Management of Cervical Cancer and Human Papillomavirus in Pregnancy

Abstract

Cervical cancer during pregnancy is the most commonly detected malignant tumor. It has become a public health problem, 99% related to human papillomavirus (HPV) infection, making it the only gynecological malignant tumor of clear etiology in the world. It is diagnosed at any stage of pregnancy. Its initial presentation is observed as transvaginal bleeding in all three trimesters associated with HPV infection. If the metastasis is negative in the lymph nodes, it improves. At an early stage the prognosis is favorable, management consists of preserving pregnancy, neoadjuvant chemotherapy can be used to treat cervical cancer in pregnancy, in cases of viable pregnancies between 27- and 31-weeks’ gestation chemotherapy may be performed depending on the staging, caesarean section at 35 weeks, radical surgery and systemic chemotherapy may achieve good results depending on the stage of the tumor.

1. Introduction

Cervical cancer is a highly preventable and curable pathology, if diagnosed and treated in a timely manner, ranking as the third most common cancer in women worldwide and the second most common cancer in developing countries, where more than 85% of deaths from this cause occur. Considering that it is necessary to employ prevention strategies, since it has become a public health problem, 99% related to infection by the human papillomavirus (HPV), making it the only gynecological malignant tumor of clear etiology in the world. In addition, recent studies have established an association between vaginal microbiota composition, HPV infection, and progression to cervical dysplasia and cancer [1, 2, 3, 4].

Cervical cancer is a gynecological malignancy that is most frequently diagnosed during pregnancy, being a major challenge for women and medical specialists to make the right decisions about the therapy for the women to receive during the gestation period, which must be individualized [5]. The biomolecular test of the human papillomavirus can detect 30–100% more cancer precursors than conventional cytology and 20–50% more than cytology in liquid medium, taking into account that a woman with a positive HPV test must be studied carefully because she may have a high-grade cervical intraepithelial neoplasm or cancer, despite having a colposcopy with minimal alterations. It should be noted that a good sample for cervical cytology is also a good sample for DNA testing for human papillomavirus [6].

The polymerase chain reaction (PCR) test is used to detect HPV DNA in various forms, with a predictive value greater than 99%, being a prevalent virus in the young and sexually active population with an incidence of up to 20%, where screening should be suggested from the age of 25, the virus generates a transient infection with a duration of 8 months in low-risk HPV cases. From 10 to 40 years later, the HPV screening test continues to increase, being part of the usual control, in Europe and other countries it is used less frequently, the objective is to perform this test as routine and that it is part of the gynecological control, but there are socioeconomic factors that need to improve so that the entire population has access to these tests [7].

Genetic and molecular advances consist of new screening strategies, such as DNA methylation, to locate high-grade epithelial lesions in HPV-positive women. Detection of long non-coding RNA (lncRNA), which functions as a tumor biomarker for the diagnosis and prognosis of patients, plays an important role in the regulation of gene expression at various levels. Cuproptosis plays a role in tumorigenesis and cancer progression, in addition to the development of other biomarkers such as programmed cell death ligand 1 (PD-L1), which predict cervical cancer outcomes, risk of recurrence, and assessment of response to immunotherapy (Table 1) [13, 14, 15].

Carcinogenesis	New findings
Long non-coding RNA (lncRNA)	The identification of lncRNA is involved with cuproptosis and the pathogenesis of chemotherapy resistance, both cuproptosis and chemotherapy resistance play a role in carcinogenesis and progression. Non-coding RNAs (ncRNAs) are closely related to cancer initiation and development due to their critical role in gene expression and epigenetic modulation.
Oncoproteins	The oncogenic potential of HPV depends on the oncoproteins E6 and E7 that are expressed in cells infected by the virus and alter the cell cycle. They are considered usable biomarkers in the treatment of women with positive results, and these proteins disrupt the cell cycle
DNA methylation	It is an epigenetic process that adds a methyl group to the DNA, regulates the expression of genes, in the face of a genetic modification during its division, methylation modifies the function of DNA and acts as a regulator of gene transcription, and it allows us to know which cells present molecular changes to develop cervical cancer
Checkpoint inhibitors	Third-line treatment in metastatic cervical cancer with programmed death protein 1 (PD-1) blockade.
Differentially expressed genes	A prognostic model of risk for cervical cancer based on differentially expressed genes that are driven by histocompatibility locus antigen complex, class I, G (human) (HLA-G), and this showed a great ability to predict the overall survival of patients with cervical cancer.

Table 1.

Genetic and molecular advances in cervical cancer identified in HPV-associated cervical cancer [8, 9, 10, 11, 12].

