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Current OB/GYN > Chapter 50. Premalignant & Malignant Disorders of the Uterine Cervix >

CERVICAL INTRAEPITHELIAL NEOPLASIA

Essentials of Diagnosis

� The cervix often appears grossly normal.

� Infection with the human papillomavirus is present.

� Dysplastic or carcinoma in situ cells are noted in a cytologic smear preparation (traditional Pap smear or

liquid-based cytology).

� Colposcopic examination reveals an atypical transformation zone with thickened acetowhite epithelium and

coarse punctate or mosaic patterns of surface capillaries.

� Iodine-nonstaining (Schiller-positive) area of squamous epithelium is typical.

� Biopsy diagnosis of cervical intraepithelial neoplasia (dysplasia or carcinoma in situ).

General Considerations

Lower genital tract squamous intraepithelial neoplasia is often multicentric (ie, affecting multiple anatomic sites which

embryologically are derived from the same anogenital epithelium): cervical intraepithelial neoplasia (CIN), vaginal

intraepithelial neoplasia (VAIN, see Chapter 49), vulvar intraepithelial neoplasia (VIN, see Chapter 49), and perianal

intraepithelial neoplasia (PAIN). Approximately 10% of women with CIN have concomitant preinvasive neoplasia of

the vulva, vagina, or anus. Conversely, 40–60% of patients with VIN or VAIN have synchronous or metachronous

CIN.

Cervical intraepithelial neoplasia (CIN), formerly called dysplasia, means disordered growth and development of the

epithelial lining of the cervix. There are various degrees of CIN. Mild dysplasia, or CIN I, is defined as disordered

growth of the lower third of the epithelial lining. Abnormal maturation of the lower two-thirds of the lining is called

moderate dysplasia, or CIN II. Severe dysplasia, CIN III, encompasses more than two-thirds of the epithelial

thickness with carcinoma in situ (CIS) representing full-thickness dysmaturity (Fig 50–1). While histologically

evaluated lesions are characterized using the CIN nomenclature, cytologic smears are classified according to the

Bethesda system, which was most recently revised in 2001 (Table 50–1). Briefly, atypical squamous cells are divided

into those of undetermined significance (ASC-US) and those in which a high grade lesion cannot be excluded (ASC-

H). Low-grade squamous intraepithelial lesion (LSIL) encompasses cytologic changes consistent with koilocytic atypia

or CIN I. High-grade squamous intraepithelial lesion (HSIL) denotes the cytologic findings corresponding to CIN II

and CIN III. CIN may be suspected because of an abnormal cytologic smear, but the diagnosis is established by

cervical biopsy. Spontaneous regression, especially of CIN I, occurs in a significant number of patients, allowing for

expectant management with serial cytologic smears in the reliable patient. A certain percentage of all dysplasias,

especially high-grade lesions, will progress to an invasive cancer if left untreated. Because it is not presently possible

to predict which lesions will progress, it is recommended that all patients with CIN II and CIN III be treated when

diagnosed. The only exception to this recommendation concerns adolescents, in whom CIN II may be followed, as

spontaneous regression is substantial and the risk of cancer almost nil.

Figure 50–1.

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Changes in the terminology for cervical intraepithelial neoplasia.

(Courtesy of UpToDate in Oncology.)

Table 50–1. The Bethesda System 2001.

Specimen Type

Specimen Adequacy

General Categorization (optional)

Automated Review

Ancillary Testing

Interpretation/Result

Indicate conventional smear (Pap smear) vs. liquid-based vs. other

Satisfactory for evaluation (describe presence or absence of endocervical transformation zone component and any

other quality indicators, eg, partially obscuring blood, inflammation, etc)

Unsatisfactory for evaluation. . . (specify reason)

Specimen rejected/not processed (specify reason)

Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of

(specify reason)

Negative for intraepithelial lesion or malignancy

Epithelial cell abnormality: See Interpretation/Result (specify squamous or glandular as appropriate)

Other: See Interpretation/Result (eg, endometrial cells in a woman 40 years of age)

If case examined by automated device, specify device and result

Provide a brief description of the test methods and report the result so that it is easily understood by the clinician

NEGATIVE FOR INTRAEPITHELIAL LESION OR MALIGNANCY (when there is no cellular evidence of

neoplasia, state this in the General Categorization above and/or in the Interpretation/Result section of the report,

whether or not there are organisms or other non-neoplastic findings)

ORGANISMS:

Trichomonas vaginalis

Fungal organisms morphologically consistent with Candida spp.

Shift in flora suggestive of bacterial vaginosis

Bacteria morphologically consistent with Actinomyces spp.

Cellular changes consistent with herpes simplex virus

OTHER NON-NEOPLASTIC FINDINGS (Optional to report; list not inclusive):

Reactive cellular changes associated with inflammation (includes typical repair)



Epidemiology & Etiology

Prevalence figures for CIN vary according to the socioeconomic characteristics and geographic area of the population

studied, from as low as 1.05% in some family planning clinics to as high as 13.7% in women attending sexually

transmitted disease (STD) clinics. CIN is most commonly detected in women in their 20s, the peak incidence of

carcinoma in situ is in women ages 25–35 years, whereas the incidence of cervical cancer rises most significantly

after the age of 40 years.

The epidemiologic risk factors for CIN are similar to those for cervical cancer and include multiple sexual partners,

early onset of sexual activity, a high-risk sexual partner (history of multiple sexual partners, human papillomavirus

(HPV) infection, lower genital tract neoplasia, or prior sexual exposure to someone with cervical neoplasia), a history

of STDs, as well as cigarette smoking, human immunodeficiency virus (HIV) infection, acquired immune deficiency

syndrome (AIDS), other forms of immunosuppression, multiparity, and long-term oral contraceptive pill use.

HPVs are a prime etiologic factor in the development of CIN and cervical cancer. In fact, most of the above behavioral

and sexual risk factors for cervical neoplasia become statistically insignificant as independent variables after adjusting

for HPV infection. Analyses of cervical neoplasia lesions show the presence of HPV in more than 80% of all CIN

lesions and in 99.7% of all invasive cervical cancers.

Infection with HPV is extremely common and varies with the patient's age. In the United States, the prevalence of

detectable HPV infection rises from 1% in newborns, to 20% in teenagers, to 40% in women 20–29 years of age,

with a slow decline thereafter to a plateau of 5% in women age 50 years and older. Condoms are not as protective

against HPV as they are against other sexually transmitted diseases as transmission can occur from labial-scrotal

contact.

Radiation

Intrauterine contraceptive device (IUD)

Glandular cells status posthysterectomy

Atrophy

OTHER

Endometrial cells (in a woman 40 years of age) (Specify if negative for squamous intraepithelial lesion)

EPITHELIAL CELL ABNORMALITIES

SQUAMOUS CELL

Atypical squamous cells of undetermined significance (ASC-US) cannot exclude HSIL (ASC-H)

Low-grade squamous intraepithelial lesion (LSIL) encompassing: HPV/mild dysplasia/CIN

High-grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, CIN 2

and CIN 3/CIS

Squamous cell carcinoma

GLANDULAR CELL

Atypical (AGC)

endocervical cells

endometrial cells

glandular cells not otherwise specified (NOS)

Atypical, favor neoplastic

endocervical cells

glandular cells NOS

Endocervical adenocarcinoma in situ (AIS)

Adenocarcinoma

endocervical

endometrial

extrauterine

not otherwise specified (NOS)

OTHER MALIGNANT NEOPLASMS: (specify)

Educational Notes and Suggestions (optional)

Suggestions should be concise and consistent with clinical follow-up guidelines published by professional

organizations (references to relevant publications may be included)



More than 90% of immunocompetent women will have a spontaneous resolution of their HPV infection over a 2-year

period and only approximately 5% will have cytologically detectable CIN. Women who have persistent HPV infections,

especially with high viral loads, have a higher likelihood of developing CIN and cervical cancer.

The vast majority of women infected with HPV do not develop CIN or cervical cancer. This suggests that infection with

HPV alone is insufficient for the development of CIN or cervical cancer and underscores the importance of other

cofactors, such as cigarette smoking or immunosuppression.

There are more than 100 HPV types, half of which infect the anogenital epithelium. Based on their malignant

potential, HPV subtypes are categorized into low-risk and high-risk types. Low-risk HPV types (eg, types 6, 11, 42,

43, and 44) are associated with condylomata and low-grade lesions (CIN I), whereas high-risk HPV (such as types

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) is, in addition to high-grade lesions (CIN II and CIN

III), found in invasive cancer.

Cigarette smoking and HPV infection have synergistic effects on the development of CIN, and cigarette smoking is

associated with a 2- to 4-fold increase in the relative risk for developing cervical cancer. Cigarette smoke carcinogens

have been found to accumulate locally in the cervical mucus, and the cumulative exposure as measured by pack-

years smoked is related to the risk of developing CIN or carcinoma in situ. However, the mechanisms by which

cigarette smoking contributes to cervical carcinogenesis are poorly understood.

