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Benign And Malignant Anal Tumors

Laurence R. Sands, MD
Assistant Professor of Clinical Surgery
University of Miami
School of Medicine
Miami, FL

A variety of tumors, both benign and malignant, may affect the anal region. Anal tumors represent a very small proportion of large bowel tumors, accounting for only 1.5% - 4% of all such malignancies. Their incidence is 1/20 that of rectal adenocarcinoma.

It has been said, "diseases of the rectum are, perhaps, as common in their occurrence as any which afflict man; and, as a rule, their pathology, symptomatology, diagnosis, and treatment are not well understood".(1) This statement certainly applies to the vast variety of tumors that affect the anal region. Perhaps the greatest confusion with anal tumors exists in their classification. One must distinguish between lesions of the anal canal and anal margin particularly because treatment of these lesions is different. In fact, it is often confusing reviewing the literature regarding anal tumors since one is never certain that these tumors were classified correctly. This is due, in part, to disagreements regarding the definition of the anal canal and the anal margin. The anatomic boundaries used to distinguish the anal canal from the anal margin will determine the relative incidence of tumors at these two sites.(2)

The anatomic anal canal is typically defined as the region from the dentate line to the anal verge, while the surgical anal canal is defined as the area from the anorectal junction and extending to the anal verge. This surgical anal canal relates directly to the entire length of the internal sphincter muscle. The anal margin has been defined as the area from the intersphincteric groove extending to 5 centimeter onto the perineum. In order to simplify the classification of these tumors, many surgeons suggest that tumors of the anal margin are those that are distal to the dentate line, while tumors of the anal canal lie proximal to the dentate line.

There is a wide variation of epithelial tissue in the anal canal that gives rise to the tumors of this region. Proximal to the dentate line, the rectum is lined with columnar epithelium, while distal to the dentate line there is squamous epithelium. The anal transition zone, which lies 6 to 12 millimeters proximal to the dentate line, consists of a variety of cell types including cuboidal, columnar, squamous, and transitional epithelial cells. This relatively unstable zone gives rise to many different types of neoplasms that develop around the anus.

The epidermoid cancers of the anus can be classified as squamous cell cancers, basaloid tumors, or mucoepidermoid tumors. Squamous cell cancers that are well differentiated tend to arise from the anal margin while the poorly differentiated lesions may arise from the anal canal. Basaloid tumors originate from the anal transition zone. They resemble basal cell cancers of the skin; however, these anal lesions tend to metastasize more frequently. Mucoepidermoid tumors are rare. They occur in the anal canal, produce both mucus and keratin, and behave similarly to squamous cell cancers.

Epidermoid cancers of the anal canal spread via the lymphatic channels of the lower rectum and therefore involve lymph nodes of the superior hemorrhoidal complex as well as the deep pelvis. Inguinal lymph node involvement is also commonly seen with these tumors. In fact, there are some studies that predict that inguinal lymph node involvement may be present in later stages of this disease as the proximal lymphatic channels of the lower rectum become saturated with tumor cells thereby causing malignant cells to travel backward along the lymphatics and subsequently involve the inguinal region.(3) It is also likely that the degree of tumor differentiation determines whether lymphatic spread occurs. Squamous cell cancer of the anal margin spreads in a similar manner to skin cancers. Inguinal nodes may be involved with these lesions as often as 40% of the time.

Epidermoid cancers of the anus most commonly occur in the sixth and seventh decades of life. Anal canal tumors more commonly occur in women while anal margin lesions most often affect men. The most common symptoms associated with these lesions are rectal bleeding, deep-seated anal pain, mucous discharge per anus, incontinence, and the feeling of a mass in the anal region. The history of these symptoms is important in considering the diagnosis. A careful sexual history should also be obtained as homosexual males and those engaging in anoreceptive intercourse may be at higher risk for the development of this disease. A history of other sexually transmitted diseases is important, particularly a history of anal condyloma. Other risk factors for developing anal cancer include chronic inflammatory disease states of the anal region, such as perianal Crohn's disease, leukoplakia, previous pelvic radiation, and chronic fistulae disease.(4)

