skin. Thus, a finger examining the anal canal first passes the perianal skin, the squamous epithelium of the distal anal canal, the transition zone, and finally reaches the rectal mucosa. Separating tumors that arise in the anal canal from those of the perianal skin is important because their biologic behavior and, consequently, the treatments are distinctly different.
 FIGURE 25-1. Anatomy of the anus with histologic pattern schematically illustrated. |
 FIGURE 25-2. Normal anal canal. The epithelium of the transition zone (center, right) resembles the transitional epithelium of the lower genitourinary tract. (Original magnification × 100.) |
▶ CARCINOMA OF THE PERIANAL SKIN AND ANAL MARGIN
Neoplasms of the anal margin and perianal skin include squamous cell carcinoma, Bowen’s disease, Paget’s disease, and basal cell carcinoma. It is generally accepted that wide surgical excision is an adequate treatment for lesions of the
perianal skin (Figure 25-4).119 Management of these conditions is discussed in Chapter 9. Carcinomas of the anal margin have a better prognosis than that of tumors of the anal canal. Mendenhall and colleagues reviewed the experience at the University of Florida, Gainesville, of squamous cell carcinoma of the anal margin.95 They concluded that superficial, well to moderately differentiated T1 cancers of the anal margin may be successfully treated with radiotherapy alone or by local excision. However, because stage T2 lesions have an increased risk for lymph node metastases to the groin, they recommended radiotherapy to the primary tumor in conjunction with elective inguinal lymph node radiation. Concurrent chemotherapy may also be prudent for T2 or greater tumors.5 Abdominoperineal resection (APR) is reserved for those who have complications secondary to the radiation therapy or locally recurrent disease.5,95 Greenall and coworkers reported the results of treatment of 48 patients with anal margin lesions.57 Local excision was associated with a corrected 5-year survival rate of 88%, but 46% of these individuals developed a local or regional recurrence. Additional treatment contributed to the satisfactory results, but APR did not improve survival.
perianal skin (Figure 25-4).119 Management of these conditions is discussed in Chapter 9. Carcinomas of the anal margin have a better prognosis than that of tumors of the anal canal. Mendenhall and colleagues reviewed the experience at the University of Florida, Gainesville, of squamous cell carcinoma of the anal margin.95 They concluded that superficial, well to moderately differentiated T1 cancers of the anal margin may be successfully treated with radiotherapy alone or by local excision. However, because stage T2 lesions have an increased risk for lymph node metastases to the groin, they recommended radiotherapy to the primary tumor in conjunction with elective inguinal lymph node radiation. Concurrent chemotherapy may also be prudent for T2 or greater tumors.5 Abdominoperineal resection (APR) is reserved for those who have complications secondary to the radiation therapy or locally recurrent disease.5,95 Greenall and coworkers reported the results of treatment of 48 patients with anal margin lesions.57 Local excision was associated with a corrected 5-year survival rate of 88%, but 46% of these individuals developed a local or regional recurrence. Additional treatment contributed to the satisfactory results, but APR did not improve survival.
 FIGURE 25-3. Cross section of a normal gland (A) and an anal duct (B). (Original magnification × 250; courtesy of Rudolf Garret, MD.) |
Recommendation
It is self-evident that any suspicious finding around the anus should be examined by biopsy. If the lesion is confirmed to be a malignant neoplasm, the usual treatment is to perform wide local excision because these lesions tend not to
metastasize (see Figure 9-75). The defect created by excision can be left to granulate, covered by a split-thickness skin graft or, in some instances, may be closed by rotating a flap of adjacent skin such as described in Chapter 11.
metastasize (see Figure 9-75). The defect created by excision can be left to granulate, covered by a split-thickness skin graft or, in some instances, may be closed by rotating a flap of adjacent skin such as described in Chapter 11.
