Clinicians from various areas of practice may encounter HPV-related dysplasia and struggle to understand the signifiance of various histological diagnoses. Typical examples of scenarios where this may come up:
- A surgeon excises a hemorrhoid or anal skin tag/polyp, and the pathology report incidentally mentions a diagnosis of anal dysplasia.
- An endoscopist notices a visually atypical area on a colonoscopy or flexible sigmoidoscopy and the pathology reveals dysplasia.
- A perianal or perineal lesion is biopsied and pathology shows dysplasia.
For a complete and thorough reference to the proper interpretation of anogenital HPV-related pathology, please see the LAST project.
Low grade lesions / LSIL
Low grade HPV-related lesions (low-grade squamous intraepithelial lesion, LSIL) represent a proliferative HPV infection – the virus is getting the squamous cells to make more copies of the virus and release them on the epithelial surface for exposure to other people. The basal layer of the epithelium contains atypical cells, and the upper layers often show koilocytes (cells with a prominent perinuclear halo).
LSIL can be either flat and not grossly visible, or exophytic and visible/palpable, e.g. warty. Flat LSIL can also be referred to as AIN1 on pathology reports; the descriptions are interchangeable. LSIL in a warty/verrucous form may be called LSIL, AIN1, or a condyloma accuminatum on pathology reports.
LSILs are usually caused by low-risk types of HPV (e.g. types 6 and 11), but there is some evidence that LSILs can also be caused by high-risk HPV types (see Siegenbeek van Heukelom et al. for more details).
LSILs are generally harmless and do not usually need to be treated. There is some preliminary evidence that a small percentage of LSILs (perhaps those caused by high-risk HPV types) may progress to HSIL over time in high-risk patients, but this is far from settled. (See Jongen et al.)
High grade lesions / HSIL
High grade squamous intraepithelial lesions (HSIL) are caused by high-risk/oncogenic HPV types (e.g. 16, 18, and many others). These are tranformative infections that have malignant potential. Atypical cells extend upwards from the basal layer and may involve the entire epithelium, but do not invade below the basement membrane.
The rate of progression from HSIL to invasive cancer has not been conclusively established, and may vary depending on age, degree of immunosuppression, HPV strains involved, and extent of HSIL in the anus. (See Berry-Lawhorn and Palefsky). In most patients, the annual rate of progression is likely less than 5% per year; in some very high-risk patients, progression rates may be much higher.
Most patients with anal HSIL will not progress to cancer, or will only do so after many years. This is a crucial point to emphasize to patients.
In the anal canal, HSIL usually presents as a flat lesion that may be invisible without magnification and the addition of stains such as acetic acid or Lugol’s iodine. Advanced anal HSILs may be grossly visible as a well-demarcated opaque white patch, sometimes with prominent vasculature.
In the perianal area, where the skin is more keratinized, HSIL often presents as flat, coarse, granular areas of skin that may have small areas of ulceration or prominent vessels.
This is a crucial point to recognize: HSIL that is palpable or indurated, whether in the anal canal or in the perianal area, is concerning for an invasive cancer. If you perform a superficial biopsy of a palpable/indurated lesion and the result is HSIL, you have not ruled out cancer. The pathologist needs to see the full thickness of the lesion in order to see whether any abnormal/invasive squamous cells are found below the basement membrane. If all you provide is the tip of the iceberg, you have not provided enough tissue to tell you about the rest of the ice!
AIN2 vs. AIN3 – what’s the difference?
HSIL is often subcategorized as AIN2 (abnormal cells involving up to 2/3 of the epithelial surface) or AIN3 (involving the entire thickness of the epithelium). There is very poor inter-observer agreement for the diagnosis of AIN2 – some pathologists will call the same sample LSIL and others will is HSIL. In fact some AIN2 lesions are actually LSILs! That is, some lesions that look like HSIL histologically are actually caused by low-risk HPV strains, and thus do not really have malignant potential.
AIN2 is only a true HSIL if a supplementary p16 stain been done by the pathologist and it is diffusely positive. If your pathologist has not done a p16 stain on an AIN2 sample, please ask them to do so.