Anal cancer

Incidence increasing with an estimated 9000 cases  per year in US.

In 2023 there was an estimated 9760 new cases and 1870 estimated deaths.

Anal canal cancers are defined as tumors that develop from mucosa that cannot be entirely seen when the buttocks are pressed together.

Perianal cancers, arise within the skin distal to or at the squamous  mucocutaneous junction, and can be visualized completely, when the buttocks are pressed together, and are within 5 cm of the anus.

An estimated 9700 new cases: 3180 in males and 6580 in females of anal cancer, involving the anus, anal canal, or anal rectum will occur in the US in 2023.

An estimated 1870 deaths from anal cancer will occur in the US in 2023.

Incidence of 0.5 to 2 new cases in 100,000 per year.

4% of all lower gastrointestinal cancers, and 1% of all G.I. cancers.

Historically associated with older women, particularly in the urban and HIV populations.

The suppression of the immune system by immunosuppressive drugs, or HIV infection facilitates the persistence of HPV infection of the anal region.

People with HIV have an approximate 15 to 35 fold increase likelihood of anal cancer compared with the general population.

Increasing risk in men and women in the U.S. at about 3%/year and among white women 4% and among black men 6%.

The incidence of anal cancer is increased in patients with solid  organ transplant recipients and in patients with autoimmune diseases.

Slight female predominance 1.5:1.

Estimated 6239 cases and 780 deaths attributed to AC in 2012.

Incidence of squamous cell carcinoma of the anus in white males 0.71 per 100,000 increasing approximately 2.6% per year from years 1993-1996.

In 2006 the incidence rate per 100,000 individuals was 1.5 (SEER).

The incidence of squamous cell carcinoma of the anal canal continues to rise annually in the US by 2.2% per year.

The incidence in homosexual men estimated to be 25-37 cases per 100,000 men, with a relative risk of anal malignancy 84 times that of the general population in homosexual men with AIDS.

Among homosexual men with genital warts the relative risk of developing such a lesion is 12.6.

Risk factors include persistent HPV infection a history of anal condylomas and immunosuppression therapy or HIV infection.

Anal carcinoma is associated with HPV infection, a history of receptive anal intercourse, or sexually transmitted disease, history of cervical, vulva, vaginal cancer, immunosuppression of solid organ transplantation, or HIV infection, hematologic, malignancies, and certain autoimmune disorders, and smoking.

More than 90% of anal cancer cases are linked to HPV.

Anal cancer is caused by human papillomavirus (HPV) infection, particularly HPV 16 and it is preceded by high-grade squamous intraepithelial lesion, a pre-cancerous growth that is known as anal intraepithelial neoplasia.

80-90% of squamous of carcinomas of the anus are HPV or p16 positive and often have PIK3CA mutations.

Among patients with biopsy proven anal high-grade squamous intraepithelial lesion, the risk of anal cancer can be lowered with treatments for such lesions: ablation or excision, topical 5FU or imiquimod.

The risk of anal cancer is rising with data suggesting that persons engaging in certain sexual practices, such as receptive anal intercourse, or persons with a high lifetime number of sexual partners are at an increased risk of anal cancer.

These practices may have led to an increase in the number of individuals at risk for infection with human papillomavirus (HPV).

HPV infection is strongly associated with anal cancer development and may be a necessary step in its carcinogenesis,

In HIV positive patients the risk for developing anal squamous cell carcinoma is 40-80 fold higher compared to the general population.

Worse colostomy free survival and higher recurrence rates are associated with lower post treatment CD4 count, as immmunity plays a role in both the development of this lesion and increased rate of recurrence among patients with HIV.

Squamous cell carcinoma accounts for approximately 85% of all cases of AC.

Squamous cell carcinoma of the anal canal is a malignancy comprising only 1.5% of all gastrointestinal malignancies.

The remaining cases of anal carcinoma are adenocarcinoma 10%, and other types 5%.

Variants of squamous carcinoma of the anal canal, are cloacogenic and large cell keratinizing and large cell non-keratinizing or basaloid carcinomas.

Lymph drainage of anal cancer tumors depends on the location in the anal region: cancers in the perianal skin, and region of the anal canal, distal to the dentate line drain mainly to the superficial inguinal nodes.

Lymph drainage, at and proximal to the dentate line is directed to the anal rectal, perirectal, and paravertebral nodes, and to some of the nodes in the internal iliac system.

More proximal cancers drain to perirectal nodes, and to nodes  in the inferior mesenteric system.

Distal cancer present with higher incidence of inguinal node metastases.

Squamous cell cancer of the anus develops in patients with genital warts with a latent period of 5-40 years.

Incidence in women about 0.95 per 100,000.

Recent studies reflect human papillomavirus as the cause of anal intraepithelial neoplasia, and anal cancer frequently seen in young patients involved in receptive anal intercourse, in patients with HIV and in individuals with multiple sexual partners.

Evidence is accumulating indicating that oncogenic types of human papillomavirus, subtypes 16, and 18 are etiological linked to squamous cell carcinoma of the anal canal.

