Kelli Bullard Dunn, M.D., F.A.C.S., F.A.S.C.R.S
Department of Surgery and Surgical Oncology
Roswell Park Cancer Institute and the
University at Buffalo/State University of New York
Introduction:Anal and perianal tumors are uncommon and account for only about 2% of all colorectal malignancies. Therapy for these lesions depends upon the type of neoplasm, its location, size, and stage.
Anatomic definitions of the anal and perianal region have been confusing and controversial. Traditionally, neoplasms of the anal canal have been divided into those affecting the anal margin and those affecting the anal canal based upon the pattern of lymphatic drainage. Lymphatics from the anal canal proximal to the dentate line drain cephalad via the superior rectal lymphatics to the inferior mesenteric nodes and laterally along both the middle rectal vessels and inferior rectal vessels through the ischiorectal fossa to the internal iliac nodes. Lymphatics from the anal canal distal to the dentate line usually drain to the inguinal nodes. These channels can also drain to the superior rectal lymph nodes or along the inferior rectal lymphatics to the ischiorectal fossa if primary drainage routes are blocked with tumor. As a result, many surgeons have defined the anal canal as the region between the dentate line and the upper margin of the anal sphincter[2, 3]. Others, however, have based the definition on surgical landmarks such as the anal verge and sphincter complex, and, as such, describe the anal canal as extending from the anal verge to the upper margin of the anal sphincter.[4, 5] Similarly, the anal transition zone has traditionally been considered to encompass the tissue between the dentate line and upper sphincter; however, increasingly it is understood that this region may extend for several centimeters into the rectum. Because therapy for anal and perianal tumors is determined in large part by location, it is critical that there is universal understanding of anatomic landmarks in this region. For this reason, Welton and others have suggested a new system of terminology (Table 1). This system replaces the terms anal canal and anal margin with the terms intra-anal and perianal. These authors further define the anal transition zone as a “region of variable height where squamous metaplasia is found as a normal variant”. For the purpose of this syllabus, these new terms will be used.
Low- and High-grade Squamous Intraepithelial LesionLike anatomic terminology, pathologic terminology in anal and perianal disease has been confusing. Bowen's disease refers to squamous cell carcinoma in situ of the anus. Pathologically, carcinoma in situ and high-grade squamous intraepithelial dysplasia appear identical. Furthermore, the term anal epithelial neoplasia (AIN) has been utilized because of the clinical and pathologic similarity of this disease to cervical intraepithelial neoplasia (CIN). Like CIN, AIN is a precursor to an invasive squamous cell carcinoma (epidermoid carcinoma), and is generally classified as AINI (least dysplastic), AINII, or AINIII (most dysplastic). In an attempt to better clarify these pathologic categories, it has been suggested that the term low-grade squamous intraepithelial lesion (LSIL) replace AIN I and low-grade dysplasia, and that the term high-grade squamous intraepithelial lesion (HSIL) replace AIN II, AIN III, CIS, Bowen’s disease, and moderate to severe dysplasia.
Perianal dysplasia and anal cancer are associated with infection with the human papilloma virus, especially HPV types 16 and 18. The incidence of both dysplasia and epidermoid carcinoma of the anus has increased dramatically among HIV-positive, homosexual men. This increase is thought to result from increased rates of HPV infection along with immunosuppression. Although LSIL is thought to have relatively low risk of malignant transformation, HSIL is considered a premalignant lesion. In the past, these lesions have been treated with wide local excision and flap reconstruction of the anal canal, a disfiguring and morbid operation. More recently, we have come to understand that HSIL can be adequately treated with biopsy, ablation, and close surveillance.[6, 9-11]
Because of a high recurrence and/or reinfection rate, these patients require extremely close surveillance. High-risk patients should be followed with frequent anal Papanicolaou (Pap) smears every 3 to 6 months. An abnormal Pap smear should be followed by an examination either in the office or in the operating room. HSIL may appear as a plaque-like lesion, or may only be apparent with high-resolution anoscopy and application of acetic acid and/or Lugol's iodine solution. This technique shows areas with abnormal telangectasias that are consistent with high grade dysplasia (HSIL). Once visualized, these areas can be biopsied and ablated (usually with cautery). A recent large series of 246 patients treated in this fashion demonstrated very few complications (4%) and progression to invasive cancer in only 1.2%. This technique has replaced the mapping method of random biopsies and many centers now consider high definition anal microscopy and frequent Pap smears to be the optimal way to treat these patients.[11, 12] With this technique, even extensive disease does not usually require radical resection with flap closure.