The physical examination of patients with anorectal complaints should be complete. This includes inspection of the perianal skin, digital rectal examination, anoscopy, and proctoscopy. Bilateral groins should be palpated for any lymphadenopathy. The location of any anal masses should be carefully noted and biopsies should be performed. These biopsies are usually confirmatory for cancer. If the patient cannot tolerate an office examination or biopsies, then an examination under anesthesia is warranted. Colonoscopic surveillance for patients with anal cancer may be performed but is probably not necessary.(5)

Careful inspection of the perineum for condyloma should be performed. There appears to be a strong correlation between anal condyloma and anal cancer.(6) Anal condyloma is caused by the human papilloma virus (HPV), which has also been implicated in the pathogenesis of anal cancer.(7) Condyloma may become dysplastic and develop into cancer. In addition, human papilloma virus genotypes 16 and 18 have been linked to both cervical cancer as well as anal cancer, thereby supporting the fact that anal cancer may be linked as a sexually transmitted disease. Many anal cancers harbor HPV DNA as detected by chemical analysis. HPV is more often seen in patients with AIDS, thereby possibly linking the development of anal cancer to those individuals infected with the AIDS virus.

Anal intraepithelial neoplasia (AIN) may be a precursor to the development of invasive anal cancers. AIN is a term that is used to describe dysplastic changes of the epithelium of the anal canal. These dysplastic changes typically show a loss of cellular maturation in addition to cellular crowding, abnormal mitoses, and increased nuclear chromatin granules. These are features that have typically been seen in cervical intraepithelial neoplasia. AIN I changes are limited to the lower third of the epithelium, while AIN II changes involve the lower two-thirds of the epithelium, and AIN III represents full thickness changes.

The natural history of AIN is essentially unknown. However, it is thought that condyloma may become dysplastic and then progress through the various stages of AIN and will ultimately become invasive anal cancer. Human papilloma virus type 16 has been identified as a causative agent in AIN. However, HPV infection alone is probably not sufficient to cause changes that may ultimately result in anal malignancies. Other agents that may act synergistically with HPV in this cancer transformation possibly include Epstein- Barr virus, cytomegalovirus, herpes simplex virus 2, cellular events, or other endogenous gene products. In addition, systemic immunosuppression seems to play a role in the development of anal malignancies. AIN seems to be rather prevalent in the immunosuppressed patient population and has been shown to be present in as many as 50 % of the immunosuppressed patients studied compared to less than 1% of the population at large.(8,9)

The true malignant potential of AIN is uncertain. Much of the data available is speculative and based upon women with cervical intraepithelial neoplasia. Studies have shown, however, that AIN discovered incidentally and followed with this entity have never developed into anal cancer.(10) However, patients with AIN III may be at higher risk of developing anal cancer. One study has shown 5 of 32 patients with AIN III developed anal cancer with a median follow-up of 18 months.(11) To complicate matters further, there is some data to suggest that both AIN I and II may progress to AIN III over some length of time.(12)

It is for this reason that some have advocated performing anal colposcopy, a procedure that can better characterize the contour, color, vascular pattern, and texture of anal lesions in order to distinguish which lesions may be histologically worrisome. This procedure may allow a physician to distinguish between low grade and high grade intraepithelial lesions in a similar manner to the management of cervical lesions.(13)

Patients with AIN are often asymptomatic. Occasionally, the patient may complain of some perianal itching and condyloma may be seen on initial examination. These lesions may be present either at the anal margin or within the anal canal. The patients should undergo a thorough physical examination with the use of anoscopy, proctoscopy, anal colposcopy, and biopsy if the lesions are suspected.

The management of AIN is difficult to determine since the natural history of the disease is not entirely understood. Since AIN I and AIN II are unlikely to progress to frank malignancy, a conservative and observant approach may be undertaken. AIN III may pose a greater risk, and therefore surgical treatment should be strongly considered after the patient's surgical risk has been fully assessed. Immunosuppressed patients are more prone to post-operative infections and delayed wound healing. Therapy may include wide local excision with either primary closure or the use of skin grafts, laser vaporization, or cryotherapy. For wide areas involved with AIN III, excision with some type of flap advancement may be warranted.

