Five things you should know about HPV and Anal Cancer

1. HPV (Human Papillomavirus) and anal squamous cell carcinoma (ASCC)

Although still rare, the incidence of anal carcinoma has been increasing, having doubled in the last two decades. More than 90% of anal squamous cell carcinoma (ASCC) is caused by HPV infection . There are more than 100 subtypes of HPV, but some were demonstrated to be more carcinogenic, especially 16 and 18. Populations at higher risk for ASCC are: HIV infected patients, men who have sex with men, patients who perform anal receptive intercourse, tobacco smokers, patients with chronic immunosuppression and women with cervical dysplasia.

2. Physiopathology of precursor lesions

Most of what is known about the physiopathology of anal dysplasia comes from what is known about cervical dysplasia. Similarly to cervical cancer, which occurs in a transformation zone in the cervix, ASCC also occurs in a transformation zone, the ATZ (anal transformation zone), where the mucosa transitions to nonkeratinized squamous epithelium. The ATZ is located proximal to the dentate line and extends for 0.5 to 1.5 cm distally. Because constant transformation of columnar cells into squamous cells is occurring in this area, this region is very susceptible to HPV infection.

The HPV virus integrates into the DNA of the host, disrupting the gene E2, which inhibits proteins E6 and E7, and, consequently, the tumor suppressor gene p53, leading to dysplasia. This dysplasia can be: - initially very mild or mild - and these lesions are called low-grade squamous intraepithelial lesion (LSIL) - or they can evolve to moderate or severe dysplasia or even in situ carcinoma. These lesions are called high-grade squamous intraepithelial lesions (HSIL) .

These lesions were initially classified as anal intraepithelial neoplasia (AIN) grades I, II, and III. However, as this led to uncertainty regarding the significance of AIN II lesions, a new standardization was made, in which AIN I corresponds to LSIL and AIN II, IIIand in situ carcinoma, to HSIL. It is believed that treating HSIL may prevent its evolution to invasive carcinoma.

3. Surveillance and screening methods

Early detection of ASCC is correlated with higher survival and since precursor lesions can be diagnosed and treated, it is believed that this disease is potentially preventable with adequate preventive measures, as it has been occurring with cervical carcinoma - deaths from cervical carcinoma have decreased remarkably since the introduction of screening methods and, more recently, vaccination.

There is actually no consensus regarding what patients should be enrolled in an intensive screening program, but risk factors must be assessed individually, and the following populations should be considered for anal cancer screening:

• HIV-positive men aged >25 y regardless of sexual orientation
• HIV-positive women aged >25 y
• HIV-negative MSM aged >40 y
• Women with high-grade cervical or vulvar lesions or cancer aged >40 y
• All men and women with perianal condyloma/high-grade squamous intraepithelial lesion aged >25 y
• Solid organ transplantation recipients and patients with other forms of immunosuppression aged >25 y

Currently, there are some methods employed for screening: Anal Pap smear or anal cytology: is one of the most available methods to identify individuals who might benefit from a more intensive screening program. Sensitivity and specificity of anal cytology is quite limited (50–80% of sensitivity and 40-60% of specificity), but it is a simple and inexpensive method, being justifiable as screening tool for high-risk populations for its cost-effectiveness. Anal cytology can present with 4 different results:

• normal
• LSIL
• HSIL
• ASCUS (atypical squamous cells of undetermined significance)

Patients with all results except for normal should be referred to high resolution anoscopy.

• High resolution anoscopy (HRA): is performed with a colposcope either in the office or in the operating room and allows visualization of lesions that would go unnoticed under conventional anoscopy. Biopsy guided by HRA is considered the gold-standard method for identifying HSIL. The advantage of this method is that it allows treating the lesions under direct vision at the moment of the exam.
• HPV testing: The presence of HPV, especially subtypes 16 and 18, is associated with the majority of anal cancers, so screening for the presence of high-risk HPV might estimate the risk for dysplasia. However, due to the high prevalence of various types of HPV among high-risk populations, this strategy is quite limited.

Fortunately the rate of progression of HSIL to invasive carcinoma is relatively low, about 1.3-2% per year and around 10% in a 5-year period. For this reason, it is still debatable whether HSIL lesions should always be treated or if expectant management with close follow-up is acceptable in specific situations. Treatment options include ablative therapy and use of topical agents (imiquimod, fluoracil, trichloroacetic acid). There are various algorithms for anal cancer screening, as the University of California San Francisco Anal Neoplasia Clinic, Research, and Education Center (ANCRE).

5. Vaccination

The vaccines currently available protect against either two, four or nine types of HPV. All of them protect against types 16 and 18, the most carcinogenic ones. The Centers for Disease Control and Prevention (CDC) recommends:

• Two doses of the HPV vaccine for all boys and girls at ages 11-12;
• Vaccination through age 26 for women, 21 for men, if they did not get vaccinated when they were younger.
• Vaccination of people through age 26, if they did not get vaccinated when they were younger:
  • Young men who have sex with men
  • Young adults who are transgender
  • Young adults with weakened immune systems

Although the vaccines are for some specific types of HPV, many studies suggest that crossed-protection against other types of HPV are developed with vaccination. Also, some studies have shown that the nonavalent HPV vaccine may be helpful in preventing recurrent HSIL and the progression to anal SCC, so vaccination might also have a role in secondary prevention of anal cancer.