Since our last post, a reader asked the simple question, “if the patient has an abnormal Pap smear and it is not cancer, then what is it?” Although my specialty is Maternal-Fetal Medicine, and I have no delusions (or desire) to be a cancer specialist, I have had a long interest in HPV problems and have been asked this question on many occasions. So today, let’s digress to briefly elaborate on the sort of information I will discuss with patients when questions such as this one arise…
Although almost all cervical cancer (as well as more than 50% of vaginal, vulvar, and anal cancer) are associated with HPV infections, infection by itself does not appear sufficient (in most instances) to cause cancer. Indeed, cancer occurs in only a small percentage of the women who have been infected with HPV. The time to development of cancer is usually many years and usually preceded by abnormalities of the cervical cells that are confined to the epithelium (intraepithelial neoplasia or dysplasia) and do not invade the underlying tissues. Risk factors mentioned previously (e.g., persistence of a ‘high risk’ HPV type, smoking, immunosuppression, early age of exposure to HPV, HIV infection) may increase the likelihood and accelerate the rate of developing invasive cervical cancer.
The full spectrum of cervical abnormalities can readily be detected with the Pap test. It is true that the Pap test may not detect these abnormalities if the surface of the cervix and the cervical canal are not adequately sampled, the areas of cervical abnormalities are not readily accessible (e.g., high in the cervical canal) or just missed, or the test is either misread or cannot be read due to other factors. The advantage of routine screening is that regular sampling (on a schedule recommended by your provider and appropriate to your circumstances) reduces the contribution of these factors to a ‘false negative’ result and usually some abnormality will be detected long before a serious problem has developed. The recent introduction of liquid-based cytology has increased the likelihood of detecting these abnormalities and offers the additional advantage of being able to be used for ‘reflex’ HPV-typing to check for the presence of a ‘high risk’ HPV type if a cytologic (cellular) abnormality is discovered.
The epithelium (‘skin’ surface) that lines the cervical canal and covers a good portion of the cervix that sits in the vagina starts out early in life as a protective barrier that is only one cell layer thick (columnar epithelium). The vaginal epithelium, on the other hand, is many cell layers thick (squamous epithelium) and there is a progressive transition in this type of epithelium from the plump, actively dividing cells at the base of the epithelium to the most superficial layers where the cells are flattened, relatively inactive, and eventually detach and fall off the surface. (The vaginal epithelium is much like the skin that covers our body, but it does not contain certain substances (keratins) that make the outer skin ‘tougher’ and more of a barrier to fluid loss). Whether columnar or squamous, both epithelia sit on a structure called the ‘basal membrane’ that separates the epithelium from deeper tissue layers.
Around the time of puberty, the outer cervical epithelium begins to undergo a transition from the original columnar epithelium to a squamous epithelium under the influence of normal hormonal and pH changes within the vagina. This transition is called squamous metaplasia and the area that undergoes these changes is called the transformation zone (TZ). The TZ, especially, during the time of transition, is very sensitive to environmental influences such as HPV and ‘cofactors’ that can eventually lead to the loss of usual cell control mechanisms (proliferation, DNA replication, and contact inhibition). Indeed, most cervical intraepithelial neoplasia or ‘lesions’ (for lack of a better term, “precancer”) and cancer arise in the TZ. This is probably also why women who become sexually active earlier in life before the normal TZ changes are complete are at greater risk for cervical precancerous lesions and even cancer if exposed to HPV at this time. The difference between the intraepithelial precancerous lesions and cancer is that cancer cells not only begin to proliferate uncontrollably, but they are also able to breech the basal membrane on which the epithelium sits and invade the underlying tissues. Intraepithelial lesions are confined to the epithelium and while they are there, they are NOT cancer, regardless of how nasty they may look.
Although the nomenclature has changed through the years, today, we basically divide abnormalities of the cervical squamous epithelium into low-grade intraepithelial lesions (LSIL, previously termed mild dysplasia or CIN 1), high grade intraepithelial lesions (HSIL, which includes the previously termed categories of moderate and severe dysplasia, or CIN 2/3, and carcinoma in situ (CIS)), and invasive cancer. There are other categories including atypical squamous cells of undetermined significance (ASCUS) (sounds like the ‘rodents of unusual size’ in "The Princess Bride," doesn’t it?!?) and a small percentage of cervical cancers arise from the glandular cells of the columnar epithelium (adenocarcinomas), and many of these are also associated with HPV infection, but for the sake of clarity, brevity, and my own sanity, these abnormalities will not be discussed by me herein.
There are now numerous studies in the literature that have tracked the natural history of HPV infections and cervical dysplasia, but I have selected two that are representative and present a spectrum of the information currently available. Moscicki and colleagues (Lancet 2004;364:1678-83) followed prospectively 899 women age 13-22 years of age who tested positive for HPV DNA. Of these, 260 (29%) were diagnosed with LSIL by cytology and of those who were, 61% had regressed by 12 months’ follow-up and 91% by 36 months’. Only 3% progressed to an HSIL lesion (and none developed cervical cancer) over that same period of time. In another study presented at the recent meeting of the North American Society for Pediatric and Adolescent Gynecology, Dr. Michelle Vichnin reported the results of follow-up on 195 women age 21 or less who were referred to their colposcopy clinic for an abnormal Pap test. Among these women, the average age of first intercourse was 14.9 years and the average age of the first ‘abnormal’ Pap test was 18 years. Thirty-four (17.4%) had biopsy proven HSIL and 13 developed their high-grade disease in 3 years or less after becoming sexually active. HSIL is invariably associated with infection with high risk HPV types and persistence and amount of HPV DNA that is found in the tissues is directly correlated with progression to invasive cervical cancer over time if the woman is not treated.