This chapter deals primarily with APGO Educational Topic Area:
TOPIC 52 CERVICAL DISEASE AND NEOPLASIA
Students should be able to outline appropriate screening for cervical neoplasia as well as management of patients with abnormal screening. They should be able to discuss pathogenesis of cervical cancer and to identify risk factors, common presenting signs and symptoms, and physical examination findings.
Clinical Case
A 27-year-old comes to see you because her Pap smear shows atypical cells. Her primary care physician stated that she would need a procedure and that this could signify cervical cancer. She is clearly concerned.
Although the incidence and mortality from cervical cancer have decreased substantially in the past several decades among women in the United States, cervical cancer remains the third most common gynecologic cancer. In countries where cytologic screening is not widely available, cervical cancer remains common. Worldwide, it is the second most common cancer among women (after breast cancer) and the most common cause of mortality from gynecologic malignancy, accounting for more than 250,000 deaths per year.
Cervical cancer can be thought of as a preventable cancer. It is preceded by an identifiable precursor lesion (cervical intraepithelial neoplasia [CIN]) that may (but not always) progress to invasive cancer. CIN can be easily detected by an inexpensive and noninvasive screening test (Pap test) that may be augmented with supplemental tests such as human papillomavirus (HPV) DNA typing and a follow-up diagnostic procedure (colposcopy). CIN is treatable with simple and effective therapies, including cryotherapy, laser ablation, loop electrosurgical excision procedure (LEEP), and cold knife cone biopsy, all of which have high cure rates. It is also one of only a few cancers for which a vaccine exists that may have a significant impact in reducing an individual’s risk.
CERVICAL INTRAEPITHELIAL NEOPLASIA
Etiology
Cervical cancer and CIN are caused by HPV. Of the approximately 100 types of HPV, about 30 infect the anogenital tract. Approximately 15 of these types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) are associated with cancer and are known as high-risk HPV types. The majority of cervical cancers are caused by just four of these high-risk HPV types: 16, 18, 31, and 45. Low-risk HPV types are not associated with cancer. However, low-risk types 6 and 11 are associated with genital warts (condylomata acuminata) and with low-grade squamous intraepithelial lesions (LSILs).
HPV infects the cells of the cervix. The size and shape of the cervix change depending on age, hormonal status, and number of children (parity). The upper part of the cervix that opens into the endometrial cavity is called the internal os; the lower part that opens into the vagina is called the external os. The exterior portion of the cervical canal is called the ectocervix, and the interior cervical canal is called the endocervical canal. The walls of the endocervical canal contain numerous folds and plicae.
The histology of the cervix is complex (Fig. 47.1A,B). Overlying the fibrous stroma of the cervix is the cervical epithelium, a meshwork of cells. The epithelium is of two types: columnar (glandular) and stratified nonkeratinizing squamous epithelia. The columnar epithelium consists of a single layer of mucus-secreting cells that are arranged into deep folds or crypts. The area where the two types of epithelia meet is called the squamocolumnar junction(SCJ). The SCJ is clinically important, because it is the site where over 90% of cervical neoplasias arise. During childhood, the SCJ is located just inside the external os. Under the influence of hormones and the acidification of the vaginal environment during puberty, subcolumnar cells undergo metaplasia, a process of transformation. The metaplasia of these cells causes the SCJ to “roll out,” or evert, from its original position inside the external os to a position on the enlarged cervical surface. Columnar epithelium is also rolled onto the cervical surface, where it is exposed to vaginal secretions, irritants, and a changing hormonal milieu. The area between the original SCJ and the active SCJ is called the transformation zone (TZ). As metaplasia continues, the metaplastic epithelium covers and eventually becomes indistinguishable from the original squamous epithelium. Glands within the columnar epithelium may become trapped during this metaplastic activity by squamous epithelium, causing Nabothian cysts. These cysts are not considered pathologic but are a normal consequence of the dynamic histology of the cervix.
FIGURE 47.1. Anatomy of the cervix. (A) The cervix and the transformation zone. (B) Anterior view of the cervix and exocervix. (c) Different locations of the transformation zone and the squamocolumnar junction during a woman’s lifetime. The arrows mark the active transformation zone. (Based on Berek JS. Berek and Novak’s Gynecology. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:563–565.)
