Cervical cancer in pregnancy and PREVENTION PRIOR to starting Assisted Reproduction Treatment

How many times have you asked yourself if you are actually doing things right? And if your doctor is teaching you that the best way to prevent uterine cancer is with a physical examination and a simple study called Pap Smear or Cervical Cytology, the best way to accompany it is with a Colposcopy. Visit our infographics related to the topic.

Today we will review a very common theme in our population that its prevalence of 1 to 3% of women diagnosed with cervical cancer are pregnant or postpartum at the time of diagnosis. For this reason at IREGA, our patients prior to their reproductive treatment always monitor our patients to improve their quality of life because around half of these cases are previously diagnosed, and the other half are diagnosed within 12 months after delivery. . Cervical cancer is one of the most common malignancies in pregnancy, with an estimated incidence of 0.8 to 1.5 cases per 10,000 births, something that is usually more common in the population at extreme ages <18 years and > 35 years.

Most patients are diagnosed at an early stage of the disease. This is probably the result of routine prenatal screening, but it is also possible that advanced-stage disease interferes with conception. The course of the disease and the prognosis of cervical cancer in pregnant patients are similar to those of non-pregnant patients, but there are always exceptions that must be made independent of cases.

There are no data from large randomized trials on which to base recommendations for the care of pregnant patients with cervical cancer. Therefore, treatment is based on evidence from randomized trials in non-pregnant women, the findings of observational studies of pregnant women, and the unique medical and ethical considerations underlying each individual case. Treatment should be individualized and based on the stage of the cancer, the woman’s desire to continue the pregnancy and the risks of modifying or delaying therapy during pregnancy.

CLINICAL PRESENTATION

Cervical cancer is often first suspected when a screening test for the disease is abnormal. In general, the rate of significant cytological abnormalities among obstetric patients has been reported to be 5 to 8% and is similar to that of the non-pregnant population.

The symptoms and signs of cervical carcinoma in pregnancy depend on the clinical stage and the size of the lesion. In two series, all pregnant patients with stage IA and 50 percent of those with stage IB carcinoma were asymptomatic at the time of diagnosis, and their disease was detected by routine cancer screening. Patients with stage IB symptomatic disease presented abnormal vaginal discharge or bleeding; Patients with more advanced disease also had pelvic pain, sciatic-type leg pain, flank pain, chronic anemia, and difficulty breathing. Since many of these symptoms are similar to those associated with a normal pregnancy, the diagnosis of cervical cancer may be delayed in pregnant women.

Then can I get a pap smear during pregnancy? It is right.

A gross cervical lesion can be observed or palpated at any gestational age. The ability to detect early malignancy by physical examination may be limited by the normal cervical changes associated with pregnancy, such as ectropion, stromal edema, and maturation. Also, the normal decidual reaction of the cervix may resemble carcinoma.

DIAGNOSTIC EVALUATION

Women with clinical findings: Cervical cytology to exclude cervical cancer is part of the diagnostic evaluation of abnormal vaginal bleeding in pregnancy.

A biopsy of a serious lesion suspected of malignancy should be performed. Women with pathologic confirmation of cervical cancer or preinvasive disease should be referred to a gynecologic oncologist for staging or a gynecologist experienced in this area. Shunting is also indicated if the cervical mass is suspected, a negative biopsy should be performed for invasive carcinoma but the results of the biopsy are not diagnostic.

Women with abnormal cervical cytology: Treatment of women with abnormal cervical cytology during pregnancy should follow the 2012 Bethesda consensus guidelines.

  • Women under 20 years of age have a high prevalence of human papillomavirus (HPV) infection and minimally abnormal cytology tests (atypical squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial lesions [LSIL] ). The spontaneous resolution rate of these abnormalities is 90%, and the risk of invasive cancer is very low. Therefore, colposcopy can be omitted during pregnancy, but cytology should be repeated after delivery.
  • ASC-US and LSIL in pregnant women older than 20 years can be managed as in non-pregnant patients, with the exception that it is acceptable to defer colposcopy at least six weeks after delivery. Atypical Squamous Cell Assessment (ASC-US and ASC-H) “and” Cervical Cytology: Assessment of Low-Grade Squamous Intraepithelial Lesions (LSIL) “.
  • Colposcopy is recommended for all adolescents and non-adolescents with atypical squamous cells in whom high-grade squamous intraepithelial lesion (ASC-H), high-grade squamous intraepithelial lesions (HSIL), and atypical glandular cells ( AGC).

