Cervical Dysplasia and Cancer in Pregnancy - 6

Our last post detailed the management of a pregnant woman who was found to have multifocal carcinoma in situ and microinvasive squamous cell carcinoma of the cervix early in pregnancy. Although she had a successful outcome from the management approach used in her case, I thought of several questions after finishing the post that might come to the minds of our readers: Are there risks to a pregnancy from the diagnostic and surgical procedures (cervical biopsies, conization, and cerclage) that were performed on our patient? Are there long-term risks of these procedures to future pregnancies if invasive cancer is not found? What is the natural history of high-grade intraepithelial lesions during pregnancy and afterwards when microinvasive disease is NOT found during the evaluation? What is the best route of delivery in the face of high grade intraepithelial lesions (not invasive cancer)? To answer some of these questions, let’s turn to past experience and some reports in the recent literature.

First, there are risks to ANY surgical procedure during pregnancy and though relatively small under these circumstances, must be balanced against the benefits. Because of the normal increases in blood flow to the uterus and cervix that occur during pregnancy, significant hemorrhage may occur even when a simple cervical biopsy is performed. The risk of bleeding is proportional to the area biopsied and when a large ‘biopsy’ such as a ‘cold knife conization’ is performed the amount of bleeding can be considerable both during the procedure and the post-operative period. In our case, we chose to perform a cervical cerclage as a means of both minimizing the risk of bleeding and providing some protection from premature labor under these circumstances and controlled additional bleeding using electrocautery after the specimen was obtained.

Other providers may choose to perform the entire conization, or even simply a wider biopsy of the TZ, during pregnancy using a LEEP (loop electrosurgical excision procedure) as a means of minimizing bleeding. Still others prefer the use of the CO2 laser, but the downside of these latter approaches is the ‘surgical margins’ may be obscured due to heat damage (thermal injury) and that can complicate interpretation of the presence and the depth of invasion. All of these procedures have the potential to increase the risk of premature rupture of membranes, premature delivery, intrauterine infection, and even pregnancy loss during the pregnancy, but these are surprisingly uncommon occurrences, particularly if the surgical procedures are performed prior to 24 weeks.

There are some long-term risks to both fertility and pregnancy success when cervical conization has been performed. We have known for years that scarring after extensive conization, particularly if heavy cauterization of deeper tissues was required, or infectious complications followed the procedure, can lead to stenosis (narrowing) of the cervical canal and even complete occlusion in some cases. This could impair fertility by preventing the transit of sperm into the uterus or increase the risk for obstetrical complications (such as failure to dilate in labor, lacerations, or even cesarean sections).

These procedures also “shorten” and distort the normal configuration of the endocervical canal and destroy endocervical glands that produce the mucous that is involved in the ‘capacitation of sperm’ (important for efficient ‘fertilization’) and the protection of the uterine cavity from ascending infections. Pregnancy consequences of these results are summarized in a metaanalysis of 27 studies last year by Kyrgiou and colleagues (Lancet 2006;367:489-98) in which pregnancy outcomes following cervical conization procedures were evaluated. These investigators found that prior cervical conization was associated with increased risk (generally 2- to 3-fold) in subsequent pregnancies for premature rupture of membranes, preterm delivery, low birth weight, and cesarean delivery. High conizations can disrupt the internal cervical os and lead to cervical incompetence.

Of course, there are also risks of incomplete evaluation of high-grade intraepithelial disease and microinvasive cervical cancer, the greatest being that there might be more extensive disease present than previously thought. If you recall, the patient featured in our case report had “multifocal areas of carcinoma in situ and microinvasion.” Such high-grade disease may encompass a wide surface area and it is not uncommon, even in experienced hands, to find disease in the surgical margins of a conization specimen (indicating incomplete resection) when the final pathology report returns. A recent study by Phongnarisorn (Int J Gynecol Cancer 2006;16:655-9) actually reviewed 129 hysterectomy specimens from women who had cervical conizations with residual high-grade disease or microinvasive disease in the original surgical margins. Of these, 57 (44.2%) had residual high-grade intraepithelial lesions and 20 (15.5%) residual invasive carcinoma (18 were microinvasive and 2 were frankly invasive). Fortunately, with truly ‘microinvasive’ disease, there is only about a 1% chance of having positive lymph node involvement and no more than about 0.2% chance of actually dying from cervical cancer if appropriate therapy is instituted and the patient continues in regular follow-up.