Incidence in the general population is 0.9 per 100,00 people.

Incidence in men involved in receptive anal intercourse is 35 per 100,00 persons.

Regional nodes are the inguinal, internal iliac, perirectal lymph nodes.

Tumors below the dentate line drain to the inguinal and femoral nodes and tumors above the dentate line drain into the perirectal and paravertebral nodes.

When patients present with symptoms, the tumor is often detected by digital rectal exam and clinical assessment including palpation of inguinal nodes.

Approximately 45% of patients with anal carcinoma present with rectal bleeding, while approximately 30% have either pain or sensation of a rectal mass.

Evaluation includes the direct visualization of the anal mass with physical exam and colonoscopy to determine tumor size, location and extent.

Anoscopy  and proctoscopy performed to evaluate tumor extension and enable a biopsy.

CT, MRI scans are useful to assess invasion into surrounding organs and involvement of pelvic or inguinal lymph nodes.

CT of the chest is performed to evaluate for pulmonary metastases.

PET/CT scanning can verify staging before treatment.

PET/CT scanning increases the sensitivity for diagnosing lymph node involvement, and changing the stage of the disease.

The increased use of more sensitive imaging techniques has found increased lymph node positivity in recent years.

HIV testing should be performed if the patient’s HIV status is unknown.

The  prognosis of anal carcinoma is related to the size of the primary tumor in the presence of lymph node metastasis.

Older studies revealed 50% of anal carcinomas were localized at initial diagnosis with an 80% five year survival rate.

Approximately 29% of patients had anal carcinoma already spread to regional lymph nodes at diagnosis with a 60% five year survival.

Male status and positive lymph nodes and tumor size greater than 5 cm are independent prognostic factors for disease free survival in patients  with anal cancer treated with 5FU and radiation and either mitomycin or cisplatinum.

Patients with HPV negative and or p16 positivity have improved overall survival in patients with anal carcinoma.

The 12% of patients presenting with this metastasis had a 30% five year survival rate.

Staging is performed by MRI and/or PET.

Women require full gynecological examination to assess local invasion into the posterior vagina and to ascertain the presence of HPV associated conditions.

Because of the entire sensitivity in detecting regional lymph node involvement PET scan is increasingly commonly used for staging prior to treatment.

Surgical management with and abdominal perineal resection was formally used and has been replaced by chemoradiation using 5-FU/mitomycin squamous cell lesions.

The role of surgery is now confined to node negative distal anal canal, and anal margin carcinomas less than 2 cm in diameter, for which wide local excision with negative margins is curative, and to salvage therapy for recurrences post chemoradiation.

Combination chemotherapy and radiation demonstrates complete pathologic response in a very high percentage of patients.

Survival outcomes vary widely, with a five-year survival rate of 82% for localized disease, 66% for regional disease and only 34% for metastatic disease.

Combinations of mitomycin C and 5FU is the standard of care along with radiation leading to complete tumor aggression in 80 to 90% of patients, with local recurrent failure rates of about 15%.

Because of organ preservation chemoradiotherapy is the first line treatment for anal cancer and surgical resection is reserved for salvage treatment for residual or recurrent disease.

For patients with locoregional recurrence, salvage abdominal peroneal resection is recommended, which can achieve disease control in up to 77% of patients.

The standard of care for locally advanced anal cancer is definitive pelvic chemoradiotherapy.

This  principle holds the patient with positive periotic lymph nodes that can be included in the radiation field, although with limited data support.

Generally mitomycin/5FU or Mitomycin/capecitabine are administered concurrently with radiation: cisplatinum is an alternative.

In the metastatic setting chemotherapy is considered standard of care however the addition pelvic radiotherapy in the metastatic setting prolongs survival (Wang Y).

The most common sites of anal cancer, metastasize outside of the pelvis, or the liver, lung, and extrapelvic lymph nodes.

Only 10 to 20% of patients with anal carcinoma present with extra pelvic metastatic disease.

The addition of radiation to chemotherapy for metastatic disease, results in longer median overall survival.

The rates of grade 2 or greater complications to chemoradiation include hematologic, dermatologic, gastrointestinal, and genitourinary adverse events.

Most squamous cell carcinomas of the anus express EGFR, while KRAS mutations are uncommon.

XELOX-XRT In a phase 2 study showed complete response rate of 100% and a 89.5% three years time to treatment failure.

Efficacious agents in metastatic disease include carboplatinum/paclitaxel, docetaxel, cisplatinum and 5FU.

PD-1 inhibition his promising activity in patients that have progressed on chemotherapy.

PD – L1 inhibitors have been shown to have complete remissions in patients with anal carcinoma.

Patients need to undergo extensive surveillance in this situation to manage disease recurrence.

Follow up examinations, including evaluation of nodal areas, rectal exams and for stages II-IV  annual CT scan of chest abdomen and pelvis and or annual MRI of the abdomen pelvis, for three years is recommended.

ctDNA testing may be an improved way to follow up for anal squamous cell carcinomas.

HPV vaccination is recommended to prevent disease.

Leave a Reply

Your email address will not be published. Required fields are marked *