Women and AIDS:
Cervical Intraepithelial Neoplasia
by Leslie Hanna
Terminology
Dysplasia and cervical intraepithelial neoplasia (CIN) are
different terms or names for the same condition. Dysplasia
simply means abnormal tissue development; while dysplasia
is still sometimes used to mean CIN, the term is not used
as frequently as in the past. Squamous intraepithelial lesions
(SIL) is another term that is used with regard to CIN, and
describes the type of cervical cells that undergo changes
in 80% of cervical neoplasia.
Both terms--dysplasia and CIN--remain in use today. Despite
the fact that the interchangable use of these terms can
be confusing, the important thing is to understand what
this type of abnormal tissue development means (it is a
precursor to cervical cancer) and that the severity of the
condition when detected has prognostic or predictive value
(regardless of the system used to describe it). --L. Hanna
Cervical intraepithelial neoplasia (CIN) is now used to describe
what was once called dysplasia:
- CIN I = minimal dysplasia
- CIN II = moderate dysplasia
- CIN III = severe dysplasia or carcinoma in situ
- CIN III, severe dysplasia and carcinoma in situ are
all different names for the same thing--early cervical
cancer. While approximately one-third of all cases of
CIN I will resolve in time, the rest will progress.
All degrees of CIN, however, require immediate colposcopy.
-- L. Bardaro
Introduction
Cervical intraepithelial neoplasia (CIN) is a condition characterized
by new growth (neoplasia) in the normal tissue (epithelium)
of the cervix, the lowest portion of the uterus leading
into the vagina (see diagram on page 33). A diagnosis of
CIN means that abnormal tissue has been detected in a woman's
cervix. In addition to CIN, other types of lower genital
tract neoplasias reported in women with HIV include vulvar
intraepithelial neoplasia (VIN) and perianal intraepithelial
neoplasia (PIN or AIN, anal intraepithelial neoplasia).
CIN is much more common than the other types of genital neoplasia
in women with HIV. The tissue changes that signify CIN are
premalignant, or precancerous; CIN is essentially a precursor
to invasive cervical cancer. Since the most recent revision
of the official Centers for Disease Control and Prevention
(CDC) case definition of AIDS in 1993, invasive cervical
cancer is an AIDS-defining illness in women with HIV infection.
In the U.S. alone, nearly 16,000 new cases of cervical cancer
and nearly 5,000 deaths from cervical cancer occur each
year, and 600,000 more women are diagnosed with CIN. The
incidence rates of both CIN and cervical cancer are elevated
in women with HIV. Since the primary medical goal for women
with HIV is to reduce sickness and death, prevention of
cervical cancer necessitates routine screening for CIN and
early, aggressive intervention.
What is CIN?
CIN may be mild, moderate or severe. Several terms may be
used to describe this condition, including dysplasia, CIN
and squamous intraepithelial lesions (SIL). The term CIN
is used in this article because it is arguably the most
popular term in use today.
The abnormal tissue of CIN is collectively composed of cells
that have undergone abnormal, individual changes, and which
have formed lesions in the cervix. Cervical lesions can
regress (grow smaller and disappear), persist or progress
to early cervical cancer, more formally called cervical
carcinoma in situ, and finally invasive cervical cancer.
Moderate or severe CIN (high-grade SIL, CIN II-III) is more
likely to persist or progress. Mild CIN (low-grade SIL,
CIN I) often regresses without any treatment, overcome by
a successful immune system defense.
What Causes CIN?
The single most frequent cause of CIN is infection with human
papillomavirus (HPV), the virus that causes genital warts
and common skin warts. There are many types of HPV; some
types are relatively harmless, but others can cause aggressive
disease.
HPV is one of the most common sexually transmitted diseases
in the U.S. About one-third of the more than 60 identified
types can be sexually transmitted. Several types cause visible
genital warts, or condyloma acuminata; certain other sexually
transmitted types lead to cervical, vulvar and anal cancers.
The types that are oncogens, or cancer-causing agents, are
not associated with genital warts and are usually detectable
only by Pap smear screening. Tests for HPV type exist but
are expensive and largely unavailable.
