Screening and detection
At present, there are no national guidelines for routine screening for anal cancer. As the risk factors for anal cancers are known, screening patients for AIN using anal swabs and Papanicolaou test at least in high-risk groups may be a potential screening method. Some centers in the US have started screening for AIN in HIV cohorts using anal cytology (EXPLORE study).
At present, this is probably only appropriate as part of a trial in high-risk groups in the UK, and further studies are warranted to explore its effectiveness.37 The pathophysiological characteristics of anal cancer are similar to those of other intraepithelial neoplasms found on the cervix, penis, oral tissue, and vulva.
As for the grading and results of anal pap tests, the Bethesda 2001 system46 categorizes cervical disease in increasing order of severity. As anal cytologic findings demonstrate similar histologic changes, they are graded the same way:
- Negative: negative for intraepithelial lesion or malignancy
- AIN: anal intraepithelial neoplasia, as seen in histology
- ASCUS: atypical squamous cells of undetermined significance
- ASC-H: atypical squamous cells suspicious for HSIL
- LSIL: low-grade squamous intraepithelial lesion
- HSIL: high-grade squamous intraepithelial lesion
- SCC: squamous cell carcinoma
High-resolution anoscopy is a procedure using a high-resolution magnifying instrument called an anoscope to identify abnormal cells. If the Pap test shows abnormal findings, ASCUS, LSIL, or HSIL, the patient should be further evaluated with HRA and biopsy46
- If AIN 1 (LSIL) is found at biopsy, routine follow-up should be performed every 6–12 months.
- For patients with AIN 2 or 3 (HSIL), therapy is recommended. Observation with repeated evaluation is an option for patients with AIN 1 (LSIL).
Methods of detection of the HPV on cytology smears and tissue samples include
- Nucleic acids hybridization assays, eg, Southern blot;
- Signal amplification assays, eg, Hybrid capture 2
- Nucleic acids amplification assays, eg, genome sequencing, microarray, and polymerase chain reaction.47
Encouraging good behavioral interventions, such as cigarette smoke and limiting sexual partners, would likely affect HPV transmission. Practicing safer sex, such as by increased condom use, may also be effective in reducing HPV transmission.48 Male circumcision has also been effective at reducing the risk of transmission of HPV and cervical cancer.49
There have also been phase II/III trials of therapeutic vaccinations against HPV infection. A fusion vaccine of the HPV-16 protein and the M. bovis protein has been associated with clearance of HPV at 48 weeks.50Moreover, the introduction of HPV vaccines has demonstrated the quadrivalent vaccine to be effective in preventing AIN in males.51 Research into this field continues.
The future remains optimistic for anal cancer management. As metastatic disease is less responsive to combined chemotherapy and radiation treatment, novel techniques have been studied to improve survival. There is currently a debate as to whether mitomycin should replace cisplatin for chemoradiation of anal cancers. The ACT II trial has shown mitomycin and 5-FU to be the gold standard treatment.51
Targeted therapies utilizing biomarkers have also been studied for their potential to personalize treatment for responses to chemoradiation for patients with anal cancer.
These include, for example, targeting of the highly expressed epithelial growth factor receptor (EGFR) receptor by the monoclonal antibody cetuximab (Erbitux), by cisplatin, or by 5-FU, as well as radiation and VEGF in anal carcinoma. These processes employ humanized anti-VEGF monoclonal antibodies, which are already well-established in the treatment of metastatic breast, colorectal, renal, and non–small-cell lung carcinoma.
However, their effect on prognosis remains undetermined and are of only limited benefit in colorectal cancer. A recent trial showed anti-EGFR (Cetuximab) combined with chemoradiotherapy to be too toxic to deliver.52 In terms of treatment stratification, p16INK4a is also strongly associated with relapse in SCC of the anus and suggests targeting the EGFR in poor risk/recurrent anal cancer.52–54 Long-term follow-up of these techniques is warranted.