THE HUMAN PAPILLOMAVIRUS & THE CERVICAL CANCER CONNECTION

REBECCA B. SINGSON, M.D., F.P.O.G.S.

Cervical cancer is the most common cancer in the female reproductive

system. It is the second most common cancer afflicting females second only

to breast cancer. What most people don't realize is that cervical cancer

is now recognized to be the first identified virally induced cancer in

women.1 Research over the last few years has provided overwhelming

evidence that infections with a high risk type of cancer-inducing Human

papillomavirus (HPV) is necessary for the development of cancer.2

Understanding what can cause it and knowing how to monitor cervical cancer

progression makes it one of the most highly preventable cancers afflicting

the female.

Was the Pap Smear Not Doing the Job?

There is no doubt that the introduction of cervical cytology introduced by

Papanicolau (thus called the Pap smear), had a major impact in bringing

about a significant reduction in the incidence of and mortality resulting

from cervical cancer in many countries.3 Applying this massive screening

program some fifty years ago has resulted in a 50-70% reduction of

mortality resulting from cervical cancer. However, even in highly

developed countries, this impact has not reached the desired levels

expected from implementing a massive screening program because it has not

resulted in the eradication of the disease and women are still dying from

it.4

A recent critical review of evidence-based data showed that a single Pap

smear misses up to 50% of cervical cancer precursor lesions.5 That's one

out of two!! Knowing this makes us now partly understand why cervical

cancer continues to occur at such unacceptably high incidence rates, even

in countries where the government spends money to subject its population

to massive screening.

Understanding What Causes Cervical Cancer: the Viral Connection

Although the sensitivity of the Pap smear in picking up cervical cancer

has not changed much in the last 10 years, there has been rapid growth in

our knowledge as to what causes cervical cancer. Research has shown that

the human papillomavirus is present in 99.7% of cervical cancers.2

What is this Wart-Causing Human Papillomavirus?

The human papillomavirus (HPV) is a double stranded DNA virus which

infects the surface cells lining our tissues called epithelial cells.

There are more than 70 distinct site-specific types (meaning they will

grow on one part of the body but not on another). Of these, about 35 types

are found in the anus and the genital areas, causing warts and cervical

cancer, the most notorious being types 16 and 18.

These infections are considered sexually transmitted and are among the

most common sexually transmitted diseases in most countries affecting up

to 40% of women with a yearly incidence of 10-15%6 . Many of the HPV

infections do not show any signs of symptoms, and are therefore

subclinical. It has been found that infections are relatively short-lived

lasting usually 8-10 months.7 This indicates that our bodies are indeed

capable of clearing the virus which is why in women over 30 years old, the

prevalence drops down to 5-10%. Persistent infections, however, are found

in 5-10% in women over 35 years old.6 It is in this group of women who are

not able to clear the virus from their bodies that cancer in the cervix

now has a chance to progress. Research in the last 10 years has consistently detected HPV in more than 90% of cases of cervical cancer, and in some studies, have found

it in all cases.1

Is There a Way to Test if You are Positive for the Human Papillomavirus?

Because of advances in our knowledge linking the human papillomavirus to

the causation of cervical cancer, it became necessary to develop HPV tests

that would indicate if the woman was positive for the high-risk strains of

the virus that would increase her risk for cervical cancer. The HPV DNA

test using the Hybrid Capture II System, developed by a company called

DIGENE, recently came out with a commercially available test which has a

sensitivity of >90%1 and a negative predictive value of over 90%8.

The test entails taking cervical swabs, much like a Pap smear, using the

brush from the Digene Cervical Sampler. Pap smear collected with a broom

collection device and rinsed in the ThinPrep System PreservCyt@ solution

may also be used to provide the same specimen for HPV testing. (You see,

Pap smears are done in 2 ways: the conventional way is by smearing the

cervical swab on a glass slide; the latest way is to use the broom

collection device with the ThinPrep System. The latter has the advantage

of providing the sample to test for HPV testing in case you deem it

necessary. So, you can in fact ask your gynecologist to perform the test

when you get your next Pap smear. There have even been been studies in

China and in Canada where the women performed the swabs on themselves by

inserting the cervical brush intravaginally, trying to reach the cervix,

referred to as self-collection which also yielded satisfactory results The

Digene HPV DNA test is the only FDA-approved test for detecting HPV.

