- What is a Pap
smear? What is a colposcopy?
A Pap smear is a procedure in which cells
are scraped from the cervix
(the lower, narrow end of the uterus
that serves as a channel between the uterus and the vagina)
and examined under a microscope. A Pap smear is used to detect cancer and
cellular changes that may lead to cancer, as well as non-cancerous conditions
like infection or inflammation.
A colposcopy is a procedure in which the vagina and cervix are examined
using a lighted magnifying instrument called a colposcope. The vagina and
cervix may be biopsied
during a colposcopy so that tissue
samples can be examined under a microscope for abnormal
cells. A colposcopy may be prescribed
if a Pap smear detects certain abnormal cellular conditions.
- What is human papillomavirus (HPV)?
There are more than 100 types of human papillomaviruses (HPV). HPV is one
of the most common sexually transmitted diseases (STDs), and more than 30
of the different types of HPV can be transmitted through sexual contact. While
some types of HPV may cause warts
to appear around the genitals, HPV infections also may occur without any obvious
symptoms.
The U.S.
Food and Drug Administration (FDA)
has approved the use of a test for HPV as a screening tool for cervical cancer
in conjunction with a Pap smear or cytology.
Oncogenic HPV DNA testing (or "triage") for patients with ASCUS has proven
to be a useful alternative to referring patients for immediate colposcopy
to detect CIN3 and cancer (greater or equal to CIN3). A 2004 conference of
the International Agency for Research on Cancer concluded that there was sufficient
evidence that HPV DNA testing could be used as a primary screening test in
women age 30 and older.
- Why are HPV16 and HPV18 important?
Of the types of HPV that increase risk for certain types of cancer, HPV16
is the most common among women in the general population. Large case studies
have shown that approximately 50 percent of women with CIN3 or cervical cancer
are infected with HPV16. Additional research suggests that 60 percent to 70
percent of cervical cancer cases worldwide are caused by either HPV16 or HPV18.
Virtually all remaining cases of cervical cancer are caused by other oncogenic
HPV types.
- What are ASCUS and LSIL?
ASCUS and LSIL are acronyms for two mild abnormalities
detected by Pap
tests. ASCUS stands for "Atypical Squamous Cells
of Undetermined Significance," and LSIL stands for "Low-grade
Squamous Intraepithelial Lesion."
A diagnosis
of ASCUS means that the nature of the abnormality is uncertain or equivocal.
A diagnosis of LSIL means that there is a more definite, but still mild, abnormality.
Study Findings
- What were the goals of the ALTS and the
Portland Kaiser Permanente studies?
The National
Cancer Institute (NCI)
organized and funded ALTS (the ASCUS/LSIL Triage Study for Cervical Cancer)
to help resolve the controversy over what physicians
and women should do about ASCUS (equivocal) and LSIL (mildly abnormal) Pap
test results*. Most of these abnormalities will go away without treatment,
but some may lead to a precancerous condition or cancer. This analysis
of the ALTS data provided the opportunity for researchers to determine whether
women with equivocal Pap smear results, who also tested positive for HPV16,
had a greater risk for CIN3 or cervical cancer than women with equivocal Pap
smear results who tested positive for other oncogenic types of HPV.
The Portland study was designed to examine the natural history of HPV infection
and cervical neoplasia
(abnormal and uncontrolled cell growth)**. Additionally, this study allowed
analysis of whether testing specifically for HPV16 and HPV18, in addition
to overall testing for all HPV oncogenic types, might help identify women
at particularly high risk for CIN3 or cervical cancer.
- What were the results of these studies?
In their analysis of ALTS data, Castle et al. found that 542 women in the
study group developed CIN3 or cervical cancer. Those who tested positive for
HPV16 had 38 times the risk for CIN3 or cervical cancer than women in the
study who were HPV negative. Women who tested positive for other oncogenic
HPV types had seven times the risk for these conditions than women who tested
HPV negative. The authors concluded that patients with a positive HPV16 diagnosis
may require more aggressive management than those who test positive for another
oncogenic HPV type or who are HPV negative.
Khan et al. found that women in the Portland study who tested positive
for HPV16 or HPV18 were diagnosed with CIN3 or cervical cancer more often
than women who tested positive for another oncogenic HPV type, or women who
tested negative for HPV. Additional analysis of women with normal Pap smear
results at study enrollment provided further evidence for the observed risk
differences. The authors concluded that screening for HPV16 and HPV18 separately
from other oncogenic HPV types may identify women at the greatest risk of
CIN3 and cervical cancer, while allowing for less aggressive management of
cases of other oncogenic HPV infections.
