This chapter should be cited as follows:
Robbins T, Saso S, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.415753

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 14

Surgical problems

Volume Editor: Professor Andrew Shennan, King’s College London, UK

Chapter

Management of the Obstetric Patient with Malignancy

First published: February 2021

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By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
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INTRODUCTION

The incidence of cancer during pregnancy is estimated at 1 per 1000 pregnancies.¹ Although uncommon, cancer during pregnancy is increasing, as highlighted in the International Federation of Gynaecology and Obstetrics (FIGO) Cancer Report published in 2018. This rising incidence cannot be explained solely by advancing maternal age.^2,3,4

This chapter discusses malignancies presenting during pregnancy that require surgical intervention. Breast cancer is the most common malignancy presenting during pregnancy.¹ The most common gynecological malignancies presenting during pregnancy originate from the cervix and ovary.⁵ Endometrial, vulval and vaginal cancers are rare during pregnancy. Beyond breast cancer, the other non-gynecological malignancies most commonly seen during pregnancy are hematological such as leukemia and lymphoma, and melanoma.¹ Melanoma, the hematological cancers, and lung cancer are the only malignancies reported to metastasize to the placenta and fetus.^2,6 Cancers whose management is predominantly non-surgical, such as Kaposi’s sarcoma, that may present in pregnancy, particularly in the context of HIV, are not covered in this chapter. Gestational trophoblastic disease is not included here for the same reason.

A cancer diagnosis is difficult for any patient. However, during pregnancy unique challenges are faced in balancing maternal and fetal or neonatal risks and benefits. Providing quality care involves clear communication, understanding the woman’s and family’s wishes and individualizing management based on these and other factors. A multidisciplinary approach is essential. The team should include oncologists, obstetricians, neonatologists and psychological support where possible. Discussion should include the potential impact of treatment on the woman’s fertility and any fertility-sparing options where appropriate.

Clinicians should remain vigilant to symptoms presenting during pregnancy, particularly if persisting. Non-specific symptoms of malignancy can be confused with common symptoms and presentations during pregnancy such as lethargy, nausea and vomiting, abdominal pain, breast changes and anemia. Late presentation and diagnosis can impact on prognosis and physiological changes during pregnancy may make examination more challenging.

Both open and laparoscopic surgery if required for the management of malignancy, can be carried out safely during pregnancy. The most appropriate surgical modality will depend on the gestation of the pregnancy, the procedure planned, the available surgical expertise and resources. The physiological adaptations of pregnancy should be considered as these may impact on surgical care. Airway management is more challenging during pregnancy due to laryngeal edema. Regional or local anesthesia are generally preferable where possible, but will be dependent on the type of surgical procedure. Aspiration prophylaxis should be administered. Uterine displacement with a lateral tilt of the patient will reduce venocaval compression and should be considered in all supine operative positioning. Laparoscopic surgery during pregnancy is safe when performed by an experienced laparoscopist with appropriate training.⁷ Port placement should be carefully considered dependent on uterine size and insufflation of pneumoperitoneum should be gradual. Pregnant women with malignancy are at high risk of venous thromboembolism, prolonged immobility associated with surgery is a further risk factor. Women should be counseled regarding their risk of thrombosis and offered appropriate prophylaxis.

GYNECOLOGICAL MALIGNANCIES IN PREGNANCY

Cervical cancer

Introduction

Cervical cancer is the second most common malignancy affecting women globally.¹ Of deaths due to cervical cancer, 90% occur in low- and middle-income countries (LMICs).

In 2018 the World Health Organization (WHO) issued a call to action to eliminate cervical cancer as a public health problem.⁸ A triple intervention strategy was set out, establishing global targets to be reached by 2030. The 90–70–90 targets are:

• 90% of girls fully vaccinated with HPV vaccine by the age of 15 years
• 70% of women screened with high performance tests two times per life by 35 and 45 years of age
• 90% of women identified with cervical disease to receive treatment.

