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Case 6

Abnormal Papanicolaou (Pap) Test
A 28-year-old woman (G1P0010) presents to her gynecologist for a yearly examination. She has no
complaints and no history of medical problems or prior surgery. She is interested in birth control
and would like to take oral contraceptive pills.

What elements of the patient’s history are important in addition to her medical history?
What aspects of routine health maintenance are part of a yearly gynecologic visit in a
reproductive-aged woman?
It is important to learn about the patient’s prior pregnancies and their outcomes, her menstrual history,
history of sexually transmitted diseases (STDs), and any past abnormal Pap tests. Social history is also
significant. Discussion of smoking, alcohol and drug use, and sexual orientation and sexual history is also
At a yearly gynecologic visit, the physician should perform a complete physical examination,
including a breast and pelvic examination. A pelvic examination should include both visual examination of
the female genitalia using a bivalve speculum and a bimanual examination to palpate the cervix, uterus,
and adnexa. A Pap test should be performed, and tests for STDs should be considered, particularly for
chlamydia, which is often asymptomatic. The patient should be instructed in breast self-examination.

The patient reports that she had her first period at 12 years of age. Her menses are regular; they
occur every 4 weeks and last for 5 days. Occasionally, she has mild cramps. She estimates that she
has had about 10 to 12 sexual partners. Her only pregnancy ended in an elective termination 12

years ago. She states that she has never had gonorrhea or chlamydia, but a few years ago she did
receive treatment for genital warts. She thinks she may have once had an abnormal Pap smear, but
she is not sure about the details of the abnormality and never returned to the clinic. The patient is
unmarried and works as a sales clerk. She smokes one to two packs of cigarettes per day, consumes
alcohol occasionally, and denies drug use.
Pelvic examination is unremarkable. A Pap test is performed, and DNA probe for gonorrhea
and chlamydia are obtained.

When should screening for cervical cancer take place?
Screening for cervical cancer has decreased both the incidence of the disease and the associated mortality
rate. In 2002, the American Cancer Society issued new recommendations for cervical cancer screening,
which were endorsed by both the Gynecologic Cancer Foundation and the Society of Gynecologic
Oncologists. Screening should begin about 3 years after the onset of vaginal intercourse, but no later than
age 21 years. Traditional Pap smears should be obtained yearly, but liquid-based Pap tests may be
performed every 2 years. For women older than age 30 with three prior consecutive normal Pap tests, the
screening interval may be extended to one test every 2 to 3 years. Women over age 30 can have a Pap
smear with high-risk HPV DNA testing; if both are negative there is a negative predictive value of 99.7%
(the patient is 99.7% unlikely to develop cervical cancer over the next 3 years). Therefore, screening is
done every 3 years when performing both a Pap and HPV test. Women over the age of 70 who have had
at least three normal Pap tests and no abnormal tests in the previous 10 years may choose to stop testing
after discussion with their physician. Also, screening is not necessary in women who have undergone
hysterectomy with cervical removal unless the surgery was done as treatment for cervical cancer or

cervical dysplasia. Women who are chronically immunosuppressed, such as those with HIV infection or
organ transplants, should continue getting Pap tests at the usual interval.
Although the new recommendations state that women over the age of 70 may consider
discontinuing routine cervical cancer screening under certain circumstances, a misperception exists that
Pap tests are unnecessary in postmenopausal and elderly women. Approximately 11 million women in the
United States older than 65 years of age have not had cervical cancer screening in the past year.
Unfortunately, about 25% of all cervical cancers and 41% of all cervical cancer deaths occur in this age
group. Pap testing remains important throughout a woman’s life.

After the physician and patient discuss the use of contraceptives and prevention of STDs, the
patient is given a prescription for oral contraceptive pills. The physician strongly recommends that
the patient stop smoking, particularly because of the increased risk of deep venous thrombosis in
smokers who take oral contraceptives. The physician tells the patient that the office will call with
her test results and reminds her to return next year for a yearly examination.
One week later, the physician receives the test results. The gonorrhea and chlamydia tests
are negative, but the Pap test shows a low-grade squamous intraepithelial lesion (LSIL), changes
associated with HPV, and cervical intraepithelial neoplasia grade I (CIN I).