The metaplastic cells within the TZ represent the newest and least mature cells in the cervix, and it is thought that they are the most vulnerable to oncogenic change. The rate of metaplasia is highest during adolescence and early pregnancy. During perimenopause, the new SCJ recedes upward into the endocervical canal, often out of direct visual contact (see Fig. 47.1C).
HPV infection of cervical cells may or may not result in neoplastic change. Most HPV infections are transient, indicating that the host’s immune system is able to eradicate the virus before it can cause neoplastic changes in cervical cells. It is likely that several as-yet unidentified host or environmental factors act as cofactors. If the HPV DNA is not integrated into the host genome, encapsulated virions are produced that are expressed histologically as “koilocytes,” cells with shrunken or withered-appearing nuclei surrounded by perinuclear clearing. If HPV DNA is integrated into the host DNA, the expression of the cell’s regulatory genes may be altered, leading to the transformation of the cells into intraepithelial lesions or cancer.
Risk Factors
Several factors have been identified that may increase the risk of cervical neoplasia (Box 47.1). A higher incidence of HPV infection and progression of intraepithelial neoplasia is seen in immunosuppressed patients, including those infected with human immunodeficiency virus as well as those who are organ transplant recipients, who have chronic renal failure or a history of Hodgkin lymphoma, or who have undergone immunosuppressive therapy for other reasons. Another factor is cigarette smoking. The risk of cervical cancer is 3.5 times greater among smokers than among nonsmokers. Carcinogens from cigarette smoke have been found in high concentrations in the cervical mucus of smokers, suggesting a plausible biologic explanation for this association. First intercourse at a young age may increase a woman’s risk of cervical neoplasia because of the high rate of metaplasia that occurs in the TZ during adolescence and a higher proportion of new or immature cervical cells in this region.
BOX 47.1 Risk Factors for Cervical Neoplasia
• More than one sexual partner or a male sexual partner who has had sex with more than one person
• First intercourse at an early age (younger than 18 years)
• Male sexual partner who has had a sexual partner with cervical cancer
• Smoking
• Human immunodeficiency virus infection
• Organ (especially kidney) transplant
• Sexually transmitted disease infection
• Diethylstilbestrol exposure
• History of cervical cancer or high-grade squamous intraepithelial lesions
• Infrequent or absent Pap screening tests
Persistent HPV infection increases the risk of persistent or progressive cervical dysplasia. HPV 16 infection is more likely to be persistent than infections caused by other oncogenic HPV types. Individuals may possess a genetic susceptibility to cervical cancer, but the relative risks are small.
Classification
The goal of all cervical cancer classification systems is to establish management guidelines that decrease the likelihood of progression of precursor lesions to more advanced lesions. The 2001 Bethesda System is the most widely used system in the United States for reporting and classifying cervical cytologic studies. Established in 1988 and updated in 1991 and 2001, the Bethesda Classification outlines the various possible results of the Pap test, specifies accepted methodologies of reporting the Pap results, and provides for interpretation of findings. This categorization allows for defined management options regarding the initial results of the Pap test (Box 47.2). Details about how the Pap test is performed are found in Chapter 1. Guidelines for cervical cancer screening are found in Chapter 2.
The classification used by the Bethesda system divides epithelial lesions into two categories: squamous lesions and glandular lesions. In both categories, lesions are either precancerous or cancerous. Squamous precursor lesions are described as either atypical squamous cells (ASCs), LSILs, or high-grade squamous intraepithelial lesions (HSILs), whereas cancerous lesions are termed invasive squamous carcinoma. ASC is further divided into ASC of undetermined significance (ASC-US) and ASC–cannot exclude HSIL (ASC-H). Precancerous glandular lesions are classified as atypical(AGC); atypical, favor neoplastic; and endocervical adenocarcinoma in situ (AIS). Cancerous glandular lesions are classified as adenocarcinoma. AGC is also classified as endocervical, endometrial, or not otherwise specified (NOS).