In low-resource settings, weaker health systems are likely to make the progress towards WHO targets more challenging. A public health approach with appropriate financing mechanisms and integrated primary health care systems are essential to achieve these targets. A recent study predicts that vaccination alone can reduce the number of cervical cancer cases by 89% over the next century, averting 60 million cases in LMICs.⁹

The incidence of cervical cancer during pregnancy is reported to be between 0.1 and 12 per 10,000 pregnancies.^10,11,12 Most cases are detected early in resource-rich settings. Women who have previously been treated for abnormal cells or cancer ideally require pre-pregnancy counseling and consultant-led care in a preterm birth surveillance clinic, where these resources are available. In high-income settings, clinical challenges remain in improving outcomes for women with advanced disease, preserving fertility in younger women, and incorporating newer technologies into care.¹² However, in low-resource settings, where the burden of disease is highest and where access to vaccination and routine screening is poor, many women present late.

Physiological changes during pregnancy

The cervix undergoes morphological changes during pregnancy including an increase in volume, vascularity and inflammatory changes.^13,14,15,16 The appearance of a cervical ectropion is more common in pregnancy with eversion of the endocervical columnar epithelium on to the ectocervix.¹⁴ Examination of the cervix may be more challenging during pregnancy due to these physiological changes. An Arias-Stella reaction has been defined as hormone-related atypical changes in the glandular epithelial cells associated with the presence of chorionic tissue. Described originally in 1954 by Javier Arias-Stella, relating to the endometrium of the uterine corpus, the histological findings have since been noted in other sites including the endocervix.¹⁷

Pre-invasive disease

Human papilloma virus and cervical intraepithelial neoplasia

Human papilloma virus is a non-enveloped double-stranded DNA virus that infects the epithelium including skin or mucus membranes. There are around 40 HPV genotypes known to affect the anogenital tract in women and men.¹⁸ Resulting infections can cause a spectrum of consequences from warts to dysplasia, to carcinomas. The genotypes are grouped into high- or low-risk dependent on their oncogenic potential. HPV 16, HPV 18 and HPV 45 are high-risk genotypes. Nearly all high-grade squamous intraepithelial lesions (HSIL) and cervical squamous cell carcinomas are etiologically related to HPV infection.¹⁹

Pre-cancerous changes in the cervical epithelium arise most commonly at the transformation zone where the endocervical canal meets the external part of the cervix or ectocervix. Cervical intraepithelial neoplasia (CIN) is classified based on the depth of the abnormal cells seen on diagnostic or excision (treatment) biopsy. Less commonly abnormalities arise within the endocervical canal, resulting in cervical glandular intraepithelial neoplasia (CGIN).

Histological grading of pre-invasive disease is shown in Tables 1 and 2.

A major contributing factor to the etiology of cervical neoplasia is persistent infection with high-risk genotypes of HPV, particularly HPV 16 and 18. National screening programs aim to reduce the incidence of and mortality from cervical cancer through population-based screening of eligible women, and treatment of early abnormalities.²⁰ Cervical screening programs have traditionally used liquid-based cytology or Papanicolaou smears to detect cytological abnormalities. However, more recently some national screening programs, for example in the UK, have moved towards the use of high-risk HPV typing for the triage of women with borderline or low-grade cytology results. This allows those women with borderline changes or low-grade dyskaryosis who test negative for high-risk HPV to be returned to routine recall for screening, while those who test positive for high-risk HPV are directly referred for colposcopy.

Standard colposcopy involves using a binocular colposcope to examine the cervix following staining and taking biopsies where appropriate.²¹ UK guidelines recommend avoiding routine screening during pregnancy and deferring this until 6 weeks postpartum. Cervical smears or cytology are not recommended in pregnancy due to reduced accuracy. Decidual cells are often mistaken for atypia. The morphological changes to the cervix associated with pregnancy may appear suspicious to an inexperienced clinician. However, cervical lesions with a suspicious appearance should warrant urgent referral to an accredited colposcopist. Women identified with abnormal cytology should be referred for colposcopy in the late first or early second trimester. Women with low-grade changes triaged to colposcopy on the basis on a positive high-risk HPV test can have assessment delayed until after delivery. Pregnant women with borderline nuclear changes or low-grade dyskaryosis rarely have high-grade changes at colposcopy that require biopsy during pregnancy. The primary aim of colposcopy during pregnancy is to exclude invasive disease and to defer biopsy or treatment until after delivery. Pregnancy increases the risk of hemorrhage following biopsy or treatment. The safety of delaying treatment during pregnancy has been demonstrated in a number of cohort and retrospective uncontrolled studies.^14,20 If there is suspicion of invasion, then a biopsy adequate for diagnosis should be performed. Directed biopsies should be taken from the most dysplastic area for histological diagnosis. Biopsy should be taken during pregnancy if invasion is suspected. The risk of hemorrhage is significant during pregnancy due to increased vascularization of the cervix. Therefore, biopsies should be taken in facilities with resources to manage this potential complication.