 FIGURE 25-4. Ulcerating squamous cell carcinoma of the buttock. A: The lesion has been excised. B: A rotation flap of full-thickness skin covers the defect. |
▶ CLASSIFICATION OF ANAL CANAL TUMORS
Several histologic types of tumors are identified in the anal canal: epidermoid (squamous cell) and mucoepidermoid carcinoma, transitional-cloacogenic carcinoma, adenocarcinoma, and malignant melanoma. Some physicians regard transitional-cloacogenic carcinoma as a manifestation of epidermoid carcinoma,109,113 whereas others believe it is a separate entity that arises from the transition zone of the anal canal with different morphologic and clinical features.47,78 Although it is true that transitional-cloacogenic carcinomas are generally recognizable as a distinct group of tumors, there is some overlap with standard epidermoid carcinomas. They, therefore, form one part of a spectrum that ranges from pure transitionalcloacogenic tumors through lesions with mixtures of squamous elements to those with purely squamous differentiation. The Memorial Sloan-Kettering Cancer group recommends that tumors be classified as squamous or basaloid (transitionalcloacogenic) according to the predominant cell type, although the authors recognize that this may be quite subjective and dependent on tissue sampling.56 With the exception of melanoma, the clinical behavior of carcinoma of the anal canal appears to be relatively independent of the morphologic subtype when compared stage for stage and grade for grade.
Epidermoid (squamous cell) carcinoma accounted for the majority of the tumors of the anal canal in that reported by Corman and Haggitt (almost two-thirds), whereas transitional-cloacogenic carcinomas comprised approximately one-fourth, and melanomas made up the remainder (14%).27
▶ EPIDERMOID OR SQUAMOUS CELL CARCINOMA OF THE ANUS
Incidence
Epidermoid carcinoma of the anus is a rare condition. It can be multifocal in the anal canal as well as in the perianal skin, perineum, and vulvar areas. Most published articles describe each institution’s rather limited experience. Failes and Morgan reported 59 patients over a 20-year period; Sawyers and colleagues reported 42 patients over a period of 35 years (2.4% of cancers of the colon, rectum, and anus); and Cattell and Williams reported a 1.7% incidence of epidermoid carcinoma in 600 rectal and anal neoplasms.19,41,137 Grinnell noted a 1.8% incidence of epidermoid carcinoma in colorectal cancers.59 Golden and Horsley reported on 26 patients, an incidence of 1.8% of all colorectal cancers.49 Beahrs and Wilson at the Mayo Clinic in Rochester, Minnesota, reported on 113 patients with epidermoid carcinoma, an incidence of approximately 1% of all colorectal carcinomas seen during the 20-year review.9 Stearns and Quan (see biographies in Chapter 24) identified 234 epidermoid carcinomas, which represented approximately 3.9% of all malignant tumors detected in the terminal 18 cm of the alimentary tract.148 The annual incidence of anal cancer among men in the United States is 1.4 per 100,000, but in men who have sex with men the incidence has been estimated to be as high as 37 in 100,000.123
As of the publication of this text, the NCI SEER database (November 2011) includes 5,820 patients with anal cancer, 2,140 men and 3,680 women.101 This data, based on patients from 2004 to 2008, found the median age to be 60 years. The incidence is highest in white women and black men, and there is an increasing trend in both men and women. Overall survival from 2001 to 2007 was 65%. However, African American men had the lowest survival (50%). Half of the anal cancers were localized and one-third had spread to regional lymph nodes at the time of diagnosis. The incidence by race and stage at diagnosis are shown in Tables 25-1 and 25-2.