BOX 47.2 The 2001 Bethesda System
Specimen Type
Indicate conventional smear (Pap smear) vs. liquid based vs. other
Specimen Adequacy
• Satisfactory for evaluation (describe the presence or absence of endocervical/transformation zone component and any other quality indicators, e.g., partially obscuring blood and inflammation)
• 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)
General Categorization (optional)
• Negative for intraepithelial lesion or malignancy
• Epithelial cell abnormality: See Interpretation/Result (specify squamous or glandular as appropriate )
• Other: See Interpretation/Result (e.g., endometrial cells in a woman 40 years of age)
Interpretation/Result
Negative for Intraepithelial Lesion or Malignancy
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 Nonneoplastic Findings (Optional to Report; List Not Inclusive)
• Reactive cellular changes associated with
• inflammation (includes typical repair)
• radiation
• intrauterine contraceptive device
• Glandular cells status post hysterectomy
• 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/cervical intraepithelial neoplasia (CIN) 1
• High-grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, carcinoma in situ/CIN 2 and CIN 3
• with features suspicious for invasion (if invasion is suspected)
• Squamous cell carcinoma
Glandular Cell
• Atypical
• endocervical cells
• endometrial cells
• glandular cells
• Atypical
• endocervical cells, favor neoplastic
• glandular cells, favor neoplastic
• Endocervical adenocarcinoma in situ • 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).
Modified from The 2001 Bethesda System: Terminology for Reporting Results of Cervical Cytology. Journal of the American Medical Association (2002;287:2114-2119).
Before the intraepithelial lesion terminology was created, the term cervical intraepithelial neoplasia was used, and lesions were graded as CIN 1, CIN 2, or CIN 3. The CIN classification system replaced an even earlier classification scheme that used the term dysplasia and classified precancerous lesions as mild, moderate, or severe. With each revision, the terminology for cervical cancer results has become more precise and reflects the current scientific understanding of the progression of cervical cancer. The CIN terminology, however, is still used with the current Bethesda terminology. LSIL encompasses HPV infection, mild dysplasia, or CIN 1. HSIL encompasses CIN 2 and CIN 3. CIN 3 is also designated carcinoma in situ (CIS) (Table 47.1).
Despite decades of study, the natural history of cervical intraepithelial lesions is still not completely understood. The once widely held concept that low-grade lesions are necessary precursors to the high-grade lesions that, in turn, may progress to invasive cancer has been questioned as the sole pathogenesis. It has been observed, for example, that many women present with CIN 2 or CIN 3 without prior CIN 1 lesions. Although multiple longitudinal studies have attempted to document the rates of “progression” and “regression” of CIN, results of these studies must be interpreted with caution due to varying methods of diagnostic criteria, populations, and duration of follow-up.
Evaluation of Abnormal Pap Test Results
An abnormal cervical cytologic finding from a Pap test should be followed by visual inspection of the vagina and a bimanual examination. The first objective is to exclude the presence of invasive carcinoma. Once this has been accomplished, the objectives are to determine the grade and distribution of the intraepithelial lesion. Options for evaluation include repeat cytology, HPV DNA testing, colposcopy with directed biopsies (see Chapter 34), and endocervical assessment.
Colposcopy and Endocervical Curettage
Colposcopy with directed biopsy has been the standard of care for disease detection and remains the technique of choice for treatment decisions. A colposcope is a binocular stereomicroscope with variable magnification (usually 7× to 15×) and a light source with a green filter to aid in the identification of abnormal-appearing blood vessels that may be associated with intraepithelial neoplasia. With colposcopy, areas with changes consistent with dysplasia are identified, allowing directed biopsy (i.e., biopsy of the area where dysplasia is most likely). Colposcopic criteria such as white epithelium, abnormal vascular patterns, and punctate lesions help identify such areas (Fig. 47.2). To facilitate the examination, the cervix is washed with a 3% to 4% acetic acid solution, which dehydrates cells, causing those with large nuclei (i.e., those undergoing metaplasia, dysplasia, or HPV infection), to appear white. Lesions usually appear with relatively discrete borders near the SCJ within 10 to 90 seconds of acetic acid application. Tissue samples for biopsy can be collected; the number of samples obtained will vary depending on the number and severity of abnormal areas found.
Visualization of the entire SCJ is required for a colposcopy to be considered satisfactory. If the SCJ is not visualized in its entirety, or if the margins of abnormal areas are not seen in their entirety, the colposcopic assessment is termed unsatisfactory, and other evaluations such as cervical conization and endocervical curettage (ECC) are indicated. In this procedure, a small curette is used to collect cells from the endocervical canal. An endocervical brush can be used to retrieve additional cells dislodged in the curette specimen. This endocervical sample is obtained so that potential disease farther inside the cervical canal, which is not visualized by the colposcope, may be detected. The cervical biopsies and ECC are then submitted separately for pathologic assessment.