Treatments for cervical intraepithelial neoplasia

Treatments for CIN aim to remove or destroy the abnormal cells, while preserving cervical function. They can be broadly divided into excisional or ablative methods. Excisional methods include:

• Cold knife conization
• Laser conization
• Needle excision of the transformation zone (NETZ)
• Large loop excision of the transformation zone (LLETZ).

These allow comprehensive histological examination of the excised tissues and the whole transformation zone with precise evaluation of excision margins. Ablative methods include:

• Laser ablation
• Radical diathermy
• Cold coagulation cryotherapy.

These methods destroy the transformation zone and, therefore, preclude histological evaluation. It is important to have an accurate pre-treatment biopsy taken at an earlier visit to confirm the diagnosis prior to proceeding with such treatments.

Clinical management

Presentation

Pregnant women with cervical cancer may present with common, non-specific symptoms including irregular bleeding particularly postcoital bleeding, abnormal vaginal discharge, and back or pelvic pain. Symptoms are often related to late-stage disease. Advanced-stage disease with spread into surrounding tissues and organs may cause symptoms such as hematuria, other bladder or bowel symptoms, bony pain, lower limb edema or flank pain due to hydroureter or hydronephrosis. Early-stage disease may be asymptomatic and an incidental finding on routine pelvic examination or cytology. A clinically suspicious looking cervix during pregnancy, for example with a necrotic, friable lesion, should prompt further investigation with colposcopic examination. Postcoital bleeding may also be due to cervical ectropion, cervical polyps or infection with Chlamydia trachomatis. However, more sinister pathology should be considered and ruled out.

Imaging

Magnetic resonance imaging (MRI) is safe in pregnancy. MRI has been shown to have the best sensitivity and specificity in assessing the size of cervical lesions.^22,23,24 It allows delineation of the size of the lesion, extent of local and regional spread as well as a detailed assessment of lymph nodes. Gadolinium, an intravenous contrast medium used to improve the diagnostic accuracy of MRI, crosses the placenta and is excreted by the fetal kidneys. Gadolinium enhanced MRI is not associated with congenital anomalies at any gestation. However, it has been associated with an increased risk of stillbirth, neonatal death and rheumatological, immunological and infiltrative skin disorders in the offspring.²⁵ Therefore, the use of gadolinium enhanced MRI is not recommended during pregnancy,²⁶ unless the benefits clearly outweigh the risks to the fetus.²⁷

Computed tomography (CT) may be performed if considered essential for assessing metastatic disease during pregnancy. Abdominal shielding and low-dose radiation should be considered to minimize risks to the fetus if pregnancy is continuing. Use of fluorine-18-labeled fluorodeoxyglucose positron emission tomography (¹⁸FDG PET) CT during pregnancy should be carefully considered, weighing up the benefits to the mother with the small risk of radiation to the fetus.^28,29

Diagnosis

Diagnosis requires a biopsy for histological review, ideally by an experienced gynecological pathologist where available. Information regarding pregnancy status should be provided on requests for histological examinations allowing associated changes to be taken into consideration. Physiological decidual changes in pelvic nodes have the potential to mimic malignant changes particularly in squamous cell carcinoma of the cervix.³⁰ In pregnant women presenting with abnormal findings at colposcopy, biopsies should be taken if invasion is suspected. This should be performed by a senior clinician, in an appropriate setting where possible, as the risk of hemorrhage following biopsy is higher.

Staging

In 2018, FIGO published a revised staging for carcinoma of the cervix (Box 1).²² Staging systems aim to define the anatomical extent of disease and differentiate outcomes in relation to this. Staging will be considered when deciding ongoing management, prognosis and aids in clear communication between clinicians. The updated classification from FIGO allows for the inclusion of imaging and pathological assessment of the pelvis and lymph nodes. FIGO acknowledge clinicians may need to exercise flexibility according to available resources, particularly in low-income countries where the burden of disease is highest. In low-resource settings clinicians may continue to assess the patient clinically and use this as the basis for staging. Clinical staging traditionally involved examination under anesthesia, cystoscopy, proctoscopy, chest x-ray and review of pathology.

