Anal Squamous Cell Carcinoma

Anal squamous cell carcinoma is a rare cancer that develops in the tissues lining the anal canal or around the anus. It affects about 11,000 people in the United States each year and is usually linked to infection with certain types of human papillomavirus (HPV). When caught early, this cancer is often curable.

Table of contents

• What is Anal Squamous Cell Carcinoma?
• Associated Anatomy
• Symptoms and Warning Signs
• Causes and Risk Factors
• How to Lower Your Risk
• Diagnosis and Testing
• Treatment Options
• Outlook and Survival

What is Anal Squamous Cell Carcinoma?

Anal squamous cell carcinoma is the most common type of anal cancer, making up more than 80% of all anal cancers^[1][4]. It develops in the squamous cells, which are flat cells that line and protect the anal canal and the area around the anus^[4].

This cancer accounts for approximately 4% of all cancers of the lower digestive tract^[2][6]. The incidence of anal cancer has increased during the second half of the 20th century, with rates growing by more than 2.9% compared to the decade of 1992-2001^[6].

Like cervical cancer, anal squamous cell carcinoma is primarily linked to human papillomavirus (HPV) infection. In both diseases, HPV-related inflammation leads to abnormal cell changes that can progress to cancer^[3].

Associated Anatomy

• Anal canal
• Anus
• Rectum
• Anal squamocolumnar junction

The anal canal is the lower part of the digestive system. The anus is the opening where stool leaves the body^[1]. Anal squamous cell carcinoma develops at the anal squamocolumnar junction, a special area where different types of cells meet^[3].

Symptoms and Warning Signs

The symptoms of anal squamous cell carcinoma can be similar to those of common conditions like hemorrhoids, which is why it’s important to get checked by a healthcare provider^[1].

The most frequent symptom is rectal bleeding, which occurs in about 45% of patients^[6]. Other signs of anal cancer include^[1]:

• Rectal bleeding or bloody stools (most common)
• Pain or fullness in the area that feels like constantly needing to have a bowel movement
• Changes in bowel habits or what stools look like, such as having thinner stools
• A lump or mass at the anal opening
• An itchy anus

Having one or more of these symptoms doesn’t mean you have anal cancer. However, you should talk to a healthcare provider if symptoms get worse or don’t improve within a few days^[1].

Patients with anal cancer often delay seeking medical care, and the diagnosis is sometimes significantly delayed while they receive treatment for other benign conditions like hemorrhoids^[3].

Causes and Risk Factors

The main cause of anal squamous cell carcinoma is infection with certain types of human papillomavirus (HPV). In one study, HPV DNA was detected in 73% of anal cancer specimens for serotype 16, and in 84% of specimens for serotypes 16, 18, or both^[3]. The same strains of HPV that can lead to cervical cancer can also lead to anal cancer^[1].

It’s important to know that most people with HPV don’t get anal cancer, and not everyone with anal cancer has HPV^[1]. HPV infection is very common and doesn’t usually cause symptoms, so most people who have it are completely unaware^[1].

Several factors may increase your chance of developing this condition^[1][6]:

• Engaging in unprotected anal sex as the receiving partner, regardless of sex. Having many sexual partners increases risk for HPV and anal cancer.
• Not being vaccinated against HPV. The vaccine protects against the HPV strains linked to cancer.
• Having HIV. HIV weakens the immune system, so it’s not as good at fighting off viruses like HPV. Some people with anal cancer have both HPV and HIV infections.
• Being immunocompromised. Several conditions, not just HIV, can weaken the immune system and increase risk. Medicines that weaken immune response can also play a role.
• Having cancers that affect the genitals, especially vulvar, vaginal, or cervical cancer.
• Smoking. People who smoke are more likely to develop cancer of all kinds.
• A history of sexually transmitted diseases
• Immunosuppression after organ transplantation
• Haematological or immunological disorders

How to Lower Your Risk

There’s no guaranteed way to prevent anal cancer. However, you can reduce your chances by taking the following steps^[1]:

• Don’t start smoking and quit if you do
• Use condoms when you have anal sex
• Get the HPV vaccine if you’re eligible for it. This vaccine not only prevents anal cancer, but also cancers of the mouth and throat, cervical cancer, and penile cancer.
• Ask a healthcare provider if you’d benefit from cancer screenings

Healthcare providers don’t typically screen for anal cancer. However, if you have a lot of risk factors, screenings like an anal pap test or an anal HPV test may be a good idea. This is especially important as anal cancer doesn’t always cause symptoms in the early stages. These tests check a sample of tissue for abnormal cells or the HPV virus^[1].

Anal squamous cell carcinoma develops from a precancerous lesion called high-grade anal intraepithelial neoplasia (AIN-II, AIN-III). The presence of AIN in high-risk groups, especially HIV-positive patients, is an indication for ongoing surveillance by means of high-resolution anoscopy, close follow-up, topical medications, or other methods^[3].

