Cancerul de canal anal - aspecte legate de diagnostic și tratament

Background

1. Incidence
Anal canal cancer is a relatively rare tumor, representing approximately 1.5% of all digestive cancers in the United States(1). It is approximately 20 to 30 times rarer than colon cancer, but its annual incidence is increasing, reaching up to 4000 cases, with a female predominance(2). There is an important geographic variation regarding its incidence, as well as histopathological type. Therefore, in the United States, up to 80% of anal cancers are represented by squamous-cell carcinomas, while in Japan adenocarcinomas account for the same percent(3). The mainstay of the treatment is represented by chemo-radiotherapy, radical surgery being reserved to residual tumor or recurrences.
 

2. Histopathology
Depending on the lining epithelium, anal canal is divided into three regions:

• colorectal zone: located proximally and containg columnar epithelium;
• transitional zone: spread over a distance that varies between 0 and 12 mm that contains a pseudostratified type of epithelium resembling the urothelial one. A transformation zone is unanimously accepted in uterine cancer. Some authors propose a rectal “transformation” zone in which squamous cell metaplasia covers the normal cylindrical epithelium and the upper extension can sometimes reach 10 cm. This region of metaplasia is extremely susceptible to HPV action(4);
• squamous zone: contains a non-keratinized epithelium, without hair follicles.

Squamous-cell carcinoma represents approximately 75-80% of all anal cancers(5). The remainder histopathological varieties are much rarer and are represented by: adenocarcinoma (19%)(6) and melanomas (4%). Leiomyosarcomas, lymphomas and small cell carcinomas (similar in terms of evolution and prognosis to lung small cell carcinomas), undifferentiated carcinoma or anal GIST - only 17 cases described in literature up to 2003(7) - have also been reported. 
Concerning anal margin neoplasia, these are represented by:

• Bowen disease (in situ squamous-cell carcinoma);
• invasive squamous-cell carcinoma;
• Paget disease;
• basal cell carcinoma: an extremely rare tumor, approximately 20 cases having been reported in 20 years(28), that is of good prognostic.
• verrucous carcinoma: also known as Buschke-Lowenstein disease. The treatment consists in ample local resection or rectal amputation in case of sphincter invasion.

3. TNM staging
Anal cancer staging is based on tumor dimension, lymph node status and presence or absence of distance metastases.
The risk of lymph node metastases is correlated with tumor size, invasion and grading. Thus, based on a study conducted in 2003, lymph node metastatic rate in relation to T status has been the following: T1 - 0%; T2 - 8.5%; T3 - 29%; T4 - 35%(16). Approximately 10-30% of the patients present with inguinal metastases at initial diagnosis and another 10-22% develop them during the course of their disease(17). 
Distance metastases can be found in 10-17% of the patients at the time of the diagnosis, liver, lung and bone metastases being the most frequent(18).
4. Risk factors

• Benign perianal pathology - perianal fissures and fistulas determine a chronic local inflammation that can lead to genetic alterations and have been incriminated as being etiologic factors. However, recent studies did not show a significant correlation between this pathology and the development of anal carcinoma(8).
• Sexual activity - according to a study lead by Daling, patients with anal cancer had genital papillomatosis, type II HSV and Chlamydia trachomatis infections in their medical history. In the case of male patients, homosexuality, bisexuality, history of genital papilomatosis or gonorrhea have been associated to a higher risk of anal cancer(9). Another study, published in 1997, adds to the risk factors, for females: history of gonorrhea, uterine cervix dysplasia, more than 10 sexual partners, anal sexual intercourse; for male patients:  syphilis is another risk factor(10).
• HPV infection - it is the widest spread sexually transmitted infection in Europe(11). Anal HPV infection can be clinically inapparent or it may manifest as condyloma. Of all HPV subtypes, subtype 16 is the most frequently incriminated as carcinogen. In a study conducted in 1991, HPV has been found in 85% of anal cancer patients(12). Viral transmission is not influenced by the use of condoms as it is localized at the base of the penis and scrotum.
• Cigarette smoking - a study conducted in the early 1990s highlighted a relative risk of 1.9 for the patients that smoke 20 packs of cigarettes/ year and one of 5.2 for those smoking over 50 packs of cigarettes/year(13). Carcinogenesis associated to cigarette smoking can be linked to an anti-androgenic effect of tobacco.
• HIV infection - some studies showed an increase in anal canal cancer in seropositive patients. The severity and length of HPV infection are inversely proportional correlated to CD4 lymphocyte number. Immunocompromised patients, either due to HIV infection or to post-transplantation status or chemotherapy, have an increased risk of HPV infection and progression to squamous cell carcinoma(15).