What is the significance of LSIL?
What is the relationship between HPV infection and cervical dysplasia?
What are the risk factors for cervical dysplasia in this patient?
What is colposcopy?
What follow-up is appropriate in this case?

To standardize the reporting of Pap test results, the Bethesda System was introduced in the late 1980s.
The term low-grade squamous intraepithelial lesion, or LSIL, includes the cytologic changes caused by
HPV and mild dysplasia (CIN I). The term high-grade squamous intraepithelial lesion, or HSIL, includes
moderate (CIN II) and severe dysplasia (CIN III), as well as carcinoma in situ. Another common
Bethesda System diagnosis uses the term atypical squamous cells of undetermined significance
(ASCUS), which denotes an abnormality that exceeds the usual changes of an inflammatory process but
is not severe enough to qualify as dysplasia. Virtually all dysplastic lesions of the cervix are associated
with HPV infection, although most women who are infected with HPV never develop cervical dysplasia.
HPV also causes genital condyloma, but infected women may have no symptoms. More than 70 different
serotypes of HPV have been identified. Types 16 and 18 cause 70% of cervical cancers, and types 6 and
11 cause 90% of genital warts. Host integration of the E6 and E7 HPV genes can cause immortalization
of human genital epithelial cells and may contribute to the development of carcinoma.
Risk factors for cervical dysplasia and cervical cancer include early age at first intercourse, large
number of sexual partners, multiparity, and a history of STDs. Other important risk factors include
smoking, lower socioeconomic status, and exposure to diethylstilbestrol in utero. Many of these risk
factors are likely to be related to the risk of exposure to HPV, a sexually transmitted virus that is widely
present in the general population. Depending on the population tested and the technique used, 9% to
38% of women are positive for HPV. In some high-risk populations, the prevalence may be as high as
50%. This patient’s risk factors include an early age at first intercourse, multiple sexual partners, a history
of genital warts (which indicates exposure to HPV), and tobacco use.
It is important for patients with LSIL to be observed closely. In adolescents, the Pap smear can be
repeated in a year, and if still abnormal, a colposcopy can be performed. In adults and high-risk
adolescents, colposcopy should be performed. Colposcopy, an office procedure, involves examination of

the cervix under a stereoscopic, binocular, low-magnification microscope. The colposcope is used to view
the cervix while a dilute acetic acid solution is applied. The acetic acid causes abnormal areas of the
cervix to turn white. These areas are referred to as “acetowhite epithelium.” The practitioner must take
care to examine the entire squamocolumnar junction and transformation zone (area of squamous
epithelium that replaced the original glandular columnar epithelium via a normal metaplastic process)
because these areas are the most common sites for dysplastic lesions. Condylomata and low- and highgrade dysplastic lesions have a characteristic appearance that can include acetowhite changes, abnormal
blood vessels, mosaicism, and punctation. The practitioner identifies abnormalities and biopsies the most
atypical areas for histologic analysis. Endocervical curettage (ECC) is used to sample the endocervical
Once LSIL has been confirmed histologically, there are several treatment options. The most
common option is to continue with frequent Pap tests every 6 months for 2 years. Conservative
management is the treatment of choice for mild cervical dysplasia. Local excision or ablation may be
warranted in patients with persistent lesions. Electrocautery, cryotherapy, and laser ablation may all be
performed in the office or as outpatient surgery.

The physician calls the patient and recommends that she schedule an appointment for colposcopy
in the next 1 or 2 months. However, she does not return for a follow-up visit. She comes to the
office 8 years later reporting vaginal spotting after sexual intercourse that has persisted for the last
5 months. She has no new medical problems and has continued to smoke one to two packs of
cigarettes per day. Since her last visit to your office, she has not had a gynecologic examination.
Pelvic examination reveals a friable cervix without gross lesions. The uterus and adnexa are
otherwise of normal size and contour. A Pap test shows a high-grade squamous intraepithelial
lesion and changes associated with HPV.