Elaboration: Dr. María Fernanda Calderón León.

Cervical cancer accounts for 8.7% of all cancers diagnosed during pregnancy, treatment is complicated by pathophysiological changes in the relationship between the reproductive organs and the developing fetus, so relevant aspects such as termination of pregnancy are treated to administer treatment. The administration of chemotherapy treatment will depend on the stage of the cancer, fetal viability by weeks of gestation at the time of diagnosis [16].

The International Federation of Gynecology and Obstetrics (FIGO) staging of cervical cancer patients is based on clinical examination, imaging, and potential surgical findings [17]. Cervical cancer is directly related to carcinogenesis and its treatment in pregnancy is of great importance [18].

The stage of cervical cancer in pregnancy is essential to determine individual management (Table 2) [23].

• Stage I: the cancer is found only in the cervix. It is divided into two sub classifications.

  • IA1: the tumor has spread to a depth of 3 mm or less into the tissues of the cervix.

  • IA2: the tumor has spread to a depth of more than 3 mm, but not more than 5 mm into the tissues of the cervix.

• IB stage:

  • IB1: the tumor is 2 cm or smaller and has spread more than 5 mm deep.

  • IB2: the tumor is larger than 2 cm, but not larger than 4 cm.

  • IB3: the tumor is larger than 4 cm.

• Stage II: the tumor has spread from the uterus to the stroma of the cervix, but not to other parts of the body.

• Stage III: cancer has spread beyond the cervix and upper vagina, but not to the pelvic wall or lower vagina.

• Stage IV: cancer has spread to the pelvic wall, lower vagina, bladder, or rectum, or affected distant organs such as the lungs or liver.

Author	Manipulation	Results	Staging malignant tumors	Gestational age and recommendations
Beharee et al. [20]	Conization of the cervix	Conization is an appropriate and relatively safe treatment for cervical cancer patients	Treatment of stage I A1 cervical cancer	22–25 weeks pregnant
	Let the pregnancy progress and postpone treatment, until fetal maturity is reached.	When the lymph nodes are not involved and the diameter of the tumor is less than 2 cm	I A2–I B1	Before 22–25 weeks gestation
	Termination of pregnancy is recommended	Patients with lymph node involvement and a tumor diameter of less than 2 cm	I A2–I B1	Before 22–25 weeks gestation
	If the lymph node is negative or the patient has a strong desire to continue pregnancy, neoadjuvant chemotherapy may be used, until the fetus matures and is born.	The diameter of the tumor is greater than 2 cm, if the lymph node is positive, termination of pregnancy is recommended	Stage I B1	Before 22–25 weeks gestation
	Adjuvant chemotherapy to stabilize the tumor, prevent tumor progression and spread.	Adjuvant chemotherapy may be used at this stage, until fetal maturity is reached	I B2	Older than 22–25 weeks gestation
Rouen [22]	Treatment may be postponed between 20 and 33 weeks of pregnancy, until a cesarean section is performed to promote lung maturation of the fetus. The initial treatment time of delayed treatment should not exceed 32–34 weeks of pregnancy, and the pregnancy may be terminated after fetal lung maturation	Neoadjuvant chemotherapy may be used, until fetal maturity is reached.	FIGO 2018 IB1 or IIA	For patients with 14 ~ 20 weeks of pregnancy
Hammer et al. [21]	If indicated, definitive surgery is performed during the same period, delivery is performed by cesarean section	The tumor may block the birth canal. The placenta is sent for histological examination to rule out metastasis.	Women who have not received treatment.	Vaginal delivery is not chosen, as there is an increased risk of damage to the tumor, a high risk of bleeding, and a risk of spreading malignant cells
Teoh et al. [19]	In the absence of clinical or histological suspicion of invasive cancer, excision procedures during pregnancy are not recommended.	Colposcopy is recommended skipping endocervical sampling every trimester, and an excision procedure is performed after delivery.	Cervical adenocarcinoma in situ (AIS).	Conization, usually for the evaluation of biopsy-diagnosed AIS, is not recommended during pregnancy unless invasive cancer is suspected.

Table 2.

Management of cervical cancer in pregnancy according to gestational age, clinical stage of cancer [19, 20, 21, 22].

Elaboration: Dr. María Fernanda Calderón León.

Cervical cancer has three stages, the early stage has a survival rate of 92.5–93.1%, so it is vitally important to screen, detect, and treat it early [24, 25], cervical cancer, in the locally advanced stage, accounts for about 37% of cervical cancers, the median survival for this type is 15.5 months [26, 27]. In advanced, recurrent, or metastatic cervical cancer, the overall survival at 3 years is only 33% [28].

