Benign And Malignant Anal Tumors

Malignancies of the anal canal and margin are relatively uncommon; accounting for 1-2% of all neoplasms of the lower gastrointestinal tract. In 2000, approximately 3400 cancers of the anal region were diagnosed. Benign lesions such as condyloma, anal intraepithelial neoplasia (AIN), and Paget’s disease occur with a higher frequency and carry the potential risk of malignant transformation. As a result, colorectal surgeons are faced with the difficulties of diagnosing, treating, and the long-term follow-up of patients with these disease processes.

Anal canal cancers

Much of the confusion and difficulty in managing these lesions lies in the lack of consistent and accepted classification schemes. The first issue is to distinguish the anatomic location of the tumor. To the practicing colorectal surgeon, the anal canal runs from the top of the anorectal ring to the intersphincteric groove, and corresponds to length of the internal sphincter. The anal margin begins at the intersphincteric groove and extends 5cm out onto the perineal skin circumferentially. The second issue is related to the various cell types in this region. Tumors of the anal region can be of epidermoid, transitional or cloacogenic, basaloid, melanin, or hematopoetic origin. The proximal anal canal contains columnar mucosa, which becomes transitional epithelium and finally squamous epithelium more distally out to the anal margin. The squamous epithelium of the proximal anal canal is nonkeritinizing, which tends to give rise to poorly differentiated, basaliod lesions. In contrast, the distal anal canal contains keratinizing epithelium so the tumors of this area tend to be well-differentiated and epidermoid in histology. The distribution of the histologic types of anal cancer is: squamous cell 60-47%, cloacogenic 27-20%, adenocarcinoma 18-15%, other 11-2%^1,.

Squamous cell cancer

Epidermoid cancers of the anal canal most commonly occur in women in their 50’s or 60’s. However, the longer life expectancy of patients with HIV and the significant increased risk of anal cancer are causing the demographics to shift toward younger, HIV+ males. Anal bleeding is the most common presentation for anal canal cancers, occurring in over 50% of patients. Pruritus ani, anal pain, tenesmus, mucus discharge, change in bowel habits, or a mass are other common presenting symptoms. Due diligence must be performed when evaluating these symptoms because of the high coexistence of many benign lesions of the anus and anal cancer. Therefore, the examination should include close inspection, digital exam, anoscopy, proctoscopy, and palpation of inguinal lymph nodes. Once the diagnosis of an epidermoid anal cancer has been made, computed tomography (CT) of the abdomen and pelvic and a chest x-ray should be obtained for staging purposes since there is dual lymphatic drainage to the portal and systemic nodal basins. The inguinal region should also be examined and any suspicious nodes should be biopsied. Transanal ultrasound may be useful to determine depth of invasion or involvement of the sphincter complex. Tumors of the anal canal are staged clinically as shown below.

AJCC staging for anal canal cancers

The greatest risk factor for the development of a squamous cancer of the anal region is infection with the human papillomavirus (HPV). Serotype HPV-16 appears to have the most frequent association with high-grade anal intraepithelial neoplasia (AIN) and anal cancer, occurring in roughly 73% of patients. The other known serotypes are more frequently associated with low-grade AIN and much less often associated with high-grade dysplasia. The presence of HPV or a particular serotype is of no prognostic information. The topic of AIN will be addressed below along with Bowen’s disease. Other factors associate with an increased risk of developing anal cancer are related to sexually history such as anal receptive intercourse, greater than 10 sexual partners, history of other sexually transmitted diseases, history of cervical, vulvar, or vaginal cancers, and immunosuppression with either HIV or solid organ transplantation. There is some evidence linking cigarette smoking and long-term use of corticosteroid use (either systemic or topical to perineum) to the development of anal cancers. There does not appear to any increased risk of anal cancer associated with hemorrhoids, fissures, fistulas, or inflammatory bowel disease¹.

Infection with human immunodeficiency virus has had a significant impact on the natural history of AIN, anal cancer, and their management. Frisch et al. reported a significantly increased risk of HPV associated cancers in HIV+ patients compared to HIV- patients. Regarding anal neoplasia, the relative risk of AIN III and invasive cancer was 60.1 and 37.9, respectively, for HIV+ men and only 7.8 and 6.8, respectively, for women. The risk of high grade neoplasia and cancer in this patient population is greater in the anal canal than on the anal margin. The relative risk of high grade dysplasia and recurrence after resection is also significantly higher in HIV+ males. Despite the improved survival of HIV+ patients with the use of highly active antiretroviral therapy (HAART), the incidence or outcome of HIV associated anal cancer has not changed since the introduction of HAART.