Age and Gender
Epidermoid carcinoma can occur at almost any age, but absent human immunodeficiency virus (HIV)-positivity, the condition is usually found in the sixth and seventh decades. As mentioned previously, most studies have shown a preponderance of carcinoma of the anal canal in women. In Sweden, the annual age-adjusted incidence per 100,000 population for squamous cell carcinoma is 1.40 for women and 0.68 for men. However, where there are centers with a large patient population of men at high risk, the female-to-male ratio may approach unity.37
Predisposing Conditions and Etiology
An increased incidence of anal cancer is seen with a number of anorectal inflammatory conditions, such as chronic anal fistula (see Chapter 14) and anal condylomata, as well as in those with HIV infection (see Chapters 9 and 10). This includes patients with Crohn’s disease (see Chapter 30). An association
with smoking, anoreceptive intercourse, and immunosuppression has also been described. A relationship with human papillomavirus (HPV) types that are known to be associated with cervical and other genital cancers has been established. Individuals who engage in anal intercourse and who are infected with HPV type 16 have a relative risk of developing anal canal cancer as high as 33% over the general population.76 Palmer and colleagues affirmed that both HPV types 16 and 18 are involved in the development of anal and genital squamous cell carcinoma.108 Youk and associates identified HPV type 16 in all 21 of their patients with anal cancer.166 High-risk HPV is found in 85% of patients with anal squamous cancer, depending on the assay used. Holmes and associates found associations between positive herpes simplex virus 2 titer, cigarette smoking, a prior positive or questionable cervical Papanicolaou smear, and an increasing number of sexual partners with the development of anal cancer.65 An increased incidence of cancers in the anogenital region has also been observed in patients who have undergone renal transplantation, presumably as a consequence of immunosuppression.117 Anal cancers have occurred following radiation therapy for pruritus.37
with smoking, anoreceptive intercourse, and immunosuppression has also been described. A relationship with human papillomavirus (HPV) types that are known to be associated with cervical and other genital cancers has been established. Individuals who engage in anal intercourse and who are infected with HPV type 16 have a relative risk of developing anal canal cancer as high as 33% over the general population.76 Palmer and colleagues affirmed that both HPV types 16 and 18 are involved in the development of anal and genital squamous cell carcinoma.108 Youk and associates identified HPV type 16 in all 21 of their patients with anal cancer.166 High-risk HPV is found in 85% of patients with anal squamous cancer, depending on the assay used. Holmes and associates found associations between positive herpes simplex virus 2 titer, cigarette smoking, a prior positive or questionable cervical Papanicolaou smear, and an increasing number of sexual partners with the development of anal cancer.65 An increased incidence of cancers in the anogenital region has also been observed in patients who have undergone renal transplantation, presumably as a consequence of immunosuppression.117 Anal cancers have occurred following radiation therapy for pruritus.37
TABLE 25-1 Incidence Rates by Race | |||||||||||||||||||||||||||
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TABLE 25-2 Stage Distribution and 5-Year Relative Survival by Stage at Diagnosis for 2001-2007, All Races, Both Sexes | ||||||||||||||||||
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Several reports have suggested a significantly higher incidence in patients with Crohn’s disease.145 Although it is unlikely that a patient with an anal fistula or with condylomata would be treated with expectant observation, individuals with Crohn’s disease are often managed in this way. Therefore, it is important to perform a biopsy of any unusual lesion. It may even be good counsel to suggest random anal biopsies or biopsy of the fistula/sinus tract at intervals for patients with this condition.
Frisch and colleagues examined the risk of anal cancer developing in individuals who harbored benign anal lesions, including fissures, fistulas, perianal or perirectal abscesses, and hemorrhoids.46 Whereas these investigators concluded that there was a strong temporal association between the diagnosis of benign anal lesions and that of anal cancer, their data did not support the view that there was an association for these diagnoses.
