CIN IN PREGNANCY

Managing pregnant patients with cervical intraepithelial neoplasia

By Alex Ferenczy, MD

Your patient has CIN, a precursor to cervical cancer. How do you manage her pregnancy? An expert pathologist provides algorithms and a step-by-step guide for safely biopsying a pregnant cervix—when appropriate.

Patients can become very anxious and frustrated when they discover they have cervical squamous cell carcinoma, the most frequent gynecological malignancy during pregnancy. The good news is that only 3% of all cervical cancers complicate pregnancy—including the 12 months postpartum—and only 0.05% of all pregnancies are associated with cervical cancer.¹ Even better news is that the percentage of pregnant patients with a precursor to cervical cancer is no higher than that of nonpregnant patients matched for age and demographic characteristics.²

My goal here is to review the current man-agement for pregnant patients with cervical intraepithelial neoplasia (CIN) diagnosed via cytology, colposcopy/biopsy, or both. In doing so, I'll provide guidelines for referring pregnant women with an abnormal Pap test for colposcopic evaluation. In many ways, these are similar to guidelines for nonpregnant patients, but with some important differences: For one thing, if your pregnant patient has CIN (regardless of grade), it's better to postpone biopsy to the postpartum period. For another, you should avoid evaluating the endocervical canal of a pregnant woman.

But there are two groups of patients for whom histological diagnosis is absolutely mandatory: (1) those with invasive cancer or a suspicion of invasion, and (2) women with a combination of high-grade squamous intraepithelial lesion (SIL) Pap and unsatisfactory colposcopy after the second trimester. Finally, if your patient has high-grade cytology and complex management problems, it's best to refer her to a physician with expertise in the field for making appropriate diagnostic and therapeutic decisions.

Cervical cytology is the best screening approach in pregnancy

The most effective way to detect preinvasive disease during pregnancy is similar to what's best for nonpregnant patients: cervical cytology. Antenatal visits are the ideal opportunity to screen for cervical cancer and its precursors, especially in women who've never been screened.

Nearly all laboratories in the United States use the Bethesda system (TBS) to report cytology test results.³ Among the cellular collection devices that have been evaluated during pregnancy, the Ayer's spatula or plastic broom-type samplers stand out. These seem to be the least traumatic to the cervical epithelium and result in relatively few unsatisfactory test results. Also, if you're using liquid-based cytology (LBC), the smooth-surfaced plastic devices—in contrast to the rough-surfaced wooden spatula—have the advantage of enhancing cell transfer into the LBC-vial. The least appropriate cell sampler—for pregnant and nonpregnant women alike—is the cotton-tip swab: 29.2% of these smears are unsatisfactory.⁴

Recently, researchers have evaluated the diagnostic accuracy of cervical slides, including liquid-based thin-layer cytology obtained mainly from nonpregnant women that failed to contain transformation zone components (endocervical or metaplastic cells). Several large-scale, prospective studies found that the presence or absence of either endocervical cells or metaplastic cells made no difference in the frequency of positive cytological diagnoses.^5-7 In view of these findings, the recently revised TBS-2001 has deleted the qualifier "satisfactory but limited by absence of transformation zone component."⁸ Such cases are now reported instead as "satisfactory and negative for intraepithelial neoplasia or malignancy," and by inference need not be repeated sooner than 1 year.⁹ The lab report, however, may include a note referring to the absence of a transformation zone component, in hopes that the next time around, clinicians will include cells from the squamocolumnar junction of the transformation zone in the sample. This should be particularly easy to do during pregnancy, because by the second trimester, most women develop an eversion of the endocervical epithelium, with the squamocolumnar junction moving well below the external os.

Managing a pregnant woman with an abnormal Pap test

Manage patients with atypical squamous cells of undetermined significance (ASC-US) in nearly the same way you'd manage their nonpregnant counterparts, namely either with (1) repeat Pap testing at 3 (rather than 4- to 6-month intervals in nonpregnant women) until two consecutive results are obtained, or (2) immediate colposcopy, or still, (3) reflex HPV DNA testing.⁹ While all three options are acceptable and safe, the preferred management option is reflex testing for 13 high oncogenic-risk HPV types (HR-HPV) using hybrid capture technology. (Of course, that's provided the cellular sample for both cytology and HPV DNA testing is obtained in the same sitting.⁹) This can be done either from residual cells in the LBC-vials or co-sampling for cytology and HPV DNA.