FIGURE 47.2. Colposcopic image of the cervix. The white epithelium and coarse mosaic pattern of the underlying capillaries in this colpophotograph are suggestive of cervical intraepithelial neoplasia. (Case Studies in Colposcopy Case #53—March 2007. Kevin J. Mitchell, MD, Chair, with pathology courtesy of Mary Chacho MD, Department of Pathology, Danbury Hospital, Danbury, CT, 2006–08 Section on the Cervix. Downloaded on 7-21-08 from http://www.asccp.org/edu/case_studies.shtml#.)
Human Papillomavirus DNA Testing
Testing for the presence of high-risk HPV DNA is now being used as an adjunct screening tool for cervical neoplasia in women older than age 30 years. It is also used as a triage tool for women with Pap test results reported as ASC-US and in the management of nonadolescent women with LSIL. HPV DNA can identify women whose Pap test results are caused by other, non–HPV-associated phenomena, such as infection, thus preventing unnecessary colposcopic evaluations. Because HPV is more prevalent in younger women and the rate of CIN 2 and CIN 3 increases with age, HPV DNA testing is more useful as a triage tool in older women. HPV DNA testing is also used in the initial workup of women with AGC.
Management Guidelines for Cervical Epithelial Cell Abnormalities
The American Society for Colposcopy and Cervical Pathology issues guidelines and protocols for the appropriate management of women with cervical cytologic or histologic abnormalities. The most recent updates to these recommendations occurred in 2006 and were published in 2007. These guidelines, including practice algorithms, are available at www.asccp.org/consensus/cytological/shtml. The following sections summarize these guidelines.
Low-Grade Squamous Intraepithelial Lesions and Atypical Squamous Cells of Undetermined Significance
A patient with an ASC-US result should either undergo reflex HPV DNA testing (on the liquid-based sample already collected) or repeat cytology at 6 and 12 months following the abnormal Pap test result. The rationale for HPV DNA testing is that a negative result obviates the need for colposcopy; patients with ASC-US who are negative for high-risk HPV DNA need a repeat Pap in 12 months. Women who screen positive for HPV DNA with ASC-US results on Pap should be managed in the same way as women with LSIL—both groups should be referred for a colposcopic evaluation. Patients with ASC-US results, who were originally not tested for HPV, and have another ASC-US (or worse) at either the 6th- or 12th-month repeat cytology screening should also be referred for colposcopy; if both repeat tests are negative, then the patient may resume routine screening. Patients with LSIL are not referred for HPV DNA testing, because 83% of LSIL patients are positive for HPV, and the test is of little prognostic significance (Fig. 47.3).
About 3% of Pap test results are reproducibly classified as LSIL. Management and follow-up are the same following colposcopy for women with LSIL and women with HPV DNA–positive ASC-US. If no CIN is found, cytologic testing is repeated at 6 and 12 months, or HPV DNA testing is repeated at 12 months. A positive result for either ASC or HPV DNA warrants a repeat colposcopy; women with negative results for ASC or HPV DNA may resume routine screening (Fig. 47.4).
FIGURE 47.3. Management of women with atypical squamous cells of undetermined significance (ASCCP). ASC, atypical squamous cells; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. (Reprinted from The Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP. A revision to this algorithm is planned for release March 21, 2013.)
aTest only for high-risk (oncogenic) types of HPV.
FIGURE 47.4. Management of women with LSIL (ASCCP). ASC, atypical squamous cells; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. (Reprinted from The Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP. A revision to this algorithm is planned for release March 21, 2013.)
aManagement options may vary if the woman is pregnant, postmenopausal, or an adolescent (see text).
Management protocols differ for adolescents and pregnant women. ASC and LSIL are more common in adolescents, defined as age 20 years or younger, and the likelihood of spontaneous regression is higher. Because HPV DNA positivity is also higher in this population, using HPV DNA screening as a triage method is not useful. Adolescents with LSIL or ASC-US may be managed with repeat cytologic testing at 12 months. Those whose repeat test results show HSILs are referred for colposcopy; otherwise, they can have a repeat Pap smear in 12 months. Pregnant women with LSIL should not undergo ECC and should not have more than one colposcopy during pregnancy. Performing colposcopic biopsy during pregnancy should be reserved for situations when there is strong clinical suspicion of cancer. The cervix should be carefully inspected colposcopically to examine for suspicious lesions. Colposcopic examination for evaluation of ASC-US can be deferred until at least 6 weeks following delivery.