Medical therapy for HPV has also been proposed. Topical immunomodulators such as Imiquimod (Aldara) have been shown to induce regression in some series.[13, 14] Topical 5-FU also has been used in this setting. Finally, the recent introduction of a vaccine against HPV may help decrease the incidence of this disease in the future.
Epidermoid carcinoma Epidermoid carcinomas are the most common anal canal malignancies, comprising 80% of these tumors. Epidermoid carcinomas include squamous cell carcinoma, cloacogenic carcinoma, transitional carcinoma, and basaloid carcinoma. The clinical behavior and natural history of these tumors is similar; like anal dysplasia, the majority of these cancers are caused by HPV infection. Epidermoid carcinoma is a slow growing tumor, and usually presents as an intra-anal or perianal mass. Pain and bleeding may be present.
Staging of intra-anal epidermoid cancer is based upon tumor size and local extension, regional lymph node involvement, and presence or absence of distant metastases (Table 2). Endoanal ultrasound increasingly is utilized to assess tumor depth and sphincter involvement. Staging of peri-anal skin cancers is similar to skin cancer staging in other parts of the body, and is based upon tumor size, local invasion, and nodal and/or distant metastases.
Epidermoid carcinoma of the peri-anal region may be treated like squamous cell carcinoma of the skin in other locations because adequate surgical margins usually can be achieved without resecting the anal sphincter. Wide local excision is usually adequate treatment for these lesions. Epidermoid carcinoma occurring in the intra-anal region or invading the sphincter cannot be excised locally, and first line therapy relies upon chemotherapy and radiation (the Nigro protocol: 5-fluorouracil, mitomycin C, and 3000 cGy external beam radiation). The majority of these tumors can be cured using this regimen. Other chemotherapeutic regimens, such as 5-FU + cisplatin, in addition to high dose radiation therapy are currently under investigation. Inguinal lymph node involvement at the time of diagnosis is a poor prognostic indicator, with few patients surviving for five years.[7, 18, 20]
Recurrence most commonly occurs in the pelvis and may be treated with radical resection (abdominoperineal resection; APR) in selected patients. Several recent series have reported outcome after “salvage” APR. Overall survival after APR appears to be 30% to 40%, but major wound complications are common (36% to 80%). Patients with persistent disease (tumor occurring within six months of completing chemoradiation) have a poorer prognosis than those with recurrent disease (tumor occurring greater than six months after completing chemoradiation).[21-23] Salvage chemotherapy and radiation have also been used with moderate success. Distant metastases are difficult to treat and median survival is only 9 months.
Verrucous Carcinoma (Buschke-Lowenstein Tumor, Giant Condyloma Acuminata) Verrucous carcinoma is a locally aggressive form of condyloma acuminate that is also thought to be related to HPV infection. Although these lesions do not metastasize, they can cause extensive local tissue destruction and may be grossly indistinguishable from epidermoid carcinoma. Wide local excision is the treatment of choice when possible, but radical resection may sometimes be required. In patients who are medically unfit for surgery, imiquimod and laser ablation have also been reported.
Basal Cell Carcinoma
Basal cell carcinoma of the anus is rare and resembles basal cell carcinoma elsewhere on the skin (raised, pearly edges with central ulceration). This is a slow growing tumor that rarely metastasizes. Wide local excision is the treatment of choice, but recurrence occurs in up to 30% of patients.[17, 26] Radical resection and/or radiation therapy may be required for large lesions.