Anal cancers may be staged by the TNM classification. It should be noted that anal canal lesions are staged differently from anal margin lesions. The details of this staging system can be seen below. Endoanal ultrasound may help to stage these tumors.

Anal Canal Tumors

Tis

Preinvasive (in situ) cancer

T0

No evidence of primary tumor

T1

Tumor occupying not more than 1/3 of the circumference or length of the anal canal and not infiltrating external sphincter

T2

Tumor occupying more than 1/3 the circumference or length of the anal canal or tumor infiltrating external sphincter

T3

Tumor with extension to rectum or skin but not to adjacent structures

T4

Tumor with extension to adjacent structures

TX

Tumor cannot be assessed

Anal Canal Tumors

N0

No evidence of regional lymph nodes

N1

Evidence of regional lymph nodes

NX

Cannot assess lymph nodes

Anal Margin Tumors

Tis

Preinvasive (in situ) cancer

T0

No evidence of primary tumor

T1

Tumor 2 cm. or less, superficial, or exophytic

T2

Tumor more than 2 cm. but less than 5 cm. or with minimal dermal infiltration

T3

Tumor greater than 5 cm or with deep dermal infiltration

T4

Tumor with extension to muscle or bone

TX

Tumor cannot be assessed

Anal Canal Tumors

N0

No evidence of LN involvement

N1

Moveable unilateral regional LN

N2

Moveable bilateral regional LN

N3

Fixed regional LN

NX

Cannot assess LN

Tumors of the anal canal are treated with combined chemoradiation protocols. Dr. Nigro first reported his experience with this modality in 1974.(14) He later reported the results of 104 patients, all having undergone chemoradiation therapy. He demonstrated a complete response in 97 of these patients and an overall survival of 88% with sphincter salvage and no need for a colostomy.(15)

Prior to Nigro's work, abdominoperineal resection with a wide perineal dissection to prevent local recurrence was the treatment of choice for patients with anal cancer.(16) A posterior vaginectomy in women was often performed as well. This procedure was associated with significant operative morbidity and an overall survival of only 50%. In addition, block dissection of the groins was performed several weeks after the APR in order to eradicate any residual disease. Prophylactic groin node dissection is currently not recommended because of the high morbidity associated with this procedure.(17)

The overall survival following abdominoperineal resection for anal canal cancer seems to be dependent upon the size of the tumor, the depth of invasion, and clinical stage, while the histologic type of tumor seems to be relatively unimportant. Local recurrence remains the most common reason for failure and seems to occur most often within 12 months of the surgery. Once local recurrence has been documented, a median survival of 9 months can be expected.(19)

Local excision of anal cancer is best reserved for lesions of the anal margin. It should only be considered for anal canal tumors in relatively infirmed patients and for lesions that are well differentiated with submucosal invasion only. Recurrence rates after local excision are variable but may be as high as 60% with 5-year survival reported between 25% and 83%.(19) Lesions confined to the submucosa may have lymph node metastases up to 30% of the time and this figure increases if the underlying sphincter muscle is involved.

Radiation alone has been use to treat these lesions as well. It may be given as external beam, interstitial implants with radium needles or iridium 192, or intracavitary therapy. External beam radiation has been associated with recurrence rates of approximately 30% and survival rates at 5 years that vary from 40% to 80%. Complications from radiation have been reported in about one third of patients. Interstitial therapy has the advantage of delivering a higher dose to the tumor bed with less overall systemic toxicity. However, pelvic lymph nodes are not adequately treated with interstitial therapy.

In 1974, Nigro et al. published his initial experience with combined chemotherapy and radiation. He felt that "surgical excision is not likely to be adequate treatment for many patients with cancer of the anal canal" and therefore believed that "the therapeutic approach should be changed to include other treatment modalities."(14) The therapy proposed consisted of mitomycin and fluorouracil started on day 1 with 180 rads of radiation per day to a total of 3000 rads over 3 weeks. Additional chemotherapy with fluorouracil was given at the completion of the radiation. Today, there have been variations of this initial plan changing the mitomycin to cis-platinum in some cases and increasing the radiation to 5000 rads. The results have been promising with improved disease free survival and improved quality of life.