Colposcopy: biopsies of lesions suspected of cervical intraepithelial neoplasia (CIN) II / III or cancer should be performed. If colposcopy does not reveal CIN II / III or suspicion of cancer, a further cytological and colposcopic evaluation should be performed after delivery, but not earlier than six weeks after delivery.

Cervical biopsies can be performed during pregnancy without a significantly increased risk of excessive bleeding. Bleeding, if found after the biopsy, can be controlled with the use of Monsel’s solution or suture. Endocervical curettage is not performed in pregnant women due to concerns that it may terminate the pregnancy, although there is no evidence to demonstrate an increased risk of termination of pregnancy.

If colposcopy in  early pregnancy is unsatisfactory, repeating the procedure in 6 to 12 weeks may result in a successful examination because the transformation zone may have “migrated” to the ectocervix, thus allowing for a successful examination at 20 weeks gestation.

Colposcopic evaluation of the cervix in pregnancy can be challenging; It should be done by a colposcopist experienced in recognizing cervical changes related to pregnancy and cancer. As an example, increased vascularization of the gestational cervix exaggerates how the immature metaplastic epithelium reacts to acetic acid, which can simulate dysplastic injury. In contrast, neoplastic cervical lesions in early pregnancy can be confused with normal squamous-column junction eversion or benign cervical decidualization. The reliability of colposcopy with targeted biopsy is unrelated to the stage of pregnancy when performed by an experienced colposcopist who is familiar with cervical changes that occur in pregnant women. The reliability of colposcopy and biopsy in pregnancy is illustrated in the following studies:

  • In a series of 612 pregnant patients with abnormal cytology, no invasive carcinoma was lost and complications from biopsies were minimal, and only two patients experienced preterm labor and delivery (both had undergone cone biopsies).
  • Similarly, another study found that colposcopy is consistent, over-estimating, and underestimating the diagnosis. The authors also noted that the reliability of colposcopy and directed biopsy was unrelated to pregnancy status.

Repeat postpartum evaluation is essential, as persistent high-grade disease is common.

Indications for conization: Traditional indications for cervical conization in the non-pregnant population are not applicable during pregnancy. Diagnostic conization in nonpregnant patients is performed to exclude invasive cancer when a puncture biopsy shows only microinvasive disease or adenocarcinoma in situ (stage IA or microscopic IB, with no clinically visible injury) because the maximum depth of invasion can only be determined by examination of all disease. injury. In contrast, diagnostic conization is only indicated during pregnancy if confirmation of an invasive disease will alter the timing or mode of delivery; otherwise, conization is postponed until the postpartum period to potentially avoid terminating the pregnancy.

If the prepartum conization is performed, the optimal time seems to be the second trimester, preferably between 14 and 20 weeks of gestation. Cervical conization should not be performed within four weeks after the estimated date of delivery because delivery may cause bleeding or extension of the recent conization wound.

Technically, pregnancy-related eversion of the squamocolumnar junction facilitates the conization procedure in pregnant women. Often, a limited wedge biopsy is all that is needed to produce an adequate diagnostic sample. Some experts suggest removing a “coin” specimen rather than a “cone” specimen to limit disruption of the endocervical canal, minimize morbidities associated with blood loss, and avoid disrupting fetal membranes [23]. If true conization is required, one option is to perform a cone cerclage whereby a cerclage is placed immediately after conization.

Possible complications of conization during pregnancy include 5% to 15% bleeding, miscarriage, premature rupture of membranes, labor / preterm labor, and infection. Fetal death is rare. It has been reported weeks after the conization procedure and, in some cases, it was attributed to chorioamnionitis. The frequency of operative bleeding greater than 500 ml is correlated with the trimester in which the procedure is performed: the risk is minimal in the first trimester, around 5% in the 2nd Trimester and around 10% in the third.