One of the key advantages that reflex HPV DNA testing has over options 1 and 2 (the repeat cytology program or colposcopy) is the greater sensitivity (nearly 100%) of a single (initial) HPV DNA test to detect the approximately 10% of high-grade CIN 2 or CIN 3 on histology in women whose initial Pap test was read ASC-US.¹⁰ This approach not only avoids unnecessary colposcopic examinations for the 40% to 60% of women with HPV-negative ASC-US, but also the test's nearly 100% negative predictive value allows a clinician to reassure patients that they're free of clinically significant lesions. Accordingly, women with HR-HPV-negative ASC-US Pap test results need only be followed with a repeat HPV Pap test at 12 months (Figure 1). On the other hand, all women with HR-HPV-positive ASC-US must undergo colposcopic exams. As long as no lesion is found—including vaginal intraepithelial neoplasia (VAIN) or condyloma or both—acceptable management options include a repeat Pap test in 12 months or HPV DNA testing at 12 months. But it's a different story for all women who again test positive for ASC-US and/or are twice HR-HPV-positive. Because these results indicate persistent HR-HPV infection, those patients must be recolposcoped (Figure 2).

Colposcopy in pregnancy: tricks of the trade

Colposcopy is the management approach to pregnant—and nonpregnant—women with Pap results in a variety of cytologic categories: "atypical squamous cells"; "HSIL cannot be ruled out (ASC-H)"; LSIL and HSIL; as well as atypical glandular cells (AGC), adenocarcinoma in situ (AIS) and invasive malignancy. Ideally, a pregnant woman should be examined by a clinician who is familiar not only with the workup of pregnant patients for colposcopy but also with colposcopic changes.

Clinicians should be prepared to deal with relaxed vaginal walls that can obscure the cervix and tenacious mucous plugs that may obscure the transformation zone and external os. Equally important is an awareness that deeper punch biopsies can produce excessive bleeding that can be difficult to control in the office. Colposcopically, immature squamous metaplasia with extensive mosaic patterns can mimic HSIL; other times, decidual stromal reactions suggest irregular, complex, new surface vessels that can be confused with invasive disease—or, when multiple, with condylomata acuminata (Figure 3).

Retracting vaginal walls. Putting a condom over the speculum helps to retract the relaxed vaginal walls, permitting you to fully visualize the gestational cervix and to push aside mucous plugs with a swab or remove them using an endocervical speculum without causing bleeding from the external os (Figure 4). Because endocervical curettage is not recommended for pregnant women, you must have expertise in recognizing the colposcopic appearance of the endocervical epithelium in the external os and outer endocervical canal. In general, unless you suspect invasion or cannot rule it out, follow up at 12-week intervals with cytology and colposcopy is recommended for pregnant women.⁹ But what if the squamocolumnar junction isn't visible? More often than not, a repeat colposcopic examination 12 weeks later will provide a satisfactory colposcopy, as endocervical eversion is likely to occur (Figure 5).

Table 1 gives the indications for histologic diagnosis in pregnancy. For typical CIN 1, a punch biopsy is not recommended; instead, repeat both the Pap and the colposcopy. An abnormal transformation zone that suggests grade 2 or 3 CIN may be evaluated by histology, mainly if you wish to correlate cytology, colposcopy, and histology.¹¹ On the other hand, you may pay a price by limiting the number of biopsies to one (to prevent excessive bleeding), because of the high false-negative rate possibly associated with a single biopsy—not only for high-grade CIN but also for early (micro-) invasive cancer. In pregnant women, false-negative histology may be as high as 70%.¹¹ Remember that confirming high-grade CIN 2/3 by histology won't change the treatment approach, which is deferred to the postpartum period.

TABLE 1
Indications for histologic diagnosis in pregnancy

Perform a punch biopsy...