Earlier guidelines for postmenopausal women with LSIL Pap test results offered repeat cytologic screening after treatment with vaginal estrogen cream as a triage option, insofar as atrophy of the vaginal mucosa may contribute to the abnormal test result. However, current guidelines recommend that postmenopausal women with LSIL and ASC-US test results be managed in the same way as the general population.
High-Grade Squamous Intraepithelial Lesions and Atypical Squamous Cells–Cannot Exclude High-Grade Squamous Intraepithelial Lesion
In the United States, approximately 0.5% of all Pap test results are reported as HSIL. The rate of HSIL decreases with age. CIN 2 or CIN 3 is identified in 84% to 97% of women with HSIL Pap test results, and invasive cancer is identified in 2%. Because the rate of CIN 2 or CIN 3 is so high in adults with HSIL cytologic findings, immediate treatment with LEEP (see below) is an acceptable management approach. The other management approach is colposcopic examination, followed by appropriate treatment and follow-up (see Fig. 47.4).
ASC-H is evaluated by colposcopy because, like HSIL, it carries a higher risk of underlying CIN 2 to CIN 3 lesions. If no CIN 2 or CIN 3 is found, the patient may be followed up by repeat screening at 6 and 12 months or an HPV DNA test at 12 months. A positive CIN 2, CIN 3, or HPV DNA result on any of these follow-up tests warrants a colposcopic examination; if results of all follow-up tests are negative, the patient may return to routine screening (Figs. 47.5 and 47.6).
FIGURE 47.5. Management of women with HSIL (ASCCP). CIN, cervical intraepithelial neoplasia. (Reprinted from The Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP. A revision to this algorithm is planned for release March 21, 2013.).
aNot if patient is pregnant or an adolescent
bIncludes referral cytology, colposcopic findings, and all biopsies
cManagement options may vary if the woman woman is pregnant, postmenopausal, or an adolescent
Atypical Glandular Cells and Other Glandular Abnormalities
Glandular cell abnormalities comprise 0.4% of epithelial cell abnormalities. The risk associated with AGC is dramatically higher than that seen with ASC. The risk associated with glandular abnormalities increases as the description in the Bethesda classification system advances from AGC-Not Otherwise Specified (AGC-NOS) to AGC, favor neoplasia and, finally, to AIS. Women with AGC of any type except for atypical endometrial cells should undergo colposcopic evaluation, HPV DNA testing, and ECC. If a woman is older than age 35 years or is at risk for endometrial neoplasia (i.e., she has unexplained vaginal bleeding or conditions suggesting chronic anovulation), endometrial sampling should also be performed. Women with atypical endometrial cells should have an endometrial biopsy and ECC.
Knowledge of HPV status in women with AGC who do not have CIN 2 or CIN 3 or glandular neoplasia allows expedited triage. Women who test positive for HPV at the time of their Pap screening test should have a repeat Pap test and HPV DNA test at 6 months; those who test negative for HPV, at 12 months. Women with a positive HPV test and an abnormal Pap test result should be referred to colposcopy; women who have negative results on both tests can resume routine screening. In contrast, if HPV status is not known, the Pap test should be repeated every 6 months until there are four consecutive negative results, before a woman can resume routine screening (Fig. 47.7).
Treatment
Both excisional and ablative techniques are used to treat CIN. The underlying concept in the treatment of CIN is that excision or ablation of the precursor lesion prevents progression to carcinoma.
Ablative Methods
Ablative methods destroy the affected cervical tissue and include cryotherapy, laser ablation, electrofulguration, and cold coagulation, all of which are outpatient procedures that can be performed with regional anesthesia. Ablative methods should be used only with an adequate colposcopy and appropriate correlation between Pap test results and colposcopically directed biopsy.
Laser therapy is now only rarely performed in the United States. Cryotherapy is a commonly used outpatient method used to treat persistent CIN 1. The procedure involves covering the SCJ and all identified lesions with a stainless steel probe, which is then supercooled with liquid nitrogen or compressed gas (carbon dioxide or nitrous oxide). The size and shape of the probe depends on the size and shape of the cervix and the lesion to be treated. The most common technique involves a 3-minute freeze followed by a 5-minute thaw, with a repeat 3-minute freeze. The thaw period between the two freezing episodes allows the damaged tissue from the first freeze to become edematous and swell with intracellular fluid. With the second freeze, the edematous cellular architecture is refrozen and extends the damaged area slightly deeper into the tissue. Healing after cryotherapy may take up to 4 or 5 weeks, because the damaged tissue slowly sloughs and is replaced by new cervical epithelium. This process is associated with profuse watery discharge often mixed with necrotic cellular debris. The healing process is complete within 2 months. A follow-up Pap test is usually performed 12 weeks following the freezing to ascertain the effectiveness of the procedure. The cure rate for CIN 1 using this technique approaches 90%.