DIAGNOSIS of Cervical Cancer

It is based on the histological confirmation of the disease in a cervical biopsy sample.

SCENARIOS

Accurate staging is critical for patient counseling and treatment planning. In 2018, the International Federation of Gynecology and Obstetrics (FIGO) expanded the list of tests and procedures that can be used in staging to include imaging and pathological findings when ava The staging system of the American Joint Committee on Cancer Tumor, Node, Metastasis (TNM).

All studies in this topic are described using the staging system used at the time of the study, but otherwise FIGO 2018 staging is the system used in this topic.

Physical Examination – Physical examination is a key element of the clinical staging process and includes evaluation of the primary tumor, uterus, vagina, parametry, groin, right upper quadrant, and supraclavicular lymph nodes. If the examination in an outpatient setting is suboptimal, we suggest performing the examination under anesthesia.

Imaging studies: In the non-pregnant population, radiological studies that can be used for FIGO staging include chest and skeleton radiographs, intravenous pyelography (IVP), and barium enema. Findings in computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and lymphangiograms can also be used for staging purposes and may be helpful in treatment planning, but are not necessary.

In pregnant women, we suggest the following approach that balances the need for maternal management information with the competitive need to limit fetal exposure to ionizing radiation.

  • A chest radiograph (with abdominal protection) is warranted to assess metastatic lung disease in all patients with cervical cancer rather than microscopic.
  • In stage IA and stage IB microscopic / very small cervical cancer (<1 cm) in which extracervical disease is unlikely, routine radiographic imaging of the urinary tract may be omitted.
  • For larger stage IB1, bulky stage IB2, or more advanced disease and / or higher-risk histology (adenocarcinoma, small cell carcinoma), an image of the urinary tract with ultrasound or MRI should be taken to rule out the disease. stage IIIB.
  • For larger stage IB1, bulky stage IB2, or more advanced disease and / or higher-risk histology (adenocarcinoma, small cell carcinoma), additional imaging of the abdomen and pelvis is extremely helpful in counseling the patient and formulating a management plan.ilable.

Ultrasonography and / or magnetic resonance imaging can be used to assess liver and urinary tract involvement. Magnetic resonance imaging has the advantage of excellent tissue contrast and represents the pelvic anatomy in three planes; therefore, it can be used to calculate tumor volume and evaluate spread to adjacent lymph nodes and organs. For the evaluation of tumor size in non-pregnant patients, the general precision of the MRI is 93% and the negative predictive value for parametrial invasion is greater than 95%. For small lymph node metastases, the precision of conventional MRI in nonpregnant patients is poor; however, once the lymph node diameter is greater than 1 cm on the short axis, the sensitivity and specificity of the MRI are 62 to 89% and 88 to 91%.

Lymphadenectomy: In selected patients who wish to continue their pregnancy but have a significant risk of lymph node metastasis, staged lymphadenectomy during pregnancy using an extraperitoneal or laparoscopic approach can provide the most definitive information on the status of lymph nodes This information is important, since patients diagnosed with high-risk disease (positive lymph nodes) should receive advice on the importance of starting immediate definitive therapy. Case reports of patients with early stage cervical cancer who underwent a successful laparoscopic lymphadenectomy during pregnancy suggest the feasibility of this approach, although this may depend on the surgeon’s preference and experience.

Endoscopy: Endoscopic staging procedures, such as cystoscopy or proctosigmoidoscopy, are rarely indicated, but if necessary, experts in this area have concluded that endoscopy during pregnancy is generally safe if performed by an experienced operator.

MANAGEMENT OF INVASIVE DISEASES

A diagnosis of invasive cervical cancer in pregnancy poses great challenges for the patient, her family, and her care providers. A careful multidisciplinary team approach is required and must take into account the wishes of the pregnant patient (and her family) regarding the preservation of the pregnancy. An algorithm provides a process to guide the management of women diagnosed with invasive cervical cancer in pregnancy.