Melbye and coworkers compared the numbers of observed cases and expected cases of anal cancer among patients with acquired immunodeficiency syndrome (AIDS) by using registries in seven health departments in the United States.94 These investigators found that there was a strikingly increased risk for the development of this malignancy in individuals with AIDS. Lorenz and associates retrospectively reviewed six patients with squamous cell carcinoma treated between 1985 and 1988.89 All were homosexual men; five had AIDS, and one was HIV positive. Because of the increased incidence of venereal disease in the homosexual population, there is increasing evidence to suggest that homosexual men are at a particular risk for the development of anal cancer.84 Piketty and colleagues found an increased incidence of anal cancer in HIV patients despite their treatment with antiretroviral therapy from this French database of HIV-positive patients.121 In addition, the incidence was higher in men who have sex with men. Even in the absence of AIDS, anal canal carcinoma, Kaposi’s sarcoma, and anorectal lymphoma are seen in younger patients and much more frequently than would be expected.34,38,69,81,99
Daling and colleagues demonstrated that two correlates of homosexual behavior, unmarried status and positive serologic test result for syphilis, are related to an increased incidence of anal cancer.33,34 Because having had syphilis and being single are associated with the practice of anal intercourse in men, but not in women, the authors suggest that this act is an independent risk factor for the development of anal cancer. Goldstone and associates recommend that all men who have sex with men with presumed benign anorectal disease undergo high-resolution anoscopy and multiple biopsies of all abnormal areas in order to look for high-grade, squamous intraepithelial lesions that represent precursors of invasive carcinoma (see Chapter 10).55 Place and coworkers opined that anal squamous cell carcinoma in an HIV-positive patient should be considered an AIDS-defining illness.123
It can be appreciated, therefore, that certain predisposing conditions are associated with the development of malignant anal canal tumors. This implies that the etiology probably represents an interaction between genetic and environmental factors.37 The genetic aspect may be related to changes in chromosome 11 (11q22) or the short arm of chromosome 3 (3p22).98
In summary, the following variables are related to the development of anogenital carcinoma:
Prior radiotherapy
Chronic anal fistula
Crohn’s disease
Smoking
Positive Papanicolaou smear
Cervical carcinoma
HPV infection
Hodgkin’s disease
Renal transplantation
Multiple partners
Positive herpes simplex virus 2 titer
HIV infection
Male homosexuality
Anoreceptive intercourse
Immunosuppression
Positive serologic test for syphilis
Anal condylomata
Anal intraepithelial neoplasia (AIN)
Current evidence indicates that the etiology of anal cancer is a multifactorial interaction among environmental factors, HPV infection, immune status, and suppressor genes.37
 FIGURE 25-5. Squamous cell carcinoma. The patient complained of a lump. (From Corman ML, Veidenheimer MC, Swinton NW. Diseases of the Anus, Rectum and Colon. Part I: Neoplasms. New York, NY: Medcom; 1972, with permission.)28 |
Signs and Symptoms
Symptoms of anal canal carcinoma include rectal bleeding, anal pain, pruritus, mucous discharge, tenesmus, the sensation of a lump in the anus, and a change in bowel habits (Figure 25-5). Rectal bleeding occurs in more than one-half of individuals. The duration of symptoms is of little prognostic significance.56 Complaints such as discharge, incontinence, change in bowel habits, pelvic pain, or the passage of stool or gas through the vagina suggest an advanced lesion.37 Tenesmus, the painful urgency to defecate, implies invasion of the sphincter mechanism. Presentation is often late, with the mean size of tumor at diagnosis between 3 and 4 cm.37 Occasionally, a patient may present with a mass in the groin, a manifestation of a metastasis before the primary tumor causes significant symptoms. The condition may also be identified incidentally upon review of the histology of a hemorrhoidectomy specimen (see later).
Examination and Biopsy
Rectal examination may reveal an ulcerating, hard, tender, bleeding mass in the anal canal or lower rectum. Examination of an advanced lesion may be excruciatingly tender and may require evaluation using an anesthetic to identify the accurate extent and to perform a biopsy of the lesion. The tumor may fungate through the anal canal and appear on the perianal skin, or it may present through a chronic draining anal fistula (Figure 25-6). The lesion can be confused with other anorectal conditions, such as an ulcerated hemorrhoid or an ulceration as a consequence of an infection.
Proctosigmoidoscopic examination usually shows that the tumor is confined to the anal canal. However, in far-advanced cases, the lesion may extend upward to involve the rectum. Conversely, a carcinoma that seems to arise within the anal canal may occasionally be a rectal cancer that has spread downward (Figure 25-7). Another possibility is implantation from a colon tumor, a particular concern if hemorrhoidectomy is performed at the time of a colectomy for cancer. Scott and colleagues demonstrated by flow cytometric DNA analysis that an anal malignancy was actually the result of a “dropped” metastasis from a sigmoid colon carcinoma.139 Biopsy of the lesion will establish its histologic nature.