The incidence of cervical neoplasia is increased in HIV-infected women, who, in some studies, have a 20–30%

incidence of colposcopically confirmed CIN. With increasing immunosuppression there is an increased risk of de novo

HPV infection, persistent HPV infection, and progressive cervical neoplasia. Since 1993, invasive cervical cancer has

been included as an AIDS-defining illness.

Pathology

On cytologic examination, the dysplastic cell is characterized by anaplasia, an increased nuclear-to-cytoplasmic ratio

(ie, the nucleus is larger), hyperchromatism with changes in the nuclear chromatin, multinucleation, and

abnormalities in differentiation.

Histologically, involvement of varying degrees of thickness of the stratified squamous epithelium is typical of

dysplasia. The cells are anaplastic and hyperchromatic, and show a loss of polarity in the deeper layers as well as

abnormal mitotic figures in increased numbers. Benign epithelial alterations, particularly those of an inflammatory

nature, the cytopathic effects of HPV, and technical artifacts may be mistaken for CIN I and CIN II.

The columnar epithelium of the mucus-secreting endocervical glands can also undergo neoplastic transformation.

Adenocarcinoma in situ (ACIS) is defined as the presence of endocervical glands lined by atypical columnar

epithelium that cytologically resembles the cells of endocervical adenocarcinoma, but that occur in the absence of

stromal invasion. The diagnosis of ACIS can be made only by cone biopsy.

Clinical Findings

SYMPTOMS AND SIGNS

There are usually no symptoms or signs of CIN, and the diagnosis is most often based on biopsy findings following an

abnormal routine cervical cytology smear. Because high-grade dysplasia probably is a transitional phase in the

pathogenesis of many cervical cancers, early detection is extremely important. Based on the American Cancer Society

guidelines, which were last revised in 2002, all women who have reached age 21 years, or who are 3 years past

coitarche, should have a pelvic examination and collection of a cytologic smear. The cervical cytology smear should

be performed annually in case of conventional Papanicolaou (Pap) smears, and biannually if using liquid-based

cytology. Once a patient is age 30 years or older and has had 3 consecutive negative smears, the time interval

between cervical cytology smears can be extended to every 3 years. Cervical cytology screening may be discontinued

at age 70 years if the patient had 3 or more consecutive normal smears in the preceding 10 years. Screening

cytology smears may also be discontinued if the patient has undergone a total hysterectomy, unless it was done for

the treatment of cervical dysplasia or cancer.

SPECIAL EXAMINATIONS

All abnormal Pap smears require further evaluation, such as visual inspection of the cervix, repeat cytology, HPV

testing, staining with Lugol's solution (Schiller test) or toluidine blue, colposcopy, directed biopsy, endocervical

curettage, or diagnostic conization (see treatment section) (Fig 50–2). The objective is to exclude the presence of

invasive carcinoma and to determine the degree and extent of any CIN.

Figure 50–2.





Repeat Cervical Cytology

There are three acceptable initial evaluation steps for patients with minimally abnormal cervical cytology smears (eg,

ASC-US): accelerated serial cytology smears, triage to colposcopy based on a positive HPV testing result, or

immediate referral to colposcopy. All patients with ASC-H, LSILs, HSILs, atypical glandular cells (AGCs), or smears

suspicious for cancer should be referred for immediate colposcopy.

Prior to performing a repeat smear for a patient with ASC-US, she should be evaluated and treated for potential

underlying conditions that might contribute to an atypical smear, such as antimicrobials for infections or hormones

for atrophic vaginitis. The cervical cytology smear should be repeated every 6 months until there are two consecutive

normal smears. The use of serial cytologic smears is important, as the false-negative rate of a single repeat smear

following an ASC-US diagnosis is as high as 33% for biopsy-proven high-grade squamous intraepithelial lesions (CIN

II/III). A second abnormal smear (atypical squamous cell [ASC] or worse) should be evaluated by colposcopy.

HPV Testing

Testing for low-risk HPV types has no role in cervical cancer prevention. Testing for high-risk HPV types has been

investigated as an intermediary test for patients with minimally abnormal cervical cytology smears (ASC-US, LSIL).

For patients with ASC-US, reflex HPV testing is the preferred approach, with triage of women who test positive for

high-risk HPV to colposcopy. Reflex HPV testing refers to the concurrent collection of a specimen for cervical cytology

and HPV testing, with the HPV testing being performed only in case of an abnormal cytologic screen. For ASC-US, this

approach is the most cost-effective and has an equal or higher sensitivity for CIN II/III at the lowest referral rate to

colposcopy compared to the two alternate approaches (accelerated serial cytology or immediate colposcopy). Women

with an ASC-US smear and a negative HPV test are followed with a cervical cytology smear at 1 year. The value of

HPV testing for the triage of patients with LSIL is limited because nearly 85% of the lesions are HPV positive. HPV

testing combined with a cervical cytology smear has been approved as a primary screening approach in the patient

age 30 years and older, who still has her uterus and has no immunosuppression. If both results are negative,

combined screening should not be repeated for 3 years. If cytology and HPV testing are positive, triaging to

colposcopy is as outlined above. If cytology is normal, but HPV test is positive, repeat cytology and HPV test in 6–12

months is recommended, with colposcopy at that point if either test is abnormal.

Schiller Test

The Schiller test is based on the principle that normal mature squamous epithelium of the cervix contains glycogen,

which combines with iodine to produce a deep mahogany-brown color. Nonstaining, therefore, indicates abnormal

squamous (or columnar) epithelium, scarring, cyst formation, or immature metaplastic epithelium, and constitutes a

positive Schiller test. Lugol's solution is an aqueous iodine preparation and is commonly used for the Schiller test.

Colposcopic Examination

Colposcopy is the primary technique for the evaluation of an abnormal cervical cytology smear. The colposcope is an

instrument that uses illuminated low-power magnification (5–15x) to inspect the cervix, vagina, vulva, or anal

epithelium. Abnormalities in the appearance of the epithelium and its capillary blood supply often are invisible to the

naked eye but can be identified by colposcopy, particularly after the application of 3–5% aqueous acetic acid solution.

CIN produces recognizable abnormalities of the cervical epithelium in the majority of patients.

Indications for colposcopy are:

Details of the colposcopy technique are described in Chapter 38.

Normal colposcopic findings are those of:

a) The original squamous epithelium, which extends from the mucocutaneous vulvovaginal junction to the original

squamocolumnar junction.

b) The transformation zone, which is the metaplastic squamous epithelium between the original squamocolumnar

junction and the active squamocolumnar junction. The original squamocolumnar junction is the junction between the

stratified squamous epithelium of the vagina and ectocervix, and the columnar epithelium of the endocervical canal.

In two-thirds of female infants, this original squamocolumnar junction is located on the ectocervix, in close to a third

Conization of the cervix.

1. Abnormal cervical cytology smear or HPV testing;

2. Clinically abnormal or suspicious-looking cervix;

3. Unexplained intermenstrual or postcoital bleeding;

4. Vulvar or vaginal neoplasia; or

5. History of in utero diethylstilbestrol (DES) exposure.



in the endocervical canal, and in a very small subset out in the vaginal fornices. During a woman's life cycle the

squamocolumnar junction "migrates" as a consequence of various hormonal and environmental influences that alter

the cervical volume and cause squamous metaplasia of everted endocervical columnar cells. Following menarche, the

squamocolumnar junction is generally found on the ectocervix, with further eversion during pregnancy. In the

postmenopausal patient, the squamocolumnar junction is frequently within the endocervical canal. This squamous

metaplasia is a dynamic process and cervical neoplasia almost invariably originates within the transformation zone. If

the new squamocolumnar junction is visualized in its entirety, the colposcopic examination is called satisfactory; if it

cannot be fully visualized, the examination is called unsatisfactory.

c) The columnar epithelium of the endocervical canal.

Abnormal findings indicative of dysplasia and carcinoma in situ (CIS) are those of:

1. Leukoplakia or hyperkeratosis, which is an area of white, thickened epithelium that is appreciated prior to the

application of acetic acid and may indicate underlying neoplasia.

2. Acetowhite epithelium, which is epithelium that stains white after the application of acetic acid.

3. Mosaicism or punctation reflecting abnormal vascular patterns of the surface capillaries. As a general rule,

capillary thickness and intercapillary distances correlate with the severity of the lesion and thus tend to be larger

and coarser in higher-grade lesions.

4. Atypical vessels with bizarre capillaries with so-called corkscrew, comma-shaped, or spaghetti-like

configurations suggest early stromal invasion (Figs 50-3, 50-4, and 50-5).

Figure 50–3.

Schematic of different types of terminal vessels as observed in the normal squamous epithelium: hairpin capillaries

(A), network capillaries (B) both found in normal states, double capillaries (C) seen in Trichomonas inflammation,

and branching vessels (D) seen in the transformation zone.

(Reproduced with permission from Johannisson E, Kolstat P, Soderberg G: Cytologic, vascular, and histologic

patterns of dysplasia, carcinoma in situ and early invasive carcinoma of the cervix. Acta Radiol Suppl [Stockh]

1966;258.)

Figure 50–4.

Schematic of punctation terminal vessels (A) and mosaic terminal vessels (B).