In 1974, Dr Nigro’s data revolutionized the treatment of cancers of the anal canal by demonstrating complete pathologic responses in patients treated with neoadjuvant chemoradiation therapy. His long-term follow-up of 104 patients treated with 30Gy and 5-fluoruracil/mitomycin achieved complete regression of the tumor in 89% of patients with an 83% 3-year survival¹. This data is comparable to or better than the results of APR alone so today, chemoradiation is the primary treatment for anal cancer. Radical surgical resection is reserved for patients with incomplete response to chemoradiation therapy or those with recurrent disease. This approach has allowed 60-70% of patients to avoid a colostomy.

There are three large, prospective, randomized trials that have really defined the chemoradiation protocol. Two of the studies by the EORTC and UKCCCR compared radiation alone to chemoradiation for the treatment of anal canal cancer^,. The protocols for each study were 45Gy alone versus 45Gy plus 5-FU and mitomycin. Both studies showed superior local control with chemoradiation versus radiation alone (EORTC had 18% and UKCCCR had 46% reduction in local recurrence). But neither study showed a difference in survival between the two groups. The final study examined the chemotherapeutic agents involved in the protocol. The RTOG/ECOG study randomized 300 patients to radiation with 5-FU alone versus radiation with 5-FU plus mitomycin. The mitomycin group demonstrated much better local control with lower colostomy rates (22% vs 9%) and better 4- year disease-free survival (51% vs 73%). However, there was no difference in overall survival between the two treatment arms. As a result, the recommend first line treatment of anal canal cancer is radiation with 5-FU and mitomycin. Other studies have looked at the use of oxaloplatin based therapies, but to date they have not shown any advantage over 5-FU and mitomycin. The inguinal lymph node basin is typically included in the radiation fields in the presence and absence of positive nodes.

Patients with anal canal cancer that are HIV+ tend to have a worse outcome compared to HIV- patients. Kim et al. compared 13 HIV+ patients with 60 HIV- patients with anal canal cancer that were treated with definitive chemoradiation. All patients received 50-54Gy and 5-FU/mitomycin as definitive therapy. The HIV+ group was younger (42 yrs vs 62 yrs) and had a higher number of males (92% vs 42%). Those that were HIV+ experienced significantly more treatment related toxicity (80% vs 30%), had fewer complete responses (62% vs 85%), and time to cancer related death in those who had persistent or recurrent disease was much shorter (1.4 yrs vs 5.3 yrs). Patients with a CD4 count lower than 200/ml do not tolerate chemotherapy well so adjustments in the regimen must be made.

Salvage surgical resection with an APR can be used for patients with residual or locally recurrent disease. There will be 10-15% of patients that will have residual disease and an additional 10-30% will develop recurrent disease. Five year overall survival after salvage surgery ranges from 24 to 47%. Salvage APR for cure is only possible when the disease is confined locally or to lymph nodes of the mesorectum. Therefore, pre-operative staging is important and should include a thorough physical exam, CT of the chest, abdomen and pelvis, and positron emission tomography (PET) scan. In the largest series to date, Memorial Sloan-Kettering Cancer Center published the results of 62 patients undergoing salvage surgery. Their actuarial 5-year overall survival was 33%, and they found that positive nodes and positive margins were independent predictors of decreased survival. The univariant and multivariant analysis showed that disease persistence and nodal positivity were predictors of increased recurrence and decreased survival. The 5-year survival for recurrent disease was 51% versus 31% for persistent disease. This study demontrates that salvage surgery for persistent or recurrent disease offers a significant chance of cure.

The role of lymph node dissection for persistent or recurrent disease to the inguinal lymph nodes is controversial. There is limited data regarding its usefulness, and positive nodes are a poor prognostic indicator. It is generally accepted that for isolated inguinal nodal disease a lymph node dissection is warranted. This is supported by the disease-free survival of 21, 81, 83 months for 3 of 5 patients in the MSK publication¹².

Anorectal melanoma

The anorectum is the 3^rd most common site for melanomas to occur after cutaneous and ocular. There is some debate regarding the origin of the melanocytes, but most evidence suggests that they arise distal to the dentate line from the transitional and squamous epithelium. However, melanocytes have been identified in the rectal mucosa just proximal to the dentate line. Anorectal melanoma is considered a great masquerader because its presenting symptoms are so similar to many benign and malignant conditions of the perianal region. Patients may present with bleeding, itching, pain, or a mass. The mass can be a pigmented polypoid lesion, mimic a thrombosed hemorrhoid, or be amelanoitc. Anywhere from 30-70% of lesions may be amelanotic, which can lead to a delay in the diagnosis.