 FIGURE 25-6. Two fistulous openings (arrows) from anal canal carcinoma. Biopsy of the tracts confirmed the presence of tumor. (From Corman ML, Veidenheimer MC, Swinton NW. Diseases of the Anus, Rectum and Colon. Part I: Neoplasms. New York, NY: Medcom; 1972, with permission.) |
Pathology
Epidermoid Carcinoma
Epidermoid carcinoma originates from the stratified squamous epithelium of the distal anal mucosa and therefore
morphologically resembles carcinoma arising from the buccal mucosa, esophagus, uterine cervix, and so forth. The tumor is composed of squamous epithelial cells that resemble normal anal mucosa to a varying extent, depending on the degree of differentiation. The more differentiated tumors have readily apparent keratin formation, either as pearls or as individual cell keratinization (Figure 25-8). The lesions can be graded based on the degree of keratinization and the nuclear morphology, and this grade correlates with the behavior of the tumor, that is, well-differentiated tumors tend to be less deeply invasive and are less likely to metastasize. More than 50% of anal canal tumors are nonkeratinizing, whereas 80% are poorly differentiated.37 This is in contrast to anal margin tumors, with 80% demonstrating keratinization and 85% being well differentiated.37
morphologically resembles carcinoma arising from the buccal mucosa, esophagus, uterine cervix, and so forth. The tumor is composed of squamous epithelial cells that resemble normal anal mucosa to a varying extent, depending on the degree of differentiation. The more differentiated tumors have readily apparent keratin formation, either as pearls or as individual cell keratinization (Figure 25-8). The lesions can be graded based on the degree of keratinization and the nuclear morphology, and this grade correlates with the behavior of the tumor, that is, well-differentiated tumors tend to be less deeply invasive and are less likely to metastasize. More than 50% of anal canal tumors are nonkeratinizing, whereas 80% are poorly differentiated.37 This is in contrast to anal margin tumors, with 80% demonstrating keratinization and 85% being well differentiated.37
 FIGURE 25-7. Adenocarcinoma of the rectum fungating through the anal canal. (From Corman ML, Veidenheimer MC, Swinton NW. Diseases of the Anus, Rectum and Colon. Part I: Neoplasms. New York, NY: Medcom; 1972, with permission.) |
Goldman and colleagues examined 15 patients with anal carcinoma by means of percutaneous and transanorectal fine needle aspiration cytology, confirming the diagnosis by this means.54 Interestingly, despite the predominance in women, neither estrogen receptors nor progesterone receptors could be detected. Surawicz and coworkers used anal cytology and biopsy to determine the presence of anal dysplasia (anal intraepithelial neoplasia) in 90 homosexual men with abnormalities of the anal canal.150 Eighty-six percent had HPV-associated abnormalities, including condylomata. Dysplasia was detected by cytology in 36% and by biopsy in 92% (27% high grade).150 The authors concluded that further studies are indicated to determine the clinical significance of the dysplastic phenomenon and its rate of progression to cancer (see also Chapter 10). Obviously, this has implications with respect to screening and to treatment.
 FIGURE 25-8. Squamous cell carcinoma of the anus. A: Carcinoma in situ. Note that there is no invasion. B: This well-differentiated squamous cell carcinoma resembles normal squamous epithelium and is producing a keratin pearl. C: Less well-differentiated lesions lose their resemblance to squamous epithelium, lack keratin pearls, and behave more aggressively. |
A careful search using mucin stains may disclose a focus of mucin-producing cells in as many as 10% to 15% of patients (Figure 25-9).97 Such tumors have been classified separately as mucoepidermoid carcinomas, but little evidence exists that differences in the behavior of this subgroup warrant its separation. A case of mucoepidermoid carcinoma of the anal canal with special reference to immunohistochemical analysis of the tumor to clarify its histogenesis has been reported.79 The staining patterns were different from those of anal squamous epithelium, confirming that mucoepidermoid carcinoma of the anus may arise from the anal transitional zone, and that it is biologically different from squamous cell carcinoma of the anus. A spindle cell carcinoma (pseudosarcoma) has been reported to be another variant.74
Squamous cell carcinoma tumor-associated antigen (SCC antigen) has been shown to be a tumor marker that seems to be related to the histologic characteristics of differentiated epidermoid tumors rather than to tumor site.120 Fontana and colleagues measured SCC antigen in epidermoid carcinoma of the anal canal in 66 patients at diagnosis, before treatment, and during follow-up.44 There did not appear to be a correlation with the primary tumor, itself, except with respect to nodal involvement. These investigators concluded that there was no prognostic value of this study at the time of diagnosis, but that the level of SCC antigen correlated well with the development of recurrence.
