Anal Cancer

Etiology

There is a clear correlation between human papillomavirus (HPV) infection, mainly HPV 16, and anal cancer. Hence, there is an increased incidence in certain populations, such as young men who have genital viral infections. A large study highlighted a correlation between both the amount of sexual activity and venereal infections and anal cancer. Earlier low-powered studies linked anal-receptive intercourse to an increased risk of anal cancer, but this has not been confirmed in a large trial. In addition to HPV, condylomata infections have been implicated in anal cancer in the general population and homosexual men. A study showed that in women with genital warts, anal cancer was associated with Human Papillomavirus and Chlamydia trachomatis. Conversely, in men with no history of genital warts, there was an association with gonorrhea infection. In addition to the etiologies mentioned above, there has been an association between acquired immunodeficiency syndrome (AIDS) and anal cancer. In patients infected with the human immunodeficiency virus (HIV), the risk of anal cancer is 40 times higher compared to the general population.[3][4]

Epidemiology

Anal cancer is a rare tumor comprising only 2.5% of all digestive system malignancies in the United States. Per data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER), the incidence of new cases in the United States was 8200, with 1100 estimated deaths in 2017. The five-year overall survival between 2007 and 2013 was 66.9%. Also, approximately 0.2% of men and women will be diagnosed with anal cancer at some point during their lifetime based on acquired data from 2012 through 2014. The men-to-woman ratio is approximately 2 to 3.5. Anal cancer is more prevalent in patients with viral genital infections such as HPV and HIV. Also, there is an increased incidence in individuals with multiple sexual partners, those who practice anal-receptive intercourse, have condyloma infections, or have AIDS.[5][6]

Pathophysiology

The pathophysiology of the development of anal cancer is believed to be directly linked to a complex inflammatory process secondary to infections such as HPV (particularly serotypes 16 and 18). In a Scandinavian study, serotype 16 was detected in 73% of anal cancer specimens, and serotypes 16, 18, or both were present in 84% of the specimens. The progression of this inflammatory process heralds the development of anal intraepithelial neoplasia (AIN), or squamous cell carcinoma in situ (Bowen disease), which is a pre-malignant condition. Anal intraepithelial neoplasia can be graded from I to III depending on the abnormalities in differentiation and maturation of the squamous layers, mitotic activity, nuclear membrane changes, and depth of those abnormalities. AIN can subsequently progress to invasive squamous cell carcinoma (SCC), and this occurs in 10% to 11% of cases. HIV-positive patients have a higher rate of conversion to squamous cell carcinoma even if AIDS is not manifested. Most anal cancers are squamous or colitogenic cancers with a few adenocarcinomas and rarely melanoma. Tumors tend to spread by local extension but also have the potential to metastasize.

History and Physical

A complete history and physical examination are quintessential in patients with anal cancer. Patients may have no symptoms or present with anal bleeding, anal or pelvic pain, weight loss, the sensation of a mass in the anus or rectum, anal irritation, prolapse of tissue, incontinence of flatus or stools, and obstipation. Due to the negative stigma associated with this diagnosis, patients usually present late for medical care. Approximately 19% of patients wait six months or more after the onset of symptoms before seeking medical attention. Moreover, misdiagnosis does occur, with some cases misdiagnosed as hemorrhoids, and in one review, this occurred in 27% of cases. A complete history is important such as past medical history, sexual activity history, and any history of venereal diseases. A complete physical examination is imperative, including digital rectal examination, inguinal lymph node palpation, and gynecologic examination in females, including screening tests for cervical cancer.