The key amendments to the updated staging system are:

• Allowing the use of any imaging modality and/or pathological findings for allocation of stage, including measurement of the primary tumor size and/or assessment of extension into surrounding tissues and organs;
• Allowing the assessment of retroperitoneal nodes by imaging and/or pathological findings and if positive designated as stage IIIC, with notation of method used for stage allocation (r = imaging, p = pathology);
• No recommendations for routine investigations – these should be decided on the basis of clinical findings and standard of care in the setting;
• The lateral extension of the lesion is no longer considered in stage IA;
• Stage IB is now further subdivided into IB1, IB2 and IB3.

Lymph node status is an important prognostic factor guiding management particularly in early stage disease. Surgico-pathological assessment of lymph node status requires advanced surgical skills, whether performed at laparotomy or laparoscopically. Since 85% of cases present in low-resource settings, the required skills and infrastructure may not be widely available. Although the gold standard to assess lymph node involvement is histopathological examination, imaging can be used as an alternative. Within the updated FIGO staging system, any woman with positive lymph nodes is automatically upstaged to IIIC.²²

Management of cervical cancer during pregnancy

While treatment may be broadly dictated by stage, other factors must be taken into consideration, particularly in pregnancy. The wishes of the woman including future fertility, availability of resources and relevant expertise are all important variables that will influence decision making.

Management of cervical carcinoma during pregnancy should take into consideration:

• Staging (including the size of primary lesion, extent of any local spread and nodal status)
• Gestation of the pregnancy
• Histological subtype.

When planning management, it is important to determine whether the overall aim of treatment is curative or palliative. This should ideally be done following an experienced multidisciplinary team discussion considering the above criteria. Other significant factors include the woman’s wishes regarding continuing pregnancy versus risk of preterm delivery or termination of pregnancy at earlier gestations and any relevant surgical or medical comorbidities including obesity. Individualized care and joint decision making together with the woman are key to quality care.

Guidelines issued following an international consensus meeting in 2019, report that pregnancy has no negative impact on oncological outcome. Therefore, pregnancy preserving management should be offered to women.²⁶ However, immediate definitive treatment should be offered regardless of gestational age of the pregnancy if any of the following are identified:²

• Presence of lymph node metastases
• Disease progression during pregnancy
• The woman’s choice.

Stage I carcinoma is strictly confined to the cervix uteri. In early stage cervical cancer surgical excision alone can be curative.¹² In stage IA1 the risk of lymph node involvement is negligible. Surgical treatment options during pregnancy include:

• Conization (diathermy, LLETZ, NETZ, cold knife)
• Simple trachelectomy (excision of the cervix 1 cm above the tumor border)
• Radical trachelectomy (vaginal/abdominal/laparoscopic/open).

Controversy exists regarding radical trachelectomy as an option during pregnancy.^31,32,33 Consensus international guidelines state that it should not be recommended during pregnancy because of high rates of obstetric and surgical complications.²⁶Decisions here will very much depend on surgical expertise.³⁴ 

Stage IA1

• Surgical excision alone can be curative
• Risk of lymph node involvement is extremely low
• Ensure adequate removal of local disease with clear margins
• Prophylactic cervical cerclage may be considered to reduce the risk of obstetric complications.

Stage IA1 with lymphovascular space invasion (LVSI), IA2, IB1

• Offer surgical excision according to expertise (conization or trachelectomy)
• Offer staging lymphadenectomy up to 22 weeks of gestation
• After 22 weeks of gestation offer neoadjuvant chemotherapy (NACT) or offer delayed treatment if woman wishes to continue pregnancy.

A staging lymphadenectomy should be offered to women with stage IA1 with LVSI, stages IA2 and IB1. This may be performed laparoscopically up to 16 weeks of gestation. Between 16 and 22 weeks of gestation, a laparotomy should be performed according to the latest international consensus guidelines. After 22 weeks of gestation nodal resection should be avoided as an insufficient number of nodes are likely to be retrieved.²⁶ After 22 weeks of gestation two options can be offered to women wishing for pregnancy preserving management – NACT or delaying treatment until after delivery with regular follow up.

Stage IB2

• Up to 22 weeks of gestation, offer either pelvic lymphadenectomy +/-NACT or NACT and then subsequent surgical staging of disease after downstaging of the tumor
• After 22 weeks of gestation, NACT (until 34 weeks) is the only pregnancy preserving option.