Perform excisional biopsy (LEEP, cold-knife cone, wedge)...

SIL—Squamous intraepithelial lesion
LEEP—Loop electrosurgical excision procedure

Approach to invasive disease. In contrast, it's imperative to document colposcopically or clinically obvious or suspected invasive disease with histology. If the invasive lesion is clinically obvious, you can do this with a punch biopsy. On the other hand, if colposcopy or punch biopsy leads you to only suspect invasion—or if punch biopsy suggests microinvasion or adenocarcinoma—you should perform a diagnostic excisional procedure. Preferably, this would be a colposcopically-oriented wedge biopsy instead of a complete cone biopsy, using either loop electrosurgery (LEEP) or cold-knife. If cytology merely suggests invasion—but a repeat precolposcopy cytology, colposcopy, and punch biopsy fail to confirm it—I advise reviewing the Pap test that was originally reported as "suggestive of invasive malignancy." If it is downgraded to HSIL, then you can delay excisional histological diagnosis to the postpartum period. The same "wait-and-see" approach is a good practice in cases in which cytology only suggests atypical glandular cells (AGC) or adenocarcinoma in situ (AIS)—and is particularly appropriate for women in their last trimester of pregnancy.

The rationale for deferring excisional procedures is to avoid unnecessary pregnancy complications. Chief of these is hemorrhage—either immediate or delayed—which is due to the increased vascularity of the pregnant cervix. In one large series of cone biopsies performed during pregnancy, the transfusion rate was as high as 9.4%.¹² Also, because excisions during pregnancy tend to be more shallow, they are rarely curative and the patient must be re-assessed anyway after cervical involution takes place at 4 months postpartum. Table 2 explains—and Figure 6 illustrates—the steps for avoiding bleeding after a punch biopsy of the pregnant cervix.

TABLE 2
Biopsying the pregnant cervix: A step-by-step guide

Condyloma in pregnancy

It's questionable whether a colposcopic exam would benefit pregnant women who have clinically visible anogenital warts but no abnormal Pap test. In one study, high-grade CIN was present in only 2% of nongestational women 25 and older with external genital warts, whereas in younger women, it was negligible.¹³ Even if colposcopy were to find high-grade CIN, you would postpone management until the postpartum period.

Warts and the risk of JORRP. It's never been proved that the newborn baby of a pregnant woman with CIN is more likely to develop juvenile onset of recurrent respiratory papillomatosis (JORRP) than that of a pregnant woman without CIN. On the other hand, an interesting finding about risk conferred by condyloma in pregnancy did emerge from a longitudinal evaluation of 57 cases of JORRP occurring in more than 10,000 births with (3,033) and without (7,902) a history of genital warts registered in the Danish National Registries. Researchers found that a maternal history of genital warts conferred a 231 times higher risk of JORRP compared to births without such a history.¹⁴ However, in this study, women with maternal warts presumably had visible lesions, so colposcopy would not have contributed to either their better ascertainment or management. In additionally, the overall risk of JORRP is very small: in this Danish study it was one per 142 births with a history of maternal genital warts.

When to remove warts. Also keep in mind that there's not yet any evidence that treating genital warts during pregnancy prevents JORRP. In fact, the likelihood is small, given that elective cesarean fails to affect the risk of JORRP compared to vaginal deliveries.¹⁴ If treatment is desired nevertheless, then you should attempt to remove warts that are located along the passage of the newborn. The techniques used most often are a weekly topical application of 80% trichloracetic acid (TCA) solution or cryotherapy for localized lesions, whereas electrofulguration or CO₂ laser vaporization under local or general anesthesia is the best way to treat extensive—but not obliterative—lesions. Ideally, you should treat a pregnant patient during the third trimester, when recurrences are low to nil compared to the first two trimesters.¹⁵ C/S is recommended only when genital warts obstruct labor.¹⁶