FIGURE 47.6. Management of women with ASC-H (ASCCP). HPV, human papillomavirus; ASC, atypical squamous cells; CIN, cervical intraepithelial neoplasia. (Reprinted from The Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP. A revision to this algorithm is planned for release March 21, 2013.)
Excisional Methods
Excisional methods remove the affected tissue and provide a specimen for pathologic evaluation. These methods include cold knife conization (CKC), LEEP (also called large loop excision of the transformation zone [LLETZ]), laser conization, and electrosurgical needle conization. These procedures are performed under regional or general anesthesia. A cone-shaped specimen is removed from the cervix, which encompasses the SCJ, all identified lesions on the ectocervix, and a portion of the endocervical canal, the extent of which depends on whether the ECC was positive or negative. Because LEEP uses electrosurgical energy, thermal damage may occur at the margins of the specimen, obscuring the histology. Thermal damage is usually not considered a problem in the evaluation of squamous epithelial abnormalities, but it may be a substantial issue in the evaluation of glandular epithelial lesions, where abnormal cells in the bottom of glandular crypts may be altered. In cases of glandular abnormalities, CKC may be more appropriate.
FIGURE 47.7. Initial workup of women with AGC (ASCCP). HPV, human papillomavirus. (Reprinted from The Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP. A revision to this algorithm is planned for release March 21, 2013.)
aIf not already obtained; test only for high-risk (oncogenic) types
bIncludes unexplained vaginal bleeding or conditions suggesting chronic anovulation
If the margins of the biopsy are not free of disease, the patient should have either repeat conization or close follow-up because of the possibility that disease remains. If the margins are positive for a high-grade epithelial lesion or CIS, the most appropriate treatment may be hysterectomy, if the patient has no desire for future childbearing. If the patient wants to preserve her fertility, colposcopy with ECC and HPV DNA testing is an acceptable management protocol.
Excisional procedures are also indicated when an ECC is positive as well as in the following situations:
• Unsatisfactory colposcopy: If the SCJ is not visualized in its entirety or if the margins of abnormal areas are not seen in their entirety during colposcopy, the colposcopic assessment is termed unsatisfactory and other evaluation such as cervical conization or ECC is indicated.
• If a substantial discrepancy is seen between the screening Pap test and the histologic data from biopsy and ECC (i.e., the biopsy does not explain the source of the abnormal Pap test). In this situation, which occurs in approximately 10% of colposcopies with directed biopsies and ECC, more tissue needs to be obtained by an excisional procedure for further testing.
CKC, LEEP, and LLETZ are associated with an increased risk of second-trimester pregnancy loss secondary to cervical incompetence, preterm labor, preterm premature rupture of membranes, and cervical stenosis. Both types of excisional procedures are also associated with the usual risks of any surgery (bleeding, infection, and anesthetic risks).
Follow-Up
After treatment for noninvasive epithelial cell abnormalities, either by ablation or excision, a period of follow-up Pap tests every 6 months for 2 years is generally recommended, with variations depending on the severity of the lesion treated. Most patients may return to a routine screening thereafter. If a subsequent Pap test is abnormal, it is evaluated in the same manner as a new abnormal Pap test. The importance of follow-up should be stressed to the patient, because of the greater risk of recurrent abnormalities.
CERVICAL CARCINOMA
Between 1950 and 1992, the death rate from cervical cancer declined by 74%. The main reason for this steep decrease is the increasing use of the Pap test for cervical cancer screening. The death rate continues to decline by approximately 4% per year. Despite the progress made in early detection and treatment, approximately 11,000 new cases of invasive cervical carcinoma are diagnosed annually, with 3,870 deaths.
The average age at diagnosis for invasive cervical cancer is approximately 50 years, although the disease may occur in the very young as well as the very old patient. In studies following patients with advanced CIN, this precursor lesion precedes invasive carcinoma by approximately 10 years. In some patients, however, this time of progression may be considerably less.