Women with genital warts should be treated for warts and
also examined for cervical HPV infection by Pap smear (cervicovaginal
cells are smeared on a slide and examined under a microscope)
and colposcopy (a technique that allows visual examination
of the living tissue of the vagina and cervix using an instrument
that is essentially a high-powered microscope). Although
the HPV types that cause genital warts are not the same
ones that are associated with cervical cancer, the sexual
exposure that resulted in genital warts might also have
resulted in infection with more virulent HPV types. Depending
on the size and location of the genital wart, treatment
options are: trichloracetic acid application, 20% podophyllin
solution application, 5% 5-fluorouracil cream, electrocautery
(with an instrument that allows the passage of electrical
current through selected tissue, in order to remove or destroy
it) or laser treatment. Cryotherapy, or freezing of the
warts, is currently falling out of favor; alpha interferon
has been used on persistent warts, and surgery may remove
large warts that do not respond to other treatments.
Because HPV is known to be the central cause of cervical
cancer around the world, the National Cancer Institute's
plans for cervical cancer prevention strategies include
the development of a vaccine targeted at genital HPV.
Cofactors that Facilitate CIN
A successful immune response can attack clones of abnormal
cells, repair abnormal DNA and prevent CIN without any medical
intervention or treatment. In the presence of other damaging
factors (cofactors), CIN and ultimately invasive cancer
may develop. If the oncogen is a particularly virulent strain
of HPV, little else in the way of cofactors may be required.
Cofactors include immunosuppression, cigarette smoking and
poor nutrition. Having other sexually transmitted diseases
(STD), particularly herpes simplex virus type 2 (HSV-2),
also may increase the risk for CIN.
HPV-related CIN has been noted in women who receive transplants
and are taking immunosuppressive drugs, as well as in women
with HIV-related immunosuppression. Studies of HPV-related
CIN in women with HIV all conclude that HIV influences the
development of CIN. A review of 5 studies reported that
HIV positive women are approximately 5 times as likely as
HIV negative women to develop CIN (Mandelblatt, 1992). Among
HIV-infected women, as immunosuppression increases, so does
the risk of developing CIN. Women with AIDS have an approximately
2-fold greater risk than asymptomatic HIV positive women
for developing CIN. Moreover, the more severe a woman's
immunosuppression, the more severe her CIN is likely to
be. CIN progresses more rapidly to cancer, and treatment
failures are more common in HIV positive women.
Some studies have shown that HIV-infected women who are injection
drug users (IDU) had higher rates of CIN than their non-drug-using
HIV positive counterparts; one theory is that IDU suffer
additional immunosuppression related to ongoing exposure
to toxins and other pathogens through drug use (Carpenter
and others, 1991; Bradbeer, 1987; Crocchiolo and others,
1988).
Cigarette smoking is known to increase the risk for squamous
cell cancer, which includes cervical cancer. (Eighty percent
of cervical cancers are squamous cell cancers.) Risk is
believed to increase with the duration and amount of smoking.
Some studies have shown increased risk for current smokers
but not for former smokers (Brock, 1989). In addition, poor
nutritional status is another known risk for CIN. Beta carotene
seems to be an especially important micronutrient; studies
have shown that women with adequate levels and intake are
at reduced risk for CIN. Folate may be another important
micronutrient for reducing risk. There have also been suggestions
that vitamin A may act to reduce HPV proliferation.
Still other risk factors are actually surrogate markers for
exposure to HPV, including having multiple sex partners,
other STD or early onset of sexual activity (at or earlier
than 16 years of age).
Finally, studies that suggest that older women and ethnic
minorities are at increased risk for cervical cancer really
have shown that a very real risk for cervical cancer is
lack of medical care, from screening to treatment. These
risks are often based on socioeconomic factors. (The explanation
for increased risk in older women is simply that women aged
60 and older are less likely to seek regular care.) Since
primary care practitioners may be providing care for many
women who do not have obstetrician/gynecologists, one efficient
approach to reducing sickness and mortality would be for
more primary care practitioners to perform routine Pap smears.
How does CIN Develop?
Most CIN as well as cervical cancer develops in the so-called
transformation zone. The transformation zone refers to an
area of the cervix where 2 types of cells and tissues meet.
Squamous epithelial cells line most of the vagina, while
the cervix and uterus are composed of columnar epithelial
cells and tissue. The transformation zone is where the 2
cell types meet and overlap, at the transition from vaginal
mucosa to uterine mucosa. This is the region most vulnerable
to attack by HPV.