Diagnosis and Testing

The diagnosis of anal squamous cell carcinoma requires several steps^[6]:

Clinical examination is the first step. During a digital rectal exam, a healthcare professional inserts a gloved, lubricated finger into the anus to feel the anal canal and rectum for growths or other signs of cancer^[12]. The examination also includes palpation of the inguinal lymph nodes^[6].

High-resolution anoscopy follows the clinical examination. During an anoscopy, a healthcare professional inserts a thin, flexible tube with a light through the anal canal and rectum. This tube is called an anoscope. A lens on the anoscope allows examination of the inside of the anal canal^[12].

Biopsy is necessary for histologic diagnosis. A biopsy is a procedure to remove a sample of tissue for testing in a lab. The sample is often collected during an anoscopy using special tools that can go through the anoscope. The sample is tested in a lab to see if it is cancer^[12]. This can be done through fine-needle aspiration biopsy or core biopsy^[6].

Imaging tests are used to show the location and size of the cancer. Tests might include ultrasound, X-ray, MRI, CT scan, and positron emission tomography scan (PET scan)^[12]. Computed tomography or magnetic resonance imaging evaluation of the pelvic lymph nodes is also necessary^[6].

If you’re diagnosed with anal cancer, you may have additional tests to see if the cancer has spread. These tests help determine the extent of the cancer, also called the stage^[12].

Treatment Options

The treatment for anal squamous cell carcinoma depends on the size of the cancer, where it is, if it has spread, and general health^[11].

Chemoradiation

The main treatment for anal cancer is a combination of radiotherapy and chemotherapy, called chemoradiation or chemoradiotherapy^[11][18]. This treatment is usually given if anal cancer has not spread, which means most people with anal cancer do not need to have surgery^[11].

For the majority of patients diagnosed with anal squamous cell carcinoma, treatment consists of radiation therapy combined with radiosensitizing chemotherapeutic agents. This treatment method has remained remarkably unchanged since its advent as the so-called Nigro Protocol in 1974^[8].

The standard regimen includes 5-fluorouracil (5-FU), mitomycin, and radiotherapy. 5-FU is infused continuously during days 1-4 and days 29-32. Mitomycin is administered on days 1 and 29 as a bolus infusion. Alternatively, oral capecitabine can be substituted for 5-FU^[8].

Prior to 1974, patients with invasive cancer were routinely scheduled for abdominoperineal amputation. After that, it was demonstrated that treatment with 5-fluorouracil and radiotherapy associated with mitomycin or capecitabine could be adequate to treat the tumor without surgery^[6].

Surgery

Surgery plays a limited role in the treatment for anal cancer^[8]. Surgery is sometimes used if^[11]:

• The cancer is small and has not spread
• Chemoradiation does not get rid of all the cancer, or it comes back
• You are not able to have radiotherapy, for example if you’ve had radiotherapy in the pelvic area before

Surgery for anal cancer usually involves removing just the part of the anus that’s affected. Local excision is considered appropriate only for selected patients with superficially invasive squamous cell carcinoma of the anus or early perianal (anal margin) SCC^[8].

If the cancer has spread or come back, you may need surgery to remove all of the anus, the rectum (which joins the anus to the bowel), and part of the bowel. This procedure is called abdominoperineal resection^[11]. This means you’ll need to have a pouch (stoma bag) fitted to the outside of your body to collect stool. This is called a colostomy. If you need a colostomy, you’ll be looked after by a specialist stoma nurse^[11].

Radical surgery is indicated for residual or recurrent cancer in the anal canal after nonoperative therapy^[8]. Currently, abdominoperineal resection is limited almost exclusively to selected patients with chemoradiation-refractory or recurrent disease^[3].

Immunotherapy

More recently, immune checkpoint inhibitors such as pembrolizumab and nivolumab have entered clinical practice as second-line agents^[8]. These may be used in second-line therapy for patients who have not responded to initial treatment^[3].

Outlook and Survival

Anal cancer is usually curable, especially when it’s caught early^[1]. Since 1980, patients with a diagnosis of anal cancer have shown a significant improvement in survival. In Europe during the years 1983-1994, 1-year survival increased from 78% to 81%, and the improvement over 5 years was between 48% and 54%^[6].

The two major factors that affect prognosis are tumor size and whether the cancer has spread to lymph nodes. Primary tumors smaller than 2 cm have a better prognosis^[10].

At presentation, most patients have T1 or T2 disease (tumors 5 cm or smaller), and fewer than 20% of patients have cancer in their lymph nodes. The 5-year survival rate for these early-stage patients exceeds 85%^[10].

Even in patients with lymph node involvement, 5-year survival rates exceed 50% in the absence of invasion into adjacent organs or distant spread of the cancer^[10].

You’ll have regular check-ups during and after any treatments. You may also have tests and scans. If you have any symptoms or side effects that you are worried about, talk to your specialists. You do not need to wait for your next check-up^[11].