Stage IB3

• NACT is the only pregnancy preserving management option
• There is a need for further research, current evidence is limited
• The role of staging lymphadenectomy is controversial.

Treatment options without the intention of preserving pregnancy:

• Can be offered in advanced disease
• Should be offered if the woman wishes
• Should be discussed within the context of local legislation regarding termination of pregnancy
• For operable disease (IA2 – IB2 <4 cm) offer a radical hysterectomy with or without a preceding hysterotomy dependent on gestational age
• For stage IB3 or above offer chemoradiation, with a preceding hysterotomy if the pregnancy is in the second trimester to reduce the risk of obstetric complications
• If lymph nodes are positive (automatically upstaged to IIIC), European Society of Medical Oncology (ESMO) guidelines recommend termination of pregnancy.

In patients with positive lymph nodes who decline termination of pregnancy:

• Consider NACT
• Inform about the lack of available data
• Inform of possible negative impact on prognosis.

Prognostic factors

Pregnancy does not affect outcomes in cervical cancer; these are comparable to those in non-pregnant women.²⁶ Prognostic factors that do influence survival are listed below:

• Staging (size, volume and depth of invasion, nodal status)
• Grade of tumor
• Histological subtype (small cell confers worse prognosis):
  • Squamous cell carcinomas are most common
  • Adenocarcinomas are increasing and account for around 20% of cervical tumors.¹² These usually present in younger women and have a worse prognosis, related to delay in diagnosis as cytology screening programs are designed to detect squamous cell abnormalities. Glandular abnormalities reduce their accuracy. HPV 18 is more specifically related to adenocarcinomas. Of adenocarcinomas 40% are mixed adeno-squamous carcinomas
  • Small cell neuro-endocrine squamous carcinomas are rare but aggressive
• Spread:
  • Direct spread to cervical stroma, parametria, vagina, body of the uterus, bladder and rectum
  • Lymphatic spread into the parametria, pelvic side wall and para-aortic nodes
  • Hematological spread is rare
• Status of resection margins in cases of surgical management.

Planning delivery

Mode and timing of delivery should be determined on a case by case basis, taking into consideration the woman’s wishes, the presence or absence of visible tumor and obstetric factors. In the presence of visible tumor delivery by cesarean section may be advisable to avoid the risk of metastatic implantation into potential episiotomy scar and reduce the risk of hemorrhage.³⁵

In women with a transabdominal cerclage in situ, elective cesarean section should be planned. The timing of delivery should be established on a case by case basis following MDT discussion, taking into account the tumor stage, ongoing management plan and obstetric issues.

Management of pregnant women with previous treatment to the cervix

In settings with a national cervical screening program, caring for women who have undergone ablative or excisional treatments for pre-invasive disease may be commonplace. Women who have CIN have a higher baseline risk of pre-term delivery.³⁶ Excisional and ablative treatments further increase this risk. The frequency and severity of adverse obstetric outcomes increases with increasing cone depth and is higher for excisional procedures compared to ablative.³⁷ These women should ideally be cared for in a specialized preterm birth surveillance clinic. Where resources are available, surveillance should include cervical length measurement via transvaginal ultrasound and may include biochemical markers such as fetal fibronectin (FFN). Risk prediction models such as the freely available QUiPP app can aid in personalized risk stratification and guiding management.^38,39 Women who have previously undergone trachelectomy require pre-pregnancy counseling regarding their higher risk of complications such as preterm prelabor rupture of membranes, chorioamnionitis, mid-trimester loss or preterm birth.

Key points

• Pregnancy does not have a negative impact on outcomes related to cervical cancer. These are similar to those in non-pregnant women.
• Management of pre-invasive disease (CIN 1–3) can be deferred until 6 weeks postpartum. However, colposcopy should be performed in each trimester to assess for any progression or development of invasive disease.
• Colposcopy during pregnancy can be technically more challenging due to physiological changes.
• Management of invasive carcinoma of the cervix during pregnancy should involve a multidisciplinary team, where possible, and care should be individualized, presenting the woman and her family with suitable options. Providing quality care involves joint decision making.
• Clear communication and psychological support should be provided to pregnant women with cervical cancer and their families, or those who have had previous treatment that confers increased risk during pregnancy.