Anatomy

Surgical anal canal spreads from ano-rectal ring (2 cm above the dentate line) to the external anal orifice. Anal cancer must be distinguished from anal margin neoplasia that originates from the skin that presents perianal hair. Some authors consider a 5 cm distance from the external anal orifice as the lateral limit(29). The correct classification of perianal neoplasia into the two mentioned categories is extremely important as those of anal margin are of better prognosis. Altogether, an erroneous classification could overestimate the role of radio-chemotherapy(30).
Pectinate line represents an extremely important landmark for the vascularization and lymph node drainage. Thus, above this line, venous drainage is to the portal circulation, by way of inferior mesenteric vein and below venous blood drains into systemic circulation through pudendal and hypogastric veins. Above the pectinate line lymphatics drain into the inferior mesenteric, but also to hypogastric and obturatory lymph nodes, while below pectinate line-especially to inguinal lymph nodes, but also to femoral ones(31).

Diagnosis

Clinical examination
Approximately 20% of patients are asymptomatic, the remainder presenting with blood loss (the most frequent symptom), local pain, palpation of a tumor mass, rectal tenesmus, pruritus. Due to the resemblance to benign perianal pathology, the diagnosis is too often delayed.
Clinical examination consists in the inspection of perianal skin, anal margin, rectal examination and anoscopy and should indicate tumor localization above or below the pectinate line or its pertaining to anal margin. Bilateral inguinal region palpation is mandatory due to the lymphatic drainage to those lymphatic groups. Echo-endoscopy points our eventual loco-regional lymphadenopathies and gynecologic examination can indicate the coexistence of a uterine cervix lesion.
The diagnostic of certainty is based on histopathologic examination. Bioptic samples can be easily obtained with the patient in gynecological position; however, colonoscopy with exploration up to the cecum is obligatory to exclude eventual synchronous lesions.
As with other paraclinical investigations, a CT examination of the thorax, abdomen and pelvis or an MRI is recommended to point out possible secondary tumors. 

Treatment

Squamous cell carcinoma represents 80% of all anal canal cancers. Untill the 1970s, standard treatment consisted in abdominoperineal rectal amputation. However, despite the radical nature of the surgical intervention, local recurrence rate was around 47% and 5-year survival rate varied between 40% and 70%(19). For patients having small lesions, a large local excision has been proposed, accompanied however by disappointing results, excepting patients with a smaller than 2 cm anal margin cancer(20). Currently, the treatment is based on chemo-radiotherapy of curative intent, surgery being reserved for patients presenting with recurrences or residual disease after primary therapy (radio-+chemotherapy). 

The place of surgery in anal canal cancer 

Up to 40% of anal cancer patients present with residual disease after the completion of primary therapy or have local tumor relapse(21). Abdominoperineal rectal amputation is the standard salvage therapy for patients who develop local recurrences. After salvage therapy, 5-year survival rate is of 22-47%(22). Patient selection for surgery is extremely important and should include a CT/MRI to exclude metastatic disease or pelvic bone invasion and, ideally, also a PET-CT, an investigation that can distinguish between post-radiotherapy changes and those of tumoral nature. Only approximately 50% of the patients with local relapse are eligible for salvage therapy. Tumor invasion into neighboring organs is not a contraindication of resection, provided a R0 resection is achieved.
Patient morbidity after “salvage” rectal amputation is high, the most important complications being those related to wound infection. Up to 66% of the patients require more than 3 months for a complete wound healing, over 35% of the patients developing perineal wound dehiscence(23). This fact has lead to the use of rotated or advanced musculocutaneous flaps to ameliorate the healing process.
Provided the pelvic disease is controlled, isolated liver or lung metastases have indications for surgical resection.
Inguinal lymphadenopathies
Up to 25% of the patients develop inguinal lymphadenopathies that are usually unilateral(24). Due to significant morbidity and the relatively low impact on survival, prophylactic inguinal lymphadenectomy is not recommended(25). Inguinal lymphadenectomy is indicated for patients with voluminous lymphatic blocks or to those with an obvious lymphadenopathy after chemo-radiotherapy(26). 
Some authors recommend for synchronous lymphadenopathies inguinal lymphadenectomy with chemo- and radiotherapy following the healing of the wound.  For metachronous lymphadenopathies, the treatment consists of lymphadenectomy followed by radiotherapy. Survival after radical inguinal lymphadenectomy can reach up to 55% in selected cases(27). 
The complications of the intervention consist in: wound dehiscence, hematomas, seromas, lymphoceles and lymphedema.   n