Immediate and definitive treatment, regardless of gestational age, is generally appropriate in the following settings:

  • Documented lymph node metastasis
  • Progression of the disease during pregnancy.
  • Choice of the patient to terminate the pregnancy.

Termination of Pregnancy – After a diagnosis of cancer, some patients will choose termination of pregnancy, which is subject to local statutes. For a patient with early-stage disease, we generally recommend radical hysterectomy with the fetus in situ and with preservation of the ovaries whenever possible.

For patients with more advanced disease, definitive treatment should be administered as in the non-pregnant patient.

Before chemoradiation, we recommend evacuating the uterus, especially if the fetus is more than 20 weeks pregnant, as this will avoid the possibility of non-lethal fetal exposure to potential teratogens. If termination is not performed prior to chemoradiation and treatment does not result in miscarriage, a medical or surgical uterine evacuation may be performed after chemoradiation, guided by the clinical setting and subject to local statutes.

Uninterrupted pregnancies: Given the complex ethical and medical problems present, the treatment of cervical cancer in women who do not choose or cannot terminate the pregnancy requires individualized consideration of the stage of the disease, treatment options, and preferences for patient and fetal viability. These cases require multidisciplinary collaboration with a gynecologic oncologist, maternal-fetal medicine specialist, and neonatologist, as well as clinical support for the associated psychosocial distress that accompanies this situation.

Getational age less than 22 to 25 weeks at the time of diagnosis. We suggest that patients undergo lymphadenectomy whenever it can be done safely. Limited data indicates that lymphadenectomy can be performed in the first and most of the second trimester without an increased risk of complications.

No evidence of nodal involvement: if nodes are negative for cancer, the treatment approach is based on the extent of cervical disease:

Stage IA1: For patients with documented (or suspected) stage IA1 cervical cancer (Table 2), we performed conization. Although only low-quality data is available, this strategy appears to be sufficient and relatively safe. In a report of eight pregnant women with IA1 squamous cell carcinoma (negative margins and no lymphovascular space compromise [LVSI]) diagnosed with cervical conization and managed expectantly for 9 to 25 weeks, no disease progression was documented prior to therapy. definitive.

It is important for patients to know that cervical conization during pregnancy may be associated with significant morbidity and perinatal complications. These include risks of excessive bleeding ranging from 5 to 15 percent and a risk of miscarriage, which is up to 15 percent with cold knife conization. The risk of complications increases with gestational age at the time of the procedure and the volume of tissue removed. Due to these risks, some have advocated the use of a coin excision, hoping to cause fewer disruptions to the endocervical canal.

While the management of stage IA1 cervical adenocarcinoma is controversial, a report in pregnant women and a growing body of evidence in studies of non-pregnant women suggest that, by stages, cervical adenocarcinoma may be treated similarly to its flaky. counterparty and has a comparable forecast.

 WOMEN WITH METASTATIC DISEASE

Patients with evidence of disease outside the cervix involving other organs (eg, liver or lungs) have stage IV cervical cancer. The prognosis associated with metastatic cervical cancer is poor, and the pregnancy is expected to make the situation even more psychologically and emotionally difficult for the patient and her family. It is important that the psychosocial needs of women in this situation are actively addressed, even while developing a treatment plan. For women with metastatic cervical cancer in pregnancy, treatment is medical and directed at disease control, not cure. Therefore, these women should be offered chemotherapy with agents in use for women with recurrent or metastatic cervical cancer who are not pregnant. The chemotherapy agents of choice (cisplatin and paclitaxel) can be started during pregnancy. (See “Systemic Therapy in Pregnancy” below and SYSTEMIC THERAPY IN PREGNANCY

Our approach to chemotherapy for the pregnant cervical cancer patient, when indicated, is summarized below:

  • The regimen of choice is the combination of cisplatin plus paclitaxel administered every three weeks for up to six cycles. There is evidence that the placenta filters cisplatin. In a study of 21 pregnant women with cervical cancer who received cisplatin during pregnancy, platinum concentrations in amniotic fluid at delivery were only 11 to 42 percent of those in maternal blood [60]. However, low levels of albumin in pregnancy produce higher levels of free cisplatin in the mother and fetus and may increase the risk of toxicity, including ototoxicity [61]. Transient neutropenia has also been reported in the newborn after intrauterine exposure to cisplatin and is a known side effect of this medication.
  • Ideally, there should be three weeks between completion of chemotherapy and delivery, so that the bone marrow can recover and allow the placenta to metabolize and clear cytotoxic drugs from the fetus. Furthermore, since the potential for spontaneous labor increases towards the end of pregnancy, it is prudent to avoid chemotherapy administration at the end of the third trimester.
  • To avoid additional toxicity, we do not use bevacizumab due to the risk of fetal harm depending on the mechanism of action of the drug and the results of animal studies.

Data on the safety of chemotherapy in pregnancy are limited. The effects of chemotherapy on the fetus depend on the gestational age, the agents used and the dose. A 2013 systematic review of 48 human pregnancy exposures to platinum derivatives for the treatment of cervical cancer at 17 to 33 weeks gestation reported that 67.4 percent of newborns were healthy at birth, and problems in most of the rest were associated with prematurity.

OUTCOME

Most studies do not suggest a difference in cancer prognosis for women with invasive cervical cancer diagnosed during pregnancy compared to nonpregnant women with invasive cervical cancer when adjusted for stage; however, the data is limited. As an example, a retrospective study compared 40 women with cervical cancer associated with pregnancy with 89 non-pregnant women with cervical cancer. Maternal survival was not significantly different in both groups after 30 years of follow-up. Another study evaluated 53 women with stage IB disease diagnosed in pregnancy [9]. Five-year survival was similar to that of non-pregnant controls and was unaffected by the timing of therapy initiation during pregnancy. A large long-term series of pregnant women with invasive cancer of the cervix reported that 5.5 percent developed a second primary, which is similar to the second primary rate in all women younger than 50 years.

The effect of cervical cancer on the outcome of pregnancy is less clear. Three small retrospective studies reported that the diagnosis of cervical cancer did not adversely affect the outcome of the pregnancy, assuming that the pregnancy was not terminated [8,66,69]. In two of these studies, the mean gestational age at delivery and preterm delivery rates, intrauterine growth restriction, and stillbirth were similar for pregnant women with and without cervical cancer; in the third, the average gestational age at delivery was 36.1 weeks, largely due to iatrogenic preterm delivery.

In contrast, a large study linking California birth / death certificates, discharge records, and cancer registry files identified 434 cases of cervical cancer in pregnant and postpartum women over an eight-year period; 136 cases were prenatally diagnosed. Compared to women without cancer, women diagnosed with cervical cancer during pregnancy or postpartum had higher rates of spontaneous and iatrogenic prematurity, with correspondingly higher rates of low birth weight and very low birth weight. These relationships were maintained even in patients diagnosed with cervical cancer for up to 12 months after delivery.

It should be noted that only one case of cervical squamous cell carcinoma with placental metastasis has been published.

SUMMARY AND RECOMMENDATIONS

  • Cervical cancer is one of the most common malignancies in pregnancy, with an estimated incidence of 0.8 to 1.5 cases per 10,000 births. Most cases are identified as a result of cervical cancer screening programs. (See ‘Introduction’ above and clínica Clinical Presentation ’above).
  • Colposcopic evaluation of the cervix in pregnancy with biopsies should be performed by colposcopists experienced in pregnancy-related changes in cervical appearance. Endocervical curettage should not be performed.
  • Diagnostic laconization is only indicated during pregnancy if confirmation of an invasive disease will alter the timing or mode of delivery; otherwise, conization is postponed until the postpartum period to avoid potentially terminating the pregnancy. (See ‘Indications and Cone Performance’ above.)
  • Staging tests are modified in pregnant women to limit fetal exposure to ionizing radiation.
  • A multidisciplinary team approach is crucial to address the complex care issues faced by a pregnant patient with cervical cancer, such as termination versus continuation of pregnancy, delay of definitive treatment, mode of therapy during pregnancy, or timing and route of delivery. (See ‘Management of invasive disease’ above.)
  • For patients diagnosed with preinvasive cervical cancer, definitive treatment should be deferred to the postpartum period.
  • Immediate and definitive treatment with termination of pregnancy, regardless of gestational age, is generally indicated if there is evidence of pathological lymph node involvement or documented disease progression during pregnancy.
  • Our approach to the treatment of women with invasive cancer of the cervix takes into account the wishes of the patient and her family regarding the preservation of the pregnancy, the gestational age of the fetus and the clinical stage of the disease in the mother:
  • For women who do not wish to continue the pregnancy after the diagnosis of invasive cervical cancer, the treatment is similar to that for non-pregnant women.
  • For women who wish to preserve pregnancy with a fetus at an early gestational age (see ‘Gestational age less than 22 to 25 weeks at diagnosis’ above):