Ovarian and fallopian tube cancers

Introduction

Ovarian cancer is the second most common gynecological malignancy diagnosed during pregnancy. Adnexal masses during pregnancy are common; however, the incidence of ovarian malignancy is very low (2–10 per 100,000 pregnancies).^15,40 The majority of ovarian masses identified during pregnancy are benign, often functional cysts and resolve within the first trimester. Differential diagnoses for benign masses that do not resolve may include dermoid cysts, endometriomas and pedunculated fibroids.⁴¹ Diagnosis during pregnancy may be more challenging because of decidualization of the ovary mimicking malignant morphology.⁴²

The epidemiology of ovarian cancer in non-pregnant and pregnant women varies considerably. Approximately 80% of deaths due to ovarian cancers outside pregnancy are related to invasive epithelial tumors, particularly high-grade serous cell carcinomas, and often present late. High-grade serous carcinomas of the ovary are now thought to arise predominantly from secretory cells of the fallopian tube where there is no barrier to peritoneal spread.⁴³ Ovarian cancer outside pregnancy often presents late with an insidious onset of vague symptoms. Women with early stage ovarian cancer are often asymptomatic. In pregnancy, ovarian masses may be diagnosed incidentally during routine ultrasound examinations. Non-epithelial ovarian cancers may present with larger masses and occasionally pregnant women present with pain due to ovarian torsion, rupture or intraperitoneal hemorrhage.⁵ When a woman presents with a symptomatic adnexal mass during early pregnancy, an ectopic pregnancy should always be considered and ruled out urgently. During pregnancy germ cell tumors, sex cord stromal tumors and borderline tumors are more commonly seen. Epithelial ovarian cancers are the least common during pregnancy and overall have a worse prognosis than non-epithelial cancers.⁵ Of ovarian cancers 5–10% are hereditary. These cases tend to present in younger women and have a more favorable clinical course..^44,45There is very limited literature regarding fallopian tube cancer during pregnancy and these should be managed as epithelial ovarian malignancy.¹⁵ 

Histological subtypes

• Germ cell tumors (dysgerminomas, teratomas, yolk sac/endodermal tumors) are the most common ovarian carcinomas diagnosed in pregnancy;⁴⁶
• Sex cord stromal tumors (thecomas, granulosa cell tumors and arrhenoblastomas);
• Borderline ovarian tumors (mucinous, serous or mixed with endometroid);
• Invasive epithelial ovarian tumors (serous, mucinous, endometroid, clear cell).

Borderline ovarian tumors

• Borderline ovarian tumors are more common in younger women;
• Borderline tumors have a low malignant potential;
• Some studies suggest borderline ovarian tumors during pregnancy exhibit more aggressive features^47,48 but these regress following delivery and outcomes remain excellent;
• Borderline ovarian tumors are characterized by higher proliferative activity than benign tumors and nuclear atypia in the absence of stromal invasion;
• They have an excellent prognosis with a 5-year survival for stage 1 disease of around 95%.

Clinical management

Presentation

Abdominal or pelvic pain are the common presenting symptoms, although one-third of ovarian carcinomas are diagnosed incidentally.² Incidental identification of ovarian or tubal masses may be via routine ultrasonography during pregnancy or at cesarean delivery.

Diagnosis

Clinical management and diagnosis of ovarian or fallopian tube cancers during pregnancy, as with all malignancies, should be coordinated by a multidisciplinary team of specialists.

• Transvaginal +/− abdominal ultrasound is safe during pregnancy, widely accessible and highly sensitive and specific for ovarian malignancy.
• MRI may be considered as an adjunctive imaging modality to further delineate complex masses and is safe in pregnancy. The use of gadolinium should be avoided.
• Tumor markers should be used with caution in pregnancy. CA125 is raised during the first trimester and postnatal period. It may be useful during the second and third trimesters. CA125 is a marker for epithelial ovarian cancers. Alpha-fetoprotein is also raised in pregnancy; however, levels may be significantly higher in women with germ cell tumors than in normal pregnancy. Inhibin B, anti-Mullerian hormone (AMH) and lactate dehydrogenase (LDH) are all markers of granulosa cell tumors and are not elevated in normal pregnancy so can be used for diagnosis.⁴⁹