Conclusions

Cervical cytologic screening in pregnancy is the best way to detect preinvasive disease during pregnancy. The preferred collection devices are plastic exocervical cell samplers that both avoid unsatisfactory samples due to bleeding and enhance cell transfer if you're using the LBC technique. Clearly, all pregnant women with a Pap test of LSIL or worse should have a colposcopic examination. If reflex HR-HPV testing is used, you should do colposcopy on those with HR-HPV positive ASC-US, whereas those with HR-HPV negative ASC-US require only repeat cytology/HR-HPV testing at 1 year. Most of the time, it's better to postpone histologic diagnosis of intraepithelial neoplasia until the postpartum period. The exceptions are women with clinically obvious or suspected invasive cervical cancer and those for whom you'd like a cyto-colpo-histologic correlation of HSIL or AIS, who require evaluation by histology. Finally, to date, there are no data to tell us whether treating anogenital warts during pregnancy prevents JORRP in the newborn.

REFERENCES

1. Hacker NF, Berek JS, Lagasse LD, et al. Carcinoma of the cervix associated with pregnancy. Obstet Gynecol. 1982;59:735-746.

2. Malone JM Jr, Sokol RJ, Ager JW. Pregnancy, human papillomavirus and cervical intraepithelial neoplasia. Eur J Gynaecol Oncol. 1988;9:120-124.

3. Smith-McCune K, Mancuso V, Contant T, et al. Management of women with atypical Papanicolaou tests of undetermined significance by board-certified gynecologists: discrepancies with published guidelines. Am J Obstet Gynecol. 2001;185:551-556.

4. Paraiso MF, Brady K, Helmchen R, et al. Evaluation of the endocervical Cytobrush and Cervex-Brush in pregnant women. Obstet Gynecol. 1994;84:539-543.

5. Woodman CB, Williams D, Yates M, et al. Indicators of effective cytological sampling of the uterine cervix. Lancet. 1989;2:88-90.

6. Sidawy MK, Tabbara SO, Silverberg SG. Should we report cervical smears lacking endocervical component as unsatisfactory? Diagn Cytopathol.1992;8:567-570.

7. Baer A, Kiviat NB, Kulasingam S, et al. Liquid-based Papanicolaou smears without a transformation zone component: should clinicians worry? Obstet Gynecol. 2002;99:1053-1059.

8. Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119.

9. Wright TC Jr, Cox JT, Massad LS, et al. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

10. Solomon D, Schiffman M, Tarone R. ALTS Study Group. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst. 2001;93:293-299.

11. Benedet JL, Selke PA, Nickerson KG. Colposcopic evaluation of abnormal Papanicolaou smears in pregnancy. Am J Obstet Gynecol. 1987;157:932-937.

12. Averette HE, Nasser N, Yankow SL, et al. Cervical conization in pregnancy. Analysis of 180 operations. Am J Obstet Gynecol. 1970;106:543-549.

13. Li J, Rousseau M-C, Franco EL, Ferenczy A. Is colposcopy warranted in women with external anogenital warts? J Lower Genital Tract Diseases. 2003;7:22-28.

14. Silverberg MJ, Thorsen P, Lindeberg H, et al. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet Gynecol. 2003;101:645-652.

15. Ferenczy A. Treating genital condyloma during pregnancy with the carbon dioxide laser. Am J Obstet Gynecol. 1984;148:9-12.

16. 1998 guidelines for treatment of sexually transmitted diseases. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-1):1-111.

Dr. Ferenczy is Professor of Pathology and Obstetrics and Gynecology, McGill University, and The Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.

Key points

• Whenever possible, defer biopsy to the postpartum period in cases of CIN (regardless of grade), and avoid evaluating the endocervical canal of a pregnant woman.

• Excisional wedge biopsy of the suspected area is the best technique to ascertain microinvasion in pregnant women.

• Histological diagnosis is mandatory for: (1) patients with invasive cancer or a suspicion of invasion, and (2) women with a combination of high-grade squamous intraepithelial lesion (SIL) Pap and unsatisfactory colposcopy after the second trimester.

• Manage patients with atypical squamous cells of undetermined significance (ASC-US) by (1) repeat Pap testing at 3-month intervals until two consecutive results are obtained, (2) immediate colposcopy, or (3) reflex HPV DNA testing.