A colposcopically directed punch biopsy of the most severely abnormal areas should be done. The transformation

zone extends into the endocervical canal beyond the field of vision in 12–15% of premenopausal women and in a

significantly higher percentage of postmenopausal women. Evaluation of the nonvisualized portion of the endocervical

canal by endocervical curettage (ECC) should be performed using a brush or curette, at a minimum, in every case in

which colposcopy is unsatisfactory, where the lesion is extending into the endocervical canal, where the colposcopic

impression does not explain the cervical cytology findings, or where ablative therapy is contemplated. ECC is not

indicated in pregnancy. In up to 20% of patients with CIN, the endocervical curettage is positive for dysplasia.

Diagnostic Conization

Following expert colposcopic evaluation, diagnostic conization of the cervix (Fig 50–2) is indicated if colposcopy is

unsatisfactory, if the lesion extends into the cervical canal beyond the view afforded by the colposcope, if there is

dysplasia on the endocervical curettage, if there is a significant discrepancy between the histologic diagnosis of the

directed biopsy specimen and the cytologic examination, if adenocarcinoma in situ is suspected, or if microinvasive

carcinoma is suspected.

Natural History

Understanding the natural history of the various degrees of CIN is central to the appropriate clinical management of

these patients. In addition to the degree of dysplasia, it is likely that the course of a specific lesion is also influenced

by a number of other factors, such as the patient's age, the inciting HPV type, the patient's immune competence, and

smoking habits. As summarized in Table 50–2, the majority of CIN I lesions will spontaneously regress without

treatment. However, 9–16% of patients with untreated CIN I are diagnosed with CIN II/III over a 2-year follow-up.

Spontaneous regression rates of CIN I overall are 60%; in young women, the rates are as high as 91%. Therefore, it

is generally reasonable to expectantly follow the compliant patient with CIN I using surveillance with serial cervical

cytology smears at 6-month intervals or an HPV test at 12 months. In the adolescent patient, observation is the

preferred management approach. Because we currently lack the means to identify individuals at risk for progressive

disease, immediate treatment might be appropriate for high-risk patients likely to be lost to follow-up, because up to

40% of these women may have persistent or progressive disease that will eventually require therapy. The majority of

high-grade lesions will persist or progress (Table 50–2), so immediate treatment is generally warranted.

Treatment

1966;258.)

Figure 50–5.

Schematic of atypical vessels: hairpinlike (A); networklike (B); and branching type (C).



1966;258.)

Table 50–2. Approximate Rates of Spontaneous Regression, Persistence, and Progression

of CIN.

CIN I CIN II CIN III

Regression to normal 60% 40% 30%

Persistence 30% 35% 48%

Progression to CIN III 10% 20% —

Progression to cancer < 1% 5% 22%



Patient management is based on the correlation of the results of the cervical cytology smear, findings at colposcopy

and biopsy, and ECC results, as well as individual patient characteristics, such as pregnancy, HIV infection, and the

likelihood of compliance with management recommendations.

Treatment options fall into one of two main categories: procedures that ablate the abnormal tissue and do not

produce a tissue specimen for additional histologic evaluation and procedures that excise the area of abnormality,

allowing for further histologic study. Prior to any therapeutic intervention an assessment has to be made as to

whether a patient qualifies for ablative therapy (eg, satisfactory diagnostic evaluation has excluded invasive disease)

or if she requires an excisional procedure (conization) for further diagnostic work-up. In most cases, conization is also

the appropriate therapeutic intervention. If the intraepithelial lesion is confined to the ectocervix, treatment with

cryotherapy, laser ablation, or a superficial excision by the loop electrosurgical excision procedure (LEEP) is

appropriate. If the lesion extends into the endocervical canal, the endocervical curettage contains dysplastic

epithelium, or the colposcopic examination is otherwise unsatisfactory, the endocervical canal must be included in the

treatment by a deeper LEEP or cone biopsy (Fig 50–6). A conization procedure is also indicated in cases of a

significant discrepancy between cervical cytology and colposcopy/biopsy results, in cases of suspected microinvasive

carcinoma or adenocarcinoma in situ.

The five most common techniques for the treatment of CIN include two ablative techniques—cryotherapy and laser

Figure 50–6.

Plan for management of the abnormal cytologic smear with visible or no visible cervical lesion. SCCA = squamous

cell carcinoma.



ablation—and three excisional procedures—cold knife conization, laser cone excision, and LEEP. Evidence from

controlled trials show that these techniques are of equal efficacy, averaging 80–90% success rates in the treatment

of CIN. Cure depends on the size of the lesion, endocervical gland involvement, margin status of any excisional

specimen, and ECC results.

CRYOTHERAPY

In cryotherapy, an office procedure not requiring anesthesia, nitrous oxide or carbon dioxide is used as the

refrigerant for a supercooled probe. The cryoprobe is positioned on the ectocervix where it must cover the entire

lesion, which at times is not easily achieved. It is then activated until blanching of the cervix extends at least 7 mm

beyond the probe in all directions in order to assure that freezing extends beyond the depth of the crypts of the

glands into which the dysplasia might be extending. Introduction of a two-cycle freeze–thaw–freeze technique has

improved efficacy. The advantages of cryotherapy include ease of use, low cost, widespread availability, and a low

complication rate. Side effects include mild uterine cramping and a copious watery vaginal discharge for several

weeks. Infection and cervical stenosis are rare. Follow-up colposcopic examinations can be unsatisfactory because of

the inability to visualize the squamocolumnar junction.

CARBON DIOXIDE LASER

Carbon dioxide (CO2) laser can be used either to ablate the transformation zone or as a tool for cone biopsies. The

laser destroys tissue with a very narrow zone of injury around the treated tissue, and is therefore both precise and

flexible. The tissue is vaporized to a depth of at least 7 mm to assure that the bases of the deepest glands are

destroyed. Posttreatment vaginal discharge may last 1–2 weeks, and bleeding that requires reexamination can occur

in a small percentage of patients. The technique is expensive and requires significant training and attention to safety,

as well as local or general anesthesia.

LOOP ELECTROSURGICAL EXCISION PROCEDURE

LEEP is the procedure of choice for treating CIN II and CIN III because of its ease of use, low cost, and provision of

tissue for histologic evaluation. LEEP uses a small, fine, wire loop attached to an electrosurgical generator to excise

the tissue of interest. Various sizes of wire loop are available. Following LEEP excision of the transformation zone,

frequently an additional narrow endocervical specimen is removed to allow for histologic evaluation while avoiding

excessive damage to the cervical stroma. Fulguration with a roller ball electrode is then used to achieve complete

hemostasis in the excision bed. LEEP can be performed as an office procedure under local anesthesia. An insulated

speculum to prevent conduction of electricity, a grounding pad, and a vacuum to remove the smoke are necessary.

Complications are less frequent than with cold knife conization and include bleeding, infection, and cervical stenosis.

COLD KNIFE CONIZATION

Cold knife conization of the cervix refers to the excision of a cone-shaped portion of the cervix using a scalpel. This

technique can be individualized to accommodate the cervical anatomy and the size and shape of the lesion. For

example, a wide, shallow cone specimen can be obtained from a young patient whose squamocolumnar junction is on

the ectocervix. In an older patient, in whom the squamocolumnar junction tends to move more cephalad into the

endocervical canal, a narrower, deeper cone is preferable. An endocervical curettage is performed after the conization

to assess the remaining endocervical canal. Cervical cone biopsy is generally done in the operating room under local

or general anesthesia. Complications include bleeding, infection, cervical stenosis, and cervical incompetence. The

need to perform the procedure in the operating room and a higher complication rate are distinct disadvantages of

cold knife conization. However, it results in a specimen devoid of any thermal artifact that may complicate the

histologic diagnosis and margin assessment seen with LEEP and laser conization. This becomes particularly important

with suspected microinvasive carcinoma and adenocarcinoma in situ.

Follow-Up

Most treatment failures are diagnosed within the first 1–2 years after therapy. Patients with positive margins or

positive ECC after an excisional procedure are at higher risk for persistent/recurrent disease than are women with

negative margins, necessitating close follow-up, including repeat endocervical sampling but not reexcision. Therefore,

careful examination should be performed, with Pap smears every 6 months for 18 to 24 months and endocervical

curettage if the endocervix was involved. Alternatively, HPV testing may be performed along with the first cytology

smear 6 months after therapy. If both are negative, annual follow-up can be established. Management of recurrent

dysplasia follows the same guidelines outlined in Fig 50–6. If a woman has completed childbearing, recurrent

dysplasia can be treated by a simple hysterectomy after invasion has been ruled out. Women with a history of

cervical dysplasia have a higher incidence of vaginal dysplasia. These women continue to need Pap smears after

hysterectomy.

SPECIAL SITUATIONS

PREGNANCY

Pregnant women routinely undergo cervical cytology screening at their first prenatal visit. As a result, it is not



uncommon that an abnormal cervical cytology smear is first discovered during pregnancy. Colposcopy is performed

for the same indications as in the nonpregnant patient. However, biopsies are limited unless there are colposcopic

signs suggestive of carcinoma in situ or invasive disease. Endocervical curettage is not performed in pregnancy

because of the potential risk of abortion and infection. The physiologic changes of pregnancy render the

transformation zone easily accessible for satisfactory colposcopy by 20 weeks' gestation in almost all women.