Diagnostic models using ultrasonic features can be used predict malignancy in adnexal masses. International Ovarian Tumor Analysis studies (IOTA) developed rules and models to distinguish between benign, borderline, malignant and metastatic ovarian tumors.^50,51,52 The IOTA simple rules classify lesions as benign, inconclusive or malignant based on 10 binary features. The ultrasonic features predictive of malignancy include presence of an irregular solid tumor, presence of ascites, at least four papillary structures, increased blood flow and the presence of irregular, multilocular tumors greater than 10 cm. The assessment of different neoplasias in the adnexa (ADNEX) model calculates the probability of five outcome categories; benign, borderline, stage I primary invasive ovarian malignancy, stage II–IV primary invasive ovarian malignancy and metastasis in the adnexa from another primary tumor.⁵³ The features included in this model are maximum diameter of the largest solid component, number of papillary projections, presence of acoustic shadows, presence of ascites and presence of more that 10 cyst locules. However, these models have not been specifically validated in a pregnant population and are not recommended for use.⁴¹ Risk of malignancy index (RMI) is not useful during pregnancy.

Staging

The 2014 FIGO ovarian, fallopian tube, and peritoneal cancer staging system and corresponding TNM is shown in Box 2.

Management

Care for suspected ovarian malignancy during pregnancy should be individualized. The management of borderline tumors is similar to outside pregnancy and these can generally be managed surgically postpartum. Early-stage disease may be managed surgically in the second and third trimesters with surgical staging including salpingo-oophorectomy, infra-colic omentectomy, pelvic-peritoneal biopsies and lymph node dissection. Care should be taken to avoid ovarian rupture and spillage. If the pelvic peritoneum and pouch of Douglas cannot be adequately examined due to the gravid uterus, postpartum restaging should be considered. For stage III and IV disease detected in the first trimester and early second trimester, complete debulking surgery adjuvant chemotherapy should be offered. For advanced disease detected in the late second and third trimesters NACT should be offered and discontinued 3 weeks before delivery. Cesarean delivery followed by cytoreductive surgery may be offered. For early stage ovarian cancer managed surgically, Cesarean delivery should be for obstetric reasons only.²

Key points

• Pregnancy does not have a negative impact on outcomes related to ovarian cancer. These are similar to those in non-pregnant women.
• The management of ovarian cancer in pregnancy should be individualized and take into account the stage, histological subtype, the woman’s wishes regarding continuation versus termination of pregnancy and future fertility wishes.
• The histological subtypes of ovarian cancers most commonly presenting in pregnancy differ to those in non-pregnant women. Germ cell tumors, sex cord stromal tumors and borderline ovarian tumors are more common during pregnancy.
• Most ovarian cancers diagnosed during pregnancy are early stage and are associated with good maternal and fetal outcomes.

Endometrial cancer

Endometrial carcinoma is extremely rare during pregnancy. Most cases are detected following endometrial curettage after miscarriage or termination of pregnancy. Endometrial cancer commonly affects postmenopausal women; however, up to 25% of cases present in premenopausal women and around 5% of cases in women under the age of 40. The incidence and prevalence of endometrial cancer is increasing globally with the highest burden of disease in high-income countries.^54,55

Unopposed estrogen stimulates endometrial proliferation and can lead to endometrial hyperplasia. This is defined as an increase in the ratio of endometrial glands to stroma when compared to the proliferative endometrium. WHO categorizes endometrial hyperplasia into two groups based on the presence or absence of cytological atypia.

Endometrial cancer has been classified as follows:⁵⁶

• Type 1
  • More common, accounts for approximately 80%
  • Usually diagnosed at early stage
  • Associated with estrogenic stimulation of the endometrium
  • Often associated with endometrial hyperplasia
  • Histologically usually grade 1 or 2 endometroid adenocarcinoma.
• Type 2
  • Includes serous, clear cell, carcinosarcoma, small cell and other rare types
  • More aggressive and associated with higher risk of metastatic disease
  • Not associated with oestrogenic stimulation of the endometrium
  • Associated with mutations in P53 tumor suppression gene.

Risks factors for endometrial hyperplasia and endometroid carcinoma include obesity, polycystic ovarian syndrome (PCOS), estrogen secreting ovarian tumors, and drug-induced endometrial stimulation such as long-term use of tamoxifen. Increased body mass index is a particularly important risk factor in younger women with endometrial cancer. Excessive peripheral conversion of androgens to estrogen occurs in the adipose tissue. Women with hereditary non-polyposis colon cancer (HNPCC) are also at increased risk of endometrial carcinoma.