The etiology of cervical cancer is HPV in more than 90% of the cases. The two major histologic types of invasive cervical carcinomas are squamous cell carcinomas (SCCs) and adenocarcinomas. SCCs comprise 80% of cases, and adenocarcinoma or adenosquamous carcinoma comprise approximately 15%. The remaining cases are made up of various rare histologies that behave differently from SCC and adenocarcinoma.
Clinical Evaluation
The signs and symptoms of early cervical carcinoma are variable and nonspecific, including watery vaginal discharge, intermittent spotting, and postcoital bleeding. Often the symptoms go unrecognized by the patient. Because of the accessibility of the cervix, accurate diagnosis often can be made with cytologic screening, colposcopically directed biopsy, or biopsy of a gross or palpable lesion. In cases of suspected microinvasion and early-stage cervical carcinoma, conization of the cervix is indicated to evaluate the possibility of invasion or to define the depth and extent of microinvasion. CKC provides the most accurate evaluation of the margins.
Staging is based on the International Federation of Gynecology and Obstetrics (FIGO) Staging Classification (Box 47.3). This classification is based both on the histologic assessment of the tumor sample and on physical and laboratory examination to ascertain the extent of disease. It is useful because of the predictable manner in which cervical carcinoma spreads by direct invasion and by lymphatic metastasis (Fig. 47.8). Careful clinical examination should be performed on all patients. Examinations should be conducted by experienced examiners and may be performed under anesthesia. Pretreatment evaluation of women with cervical carcinoma often can be helpful if provided by an obstetrician–gynecologist with advanced surgical training, experience, and demonstrated competence, such as a gynecologic oncologist. Various optional examinations, such as ultrasonography, computed tomography, magnetic resonance imaging, lymphangiography, laparoscopy, and fine-needle aspiration, are valuable for treatment planning and to help define the extent of tumor growth, especially in patients with locally advanced disease (i.e., stage IIb or more advanced). Surgical findings provide extremely accurate information about the extent of disease and will guide treatment plans but will not change the results of clinical staging. Cervical cancer is considered a clinically staged entity.
Management
The clinician should be familiar with the options for treating women with both early and advanced cervical cancer and should facilitate referrals for this treatment. Surgery or radiation therapy may be options for treatment, depending on the stage and size of the lesion:
FIGURE 47.8. Spread patterns of cervical carcinoma.
• Patients with squamous cell cancers and those with adenocarcinomas should be managed similarly, except for those with microinvasive disease. Criteria for microinvasive adenocarcinomas have not been established.
• For stage Ia1, microinvasive squamous carcinoma of the cervix, treatment with conization of the cervix or simple extrafascial hysterectomy may be considered.
• Stage Ia2, invasive squamous carcinoma of the cervix, should be treated with radical hysterectomy with lymph node dissection or radiation therapy, depending on clinical circumstances.
• Stage Ib1 should be distinguished from stage Ib2 carcinoma of the cervix, because the distinction predicts nodal involvement and overall survival and may, therefore, affect treatment and outcome.
• For bulky stage Ib and selected IIa carcinomas of the cervix, either radical hysterectomy and lymph node dissection or radiation therapy with cisplatin-based chemotherapy should be considered. Adjuvant radiation therapy may be required in those treated surgically, based on pathologic risk factors, especially in those with stage Ib2 carcinoma.
• Stage IIb and greater should be treated with external beam and brachytherapy radiation and concurrent cisplatin-based chemotherapy.
Brachytherapy delivers radiation close to the affected organ or structure. Both high- and low-dose brachytherapy are used to treat cervical cancer. The brachytherapy radiation is delivered using special apparatuses known as tandem and ovoid devices placed through the cervix into the uterus and at the apices of the vagina. The external beam radiation is applied primarily along the paths of lymphatic extension of cervical carcinoma in the pelvis.
The structures close to the cervix, such as the bladder and distal colon, tolerate radiation relatively well. Radiation therapy doses are calculated by individual patient needs to maximize radiation to the tumor sites and potential spread areas, while minimizing the amount of radiation to adjacent uninvolved tissues. Complications of radiation therapy include radiation cystitis and proctitis, which are usually relatively easy to manage. Other more unusual complications include intestinal or vaginal fistulae, small bowel obstruction, and difficult-to-manage hemorrhagic proctitis or cystitis. Tissue damage and fibrosis incurred by radiation therapy progresses over many years, and these effects may complicate long-term management.