Transitional-Cloacogenic Carcinoma
In 1956, Grinvalsky and Helwig published a study of the anatomy of the anal canal in which they detailed the features
of the transitional or “cloacogenic” zone and suggested that tumors, which arise in this area, differ from the usual epidermoid carcinomas originating in the squamous epithelium of the distal anal canal.60 They proposed the term transitional-cloacogenic for these lesions. Subsequent studies have confirmed the morphologic difference from that of the usual squamous carcinomas.78,109
of the transitional or “cloacogenic” zone and suggested that tumors, which arise in this area, differ from the usual epidermoid carcinomas originating in the squamous epithelium of the distal anal canal.60 They proposed the term transitional-cloacogenic for these lesions. Subsequent studies have confirmed the morphologic difference from that of the usual squamous carcinomas.78,109
 FIGURE 25-9. Mucoepidermoid cell pattern in an anal canal cancer. (Original magnification × 260.) |
Transitional-cloacogenic carcinomas may resemble carcinomas of urothelium to a certain extent, or they may have patterns similar to that of basal cell carcinoma of skin— hence the term basaloid because the cells at the periphery are arranged in an orderly, palisade fashion (Figure 25-10). However, this variation in cell pattern must not be confused with basal cell carcinoma. The former is a malignant tumor that frequently metastasizes, whereas the latter is relatively benign (see Chapter 9).
Those tumors resembling urothelial carcinomas are composed of islands or nests of cells that have indistinct borders and oval nuclei (Figure 25-11). A focus of keratinization is often present. As stated previously, varying amounts of squamous elements produce a spectrum of lesions ranging from purely transitional through mixed varieties to purely squamous tumors. Some examples of transitional-cloacogenic carcinoma appear to arise in the lower part of the rectum above the transitional zone, whereas others may not even involve the mucosa. The probable explanation for these phenomena is that such tumors may originate from the transitional epithelium that lines the anal ducts deep to the mucosa or in proximal ramifications of the ducts beneath the rectal mucosa.
 FIGURE 25-10. Transitional-cloacogenic carcinoma. In this tumor, the cells at the periphery tend to arrange themselves in a palisade, thus resembling basal cell carcinoma of the skin. This variant of transitional-cloacogenic carcinoma is sometimes called basaloid carcinoma. (Original magnification × 80.) |
Transitional-cloacogenic tumors form a histologically recognizable subgroup of anal canal carcinomas, but based on the grade and stage of the lesions, their behavior appears to be
comparable to that of epidermoid carcinomas of similar grade and stage (Figure 25-12). There are fewer published studies of transitional-cloacogenic tumors than that of epidermoid carcinoma, but evidence suggests that there is sufficient overlap in the epidemiology (e.g., an increased incidence in analreceptive homosexual men),25 the clinical presentation, and the results of treatment that, for the purposes of management, one should consider the two entities identical.
comparable to that of epidermoid carcinomas of similar grade and stage (Figure 25-12). There are fewer published studies of transitional-cloacogenic tumors than that of epidermoid carcinoma, but evidence suggests that there is sufficient overlap in the epidemiology (e.g., an increased incidence in analreceptive homosexual men),25 the clinical presentation, and the results of treatment that, for the purposes of management, one should consider the two entities identical.