Several weeks after the completion of therapy, patients are taken to surgery for an examination under anesthesia and a biopsy of the residual scar from the site of the tumor. If no further tumor is detected the patients are then followed. If the chemoradiation regimen fails, then salvage abdominoperineal resection is performed provided the disease is localized. The survival associated with salvage APR is approximately 50%.(20) Alternatively, the patient may receive additional chemotherapy with boosts of radiation via brachytherapy catheters or external beam to the anal region.

Anal margin tumors are typically treated by wide local excision with a 2.5 centimeter margin. A portion of the external sphincter may be excised if necessary without significantly altering fecal control. The 5-year survival rate with wide local excision of these lesions varies between 60 % and 100%. Local recurrence may be high, but repeat excision may be performed. APR may be required for extensive lesions with significant sphincter involvement. If APR is contemplated it may reasonable to attempt radiation initially. Combined chemoradiation is probably excessive in the treatment of these lesions.

Verrucous tumors of the anal region, also known as Buschke Lowenstein tumors, are a variation of a well- differentiated squamous cell cancer. They generally resemble giant condyloma acuminata, are locally aggressive, and rarely metastasize. They are best treated by wide local excision with some form of anal reconstruction with the use of anal flaps or skin grafts. APR is considered if there is extensive sphincter destruction or significant anal canal infiltration. Radiation is relatively ineffective and may in fact cause these lesions to become more aggressive.(21)

Bowen's disease is a slow growing intra-epidermal squamous cell carcinoma (in-situ) that involves the anus. Few of these will become invasive cancers.(22) The patient typically presents with symptoms of pruritus ani. The general appearance of perianal Bowen's disease is similar to psoriasis with discrete erythematous, pigmented plaques. It is now often considered AIN III and should be treated as such with wide local excision and perianal mapping of the anus.

Paget's disease may occur around the anus as it does in the breast. This disease is an intraepithelial adenocarcinoma with a long pre-invasive phase. It is a rare disease that originates from the apocrine duct glands. Until 1988, there were only 55 cases reported in the literature. The patient often presents with an erythematous, eczematous, scaly skin rash that may be difficult to distinguish from pruritus ani or perianal Crohn's disease. The diagnosis is made by biopsy, which will stain periodic Acid Schiff reagent positive. It is often associated with other underlying malignancies.(23) The treatment is typically a wide local excision with possible chemoradiation reserved for more aggressive lesions. If this therapy ultimately fails, then APR should be strongly considered.

Anorectal melanoma is a serious and life threatening condition. It represents 1% to 3 % of all melanomas affecting both men and women usually in the fifth decade of life. It typically arises from the anal canal epithelium and is most commonly associated with symptoms of bleeding, pain, weight loss, and a palpable anal mass that may not be pigmented. Biopsy is usually confirmatory of the diagnosis. The prognosis is grim whether or not radical surgery is performed with a 5-year survival of approximately 15%. Therefore, it seems reasonable to perform a wide local excision and not subject the patient to the morbidity of radical extirpative pelvic surgery. However, the few long-term survivors of this disease have been treated by APR.(24)

Anorectal sarcomas are fortunately rare tumors. The symptoms are similar to other anal lesions and include itching, pain, and bleeding. These tumors include leiomyosarcomas, rhabdomyosarcomas, fibrosarcomas, and liposarcomas. Malignant lesions are noted by the number of mitoses per high power field. These lesions have been treated with resection, chemotherapy, and radiation but remain relatively radio-resistant. Recurrence rates are noted to be high and distant metastases are frequent.(25)

In summary, there are many tumors that affect the anal region. The benign lesions as well as tumors of the anal margin may be treated by wide local excision. Anal canal cancer is most often treated with chemoradiation protocols reserving radical surgery for those that fail this initial treatment. This management has changed dramatically over the last 25 years under the influence of surgical pioneers with an improved survival and overall better quality of life.

References

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