Evaluation

In addition to a complete history and physical examination, laboratory and radiologic examinations are important. Laboratory studies include a complete blood count (CBC), chemistry panel, HIV testing in specific cases, anoscopy, and anal mass biopsy or fine-needle aspiration, as well as imaging as indicated, including CT or PET scan or an MRI. Imaging is imperative, specifically when metastatic disease is suspected. Moreover, if the diagnosis of anal cancer is confirmed, testing for HPV, gonorrhea, and chlamydia is recommended.[7]

Treatment / Management

In the past, the treatment of anal cancer was surgical resection utilizing the anterior-posterior approach. This treatment was curative in 50% of cases and was associated with significant morbidity. The current treatment modality for localized anal cancer is chemotherapy and radiation. The treatment of anal cancer, akin to many other malignancies, is dependent on the stage of disease at presentation. Tumors that are less than 2 cm with no lymph node involvement and are well-differentiated (T1N0, stage I) are treated with local excision. If adequate negative margins are attained, patients are usually observed. Conversely, if tumors are stage I (T1N0) but are poorly differentiated or are at a higher stage but not metastatic (poorly differentiated T1N0, T2-T4, and N0, or any T and N positive), are treated with chemotherapy and radiation. The regimen most widely used currently is mitomycin-C (12 mg/m intravenous (IV) bolus on day one), fluorouracil (1000mg/m/day IV continuous infusion over four days, during the first and last week of radiation), and radiation (total dose 45 Gy). This regimen afforded patients a 46% reduction in the risk of local failure. The expectation for patients is a complete response rate (CR) in 70% to 80% of cases with an overall five-year survival rate of greater than 65%. A large randomized phase III trial that involved 682 patients compared the regimen above to an intensified regimen consisting of induction with cisplatin and fluorouracil followed by cisplatin, fluorouracil, and radiation. The latter regimen did not show superiority, and in fact, the five-year local-regional recurrence rate, distant metastatic rate, and cumulative rate of colostomy favored the mitomycin-C regimen. Thus, in clinical practice, the established regimen is mitomycin-C, fluorouracil, and radiation. However, if mitomycin-C is contradicted, then cisplatin, fluorouracil, and radiation can be used. Patients presenting with inguinal lymph node involvement can receive additional radiation therapy to the area or lymph node dissection, although the latter is rarely used.

Post-treatment surveillance and assessment of local response are paramount after the therapy with chemoradiation. Anal cancers regress slowly over many weeks after the chemoradiation, sometimes up to 26 weeks following therapy.[8] It is recommended to access response by physical examination with the digital rectal examination (DRE) as well as palpation of the inguinal regions around 8 to 12 weeks following the completion of therapy. Patients who show a complete response are under close surveillance with every 3-6 month DRE, anoscopy, and inguinal node palpation for up to 5 years, along with an annual CT scan of the chest, abdomen, and pelvis for 3 years. Persistent disease at 12 weeks can be continued to monitor with close surveillance for up to 6 months following the chemoradiation, as long as there is no progression. There is a significant chance these patients will continue to regress on serial exams.[8] Any progressive disease should be further evaluated with a biopsy as well as consideration for salvage therapy should be made. For patients presenting with metastatic disease, treatment is palliative, and regimens used include fluorouracil, mitomycin-C, cisplatin, and paclitaxel, in addition to other regimens. Trials evaluating the role of immunotherapy in anal squamous cell carcinoma are currently ongoing.[9][10](A1)

Differential Diagnosis

• Chancroid
• Anal fissure/fistula
• Hemorrhoids
• Condylomata acuminatum
• Psoriasis

Staging

Anal cancer TNM staging AJCC UICC 8th edition: 

• T Stage:
  • TX Primary tumor not assessed
  • T0 No evidence of primary tumor
  • Tis High-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II-III, high-grade anal intraepithelial neoplasia)
  • T1 Tumor ≤2 cm
  • T2 Tumor >2 cm but ≤5 cm
  • T3 Tumor >5 cm
  • T4 Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder
• N Stage:
  • NX Regional lymph nodes cannot be assessed
  • N0 No regional lymph node metastasis
  • N1 Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes
  • N1a Metastasis in inguinal, mesorectal, or internal iliac lymph nodes
  • N1b Metastasis in external iliac lymph nodes
  • N1c Metastasis in external iliac with any N1a nodes
• M Stage:
  • M0 No distant metastasis
  • M1 Distant metastasis

Complications

Complications are chiefly related to treatment and include the following:

• Side effects of radiation
• Adverse effects of chemotherapy
• Decreased libido
• Bowel dysfunction
• Proctitis
• Rectal bleeding
• Surgery-associated strictures, fistulas, and wound infections