The transformation zone usually lies inside the endocervical
canal, which is why Pap smears must include samples of endocervical
cells (see below, on the Bethesda System). The placement
of the transformation zone can shift through aging, extended
use of oral contraceptives or hormones, multiple pregnancies
and births, and surgery, including cryotherapy, which was
once extensively used for treating cervical lesions and
abnormalities related to HPV. In women who have had cryotherapy,
especially multiple treatments, the transformation zone
may heal, scar over and move up inside the cervix, where
it cannot be reached for Pap smear sampling or seen on colposcopic
examination. If this is the case, a procedure called endocervical
curettage (ECC) may be required (see Cervical
Cancer Screening Issues for HIV Positive Women this
issue).
At a conference on women and HIV in San Francisco in the
fall of 1995, Michael Policar, MD, offered a "weed"
analogy to help explain the pathogenesis of CIN (how the
disease develops). The soil is the cervical tissue. The
seed is the cancer-causing agent, HPV. Fertilizer that helps
the seedling grow into a weed (cancerous growth) are cofactors
like smoking. The best weed killer is the immune system.
When some types of HPV encounter the vulnerable tissue of
the transformation zone, the virus may incorporate abnormal
viral DNA into the normal genetic material of the cells.
In a person with a strong immune system, repair often takes
place without any intervention; healthy squamous epithelial
tissue will develop and the oncogen is effectively eradicated.
The other possibility is that the abnormal DNA prevails,
abnormal cells multiply to become lesions, and CIN develops.
If abnormal DNA dominates, as may occur if a woman does
not know she has cervical HPV infection or CIN, cancer may
develop.
Treatment for CIN
Ideally, the natural immune response would be powerful enough
to eradicate any low-grade CIN or tissue abnormalities.
Observation and repeat Pap smears and biopsies can confirm
such spontaneous self-correction. Currently, there is no
treatment per se for CIN I, which either resolves or progresses
to CIN II, which is treated. If CIN does not resolve but
instead progresses, or is detected at CIN stage II or III,
treatment is needed to prevent the development of invasive
disease. CIN lesions may be treated on an outpatient or
inpatient basis. Outpatient techniques include laser vaporization
or excision and loop electrosurgical excision procedure
(LEEP); inpatient techniques include cone biopsy or cervical
(cold knife) conization, which involves removing a cone-shaped
portion of the cervical tissue, and simple hysterectomy.
Some strategies, like LEEP or cone biopsy, combine diagnosis
and treatment by removing all abnormal tissue. CIN II-III
often can be treated with outpatient techniques; higher-grade
CIN likely requires inpatient treatment.
One study showed that HIV-infected women with fewer than
500 CD4 cells/mm3 were more than twice as likely to have
recurrent or persistent CIN after LEEP (Wright and others,
1993). The key to survival for women with HIV who have been
treated for CIN is careful, regular life-long follow-up.
Abner Korn, MD, researcher and clinician at San Francisco
General Hospital (SFGH), says that "HIV positive women
with dysplasia [CIN] need careful follow-up after treatment
and often need second or third therapeutic procedures. Vigilant
surveillance and retreatment alone may be sufficient care
for these women." One important surveillance tool is
the same tool used for primary screening and prevention:
the Pap smear.
Prevention and Screening
The elevated risk for cervical cancer in women with HIV,
especially those with a history of HPV or CIN, makes prevention
of cancer and early intervention for precursor conditions
extremely important. Screening procedures are of paramount
importance for achieving the goal of preventing sickness
and death.
The most appropriate screening procedure for CIN is a topic
of debate. The debate centers on which technique(s) should
be used for screening and how often to screen. An early
study compared the 2 most widely available screening technologies,
the Pap smear and colposcopy. Results showed a high rate
of false-negative results for Pap smears compared to colposcopy
in HIV positive women. Colposcopy appeared much more reliable
than Pap smears for detecting cervical abnormalities. This
finding triggered a shift towards utilization of the more
invasive, expensive and labor-intensive colposcopic method.
Several studies later, current opinion holds that the Pap
smear is as effective in HIV positive as in HIV negative
women at diagnosing CIN. How often women with HIV should
have Pap smears and colposcopic examinations remains hotly
contested (see Cervical Cancer Screening
Issues).