Colposcopy during pregnancy can be challenging because pregnancy may produce changes in the cervical epithelium

that mimic those of cervical dysplasia. Although the gravid cervix is more vascular, directed ectocervical biopsies can

be performed safely with minimal increase in the risk of significant bleeding. After the diagnosis of dysplasia has been

established, the patient can be carefully followed with colposcopic examinations and cervical cytology smears each

trimester. Repeat biopsies are only performed for progressive lesions. Treatment is deferred into the postpartum

period. Even high-grade lesions discovered during pregnancy have a high rate of regression in the postpartum period.

Conization during pregnancy is indicated only if early invasive disease is suspected. Complications of a cone biopsy in

pregnancy include abortion, hemorrhage, infection, and incompetent cervix.

ATYPICAL GLANDULAR CELLS ON CERVICAL CYTOLOGY SMEAR

Patients with atypical glandular cells on a cervical cytology smear have a up to 50% risk of having high-grade cervical

neoplasia. The underlying lesion is most commonly CIN II or III, which is diagnosed in up to 34% of cases. Cervical

adenocarcinoma in situ, invasive cervical adenocarcinoma, and endometrial disease, including hyperplasia and

cancer, comprise the remaining 16%.

The 2001 Bethesda System divides glandular cell abnormalities into AGCs, AGC-favor neoplasia, endocervical

adenocarcinoma in situ (AIS), and adenocarcinoma. Given the high risk for significant pathology, any patient with

glandular cell abnormalities on a cervical cytology smear requires immediate evaluation, which includes, at a

minimum, colposcopy with careful evaluation of the endocervical canal. Assessment of the endometrium is

recommended in all patients older than age 35 years, in patients at any age with abnormal bleeding, in women with

AGC (endometrial cells), and in women with AGC (nonspecified cell type) (see Table 50–1). Diagnostic conization is

indicated in all cases of AGC-favor neoplasia, AIS, or suspected adenocarcinoma as well as persistent atypical

glandular cell–not otherwise specified (AGC-NOS), unless a definitive diagnosis has been made on the colposcopy

directed biopsy or endometrial sampling.

ADENOCARCINOMA IN SITU

The reported incidence of glandular neoplasia of the cervix is increasing, especially in young women, with up to 30%

of cases occurring in women younger than 35 years of age. Adenocarcinoma of the cervix represents approximately

25% of all cervical cancers and there is convincing evidence that ACIS is a precursor lesion. Half of the women with

ACIS have concomitant squamous CIN. Management is difficult. The lesion may be located high in the endocervical

canal, involve the deeper portions of the endocervical clefts, or be multifocal with skip lesions. Conization is required

to make the diagnosis. Follow-up surveillance after conization is difficult, as cervical cytology, endocervical curettage,

or endocervical cytobrush sampling each have a sensitivity of only approximately 50%. This is of particular concern

because the incidence of residual ACIS or invasive adenocarcinoma following conization for ACIS is as high as 58%

with positive conization margins, and 19% with negative conization margins. Therefore, conservative management

should be undertaken only in the young patient with a negative conization margin who is fully counseled and desires

to maintain her fertility. In all other patients, hysterectomy should be performed as a definitive therapeutic

intervention because even with negative margins, as many as 8–16% may have invasive disease on the

hysterectomy specimen. For the same reason, consideration should be given to the performance of a modified radical

hysterectomy, especially if extensive disease and positive margins were found on the preceding conization specimen.

HIV INFECTION

Management of CIN in the HIV-infected patient presents a great challenge. Following treatment, the risk of recurrent

CIN is high, especially in the immunocompromised patient with low CD4 counts and high viral loads. Recurrence rates

may reach 80% within 3 years in markedly immunocompromised women. Use of highly active antiretroviral therapy

(HAART) appears to reduce the risk of recurrent or progressive cervical neoplasia.

CANCER OF THE CERVIX

Essentials of Diagnosis

� Early disease is frequently asymptomatic, underscoring the importance of cervical cytology screening.

� Abnormal uterine bleeding and vaginal discharge are the most common symptoms.

� A cervical lesion may be visible on inspection as a tumor or ulceration; cancer within the cervical canal may

be occult.

� Diagnosis must be confirmed by biopsy.

General Considerations



Cancer of the cervix is the sixth most common solid cancer in American women. In the United States, an estimated

10,370 new cases of invasive cervical cancer are diagnosed annually, and there are 3710 deaths from the disease. In

contrast, with more than 370,000 new cases diagnosed annually and a 50% mortality rate, cervical cancer is the

second most common cause of cancer-related morbidity and mortality among women in developing countries. This

dichotomy is largely the result of a 75% decrease in the incidence of cervical cancer in developed countries following

the implementation of population-based screening programs and treatment of preinvasive disease. The average age

at diagnosis of patients with cervical cancer is 51 years. However, the disease can occur in the second decade of life

and during pregnancy. More than 95% of patients with early cancer of the cervix can be cured.

Etiology & Epidemiology

The major epidemiologic risk factors for cervical cancer are the same as those for CIN and were discussed above.

HPV is central to the development of cervical neoplasia. HPV DNA is found in 99.7% of all cervical carcinomas. HPV

16 is the most prevalent HPV type in squamous cell carcinoma, and HPV 18 the most prevalent in adenocarcinoma.

Other associated risk factors are immunosuppression, infection with HIV or a history of other sexually transmitted

diseases, tobacco use, high parity, and oral contraceptive use.

Pathogenesis & Natural History

HPV is epitheliotropic. Once the epithelium is acutely infected with HPV, one of three clinical scenarios ensues:

Integration of HPV into the human genome is associated with cell immortalization allowing for malignant

transformation. This involves an upregulation of the viral oncogenes E6 and E7. These oncoproteins interfere with

cell-cycle control in the human host cell. E6 and E7 have the ability to complex with the tumor suppressor genes p53

and Rb, respectively. The disabling of these two major tumor suppressor genes is thought to be central to host cell

immortalization and transformation induced by HPV.

Incipient cancer of the cervix is generally a slowly developing process. Most cervical cancers probably begin as a

high-grade dysplastic change (see previous section) or carcinoma in situ with gradual progression over a period of

several years. At least 90% of squamous cell carcinomas of the cervix develop from the intraepithelial layers, almost

always within 1 cm of the squamocolumnar junction of the cervix either on the portio vaginalis of the cervix or

slightly higher in the endocervical canal.

Early stromal invasion (stage IA1) up to a depth of 3 mm below the basement membrane is a localized process,

provided there is no pathologic evidence of lymphovascular space involvement. Penetration of the stroma beyond this

point carries an increased risk of lymphatic metastasis (Table 50–3). When the lymphatics are involved, tumor cells

are carried to the regional pelvic lymph nodes (parametrial, hypogastric, obturator, external iliac, and sacral) (Fig

50–7). The more pleomorphic or extensive the local disease, the greater the likelihood of lymph node involvement.

As the tumor grows, it also spreads by direct extension to the parametria.

a) Asymptomatic latent infection;

b) Active infection in which HPV undergoes vegetative replication but not integration into the genome (eg, leading

to condyloma or CIN I); or

c) Neoplastic transformation following integration of oncogenic HPV DNA into the human genome.

Table 50–3. Risk of Any Lymph Node Metastasis for Patients with Microscopic Squamous

Cell Carcinoma of the Cervix.

Depth of Tumor Invasion Risk of Lymph Node Metastasis

FIGO stage IA1

Early stromal invasion (< 1 mm) 3/1543 (0.2%)

Microinvasion (1–3 mm) 5/809 (0.6%)

FIGO stage IA2

Microscopic 3–5 mm invasion 14/214 (6.5%)

Figure 50–7.



Squamous cell carcinoma clinically confined to the cervix involves the regional pelvic lymph nodes in 15–20% of

cases. When the cancer involves the parametrium (stage IIB), tumor cells can be found in the pelvic lymph nodes in

30–40% and in the paraaortic nodes in approximately 15–30% of cases. The more advanced the local disease, the

greater the likelihood of distant metastases. The paraaortic nodes are involved in approximately 45% of patients with

stage IVA disease.

Ovarian involvement is rare, occurring in approximately 0.5% of squamous cell carcinomas and 1.7% of

adenocarcinomas. The liver and lungs are the most common sites of blood-borne metastasis, but the tumor may

involve the brain, bones, bowels, adrenal glands, spleen, or pancreas.

When cancer of the cervix is untreated or fails to respond to treatment, death occurs in 95% of patients within 2

years after the onset of symptoms. Death can occur from uremia, pulmonary embolism, or hemorrhage from direct

extension of tumor into blood vessels. Life-threatening sepsis from complications of pyelonephritis or vesicovaginal

and rectovaginal fistulas is possible. Large-bowel obstruction from direct extension of tumor into the rectosigmoid can

be the terminal event. Pain from perineural extension is a significant management problem of advanced disease.

Pathology

Approximately 70–75% of cervical carcinomas are squamous cell; the remainder are composed of various types of

adenocarcinomas (20–25%), adenosquamous carcinomas (3–5%), and undifferentiated carcinomas.