In a review of 14 pregnancies, the use of paclitaxel combined with cisplatin resulted in the birth of 14 live births, without miscarriages, with a complete response to treatment in 7.2% and a partial response in 92.9% of pregnant women with cervical cancer. Taxane treatment after the first trimester of pregnancy demonstrated obstetric and fetal outcomes that enable the treatment of cervical cancer during pregnancy [29, 30].

The goal of the chapter is to understand how to stage and treat cervical cancer during pregnancy.

2. Genetic and molecular advances in the field of cervical cancer identified in HPV-associated cervical cancer

The main advances are genetic and molecular in cervical cancer associated with the human papillomavirus [8, 9, 10, 11, 12].

Table 1 describes the genetic and molecular mechanisms associated with carcinogenesis caused by human papillomavirus in the cervix. Genetic and molecular advances consist of new screening strategies, such as DNA methylation, to locate high-grade epithelial lesions in high-risk HPV-positive women. Detection of long non-coding RNA (lncRNA), which functions as a tumor biomarker for patient diagnosis and prognosis, plays an important role in the regulation of gene expression at various levels. Cuproptosis plays a role in tumorigenesis and cancer progression, in addition to the development of other biomarkers such as programmed cell death ligand 1 (PD-L1), which predicts cervical cancer outcomes, risk of recurrence, and assessment of response to immunotherapy.

3. Management of tumor staging according to gestational age and current recommendations

Current strategies have made it possible to provide treatment during pregnancy in some common histological types of gynecological cancer, since within the search of the literature a published clinical case was found, it is a 29-year-old Chinese woman who went to the hospital after presenting intermittent vaginal bleeding since the 16th week of gestation. Reporting a history of papillary thyroid carcinoma with metastases to the lymph nodes in the neck, she indicates that she underwent radical surgery 3 years earlier. Regular postoperative examinations showed no signs of recurrence until the current admission. Gynecological examination revealed an exophytic lesion of 3 × 1 × 2 cm on the posterior lip of the cervix without invasion of the parametrium or the fundus of the vaginal sac. The patient had persistent human papillomavirus type 18 (HPV-18) infection and a serum alpha-fetoprotein (AFP) level of 235.55 ng/ml. Pathological examination of the lesion revealed large cell neuroendocrine carcinoma (LCCD) with adenocarcinoma of the cervix, which showed positive immunoreactivity for CK, cytokeratin 7, synaptophysin (Syp), chromogranin A (CgA), P16 proteína supresora tumoral, molécula de adhesión de células neuronales CD-56, and proteína Ki67 (>90%). The tumor was classified as clinical stage IB2, according to the FIGO (2018) cervical cancer staging. The patient’s wish was to continue the pregnancy, so neoadjuvant chemotherapy with cisplatin and etoposide was administered at 27 and 31 weeks, respectively. During observation of the pregnancy, there were no signs of toxicity or fetal malformation. At 35 weeks, a single live product was obtained by cesarean section with an Apgar score of 9 at 1 minute and 10 at 5 minutes, and then the patient underwent a radical hysterectomy combined with bilateral salpingectomy, with bilateral ovarian biopsy and sentinel node biopsy (Figure 1) [16].

Figure 1.

Patient in lithotomic position after vaginal delivery. Multiple genital warts are present in the right perineal region. Source: Dr. María Fernanda Calderón León.

Table 2 describes the current management of cervical cancer in pregnancy [19, 20, 21, 22].

4. Conclusions

Cervical cancer is closely related to infection by the human papillomavirus, since it is of great importance to carry out adequate screening during prenatal and gynecological control, for which there are a series of biomolecular tests whose sample collection is easy, the same as taking a sample for conventional cytology with an endocervical brush. It helps us to determine if there is HPV infection, in addition to informing what subtype it is, if it is of high, medium, and low degree of malignancy, in order to, according to the results, promote vaccination against the virus and prevent its spread. If we detect a patient with signs and symptoms of cervical cancer during prenatal care, we must take a therapeutic approach according to the gestational stage in which the patient is, and also according to the stage of the tumor. It has now been shown that pregnant women can receive chemotherapy during pregnancy without the need to delay treatment, obtaining encouraging results.

Acknowledgments

To God and to my parents.

Conflict of interest

The authors declare that they have no conflict of interest.

Notes/acknowledgments/other statements

“Thank you.”

Acronyms and abbreviations

HPV	human papillomavirus
FIGO	International Federation of Gynecology and Obstetrics