The patient, who is frightened by the bleeding, keeps her appointment for colposcopy. The
entire transformation zone and squamocolumnar junction is well visualized. A suspicious area with
abnormal vessels and mosaicism is seen on the cervix at the 3 o’clock position. Biopsies of this area
confirm severe dysplasia (CIN III). ECC is negative.

What is the pathophysiology of cervical dysplasia and cervical cancer?
What is the next step in evaluation and treatment?
CIN I and II lesions are similar in terms of their natural history. More advanced CIN III lesions are more
likely to persist and progress to invasive cancer. Although CIN I progresses to cancer in only 1% of
patients, studies have shown that approximately 30% of patients who allow their severe dysplasia to
remain untreated eventually develop invasive cancer over 10 years of follow-up. No method reliably
predicts which lesions will develop into more advanced dysplasia or to invasive cancer and which will
simply persist or regress. In addition, no dependable procedure exists to determine how rapidly the
progression to a more serious lesion may occur.
Typically, patients with severe dysplasia are counseled to undergo an excisional biopsy of the
cervix (conization or a loop electrocautery excision procedure [LEEP]). Conization of the cervix removes
a cone-shaped piece of tissue from the cervix. The biopsy can be performed by applying a cold knife cone
technique (using a scalpel) as an outpatient surgical procedure under anesthesia or as a LEEP in the office
under local anesthesia. This treatment is preferable in many cases because ablative therapies, such as
cryotherapy and laser ablation, do not provide a tissue sample for histologic diagnosis. In addition to
providing therapeutic removal of the dysplastic cells, cone biopsy may be diagnostic. It may be performed
to help clarify a diagnosis and to preclude invasive cancer in the following situations: inadequate

colposcopic examination (incomplete visualization of the transformation zone or abnormal lesions), highgrade dysplasia on endocervical curettage, adenocarcinoma in situ, significant discrepancy between
findings on Pap smear and biopsy, or possible invasive carcinoma on colposcopy (even if biopsies show
only carcinoma in situ).
Although cold knife cone biopsy is an extremely safe procedure, it does have some risks. The
most common side effect is bleeding, which may occur in less than 10% of patients. Physicians usually
take precautions by injecting the cervix with a local anesthetic mixed with epinephrine, which causes
vasoconstriction in the cervix, and by applying Monsel solution to the cervix after achieving hemostasis
with electrocautery to further coagulate bleeding. Infection occurs less commonly, and patients are
advised to avoid sexual intercourse, tampons, and douching for several weeks after the biopsy to promote
healing. Infertility is rarely associated with cone biopsy. Cervical stenosis occurs when scarring after the
procedure causes an abnormal narrowing in the opening of the cervix. This may block the entry of sperm
into the uterus or change the normal mucous secretions of the cervix, making the environment
inhospitable to sperm. Cervical deformity and possible second-trimester miscarriage through premature
cervical dilation is another rare risk of the cone biopsy. This effect is usually associated only with removal
of large portions of tissue during the biopsy. Most women do not have problems with either becoming
pregnant or carrying a pregnancy to term after a cone biopsy.

The patient undergoes a LEEP. Histologic examination confirms the presence of a CIN III lesion
and involvement of the endocervical glands. The margins of the specimen are free of dysplasia.

What is the appropriate follow-up?

The patient has been adequately treated for her CIN III lesion. However, she still requires frequent Pap
tests to ensure that a lesion does not recur. She should undergo Pap tests every 6 months for the next 2
years. After a LEEP or a cone biopsy, the physician must pay careful attention that the endocervix is
adequately sampled by the Pap test. Stenosis and scarring may make sampling of the area difficult;
however, given the extent of the lesion and the involvement of endocervical glands on the cone biopsy
specimen, routine cytologic examination is important. If Pap tests cannot adequately sample the
endocervix, ECC may be required.