SQUAMOUS CELL CARCINOMAS

Cervical squamous cell carcinomas have been classified according to the predominant cell type: large cell

nonkeratinizing, large cell keratinizing, and small cell carcinomas. The large cell nonkeratinizing variety accounts for

the majority of tumors.

VERRUCOUS CARCINOMA

Verrucous carcinoma, which has been associated with HPV 6, is a rare subtype of well-differentiated squamous

carcinoma. It is a slow-growing, locally invasive neoplasm. Histologically, this tumor is composed of well-

differentiated squamous cells with frondlike papillae and little apparent stromal invasion, but it is potentially lethal.

Radical resection is the mainstay of therapy.

ADENOCARCINOMA

Adenocarcinoma of the cervix is derived from the glandular elements of the cervix. The incidence of

adenocarcinomas, including the mucinous, endometrioid, clear cell, and serous types, has been rising over the last

several decades, especially in women younger than 35 years of age. Part of this increase may be a result of an

increasing prevalence of HPV infection and part may be a result of improvements in screening and prevention of

squamous preinvasive disease, thus leading to a histologic shift toward adenocarcinoma. When the initial growth of

adenocarcinoma of the cervix is within the endocervical canal and the ectocervix appears normal, this lesion might

Lymphatic spread of carcinoma of the cervix.



not be diagnosed until it is advanced and ulcerative. The so-called clear cell variety may be related to in utero

exposure to DES. It has a prognosis comparable to that of other adenocarcinomas of the cervix. The villoglandular-

papillary variety of adenocarcinoma of the cervix tends to occur in younger women and have a more favorable

prognosis.

ADENOMA MALIGNUM

Adenoma malignum or minimal deviation adenocarcinoma is an extremely well-differentiated adenocarcinoma that

may be difficult to recognize as a malignant process. It represents approximately 1% of adenocarcinomas of the

cervix and has been associated with Peutz-Jeghers syndrome. It occurs mainly in the fifth and sixth decades of life.

Diagnosis is often delayed because of frequently normal cervical cytology smears. Punch biopsies are often

nondiagnostic, requiring conization for further evaluation.

ADENOID CYSTIC CARCINOMA

Another uncommon variant of adenocarcinoma is adenoid cystic carcinoma. This lesion is considered more aggressive

than most cervical adenocarcinomas and occurs more commonly in black women of high parity in their sixth and

seventh decades of life. It should not be confused with adenoid basal carcinomas, which have an indolent growth

pattern.

ADENOSQUAMOUS CARCINOMA

Adenosquamous carcinomas contain an admixture of malignant squamous and glandular cells. Glassy cell carcinoma

is a poorly differentiated form of adenosquamous carcinoma and is considered to have an extremely aggressive

course. It accounts for approximately 1–2% of cervical cancers. Synchronous adenocarcinomas and squamous cell

carcinomas that invade each other are called collision tumors.

NEUROENDOCRINE CARCINOMAS

Approximately one-third of small cell carcinomas of the cervix stain positive for neuroendocrine markers. These

tumors need to be distinguished from small cell type of squamous tumors. They have a high frequency of

lymphovascular space invasion, lymph node metastases, recurrence, and poor survival. Carcinoid tumors, arising

from the argyrophil cells of the endocervical epithelium, are malignant but have rarely been associated with the

carcinoid syndrome. Because of their propensity for early systemic spread, systemic chemotherapy is an integral part

of the treatment of neuroendocrine tumors of the cervix.

OTHER MALIGNANT TUMORS

Direct extension of metastatic tumors to the cervix include those originating from the endometrium, rectum, and

bladder. Lymphatic or vascular metastases occur less often but are associated with endometrial, ovarian, gastric,

breast, colon, kidney, and pancreas carcinomas. Sarcomas, lymphomas, choriocarcinomas, and melanomas are

encountered rarely in the cervix.

Clinical Findings

SYMPTOMS AND SIGNS

Abnormal vaginal bleeding is the most common symptom of invasive cancer and may take the form of a blood-

stained leukorrheal discharge, scant spotting, or frank bleeding. Leukorrhea, usually sanguineous or purulent,

odorous, and nonpruritic, is frequently present. A history of postcoital bleeding may be elicited on specific

questioning.

Pelvic pain, often unilateral and radiating to the hip or thigh, is a manifestation of advanced disease, as is the

involuntary loss of urine or feces through the vagina, a sign of fistula formation. Weakness, weight loss, and anemia

are characteristic of the late stages of the disease, although acute blood loss and anemia may occur in an ulcerating

stage I lesion.

Physical examination findings include a grossly normal-appearing cervix with preclinical disease. As the local disease

progresses, physical signs appear. Infiltrative cancer produces enlargement, irregularity, and a firm consistency of

the cervix and eventually of the adjacent parametria. The growth pattern can be endophytic, leading to a barrel-

shaped enlargement of the cervix, or exophytic, where the lesion generally appears as a friable, bleeding,

cauliflowerlike lesion of the portio vaginalis. Ulceration may be the primary manifestation of invasive carcinoma; in

the early stages the change often is superficial, so that it may resemble an ectropion or chronic cervicitis. With

further progression of the disease, the ulcer becomes deeper and necrotic, with indurated edges and a friable,

bleeding surface. The adjacent vaginal fornices may become involved next. Eventually, extensive parametrial

involvement by the infiltrative process may produce a nodular thickening of the uterosacral and cardinal ligaments

with resultant loss of mobility and fixation of the cervix.

BIOPSY

Because of the failure of malignant cells to desquamate and the obscuring effect of inflammatory cells, it is not

uncommon for an invasive carcinoma of the cervix to exist despite a negative cytologic smear. Any suspicious lesion



of the cervix should be sampled by adequate biopsy, regardless of cytologic examination result. Biopsy of any

Schiller-positive areas or of any ulcerative, granular, nodular, or papillary lesion provides the diagnosis in most cases.

Colposcopically directed biopsies with endocervical curettage or conization of the cervix may be required when

reports of suspicious or probable exfoliated carcinoma cells are made by the pathologist and a visible or palpable

lesion of the cervix is not evident. Colposcopic warning signs of early invasive cancer in a field of CIN include

capillaries that are markedly irregular, appearing as commas, corkscrews, and spaghetti-shaped vessels with great

variation in caliber and abrupt changes in direction, often causing acute angles. Ulcerations or a markedly irregular

appearance of the cervix with a waxy, yellowish surface and numerous bizarre, atypical blood vessels are common.

Bleeding may occur also after slight irritation.

CONIZATION

In the setting of a biopsy revealing carcinoma in situ, where invasion cannot be ruled out, or in the setting of a

negative colposcopy in the face of a significantly abnormal cervical cytology smear, conization of the cervix should be

performed to determine the presence or absence of invasion. If a cervical biopsy shows microinvasive cancer (< 3

mm of invasion), a cone biopsy is necessary to rule out deeper invasion. The conization specimen should be properly

marked for the pathologist (eg, with a pin or small suture), so that the area of involvement can be specifically

localized in relation to the circumference and margins of the cervix. Conization for a lesion grossly suggestive of

invasive cancer is not indicated, as it only delays the initiation of appropriate therapy and predisposes the patient to

serious pelvic infections and bleeding. The diagnosis of such a lesion can almost always be confirmed by simple

cervical biopsy.

RADIOLOGIC FINDINGS

Chest radiographs are indicated in all patients with cervical cancer and an intravenous pyelogram (IVP) or computed

tomography (CT) urogram should be performed to determine if there is any ureteral obstruction producing

hydroureter and hydronephrosis. Magnetic resonance imaging (MRI), CT scan, lymphangiography, or positron

emission tomography (PET) scanning may demonstrate involvement of the pelvic or periaortic lymph nodes or other

sites of metastases. The sensitivities of CT, MRI, and PET for lymph node metastases in cervical cancer are

approximately 45%, 60%, and 80%, respectively. Although the latter imaging studies are not used to assign disease

stage in the International Federation of Gynecology and Obstetrics (FIGO) classification, they may be of value for

planning treatment, particularly the extent of the radiation therapy field or scope of surgery.

Clinical Staging

It is important to estimate the extent of the disease not only for prognostic purposes but also for treatment planning.

Clinical staging also affords a means of comparing methods of therapy for various stages of the disease worldwide.

The classification adopted by FIGO is the most widely used staging system (Table 50–4). Cervical cancer is staged by

clinical examination, and evaluation of the bladder, ureters, and rectum. If the lesion is clearly confined to the cervix

by office examination, only chest radiography and evaluation of the ureters by IVP or CT scan with intravenous

contrast is necessary to assign the stage. If it is not possible to evaluate the extent of local disease in the office,

examination under anesthesia with cystoscopy and proctoscopy may be necessary. Although CT scan, MRI,

lymphangiography, and PET scan may offer information helpful for treatment planning, these findings do not change

the FIGO stage of disease. The FIGO stage of disease is also not changed by surgicopathologic findings of metastatic

disease at the time of radical hysterectomy or lymphadenectomy.

Table 50–4. FIGO Staging of Cervical Cancer (Adopted from FIGO Annual Report on the

Results of Treatment in Gynecologic Cancer 1998).