The authors note that an elevated risk for HPV16 also was observed in a
natural
history study in Guanacaste, Costa Rica (Schiffman, Virology, 2005)***.
- How were these studies performed?
The ALTS study compared three different management strategies for 5,060
women with Pap tests that either showed ambiguous cytologic abnormalities
(ASCUS, 3,488 women), or low-grade
squamous
intraepithelial lesions (LSIL, 1,572 women). The study referred one-third
of the women to an immediate colposcopy, regardless of their Pap test results;
one-third to colposcopy if their initial HPV test was positive or if their
Pap test showed high-grade
squamous intraepithelial lesions
(HSIL);
and one-third to colposcopy if their Pap test showed HSIL at their enrollment
in the study or during follow-up. All three groups received additional tests
every six months for two years of follow-up and a colposcopy at the end of
the trial. Women whose test results showed cervical
intraepithelial neoplasia grade 2 (CIN2) or higher received treatment
for the condition.
The Portland study examined data on 20,514 women who received routine cytologic
screening through a prepaid health plan in Oregon. Women included in this
analysis had negative, equivocal, or mildly abnormal baseline
cervical Pap smears; suitable samples for HPV testing; and type-specific HPV
test results. Study participants received regular follow-up cytology testing
for up to 10 years following their enrollment. Practice guidelines at the
time of the study mandated treatment for women whose Pap smears showed CIN2
or higher, but some physicians also treated some patients with cervical intraepithelial
neoplasia grade 1 (CIN1).
- What were the limitations of these studies?
ALTS was a clinical
trial and, consequently, the participants in the trial may have been screened
more regularly than patients in everyday clinical management. Additionally,
the women in this study were relatively young, with a median
age of 25. A population of older women might lead to different results.
Women with cellular abnormalities in the Portland study received very aggressive
treatment—more than was mandated by clinical standards at the time or
today. Thus, results in this study may actually underestimate the risk attributable
to HPV16 and to HPV18 because of over-treatment. Additionally, there were
relatively few cases to analyze despite the study size, possibly leading to
some imprecise estimates of risk.
- What are the next steps in this area of
research?
Twenty organizations—including the American Society for Colposcopy
and Cervical Pathology (ASCCP), the American Cancer Society, and the National
Cancer Institute (NCI)—will participate in a conference in September
2005 to discuss the use of HPV DNA testing for screening and for triage of
equivocal (ASCUS) Pap smears. One of the topics of discussion is likely to
be the utility of HPV genotype detection in screening and clinical management.
The data from these recent two studies should be confirmed in other larger
studies and in other populations, perhaps even in some of the clinical trials
that are evaluating HPV DNA tests to develop more precise estimates of risk.
Also, subsequent evaluations will need to examine this question in women who
are newly infected.
To perform HPV genotyping, a reliable, FDA-approved test to distinguish
these specific HPV types will need to be developed and validated. When FDA-approved
tests that provide genotype information become available, researchers will
be better able to identify women with persistent infection, an important risk
factor for the development of precancer and cancer. Understanding the
risks associated with a persistent HPV infection and the appropriate clinical
management of these women is critical to preventing cervical cancer.
Future research will help to demonstrate whether women who test negative
for HPV16 and HPV18 can be followed and treated less aggressively than women
who test positive for these HPV types, thereby reducing the number of clinical
visits, potential over-treatment of these women, and increasing the cost effectiveness
of such testing.
###
For more information about cancer, please visit the NCI Web site at http://www.cancer.gov
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
*Castle PE, Solomon D, Schiffman M, Wheeler CM for the ALTS Group. Human
papillomavirus type 16 infections and 2-year absolute risk of cervical precancer
in women with equivocal or mild cytologic abnormalities. Journal of the National
Cancer Institute, Vol. 97, No. 14, July 20, 2005.
**Kahn MJ, Castle PE, Lorincz AT, Wacholder S, Sherman ME, Scott DR, Bush
BB, Glass AG, Schiffman M. The elevated 10-year risk of cervical neoplasia
in women with human papillomavirus (HPV) type 16 or 18 and the possible utility
of type-specific HPV testing in clinical practice. Journal of the National
Cancer Institute, Vol. 97, No. 14, July 20, 2005.
*** Schiffman M, Herrero R, DeSalle R, Hildesheim A, Wacholder S, Rodriguez
AC, Bratti MC, Sherman ME, Morales J, Guillen D, Alfaro M, Hutchinson M, Wright
TC, Solomon D, Zigui C, Schussler J, Castle PE, Burk RD. The carcinogenicity
of human papillomavirus types reflects viral evolution. Virology, Vol. 337,
2005.
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