The 1993 CDC STD Treatment Guidelines provide current recommendations
for screening for HIV positive women. The CDC recommends
an initial Pap smear when HIV infection is diagnosed; if
the results of that test are normal, the woman should have
at least one Pap smear during the next 6 months. If the
second Pap smear is also normal, the CDC recommends annual
Pap smears for screening from then on. If any Pap smear
result in an HIV positive woman indicates inflammation or
"reactive atypia," CDC recommends that she return
in 3 months for another Pap smear. If any Pap smear test
indicates SIL or atypical squamous cells of undetermined
significance (ASCUS), CDC recommends colposcopic evaluation.
CDC does not recommend routine colposcopy screening for
HIV positive women.
The SFGH guidelines for HIV positive women differ from the
CDC's. In particular, the SFGH team recommends baseline
colposcopy (their treatment recommendations are included
in the following list):
- perform baseline colposcopy at HIV diagnosis
- evaluate the entire lower genital tract for multifocal
disease (vulvar intraepithelial neoplasia [VIN] and
perianal intraepithelial neoplasia [PIN], in addition
to CIN or SIL)
- treat genital warts per routine
- if normal, repeat inspection and Pap each 6-12 months
(6 months for HIV symptomatic women, 12 months for HIV
asymptomatic women)
- colposcopically evaluate women with ASCUS, atypical
glandular cells of undetermined significance (AGCUS),
low-grade and high-grade SIL on Pap smear
- observation of biopsy-proven low-grade lesions (CIN
I)
- since women with HIV and cervical cancer are more likely
to die of cancer, do not withhold treatment solely because
of HIV disease
- cease or decrease cigarette smoking.
The main drawback of Pap smears for screening HIV positive
women is that cervical Pap smears cannot detect vulvar lesions
that women with HIV may have. However, VIN or PIN can be
detected by colposcopy (Korn, 1994).
Other Types of Genital Neoplasia and Related Concerns
Guidelines for cervical Pap smears and cervical screening
in women with HIV are limited by the nature of what is being
tested; a cervical Pap smear gives information about the
cervix alone. While the cervical Pap test is an important,
sensitive and accurate tool for that purpose, significant
neoplasias develop in extracervical genital regions as well.
A study at SFGH that involved both HIV positive and negative
women found that 15% of the HIV positive women had "only
vulvar, vaginal or perianal lesions that would not usually
be detected with Pap smears" (Korn, 1994). Although
vulvar and anal cancer has been reported in HIV positive
women, it is rare. However, this rarity does not obviate
the importance of screening for precursor conditions to
such cancers. Thus, anal Pap smears are increasingly regarded
as an important screening tool for women and men at risk.
Colposcopy is a valuable tool for detecting noncervical lesions.
It also permits more efficient diagnosis and therapy of
cervical lesions. Still, colposcopy is expensive and must
be performed by a trained clinician--classic reasons for
reluctance to routinely recommend colposcopy as a screening
measure, even for HIV positive women. All things considered,
Korn's suggestion that "a single colposcopic exam on
diagnosis of HIV or AIDS may be a cost-effective compromise"
seems eminently reasonable.
References
Brinton LA. Epidemiology of cervical cancer--overview.
IARC Scientific Publication 119: 3-23. 1992.
Bosch FX and others. Prevalence of human papillomavirus
in cervical cancer: a worldwide perspective. Journal
of the National Cancer Institute 87: 796-802. 1995.
Bradbeer C. Is infection with HIV a risk factor
for cer-vical intraepithelial neoplasia? Lancet 2:
1,277-1,278. 1987.
Brock KE and others. Smoking and infectious
agents and risk of in situ cervical cancer in Sidney, Australia.
Cancer Research 49(17): 4925-4928. 1989.
Cannistra SA and Niloff JM. Cancer of the
uterine cervix. The New England Journal of Medicine
334(16): 1030-1038. April 18, 1996.
Carpenter CJ and others. Human immunodeficiency
virus infection in North American women: experience with
200 cases and a review of the literature. Medicine
70: 307-325. 1991.
Crocchiolo P and others. Cervical dysplasia
and HIV infection. Lancet 7: 238-239. 1988.
Hirschowitz L and others. Long term followup
of women with borderline cervical smear test results: effects
of age and viral infection on progression to high-gread
dyskaryosis. British Medical Journal 304(6836): 1209-1212.
1992.
Korn AP and Landers DV. Gynecologic disease
in women infected with human immunodeficiency virus type
1. Journal of Acquired Immune Deficiency Syndromes and
Human Retrovirology 9: 361-370. 1995.