FIGO Stage Definition

Stage 0 Carcinoma in situ

Stage I Cervical carcinoma confined to the cervix (extension to the corpus would be disregarded)

Stage IA1 Invasive cervical cancer diagnosed by microscopy only

Stage IA1 Stromal invasion no deeper than 3 mm, no wider than 7 mm in horizontal spread

Stage IA2 Stromal invasion greater than 3, but less than 5 mm and no wider than 7 mm in horizontal spread

Stage IB Clinically visible lesion confined to the cervix or microscopic disease greater than stage IA

Stage IB1 Lesion not greater than 4 cm

Stage IB2 Lesion greater than 4 cm

Stage II Tumor extends beyond uterus but not to pelvic sidewall or lower third of vagina

Stage IIA Vaginal involvement without parametrial involvement



Differential Diagnosis

A variety of lesions of the cervix can be confused with cancer. Entities that must sometimes be ruled out include

cervical ectropion, acute or chronic cervicitis, condyloma acuminata, cervical tuberculosis, ulceration secondary to

sexually transmitted disease (syphilis, granuloma inguinale, lymphogranuloma venereum, chancroid), abortion of a

cervical pregnancy, metastatic choriocarcinoma or other cancers, and rare lesions such as those of actinomycosis or

schistosomiasis. Histopathologic examination is usually definitive.

Complications

The complications of cervical cancer, for the most part, are those related to tumor size or invasion, necrosis of the

tumor, infection, and metastatic disease. The natural history of the disease was outlined above. There are also

problems pertaining to treatment of the disease (eg, radical surgery or radiation therapy; see Treatment, below).

Prevention

Until now, prevention of morbidity and death from cervical cancer largely involved recognition and treatment of

preinvasive and early invasive disease. Currently, approximately 60% of women who develop cervical cancer in

developed countries either never had been screened or had not been screened in the preceding 5 years. Risk factors

must be recognized, and screening, treatment intervention, and patient education must be modified respectively.

Universal cytologic screening of all postpubertal women must be continued on a regular basis until better, more

sensitive and specific means of screening are found, and outreach into underserved areas is improved. Women with

preinvasive cervical neoplasia should be treated and followed up closely (Fig 50–6). It is important to remember that

cervical cytology smears are of limited value in detecting frankly invasive disease, with some studies finding false-

negative rates up to 50%. Sexual abstinence is an effective but impractical prophylactic measure. Education of young

women and men about risk factors and the necessity for regular screening, as well as information about the

association of HIV infection and smoking with the development of cervical cancers, is crucial.

Several HPV vaccines are currently in advanced stages of development. Gardasil a quadrivalent vaccine against HPV

16/18/6/11 received FDA approval in the United States in June 2006 for use in girls and women 9–26 years old. To

date, large trials have demonstrated that the vaccines are generally safe, well tolerated and highly immunogenic with

excellent efficacy in the prevention of persistent HPV infection and against the development of cytologic

abnormalities.

Treatment

Invasive carcinoma of the cervix spreads primarily by direct extension and lymphatic dissemination. The therapy of

patients with cervical cancer needs to address not only the primary tumor site, but also the adjacent tissues and

lymph nodes. This is generally accomplished by either radical hysterectomy and pelvic lymphadenectomy, radiation

with concomitant chemotherapy, or a combination thereof.

TREATMENT OF EARLY STAGE DISEASE (STAGE IA2 TO IIA)

Patients with early stage cervical cancer may be treated with either radical hysterectomy and pelvic

lymphadenectomy or with primary radiation with concomitant chemotherapy. The overall 5-year cure rates for

surgery and for radiation therapy in operable patients are approximately equal. The advantage of surgery is that the

ovaries may be left intact and be transposed out of the radiation field if adjuvant postoperative therapy appears

necessary, that the extent of disease can be determined surgicopathologically, and that grossly metastatic lymph

Stage IIB Parametrial involvement

Stage III Tumor extends to pelvic sidewall and/or causes hydronephrosis and/or extends to lower third of

vagina

Stage IIIA Involvement of lower third of vagina with no extension to sidewall

Stage IIIB Extension to pelvic sidewall and/or hydronephrosis

Stage IV Extension beyond the true pelvis or into mucosa of rectum or bladder

Stage IVA2 Extension into adjacent organs

Stage IVB Distant metastases

1The depth of invasion should be no more than 5 mm from the epithelial basement membrane of the adjacent most

superficial epithelial papilla to the deepest point of invasion where the cancer originates. Vascular space invasion,

venous or lymphatic, does not affect staging, but should be noted as it may affect future therapy. All macroscopically

visible lesions (even with superficial invasion only) are allotted to stage IB.

2The presence of bullous edema is not sufficient to classify a tumor as stage IVA. The finding of malignant cells in

cytologic bladder washings requires further histologic confirmation in order to be considered stage IVA.



nodes can be resected. Furthermore, surgery may be more appropriate in sexually active women with early stage

disease as radiation causes vaginal stenosis and atrophy. Adjuvant radiation with concomitant chemotherapy is

administered to selected patients at increased risk for recurrence following radical hysterectomy.

Radical Hysterectomy and Therapeutic Lymphadenectomy

Radical hysterectomy (techniques initially described by Wertheim, Meigs, and Okabayashi) with pelvic

lymphadenectomy is the surgical procedure for invasive cancer limited to the cervix (stages I and II). The operation

is technically difficult and should be performed only by those experienced in radical pelvic surgery. Surgery involves

dissection of the ureters from the paracervical structures so that the ligaments supporting the uterus and upper

vagina can be removed. When the operation is done vaginally, a deep Schuchardt (paravaginal) incision is required

for exposure. Five different types of hysterectomy have been described based upon the extent of parametrial

dissection and vaginal tissue removed (Table 50–5). Typically, a type I hysterectomy is indicated for patients with

stage IA1 disease. An alternative treatment is cervical conization in the young patient wishing to preserve fertility.

Stage IA2 to II A are treated with a type II (modified radical) or type III (radical) hysterectomy. It is rarely necessary

to remove as much vaginal tissue as was initially recommended. As long as complete tumor clearance can be

provided, a modified radical hysterectomy appears to provide therapeutic outcomes comparable to a radical

hysterectomy for stage IB and IIA disease, but with shorter operating time and lower urologic morbidity. Full pelvic

lymphadenectomy is indicated at the time of radical hysterectomy, followed by paraaortic lymphadenectomy for

tumors larger than 2 cm or those with suspicious pelvic lymph nodes. Resection of all grossly involved lymph nodes

provides a distinct survival advantage. Microscopic evaluation of the lymph nodes allows for tailoring of the

postoperative radiation field, if indicated.

Adjuvant Postoperative Radiation

Postoperative adjuvant radiation therapy with concomitant chemotherapy is indicated in women with localized

cervical cancer at high risk for recurrent disease, such as positive lymph nodes, positive or close resection margins,

or microscopic parametrial involvement. In this setting, adjuvant radiation with platinum-based chemotherapy is

superior to adjuvant radiation alone, with an improvement in the 4-year progression-free interval from 63% to 80%.

Women with intermediate-risk factors for recurrent disease, such as large tumor size, deep cervical stromal invasion,

and lymphovascular space invasion, also benefit from postoperative adjuvant radiation. These patients have an

improved 2-year recurrence-free survival of 88% with adjuvant radiation versus 79% without adjuvant therapy.

Primary Radiation with Concomitant Chemotherapy

For the treatment of early cervical cancer (stages IA to IIA), primary therapy with definitive radiation or radical

surgery followed by tailored radiation if indicated by the surgical findings produce comparable outcomes. The choice

of treatment depends on the tumor size, the general condition of the patient, and preferences of the oncologists at

the treating institution. Surgery is often preferred for young patients in the hope of preserving ovarian function. If it

is likely that the patient will need postoperative radiation therapy, transposition of the ovaries to a location outside

the radiation field can be performed. For primary radiation of cervical cancer, external beam radiation is used in

combination with intracavitary irradiation (see Chapter 54). At least five controlled trials have demonstrated the

superiority of radiation with concomitant platinum-based chemotherapy over radiation alone. This has led to the

adoption of radiation plus concomitant chemotherapy as the standard of care whenever radiation therapy is given for

the treatment of cervical cancer over a broad spectrum of disease stages.

Special Situations

Table 50–5. Types of Hysterectomy Based on Radicality.

Type of

Hysterectomy

Principles of Procedure

Type I Extrafascial hysterectomy with removal of all cervical tissue without dissecting into the cervix

itself.

Type II The uterine artery is ligated where it crosses over the ureter. The uterosacral and cardinal

ligaments are divided midway towards their attachment to sacrum and pelvic sidewall. The

upper third of the vagina is resected.

Type III The uterine artery is ligated at its origin from the superior vesical or internal iliac artery.

Uterosacral and cardinal ligaments are resected at their attachments to the sacrum and pelvic

sidwall. The upper half of the vagina is resected.

Type IV The ureter is completely dissected from the vesicouterine ligament, the superior vesical artery is

sacrificed, and three fourths of the vagina is resected.