Many recent studies have shown that the combination of HPV DNA test and

Pap smear improves the detection rate of pre-cancerous lesions of the

cervix compared to Pap smear alone.8-10

Is This Test Available in the Philippines?

Fortunately, yes. At the Makati Medical Center (MMC) and very soon, at the

Colposcopy Unit of the Asian Hospital and Medical Center. Hospitals from

all over the country can send their specimens to the MMC for testing. The

test costs 2,900 PHP and the results come out after two weeks since all

specimens are batched and ran once every two weeks for cost-effectivity.

What Does a Positive HPV Result Mean?

In women over 30, a positive result for high-risk types of HPVDNA means

that she has a potentially persistent infection which means that she has a

high risk of developing invasive cervical cancer. She should be

immediately referred for colposcopy. This procedure involves looking at

the cervix under high magnification, applying dyes to visualize abnormal

cervical tissue and performing a biopsy, when necessary, of these abnormal

areas. Women over 30 years old with a normal Pap smear but test positive

for high-risk HPV have a 116-fold risk for developing high grade

pre-cancerous lesions of the cervix compared to women who are

HPV-negative.

Women in their 20s with a positive HPV DNA result should have a repeat HPV

test after 9 months to one year. Since most HPV infections are transient,

the virus should normally be cleared in 9 months, particularly in women

younger than 30. If the test turns up to be negative, it means the

infection has resolved and the woman can be monitored subsequently with

Pap smears.

Are There Women Who Are At Increased Risk Than Others?

Since the virus is considered a sexually-transmitted disease, women who

started having contact at an age earlier than 18 are at greater risk of

acquiring the virus. Women who also have had more than 5 sexual partners

or have had partners who have had more than 5 sexual partners are also at

increased risk of being HPV positive.

It has been found that women who have had 5 vaginal births or more or have

had a pregnancy before 18 yrs. are at increased risk of developing

cervical cancer. It is possible that the immune state during pregnancy

allows the virus to exert changes in the DNA of the cervical cells, thus,

promoting cancer. It has also been found that smoking increases the risk

of cervical cancer as well as having a partner who is not

circumcised.

If any of the above conditions apply to you, it is best to test for HPV

DNA in order to know your risk for developing precursor lesions in the

cervix.

Our knowledge of cervical cancer has allowed man to create diagnostic

tests that can determine a woman's risk for developing cervical cancer. We

are at an era where cervical cancer is a highly preventable disease. To

die from it because we missed the test would be a crying shame.

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REFERENCES:

1 National Institutes of Health (NIH) Consensus Development Statement1996.
2 Walboomers JMMM, et al. Human papillomavirus, a necessary cause of invasive cervical cancer Worldwide. J Pathol.189:12-19 (1999).
3 Hakama M, et al. Effect of organized screening on the risk of cervical cancer in the Nordic countries. In Miller AB, et al (eds.): Cancer Screening. Cambridge, Cambridge University Press, 1991: 153-162.
4 Koss LG. The Papanicolau test for cervical cancerT detection: a triumphand a tragedy. JAMA1989; 261:737-43.
5 Federal study shows conventional Pap test remains most effective was to diagnose cervical cancer. ACOG Today, March 1999, 43 (3).
6 Shah KV, Howley PM Papillomavirus. In: Fields MN, et al, ed. Fields Virology, 3rd edition, Philadelphia: Lippencott Raven, 1988:2077-2109.
7 Ho GYF, et al. Natural history of cervicovaginal papillomavirusinfection in young women. N Engl J Med 1998; 338: 423-28.