Following treatment for cervical carcinoma, patients should be monitored regularly, for example, with follow-up examinations every 4 months for the first 2 years and visits every 6 months subsequently to year 5, followed by Pap tests annually to perpetuity and chest x-rays annually for up to 5 years. The 5-year survival rates for cervical cancer are listed in Table 47.2.
Treatment for recurrent disease is associated with poor cure rates. Most chemotherapeutic protocols have only limited usefulness and are reserved for palliative efforts. Likewise, specific “spot” radiation to areas of recurrence also provides only limited benefit. Occasional patients with central recurrence (i.e., recurrence of disease in the upper vagina or the residual cervix and uterus in radiation patients) may benefit from ultraradical surgery with partial or total pelvic exenteration. These candidates are few, but when properly selected, may benefit from this aggressive therapy.
PREVENTION
Preventive approaches to cervical cancer include sexual abstinence, the use of barrier protection with or without spermicides, regular gynecologic examination and cytologic screening with treatment of precancerous lesions according to established protocols, and vaccination with the HPV vaccine. It is estimated that gynecologic examination and Pap tests administered according to current guidelines may reduce cancer incidence and mortality by 40%. Limiting the number of sexual partners also may decrease the risk of sexually transmitted diseases, including HPV.
BOX 47.4 Current Guidelines for Administration of the Quadrivalent (Gardasil) and Bivalent (Cervarix) Human Papillomavirus Vaccine
• The human papillomavirus (HPV) vaccine is given as three separate 0.5-mL doses based on the following schedulea:
1. First dose: at elected date
2. Second dose: 1–2 months after the first dose
3. Third dose: 6 months after the first dose
• It is recommended as a routine vaccination for all girls aged 11 to 12 years. However, it can be given to girls as young as 9 years. Girls and young women aged 13 to 26 years who have either not yet received the vaccine or have not completed all doses also should be vaccinated.
• Sexually active women can receive either HPV vaccine. Women with previous abnormal cervical cytology or genital warts also can receive the HPV vaccine. These patients should be counseled that the vaccine may be less effective in women who have been exposed to HPV before vaccination than in women who were HPV naive at the time of vaccination. Women with previous HPV infection will benefit from protection against disease caused by the HPV vaccine genotypes with which they have not been infected.
• Testing for HPV is currently not recommended before vaccination.
• The vaccine is not recommended for pregnant women, but is safe for women who are breastfeeding.
• Current cervical cytology screening recommendations remain unchanged and should be followed regardless of vaccination status.
aMinimum interval between first and second dose is 4 weeks, between second and third dose is 12 weeks, and between first and third dose is 24 weeks. If vaccine schedule is interrupted, the series does not need to be restarted, regardless of the length of time between doses. Whenever possible, the same vaccine product should be used for all doses in the series.
From the American College of Obstetricians and Gynecologists. Human Papillomavirus Vaccination. ACOG Committee Opinion No. 467. Washington, DC: American College of Obstetricians and Gynecologists; September, 2010.
The recently developed HPV vaccine prevents transmission and acquisition of type-specific HPV through sexual and nonsexual contact. Currently, there are two vaccines on the market. One is active against oncogenic HPV types 16 and 18 as well as two types that cause genital warts, HPV types 6 and 11. The other vaccine is active against oncogenic HPV types 16 and 18, with some possible protection against types 45 and 31. These two vaccines contain virus-like particles that consist of the main structural HPV-L1 protein but lack the viral genetic material and, thus, are noninfectious. These vaccines stimulate the production of immunoglobulin G–type-specific antibodies to prevent acquisition of type-specific HPV in the genital and vulvar areas. The quadrivalent vaccine has been shown to prevent 91% of new and 100% of persistent infections.
Currently, HPV vaccines are only indicated for prophylaxis (Box 47.4). However, it is anticipated that the guidelines for their use will continue to change regarding age group, sex, and therapeutic indications. The development of new vaccines may also broaden the horizon for HPV treatment.
Clinical Follow-Up
You explain that a colposcopy is a diagnostic procedure that will provide more information. On colposcopic examination, you see the full transformation zone and notice a small acetowhite area at the 3:00 position, which you biopsy. The biopsy results demonstrate no evidence of dysplasia or cancer. You relay this information to the patient and make a plan for future follow-up with Pap smears.
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