Type V Involves the additional resection of a portion of the bladder or the distal ureter with ureteral

reimplantation into the bladder



STAGE IA1 DISEASE

The definitive diagnosis of microinvasive squamous cell carcinoma of the cervix can only be made by conization.

These patients may be treated by simple abdominal or vaginal hysterectomy. For a young woman desiring to

maintain fertility, only conization is an acceptable treatment modality for microinvasive squamous cell carcinoma with

a depth of invasion of 3 mm or less, if the conization margins are negative, and if there is no evidence of

lymphovascular space invasion. If margin and endocervical curettage are positive, the risk of residual disease is as

high as 33%. In this case, repeat conization should be performed if uterine preservation is the goal. FIGO staging is

not influenced by the presence of lymphovascular space invasion, which occurs in close to 10% of patients with stage

IA1 disease. These patients have a small but significant risk for lymph node metastases to parametrial and pelvic

lymph nodes. This subgroup of patients should therefore be treated like patients with stage IA2 disease. There is

considerable controversy regarding the existence of microinvasive adenocarcinoma and its pathologic diagnostic

criteria, which is beyond the scope of this chapter.

RADICAL TRACHELECTOMY

During the last decade, radical trachelectomy has evolved as an alternative to radical hysterectomy in carefully

selected young women with early stage (IA2 or small IB1) cervical cancer who wish to preserve fertility. A

therapeutic lymphadenectomy is performed and following radical resection of the cervix a cerclage is placed.

Experience with this technique is growing, and the oncologic outcome appears comparable to radical hysterectomy in

carefully selected patients. A review of pregnancy outcomes in women who underwent radical trachelectomy revealed

16% first trimester miscarriages, 10% second trimester losses, 19% preterm deliveries, and a 49% term delivery

rate.

BULKY CERVICAL CANCER

The management of patients with stage IB2 and bulky IIA disease is a matter of considerable debate. Proposed

management strategies include the following.

Primary Radiation Therapy with Concomitant Chemotherapy and the Option of a Subsequent Adjuvant

Extrafascial Hysterectomy

Radiation therapy is usually recommended for patients with bulky cervical cancers, recently with the addition of

concomitant chemotherapy. Many of these tumors, however, contain hypoxic central areas that do not respond well

to radiation, as is reflected in a 15–35% pelvic failure rate. This provides the rationale for the performance of an

adjuvant hysterectomy following radiation, which is associated with a significant reduction in pelvic recurrences to 2–

5%. However, the impact of adjuvant hysterectomy on extrapelvic recurrences and survival is less-well established.

Primary Radical Hysterectomy and Therapeutic Lymphadenectomy, Followed by Tailored Radiation with

Concomitant Chemotherapy When Indicated by Pathologic Findings

The potential benefits of this approach include the removal of the large primary tumor, complete surgical staging with

the opportunity to resect any grossly involved lymph nodes, and the preservation of ovarian function as ovarian

transposition can be performed if adjuvant radiation therapy is likely. If postoperative radiation becomes necessary,

the radiation field can be tailored to the surgicopathologic findings. The resection of macroscopically involved lymph

nodes has a therapeutic benefit because it improves survival to that of patients with microscopic lymph node

metastases only. A primary surgical approach should be taken in patients with acute or chronic pelvic inflammatory

disease, an undiagnosed coexistent adnexal mass, or anatomic alterations that make radiation therapy difficult.

Neoadjuvant Chemotherapy Followed by Radical Hysterectomy and Lymphadenectomy and Subsequent

Chemoradiation When Indicated by Pathologic Findings

Neoadjuvant chemotherapy, frequently three cycles of platinum-based combination therapy followed by radical

hysterectomy and lymphadenectomy, was recently proposed as a novel treatment strategy for these patients.

Neoadjuvant chemotherapy is reported to improve the resectability of bulky lesions, pelvic disease control, and

possibly long-term survival. Although this is a provocative treatment strategy, in most studies, patients ultimately

received multimodality treatment with chemotherapy, radical surgery, and radiation. Further randomized studies are

needed to determine the precise role of neoadjuvant chemotherapy in the treatment of these patients.

TREATMENT OF LOCALLY ADVANCED DISEASE (STAGE IIB TO IVA)

Patients with locally advanced cervical cancer are best treated with primary radiation (external beam plus

brachytherapy; see Chapter 54A) with concomitant chemotherapy. Extended field radiation should be considered in

the presence of paraaortic lymph node metastases documented at surgical staging or by imaging, especially when

biopsy confirmed and in the absence of other systemic metastases. The benefit of cisplatin-based combined modality

therapy over radiation alone for advanced disease has been demonstrated in at least three randomized controlled

trials, which found a 30–50% reduction in the risk of death from cervical cancer for patients treated with

chemoradiation compared to those treated with radiation alone. This difference is most significant for patients with

stage II disease (and bulky IB disease) in whom, in one study, chemoradiation, compared to radiation alone,

improved 5-year survival rates from 58% to 77%. For patients with more advanced disease, the benefits associated



with chemoradiation versus radiation alone appear less pronounced, with the same study showing a small,

statistically insignificant improvement in 5-year survival from 57% to 63%. The optimal drug regimen is not known,

but combination therapy did not show superior results over weekly single-agent cisplatin, and the latter was

associated with substantially less toxicity.

TREATMENT OF DISSEMINATED PRIMARY (STAGE IVB) AND PERSISTENT OR RECURRENT DISEASE

The use of chemotherapeutic agents in the treatment of cervical carcinoma has been discouraging. This is partly

because most patients who may be candidates for this type of treatment either present with disseminated disease or

have cancer that has already failed to respond to radical surgery or radiation therapy. Modest activity in recurrent or

disseminated cervical cancer has been observed with single-agent cisplatin, ifosfamide, paclitaxel, and vinorelbine.

There is a small therapeutic survival advantage to multiagent chemotherapy with cisplatin and topotecan.

Combination therapy using paclitaxel and platinum offers very similar outcomes, with response rates of 36%

compared to 27% for cisplatin and topotecan, and a median survival of 9.7 months compared to 9.6 months with

cisplatin and topotecan. Palliative pelvic radiation therapy may be indicated, especially for the control of hemorrhage.

If a patient develops a palpable mass in the left supraclavicular region, it can be palliated with radiation therapy with

concomitant chemotherapy, with or without resection.

TOTAL PELVIC EXENTERATION FOR ISOLATED CENTRAL PELVIC RECURRENCE OF DISEASE

Patients who develop a central recurrence of cervical cancer after primary therapy with radiation or after surgery

followed by radiation may be candidates for this extensive, potentially curative surgical procedure if a complete

evaluation fails to reveal evidence of metastatic disease. In a small proportion of patients with cancer of the cervix

treated initially with radiation, a small recurrence of the cancer may be noted centrally within the cervix. A radical

hysterectomy may be an alternative to total pelvic exenteration in this selected subgroup of patients. Surgery is the

only potentially curative method of treating cancers that persist or recur centrally following adequate radiation

therapy. In such instances, pelvic exenteration is often necessary to make certain that all of the cancer has been

removed.

Pelvic exenteration is one of the most formidable of all gynecologic operations and requires removal of the bladder,

rectum, and vagina, along with the uterus if hysterectomy has not yet been performed. This is followed by the

reconstructive phase of the procedure. Urinary diversion needs to be provided, necessitating the creation of either a

continent ileocolonic pouch or a noncontinent ileal conduit. In either case, a stoma is created in the anterior

abdominal wall. If extensive rectal resection was required, a sigmoid colostomy serves for the passage of feces. If a

low rectal anastomosis could be accomplished, a temporary diverting colostomy should be performed in all patients

who had received prior radiation. The vagina can be reconstructed using various myocutaneous flaps, such as

transverse rectus abdominis or gracilis myocutaneous flaps. Depending on the location of the lesion, an anterior

(preservation of the rectosigmoid) or posterior (preservation of the bladder) exenteration is at times an alternative.

Because of the high surgical morbidity and mortality rates, stringent criteria are necessary to justify these

procedures. Pelvic exenteration should be reserved primarily for problems that cannot be effectively managed in any

other manner. In essence, this means (a) a biopsy-proven persistence or recurrence of cervical cancer following an

adequate course of radiation therapy or radical surgery in which the recurrent or persistent tumor occupies the

central portion of the pelvis (without metastases) and is completely removable; and (b) a patient who is able to cope

with the urinary and fecal stomas in the abdomen created by the operation. Both psychological and physical

preparation of the patient for this operation and its aftermath are of vital importance. Because of the extreme

difficulties encountered in making an accurate assessment preoperatively, only about half of the patients explored for

a total pelvic exenteration will intraoperatively be confirmed to have resectable, nonmetastatic disease. The 5-year

survival rate following pelvic exenteration for recurrent cervical cancer averages 30–40%.

PALLIATIVE CARE

Comprehensive care of a patient with cancer involves in addition to antitumor therapy, good symptom relief, as well

as personal and family support. The palliative care for patients with progressive cervical cancer poses many

challenges. The emphasis should be to facilitate comfort, dignity, autonomy, and personal rehabilitation and

development, especially in the face of an incurable disease.