-For patients in whom stage IAI disease is identified (or suspected), we performed a diagnostic conization. No further treatment is warranted if they had stage IA1 disease, provided they had no further evidence of disease during follow-up. If the conization margin was positive, cesarean delivery and repeated conization six to eight weeks after delivery is indicated to rule out invasive disease. (See “Gestational age less than 22-25 weeks at diagnosis” above).

For patients with stage IA2 and IB1 tumors, we suggest surgical treatment with a simple trachelectomy or large conization (Grade 2C). We suggest not performing a radical trachelectomy (Grade 2C). (See “Gestational age less than 22-25 weeks at diagnosis” above).

-For patients with a tumor ≥2 cm, we suggest neoadjuvant chemotherapy (Grade 2C). We suggest the combination of cisplatin plus paclitaxel administered every three weeks until delivery (Grade 2C).

  • For women who wish to preserve pregnancy and whose fetus is at a later gestational age (see ‘Gestational age 22-25 weeks or later’):

-We suggest a delay in treatment until after delivery, as long as your tumor is <2 cm (Grade 2C).

-We suggest neoadjuvant chemotherapy if your tumor is ≥2 cm (Grade 2C). However, other oncologists prefer the interruption of pregnancy and the start of definitive treatment for these patients due to the high risk of recurrence. (See ‘Stage IB2 or higher’ above.)

  • Radiation therapy should not be given to women with invasive cervical cancer who want to preserve their pregnancy because it results in fetal loss or other damage. (See ‘Unfinished Pregnancies’ above.)
  • Patients diagnosed with cervical cancer and continuing their pregnancy should be followed closely until delivery. Patients who demonstrate evidence of disease progression should undergo definitive treatment.
  • For women with stage IA cervical cancer, vaginal delivery is acceptable as long as they have negative margins at the time of diagnostic conization. However, cesarean delivery should be performed in women Women diagnosed with invasive cancer of the cervix during pregnancy should undergo definitive treatment for their disease after the end of the pregnancy.
  • No additional treatment for stage IA1 disease is warranted if they wish to preserve fertility.
  • For women with stage IA2 disease or a tumor up to 4 cm in size and who wish to preserve their fertility, we proceed with a radical trachelectomy six to eight weeks after delivery. Lymphadenectomy should also be performed if not previously performed.
  • For women who do not want to preserve fertility:

-We suggest an extrafascial hysterectomy for women with stage IA1 disease instead of a radical hysterectomy, provided there is no evidence of invasion of the lymphovascular space (LVSI) (Grade 2C).

-For patients with stage IA1 disease with LVSI, IA2 or IB1 tumors, we suggest radical hysterectomy instead of chemoradiation (Grade 2C).

-For patients treated with neoadjuvant chemotherapy during pregnancy for locally advanced disease or disease with positive nodes, we proceed with a radical hysterectomy, which can be performed at the time of cesarean delivery or as a second surgical procedure.

  • Definitive treatment for women diagnosed with more advanced disease during pregnancy who delayed treatment until after delivery reflects that of the non-pregnant patient.
  • When controlling the stage of cervical cancer, the course of the disease and the prognosis of cervical cancer in pregnant women are similar to those of non-pregnant women. with higher stages of the disease. (See ‘Delivery Considerations’ above.)

Dr. Bryan A. Oliveros Galeana

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