The 1991 Bethesda Workshop. The revised Bethesda
system for reporting cervical/vaginal cytologic diagnoses:
report of the 1991 Bethesda workshop. Journal of Reproductive
Medicine 37(5): 383-386. 1992.
Wright TC and others. Treatment of cervical
intraepithelial neoplasia in HIV-infected women with loop
electrosurgical excision. First National Conference on Human
Retroviruses and Related Infections. Washington, DC. December
1993. Abstract 32.
The Bethesda System for Interpreting Pap Smear Results
The Pap smear is considered an effective screening tool for
CIN in HIV positive women. The system for reporting Pap
smear results is the Bethesda System II. This system came
into use in 1991, and is used today according to the recommendations
for managing abnormal Pap smear results known as the Bethesda
Interim Guidelines, published in the Journal of the American
Medical Association in 1992 (271: 1866).
The Bethesda System first reports on the adequacy of the
sample (e.g., if endocervical cells are present) and uses
descriptive terms for abnormal results. This system may
describe any infection detected on Pap smear, such as fungal
(e.g., candidiasis), bacterial, protozoal (e.g., Trichomonas)
or viral (e.g., cyto-megalovirus, herpes simplex virus)
infection. The results report if the Pap smear detected
inflammation, squamous cell abnormalities or glandular cell
abnormalities.
Cervical cancer is primarily a squamous cell cancer. A Pap
smear result of atypical squamous cells of undetermined
significance (ASCUS) indicates abnor-malities that do not
fit the criteria for SIL, but which are significant. An
estimated 20% of women with ASCUS results will go on to
develop SIL or invasive cancer (Hirschowitz and other).
For the details and guidelines for clinical management of
results, see the 1994 Bethesda Interim Guidelines.
The
Official Bethesda System for Reporting Cervical/Vaginal
Cytologic Diagnoses
FORMAT OF THE REPORT:
a. A statement on Adequacy of the Specimen for Evaluation
b. A General Categorization which may be used to assist
with clerical triage (optional)
c. The Descriptive Diagnosis
ADEQUACY OF THE SPECIMEN
Satisfactory for evaluation
Satisfactory for evaluation but limited by...(specify reason)
Unsatisfactory for evaluation...(specify reason)
GENERAL CATEGORIZATION (OPTIONAL)
Within normal limits
Benign cellular changes: see descriptive diagnoses
Epithelial cell abnormality: see descriptive diagnoses
DESCRIPTIVE DIAGNOSES
Benign cellular changes
- Infection
- Trichomonas vaginalis
- Fungal organisms morphologically consistent
with Candida species
- Predominance of coccobacilli consistent with
shift in vaginal flora
- Bacteria morphologically consistent with Actinomyces
subspecies
- Cellular changes associated with herpes simplex
virus
- Other
Reactive changes
- Reactive cellular changes associated with:
- Inflammation (includes typical repair)
- Atrophy with inflammation ("atrophic vaginitis")
- Radiation
- Intrauterine contraceptive device (IUD)
- Other
Epithelial Cell Abnormalities
- Squamous Cell
- Atypical squamous cells of undetermined significance:
Qualify1
- Low-grade squamous intraepithelial lesion encompassing:
- HPV2
- Mild dysplasia/CIN I
- High-grade squamous intraepithelial lesion encompassing:
- Moderate and severe dysplasia
- Carcinoma in situ/CIN 2 and CIN 3
- Squamous cell carcinoma
- Glandular Cell
- Endometrial cells, cytologically benign, in
a postmenopausal woman
- Atypical glandular cells of undetermined significance:
Qualify*
- Endocervical adenocarcinoma
- Endometrial adenocarcinoma
- Extrauterine adenocarcinoma
- Adenocarcinoma, not otherwise specified (NOS)
Other malignant neoplasms: specify
Hormonal evaluation (applied to vaginal smears only)
- Hormonal pattern compatible with age and history
- Hormonal pattern incompatible with age and history:
specify
- Hormonal evaluation not possible due to: specify
1. Atypical squamous or glandular cells of undetermined significance
should be further qualified as to whether a reactive or
a premalignant/malignant process is favored.
2. Cellular changes of human papillomavirus (HPV)--previously
termed koilocytosis atypia, or condylomatous atypia--are
included in the category of low-grade squamous intraepithelial
lesion.
Leslie Hanna is Associate Editor of BETA.
Page last updated 23 July 1996
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