• Reflex HPV DNA testing is best for high oncogenic-risk HPV types (HR-HPV) using hybrid capture technology (provided you obtain the cellular sample for both cytology and HPV DNA testing at the same sitting).

Coding for CIN in pregnancy

By Emily H. Hill, PA-C

A pregnant patient who has an abnormal Pap smear will likely be seen for additional visit(s) for evaluation and management during the prenatal period, which are reported outside the global obstetric package. All services should be reported at the time they are provided, with a diagnosis describing the immediate condition. ICD-9 codes in the 647 series (infections and parasites complicating pregnancy) or 654 (abnormalities of organs [cervix]) can be used as additional diagnoses. When these diagnoses are reported, however, some payers may deny the separate charge for E/M services.

The patient's initial E/M visit often is a discussion about appropriate evaluation and management of her abnormal Pap findings, and a colposcopy also may be performed. The established E/M level of service should be selected based on the amount of time the discussion takes, since the history and physical examination may be limited. If a colposcopy is performed the same day, a –25 modifier (significant, separately identifiable E/M service on the day of another procedure or service) should be appended to the visit code.

CPT 2003 includes significant changes in the coding options for colposcopy. New codes were introduced for colposcopy of the vulva (56820-56821) and for vaginal colposcopy (57420-57421). Revisions were also made to the codes for cervical colposcopy to help clinicians more accurately report services provided to pregnant (and nonpregnant) women. Cervical colposcopy without biopsy is reported with CPT code 57452, which includes only an evaluation of the cervix and the upper/adjacent vagina. When a biopsy is performed, report code 57455 (colposcopy with biopsy[s]) or 57460 (colposcopy with loop electrode biopsy[s]). Both codes include the colposcopy and should be reported only once regardless of the number of biopsies obtained.

The diagnosis code(s) depends on the Pap smear findings. ICD-9-CM 2003 expanded the coding for abnormal Pap smears to distinguish those findings favoring benign from those favoring dysplasia. The codes are:

795.00 Nonspecific abnormal Papanicolaou smear of cervix, unspecified

795.01 Atypical squamous cell changes of undetermined significance favor benign (AS-CUS favor benign)

795.02 Atypical squamous cell changes of undetermined significance favor dysplasia (AS-CUS favor dysplasia)

795.09 Other nonspecific abnormal Papanicolaou smear of cervix

If the findings indicate CIN 1, CIN 2, HSIL, or LSIL, then the proper code is 622.1. Code 233.1 is reported for CIN 3 and carcinoma in situ. The same ICD-9 codes can be used for any repeat Pap smear or colposcopic examinations. The diagnosis for each encounter should reflect the most specific information available at the time of the study. If the patient is HPV-positive, then 079.4 (Human papillomavirus) can be added as an additional diagnosis.

Localized treatment of anogenital warts is reported with CPT code 56501 (destruction of lesion(s) vulva; simple). Extensive disease is reported with CPT code 56502 (Destruction of lesion(s), vulva; extensive). These codes are only reported once per session regardless of the number of lesions treated.

If colposcopy is also performed, report it separately and append a –51 modifier (multiple procedures) to the service with the lesser value. The ICD-9 code 078.11 (condyloma acuminatum) should be linked to CPT code 56501 or 56502. The ICD-9 code describing the abnormal Pap smear should be linked to the appropriate colposcopy code. Linking ICD and CPT indicates to the payer the specific reason for performing each service.

Ms. Hill is President of Hill & Associates, Inc., a consulting firm specializing in coding and compliance. She teaches coding seminars for the American College of Obstetricians and Gynecologists and serves as a representative on the American Medical Association's (AMA) Correct Coding Policy Committee and the Health Care Professionals Advisory Review Board for the Relative Value Update Committee (RUC). She has also served on the AMA's CPT-5 Project, National Uniform Claim Committee, and on a Clinical Practice Expert Panel for the Centers for Medicare and Medicaid Services (formerly HCFA) Practice Expense Study.

 

Alex Ferenczy. Managing pregnant patients with cervical intraepithelial neoplasia. Contemporary Ob/Gyn Mar. 1, 2004;49:76-89.