The optimal management of anorectal melanoma is unclear due to the rarity of these tumors and because the survival for these patients is so poor. Surgery is the mainstay of therapy with either APR or WLE, as these tumors are not responsive to chemotherapy or radiation. The biologic behavior or stage of the anorectal melanoma appears to impact the outcome more than the surgical procedure used. For example, up to 60% of patients will have distant metastatic disease at the time of diagnosis and most disease recurrences are systemic. The 5-year survival for large, deeply invading, or metastatic disease is less than 10% with a median survival of 12 to 18 months. As a result, the largest series have been unable to demonstrate a difference in disease-free survival or local recurrence between APR and WLE. The thickness of the lesion does appear to have prognostic value. Examination of the patients with long-term survival suggests that a tumor thickness of <2mm correlated with improved disease-free survival where as tumor thickness of >2mm correlated with systemic recurrence and low disease-free survival¹⁵. For curable disease, both APR and WLE appear to offer similar long-term results so the decision regarding which operation to perform centers around pre-operative co-morbidities, and surgeon/patient preferences. For advanced or metastatic disease, WLE is preferred because it offers equivalent local control as APR without the morbidity of a major operation.

Anal margin cancers

Squamous cell carcinoma

The majority of tumors of the anal margin are squamous cell cancers and account for 15% of all anal cancers. They appear like squamous cell cancers occurring elsewhere on the body and as a result are treated with the same principles. Unfortunately, reports of anal margin tumors are lumped together with anal canal tumors so deciphering the optimal management can be difficult. Lesions that are T1 and well-differentiated can be adequately treated by wide local excision with a 1 cm margin or treated with RT alone. When the excision is incomplete or there is a local recurrence, a re-excision may be attempted provided that the sphincter complex in not involved or chemoradiation therapy may be an option. T2 lesions should be treated with RT to the primary tumor as well as the inguinal lymph node basin. More advanced tumors (T3-T4, N+) are treated with local and inguinal radiation therapy in conjunction with chemotherapy (CRT). One series of 19 patients showed 100% local control after radiation alone or combined chemoradiation therapy, and all patients had preservation of their sphincters. Fourteen patients remained disease free from 52 to 143 months after treatment. The authors agreed with the treatment algorithm outlined above. Salvage therapy for treatment failures include wide local excision, abdominal perineal resection, and inguinal lymph node dissection for positive nodes. Five-year overall survival and local control range depend upon the T and N stages. Five-year cancer specific survival and local control rates range from 70-89% and 67-84%, respectively.

Staging for anal margin cancer

Bowen’s disease and Anal intraepithelial neoplasia

Historically, a distinction between anal intraepithelial neoplasia (AIN) and Bowen’s disease has been made, but due to their similar pathogenesis, coexistence, and similar management they are becoming more interchangeable. Anal intraepithelial neoplasia is often referred to as dysplastic changes of the epithelium of the anal canal. The dysplasia is graded I-III based on the extent of the epidermis that is involved. When only the basalar third of the epidermis is involved with dysplasia, it is categorized as AIN I. AIN I and II are considered low-grade lesions. AIN III is diagnosed when the entire thickness of the dermis contains dysplasia, and is considered a high grade lesion. Bowen’s disease is often referred to as dysplasia of the anal margin, and is catergorized as low-grade dysplasia (1 to 2 thirds of dermis are involved) and high-grade dysplasia (the entire dermis in involved). Human papillomavirus is considered the major etiologic factor in their development. As mentioned, serotype HPV 16 can be found in 60-80% of patients with Bowen’s and AIN III, but serotype 6 and 11 are most commonly found in anal condyloma (85%) and associated with low-grade dysplasia. The mechanism of cellular transformation appears to occur when the viral proteins E6 and E7 inactivate the tumor suppressor genes p53 and Rb. The natural history of AIN III and Bowen’s disease is not entirely understood. There is a well demonstrated risk of progression from dysplasia to malignancy but incidence of malignant degeneration appears to be rather low, ranging from 2-5%. Historically, there have been reports that AIN III or Bowen’s disease has been associated with an increased incidence of malignancies of other sites, but recent reports do not support that finding^16,.