If a high-grade intraepithelial lesion is found in pregnancy with no evidence of invasion based on a thorough evaluation (colposcopy, biopsies, and conization if deemed necessary) by an experienced provider, there is fairly low risk of progression to significant invasive disease during the course of the pregnancy. Robova and colleagues (Eur J Gynaecol Oncol 2005;26:611-4) assessed persistence, progression, and regression of both low-grade and high-grade intraepithelial disease diagnosed during pregnancy and 24 months of follow-up after delivery. Of the sixty-two women with HSIL, they observed complete regression in 14 (22.6%), regression to LSIL in 17 (27.4%), persistence in 25 (40%), and progression to microinvasive disease in 6 (9.7%). Obviously, with the high risk of persistence of HSIL and progression of HSIL to invasive disease, aggressive and ongoing follow-up after delivery is indicated and this should be accompanied by a low threshold for ‘definitive therapy.’

Women will frequently ask if a cesarean delivery is indicated for high-grade intraepithelial lesions. They are usually asking two questions contained within one: Does a vaginal delivery increase the risk of disease progression? And, could I possibly give my disease to my baby? Answering the last question first, I usually tell them that high-grade lesions are the end-result of an HPV infection, but usually by the time HSIL is present, the virus has gained the ability to control cell growth, but that control is at the expense of losing the capacity to produce intact and infectious viral particles that could be passed on to other individuals. With regard to the first question, there has actually been some evidence presented in years past that a vaginal delivery actually increases the chance of disease regression. Recently, Kaneshiro and colleagues (Am J Obstet Gynecol 2005;192:1452-4) reviewed retrospectively data on 201 pregnant women with abnormal Pap tests. Regression rates for vaginal and cesarean section groups for LSIL were 58% vs 42%, respectively, and for HSIL, 53% vs 25%. Although the latter did not reach statistical significance, we can safely say that vaginal delivery certainly does not increase the risk of progression in women with HSIL.

Labels: Cervical dysplasia and cancer in pregnancy, HSIL, LSIL, microinvasive cancer

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Cervical Dysplasia and Cancer in Pregnancy - 4

Since our last post, a reader asked the simple question, “if the patient has an abnormal Pap smear and it is not cancer, then what is it?” Although my specialty is Maternal-Fetal Medicine, and I have no delusions (or desire) to be a cancer specialist, I have had a long interest in HPV problems and have been asked this question on many occasions. So today, let’s digress to briefly elaborate on the sort of information I will discuss with patients when questions such as this one arise…

Although almost all cervical cancer (as well as more than 50% of vaginal, vulvar, and anal cancer) are associated with HPV infections, infection by itself does not appear sufficient (in most instances) to cause cancer. Indeed, cancer occurs in only a small percentage of the women who have been infected with HPV. The time to development of cancer is usually many years and usually preceded by abnormalities of the cervical cells that are confined to the epithelium (intraepithelial neoplasia or dysplasia) and do not invade the underlying tissues. Risk factors mentioned previously (e.g., persistence of a ‘high risk’ HPV type, smoking, immunosuppression, early age of exposure to HPV, HIV infection) may increase the likelihood and accelerate the rate of developing invasive cervical cancer.

The full spectrum of cervical abnormalities can readily be detected with the Pap test. It is true that the Pap test may not detect these abnormalities if the surface of the cervix and the cervical canal are not adequately sampled, the areas of cervical abnormalities are not readily accessible (e.g., high in the cervical canal) or just missed, or the test is either misread or cannot be read due to other factors. The advantage of routine screening is that regular sampling (on a schedule recommended by your provider and appropriate to your circumstances) reduces the contribution of these factors to a ‘false negative’ result and usually some abnormality will be detected long before a serious problem has developed. The recent introduction of liquid-based cytology has increased the likelihood of detecting these abnormalities and offers the additional advantage of being able to be used for ‘reflex’ HPV-typing to check for the presence of a ‘high risk’ HPV type if a cytologic (cellular) abnormality is discovered.