Adenocarcinoma Adenocarcinoma of the anus is extremely rare, representing only 3% to 9% of anal carcinomas. These cancers usually result from downward spread of a low rectal cancer. Adenocarcinoma may occasionally arise from the anal glands or may develop in a chronic fistula.[28, 29] Radical resection with or without neoadjuvant or adjuvant chemoradiation is usually required.
Extramammary perianal Paget's disease is adenocarcinoma in situ arising from the apocrine glands of the perianal area. The lesion is typically plaque-like and may be clinically indistinguishable from HSIL. Characteristic Paget's cells are seen histologically. These tumors often are associated with a synchronous gastrointestinal adenocarcinoma, so a complete evaluation of the intestinal tract should be performed. Wide local excision is usually adequate treatment for perianal Paget's disease. Topical imiquimod and 5-fluorouracil have also been used in this setting.[30, 31]
MelanomaAnorectal melanoma is rare, comprising less than 1% of all anorectal malignancies and 1 to 2% of melanomas. Despite many advances in the treatment of cutaneous melanoma, prognosis for patients with anorectal disease remains poor. Overall 5-year survival is less than 10%, and many patients present with systemic metastasis and/or deeply invasive tumors at the time of diagnosis. A few patients with anorectal melanoma, however, present with isolated local or locoregional disease that is potentially resectable for cure, and both radical resection (abdominoperineal resection [APR]) and wide local excision have been advocated. Recurrence is common and usually occurs systemically regardless of the initial surgical procedure. Local resection with free margins does not increase the risk of local or regional recurrence, and APR offers no survival advantage over local excision. Because of the morbidity associated with APR, wide local excision is recommended for initial treatment of localized anal melanoma. In some patients, wide local excision may not be technically feasible and APR may be required if the tumor involves a significant portion of the anal sphincter or is circumferential. The addition of adjuvant chemotherapy, biochemotherapy, vaccines, or radiotherapy may be of benefit in some patients, but efficacy remains unproven.[32, 33]
Although several large series initially suggested that APR improved survival in these patients, a recent series with longer follow-up suggests that there is no advantage to APR over wide local excision when technically feasible. At present, we recommend wide local excision for the treatment of localize anorectal melanoma. APR may be required to treat circumferential lesions or those involving the anal sphincter.
Based upon experience with cutaneous melanoma, some surgeons advocate sentinel lymph node mapping and biopsy for anal melanoma. Although the therapeutic benefit of sentinel lymph node biopsy in this setting is unproven, it is probably a reasonable approach.
MiscellaneousOther extremely rare anal tumors include small cell carcinoma and undifferentiated carcinoma. Both have poor prognosis. Lymphoma and leukemia also rarely occur in the anus. Both are addressed by treating the underlying hematologic malignancy.
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Table 1. New terminologies in anal cancer (adapted from Welton, et al, 2004)
|Intra-anal||Cannot be visualized in its entirety while gentle traction is applied to the buttocks|
|Perianal||Can be completely visualized when gentle traction is applied to the buttocks; lies within 5 cm of the anus|
|Skin||Greater than 5 cm from the anus|
|Transformation zone||Region above the dentate line of variable height where squamous metaplasia is found|
Table 2a. TNM staging of intra-anal carcinoma.
|Tis||Carcinoma in situ|
|T1||<2 cm diameter|
|T2||>2 cm and < 5 cm diameter|
|T3||>5 cm diameter|
|T4||Invasion into adjacent structures|
|N0||No nodal involvement|
|N1||Metastasis in perirectal lymph nodes|
|N2||Metastasis in unilateral iliac and/or inguinal nodes|
|N3||Metastasis in perirectal and inguinal nodes and/or bilateral iliac/inguinal nodes|
|M0||No distant metastases|