In the past, Bowen’s disease and AIN occurred most commonly in women, but with the increase infection rate with the HIV, the incidence of AIN is now equal among women and men. Patients with Bowen’s disease or AIN can be asymptomatic or they can present with condyloma, pruritis ani, bleeding, anal discharge, or a scaly, erythematous rash-like lesion. Any unusual lesion should be biopsied. AIN I and II and low-grade dysplasia are considered low grade lesions and in the absence of a gross lesion, close surveillance is the recommended management. In contrast, Bowen’s disease and AIN III are high-grade lesions that are treated somewhat differently. All gross lesions, whether papillary or plaque-like, should be excised or ablated. This can be done with many different treatment options such as ablation with electrocautery, argon laser or CO2, topical 5-flourouracil, and photodynamic therapy. However, the treatment of choice for Bowen’s disease is wide local excision (WLE). WLE is not feasible for the anal canal so for AIN III, biopsy and ablation of gross or suspicious lesions is the preferred method of treatment. Options for surveillance include gross inspection and high resolution colposcopy. Controversy exists over the management of microscopic disease because of the risks of malignancy and recurrence. Proponents of aggressive resection site the risk of malignancy and the low rate of recurrence after wide excision with negative margins to support their approach¹⁶. In contrast, supporters of a more conservative approach contend that the risk of malignancy is low, close follow-up allows for adequate intervention of developing lesions, and wide local excision of large areas of the perineum carries significant morbidity. Infection with HPV produces a "field defect" so resection to negative margins is not necessarily going to remove all of the infected skin. The group from Cleveland Clinic compared 27 patients who underwent resection to negative microscopic margins to 15 patients with resection of gross lesions. They found a high rate of recurrence in both groups 23% versus 60%, respectively, a higher incidence of multiple recurrences in the more conservative approach, and the incidence of cancer was similar in both groups. Washington University reported their experience with WLE for Bowen’s disease in 25 patients. The recurrence rate was 13%, no cancers were identified, and they found that formal mapping was not helpful in guiding the excision¹⁷. Taking a more conservative approach to AIN III, Chang et al, reported their results of directed ablation of high-grade lesions using high-resolution anoscopy. They treated 37 patients (29 HIV+ patients) with ablation or excision of high-grade lesions. Patients were then followed every three to six months with anoscopy with biopsy and Pap smear. The HIV- group had no recurrences with a median follow-up of 32 months, and 23 of the 29 HIV+ had a recurrence during 28 months of follow-up that required further treatment. This is a safe alternative treatment option but these patients require long-term follow-up. In 1999, Cleary et al. reported a survey of the clinical practices of members of the American Society of Colon and Rectal Surgeons. They found that 96% of surgeons excised all gross lesions, and 73% of surgeons preferred observation of microscopic disease in the absence of gross lesions. Whether the treatment is observation or WLE, long-term follow-up is necessary with examinations every 6 to 12 months. Options for follow-up include physical exam with anoscopy, high resolution examination using a colposcope, or Pap smear with cytology. Identified lesions should then be biopsied and destroyed or excised. Patients with HIV should be followed much more closely at 3 to 6 month intervals.

Paget’s disease

Extramammary Paget’s disease is an intraepithelial adenocarcinoma of the skin that can involve the axilla or anogenital region. Paget cells are readily identified microscopically by their pale vacuolated cytoplasm that stains positive for mucin and their large peripheral nucleus. Cytokeratin 7 is becoming a very useful immunohistochemical stain to differentiate Paget cells from the surrounding squamous epithelium. The cells have immunohistochemistry and molecular genetic features consistent with glandular cells so they are believed to originate from perianal apocrine glands. Clinically, perianal Paget’s disease appears as well demarcated, erythematous, eczematous rash that is often associated with significant pruritis. It must be differentiated from other pathology of the perianal skin such as pruritis ani, condyloma, Bowen’s disease, squamous cell cancer, or melanoma. Unlike Bowen’s disease, there is a significant association with synchronous visceral carcinomas, with an incidence ranging 33-50%. Therefore, pre-operative endoscopic evaluation is very important.

The diagnosis is easily made with a full thickness biopsy. The treatment of choice is WLE provided there is no invasive component. Intra-operative frozen sections are important to ensure that the resection margins are free of disease because risk of recurrence and the presence of an invasive component are high. Larger skin defects may require skin grafting to assist with closure.

Memorial Sloan-Kettering reported their results of 27 patients treated over a 50 year period. They had a recurrence rate of 30% in patients with WLE and they identified an invasive cancer in 44% of the patients. Seven of the 12 patients with recurrence had positive margins from the WLE. Of the 12 patients with an invasive cancer, 5 underwent abdominal perineal resection (APR) and 6 patients received chemoradiation therapy. The 5-year overall and disease-free survival was 59% and 64%, respectively. Given the high incidence of recurrence and poor outcome associated with invasion, close follow-up is need for an extended period of time.

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