The epithelium (‘skin’ surface) that lines the cervical canal and covers a good portion of the cervix that sits in the vagina starts out early in life as a protective barrier that is only one cell layer thick (columnar epithelium). The vaginal epithelium, on the other hand, is many cell layers thick (squamous epithelium) and there is a progressive transition in this type of epithelium from the plump, actively dividing cells at the base of the epithelium to the most superficial layers where the cells are flattened, relatively inactive, and eventually detach and fall off the surface. (The vaginal epithelium is much like the skin that covers our body, but it does not contain certain substances (keratins) that make the outer skin ‘tougher’ and more of a barrier to fluid loss). Whether columnar or squamous, both epithelia sit on a structure called the ‘basal membrane’ that separates the epithelium from deeper tissue layers.

Around the time of puberty, the outer cervical epithelium begins to undergo a transition from the original columnar epithelium to a squamous epithelium under the influence of normal hormonal and pH changes within the vagina. This transition is called squamous metaplasia and the area that undergoes these changes is called the transformation zone (TZ). The TZ, especially, during the time of transition, is very sensitive to environmental influences such as HPV and ‘cofactors’ that can eventually lead to the loss of usual cell control mechanisms (proliferation, DNA replication, and contact inhibition). Indeed, most cervical intraepithelial neoplasia or ‘lesions’ (for lack of a better term, “precancer”) and cancer arise in the TZ. This is probably also why women who become sexually active earlier in life before the normal TZ changes are complete are at greater risk for cervical precancerous lesions and even cancer if exposed to HPV at this time. The difference between the intraepithelial precancerous lesions and cancer is that cancer cells not only begin to proliferate uncontrollably, but they are also able to breech the basal membrane on which the epithelium sits and invade the underlying tissues. Intraepithelial lesions are confined to the epithelium and while they are there, they are NOT cancer, regardless of how nasty they may look.

Although the nomenclature has changed through the years, today, we basically divide abnormalities of the cervical squamous epithelium into low-grade intraepithelial lesions (LSIL, previously termed mild dysplasia or CIN 1), high grade intraepithelial lesions (HSIL, which includes the previously termed categories of moderate and severe dysplasia, or CIN 2/3, and carcinoma in situ (CIS)), and invasive cancer. There are other categories including atypical squamous cells of undetermined significance (ASCUS) (sounds like the ‘rodents of unusual size’ in "The Princess Bride," doesn’t it?!?) and a small percentage of cervical cancers arise from the glandular cells of the columnar epithelium (adenocarcinomas), and many of these are also associated with HPV infection, but for the sake of clarity, brevity, and my own sanity, these abnormalities will not be discussed by me herein.

There are now numerous studies in the literature that have tracked the natural history of HPV infections and cervical dysplasia, but I have selected two that are representative and present a spectrum of the information currently available. Moscicki and colleagues (Lancet 2004;364:1678-83) followed prospectively 899 women age 13-22 years of age who tested positive for HPV DNA. Of these, 260 (29%) were diagnosed with LSIL by cytology and of those who were, 61% had regressed by 12 months’ follow-up and 91% by 36 months’. Only 3% progressed to an HSIL lesion (and none developed cervical cancer) over that same period of time. In another study presented at the recent meeting of the North American Society for Pediatric and Adolescent Gynecology, Dr. Michelle Vichnin reported the results of follow-up on 195 women age 21 or less who were referred to their colposcopy clinic for an abnormal Pap test. Among these women, the average age of first intercourse was 14.9 years and the average age of the first ‘abnormal’ Pap test was 18 years. Thirty-four (17.4%) had biopsy proven HSIL and 13 developed their high-grade disease in 3 years or less after becoming sexually active. HSIL is invariably associated with infection with high risk HPV types and persistence and amount of HPV DNA that is found in the tissues is directly correlated with progression to invasive cervical cancer over time if the woman is not treated.

Labels: Cervical dysplasia and cancer in pregnancy, HSIL, LSIL

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