Most patients with progressive cervical cancer eventually develop symptoms related principally to the site and extent

of the malignant disease. Ulceration of the cervix and adjacent vagina produces a foul-smelling discharge. Tissue

necrosis and slough may initiate life-threatening hemorrhage. If the bladder or rectum is involved in the tissue

breakdown, fistulas result in incontinence of urine and feces. Pain caused by involvement of the lumbosacral plexus,

soft tissues of the pelvis, or bone is frequently encountered in advanced disease. Ureteral compression leading to

hydronephrosis and, if bilateral, to renal failure and uremia is a common terminal event. The comfort and well-being

of the patient can be considerably enhanced even though cure cannot be effected. A foul, purulent discharge may be

ameliorated by astringent douches and antimicrobial vaginal creams or suppositories. Hemorrhage from the vagina



often can be controlled by packing the area with gauze impregnated with a hemostatic agent; occasionally emergent

radiation or hypogastric artery embolization is indicated.

Current management of severe pain combines the use of a long-acting narcotic such as morphine or a transdermal

fentanyl patch with short-acting narcotics for breakthrough pain and nonsteroidal anti-inflammatory agents.

Anxiolytics and antidepressants may be of considerable value. For patients with significant pain who are no longer

responding to oral medications, a subcutaneous or intravenous morphine drip can be started. In patients with lower

back or extremity pain, a peridural catheter can be placed and connected to a subcutaneous pump with a reservoir

for continuous morphine instillation. This method gives pain relief without the sedating effects of oral and parenteral

narcotics.

Radiation therapy may be very helpful in the relief of pain caused by bony metastases and in the treatment of lesions

that recur following primary surgical treatment of cervical cancer. In general, if initial therapy was accomplished by

adequate radiation therapy, retreatment is contraindicated because it does little good and carries the potential of

massive radiation necrosis.

Special Situations

CARCINOMA OF THE CERVIX DURING PREGNANCY

Invasive carcinoma of the cervix in pregnancy is found more frequently in areas where routine prenatal cytologic

examination is done. Abnormal cervical cytology in pregnancy calls for immediate colposcopic evaluation and any

other diagnostic modalities necessary to exclude invasive cancer (see section on preinvasive disease).

Invasive cervical cancer complicates approximately 0.05% of pregnancies. As is the case with nonpregnant patients,

the principal symptom is bleeding, but the diagnosis is frequently missed because the bleeding is assumed to be

related to the pregnancy rather than to cancer. The possibility of cancer must be kept in mind. The diagnosis and

management of invasive cervical cancer during pregnancy presents the patient and the physician with many

challenges. Pregnancy does not appear to affect the prognosis for women with cervical cancer and the fetus is not

affected by the maternal disease, but may suffer morbidity from its treatment (eg, preterm delivery).

If the pregnancy is early and the disease is stage I to IIA, radical hysterectomy and therapeutic lymphadenectomy

can be performed with the fetus left in situ, unless the patient is unwilling to terminate the pregnancy. Women at a

gestational age closer to fetal viability or who are unwilling to lose the baby may decide to continue the pregnancy

after careful discussion regarding the maternal risks. Delivery in patients with cervical dysplasia and carcinoma in situ

may be via the vaginal route. Patients with invasive cervical cancer should be delivered by cesarean section to avoid

potential cervical hemorrhage and dissemination of tumor cells during vaginal delivery. A cesarean radical

hysterectomy with therapeutic lymphadenectomy is the procedure of choice for patients with stages IA2–IIA disease

as soon as adequate fetal maturity is established.

As in the nonpregnant patient, radiation with concomitant chemotherapy is used for the treatment of more advanced

disease. In the first trimester, irradiation may be carried out with the expectation of spontaneous abortion. In the

second trimester, interruption of the pregnancy by hysterotomy prior to radiation therapy is preferred, although some

physicians advocate proceeding with immediate radiation treatment, again awaiting spontaneous evacuation of the

uterus. In selected cases with locally advanced disease in which the patient declines pregnancy termination,

consideration may be given to neoadjuvant chemotherapy in an effort to prevent disease progression during the time

needed to achieve fetal maturity. Delivery should be by cesarean section. A lymphadenectomy can be performed at

the same time. Postpartum the patient should receive chemoradiation following guidelines established for the

nonpregnant patient.

CARCINOMA OF THE CERVICAL STUMP

Early stage cervical cancer noted on a cervical stump (left in situ following supracervical hysterectomy for an

unrelated indication) should be treated with radical trachelectomy and therapeutic lymphadenectomy in the medically

fit patient. Surgery is preferred over chemoradiation in this setting as the delivery of an adequate radiation dose may

be difficult in a patient with a short cervical stump. However, radiation with concomitant chemotherapy is the

preferred treatment modality for patients with more advanced disease.

CERVICAL CANCER INCIDENTALLY DIAGNOSED AFTER SIMPLE HYSTERECTOMY

Women who are found to have microinvasive disease after a simple hysterectomy do not require any additional

therapy. Patients with invasive disease who do not have gross parametrial disease are candidates for a radical

parametrectomy, upper vaginectomy, and lymphadenectomy. This approach may be particularly desirable for young

women in whom ovarian function can be preserved or for any surgically fit women with enlarged lymph nodes that

should be resected prior to chemoradiation. Indications for chemoradiation follow the same guidelines as outlined

above.



Complications of Therapy

RADICAL SURGERY

The operative mortality rate in radical hysterectomy with lymphadenectomy has been reduced to less than 1%. The

most common complication is prolonged bladder dysfunction. Approximately 75% of patients have adequate recovery

of bladder function within 1–2 weeks after radical hysterectomy, and most patients will have satisfactory voiding

function by 3 weeks. Serious complications include fistula formation; ureterovaginal fistula is the most common type

(1–2%), followed by vesicovaginal and rectovaginal fistulas. Modified radical hysterectomy as compared to radical

hysterectomy is associated with a shorter operating time, a more rapid return of bladder function, and fewer fistulas.

Other complications are urinary tract infections, lymphocysts and lymphedema, wound sepsis, dehiscence,

thromboembolic disease, ileus, postoperative hemorrhage, and intestinal obstruction.

The surgical mortality rate from pelvic exenteration has been reduced from approximately 25% to less than 5%, but

as many as 50% of patients experience major morbidity. Complications include intraoperative and postoperative

hemorrhage, infectious morbidity, urinary fistulas or obstruction, urinary pouch dysfunction, pyelonephritis, bowel

obstruction or intestinal leaks and fistulas, stomal retraction, electrolyte disturbances, and other less common

occurrences.

RADIATION THERAPY WITH CONCOMITANT CHEMOTHERAPY

See Chapters 54A and 54B.

Posttreatment Follow-Up

Approximately 35% of patients with invasive cervical cancer will have recurrent or persistent disease following

therapy. Approximately 50% of deaths from cervical cancer occur in the first year after treatment, another 25% in

the second year, and 15% in the third year. This explains the generally accepted schedule of posttreatment

surveillance in asymptomatic patients of every 3 months in the first year, every 4 months in the second year, and

every 6 months in years 3–5. Symptomatic patients should be evaluated with appropriate examinations immediately

when symptoms occur. The most common signs and symptoms of recurrent malignant disease are positive cytologic

examination, palpable tumor in the pelvis or abdomen, ulceration of the cervix or vagina, pain in the pelvis, back,

groin, and lower extremity, unilateral lower extremity edema, vaginal bleeding or discharge, supraclavicular

lymphadenopathy, ascites, unexplained weight loss, progressive ureteral obstruction, and cough (especially with

hemoptysis or chest pain).

Prognosis

The major prognostic factors affecting survival are stage, lymph node status, tumor volume, depth of cervical stromal

invasion, lymphovascular space invasion and, to a lesser extent, histologic type and grade. After stage of disease,

lymph node status is the most important prognostic factor. For example, following radical surgery, patients with

stage IB or IIA disease have a 5-year survival of 88–96% with negative lymph nodes, compared to 64–73% in the

presence of lymph node metastases.

Table 50–6 summarizes survival rates by stage of disease. These are based on the FIGO Annual Report on the

Results of Treatment in Gynecological Cancer, in which results of treatment for each stage of cervical cancer are

reported by more than 100 participating institutions worldwide. The results are equated in terms of 5-year cure rates,

or those patients who are living and show no evidence of cervical cancer 5 years after beginning therapy.

Recurrences following radiation therapy are not often centrally located and thus amenable to exenteration

Table 50–6. Survival of Patients with Cervical Cancer Based on FIGO Stage.

Stage Number of Patients (%) Survival

1 year 2 years 5 years

IA1 860 99.8% 99.5% 98.7%

IA2 227 98.2% 97.7% 95.9%

IB 3480 98.1% 94.0% 86.5%

IIA 881 94.1% 85.6% 68.8%

IIB 2375 93.3% 80.7% 64.7%

IIIA 160 82.8% 58.8% 40.4%

IIIB 1949 81.5% 62.2% 43.3%

IVA 245 56.1% 35.6% 19.5%

IVB 189 45.8% 23.9% 15.0%



procedures. Only approximately 25% of recurrences are localized to the central portion of the pelvis. The most

common site of recurrence is the pelvic side wall.

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