 FIGURE 25-11. Transitional-cloacogenic carcinoma. A: The tumor has an in situ component resembling a transitional cell carcinoma of the urinary bladder, hence its name. B: A poorly differentiated lesion. (Original magnification × 125.) |
 FIGURE 25-12. Retroflexion with the endoscope in the rectum reveals an ulcerating lesion in the transitional zone at the top of the anal canal and lower rectum. Biopsy confirmed the presence of a cloacogenic carcinoma. |
Melanoma
The histopathology of malignant melanoma is discussed later in this chapter.
Adenocarcinoma
Adenocarcinoma of the anus is sometimes seen as a downward extension of a primary rectal tumor. However, glandular epithelium may be found on biopsy from ectopic glands of the anal wall, from sebaceous glands of the perineum, from anal fistulas, or from tumors arising in anal glands or ducts (Figure 25-13). Hobbs and colleagues found that a useful and discriminating definition of anal gland carcinoma is an anal tumor composed of “haphazardly dispersed, small glands with scant mucin production invading the wall of the anorectal area without an intraluminal component” (see later).64 As discussed in Chapter 9, the association with an underlying mucinous adenocarcinoma and Paget’s disease has been well documented.
 FIGURE 25-13. Adenocarcinoma arising from an anal gland. (Original magnification × 200.) |
Staging
No completely satisfactory method for staging anal canal tumors has been developed. Dukes’ classification is not applicable because invasion to groin nodes may occur when lymph node involvement is not evident in the resected specimen. The TNM system has been criticized because it is difficult to distinguish tumor invasion limited to the internal sphincter from that involving the external sphincter and because extension into the rectum or perianal skin does not necessarily imply a poorer prognosis.56,58 That stated, however, the staging system for anal canal cancer that has been described by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer, the system that is currently used by pathologists, tumor boards, oncologic centers, and therefore most colorectal surgeons is presented in Table 25-3.
Goldman and colleagues examined specimens from 47 cases of squamous cell carcinoma of the anus with respect to clinical stage, histologic grade, and DNA content of the tumor cells.50 Because most tumors were aneuploid, no statistically significant difference could be demonstrated with respect to DNA content and survival. The authors affirmed that histologic grade and clinical stage seem to be the best predictors of patient outcome.
Treatment
Until the middle to late 1970s, APR was believed by most surgeons to be the only curative approach to the management of anal canal carcinoma.134 Before the advent of neoadjuvant therapy, selective application of local excision could also be considered.51 The choice of treatment depended on the stage of the tumor as determined by depth of invasion. The current approach relies heavily on the success of neoadjuvant therapy. However, other modalities are first discussed in order to provide some perspective.
Local Excision
For carcinoma confined to the mucosa and submucosa or carcinoma in situ, wide local excision with or without an
anoplasty will usually be curative (see Chapter 11). For more deeply invading tumors such as those that invade the internal sphincter, local excision including the internal sphincter may also achieve cure. However, for tumors that invade more deeply than the internal sphincter, APR has, historically, been the preferred alternative. These differences in therapy based on the stage of the tumor require precise preoperative evaluation, including careful digital examination to assess the depth of invasion and endoanal ultrasound. Tarantino and Bernstein evaluated 13 consecutive patients with biopsyproven squamous cell carcinoma of the anal canal by means of endoanal ultrasound.152 These investigators proposed the following staging system:
anoplasty will usually be curative (see Chapter 11). For more deeply invading tumors such as those that invade the internal sphincter, local excision including the internal sphincter may also achieve cure. However, for tumors that invade more deeply than the internal sphincter, APR has, historically, been the preferred alternative. These differences in therapy based on the stage of the tumor require precise preoperative evaluation, including careful digital examination to assess the depth of invasion and endoanal ultrasound. Tarantino and Bernstein evaluated 13 consecutive patients with biopsyproven squamous cell carcinoma of the anal canal by means of endoanal ultrasound.152 These investigators proposed the following staging system:
TABLE 25-3 The AJCC Staging System for Anal Canal Cancer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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