Women of reproductive age are more likely to be diagnosed with endometrial hyperplasia than malignancy and this has a bearing on fertility if the patient’s family is not complete. Women with endometrial hyperplasia without atypia (previously known as simple hyperplasia) have less than 5% risk of progressing to endometrial carcinoma over 20 years. Women with endometrial hyperplasia with atypia (complex hyperplasia) have an 8% risk of developing cancer within 4 years, this rises to 27.5% after 19 years.⁵⁷ The RCOG recommends total hysterectomy as management of atypical hyperplasia, and consideration of bilateral salpingo-oophorectomy in premenopausal women to reduce the risk of future ovarian malignancy. Management should be individualized in premenopausal and the risks of future malignancy balance against the risks of surgical menopause.⁵⁸ Although total hysterectomy and bilateral salpingo-oophorectomy is standard treatment for pre-menopausal women presenting with endometrial cancer, early stage disease has been managed with progestogen and successful pregnancy outcomes have been reported.^59,60

Endometrial cancer during pregnancy is extremely rare and care should be individualized. In the unlikely scenario that a patient falls pregnant prior to management for endometrial cancer is initiated, management should be coordinated in a specialist center with a relevant multidisciplinary team. Regular fetal growth scans should be considered in light of a theoretical risk of placental dysfunction and MRI to assess tumor progression.⁶¹ Women should be counseled appropriately about modifiable risk factors such as obesity.

Vulval and vaginal cancer

Vulvovaginal cancer during pregnancy is very rare and the literature limited. The incidence is reported as 0.1 per 0.5 cases per 100,000 pregnancies.²⁶ These malignancies predominantly affect older, postmenopausal women.

Vulval cancer

• Women may present with a mass on the vulva, pruritis or ulceration;
• The course of vulval carcinoma is not affected by pregnancy;
• Most women present with early stage squamous cell carcinomas;⁶²
• Diagnosis should be confirmed with histopathology following an incisional biopsy of the lesion;
• Surgical management is radical local excision with vulvectomy +/- inguinal lymphadenectomy dependant on staging;
• Treatment of cases can be carried out throughout pregnancy, although patients diagnosed in the late third trimester may be delayed until the postpartum period;²⁶
• Meticulous hemostasis during surgical management is required due to the risk of hemorrhage associated with increased vulval blood flow during pregnancy;
• Vulval radiotherapy is contraindicated during pregnancy;
• There may be a higher risk of fetal growth restriction if previously treated with local radiotherapy, due to impaired uterine vascular supply and radiation fibrosis affecting the myometrium;⁶³
• Mode of delivery should be considered on a case by case basis and management individualized. Previous peri-urethral or peri-vaginal tissue resection are relative contraindications. Cesarean delivery may be considered to reduce the risk of wound dehiscence, if surgical management has been undertaken during pregnancy.

Vaginal cancer

• Diagnosis should be confirmed on histopathology following a biopsy from the lesion;
• MRI should be undertaken for staging;
• Individualized management with involvement of a multidisciplinary team is crucial following referral to a specialist gyne-oncology center;
• Decisions regarding continuation of pregnancy versus termination should be taken following full staging and with MDT input and psychosocial support;
• For stage I disease involving tumors in the upper third of the vagina management offered is usually radical hysterectomy, upper vaginectomy and bilateral pelvic lymphadenectomy;
• For women with more than stage I disease and tumors arising from the lower two-thirds of the vagina treatment is with radiotherapy.

BREAST CANCER IN PREGNANCY

Introduction

Breast cancer is the most common malignancy affecting women including pregnant women. Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or the postpartum period. Definitions of the postpartum period vary. A recent meta-analysis suggested this should extend up to 6 years.⁶⁴ PABC is associated with poorer prognoses related to higher grade tumors, a higher risk of metastases and estrogen receptor negative tumors that may be more common in younger women.^65,66

Diagnosis

Detection of breast cancer during pregnancy may be more challenging. Delays in diagnosis, evaluation and treatment have been associated with pregnancy.⁶⁷ Clinicians should remain vigilant and when breast cancer is suspected urgent referral to a specialist breast team for imaging and further tests should be arranged. Ultrasonography with or without mammography with fetal shielding should be performed to assess the extent of disease, lymph nodes and the contralateral breast. Ultrasound-guided core needle biopsies for a histopathological tissue diagnosis are preferable to cytology, as proliferative changes during pregnancy often lead to inconclusive results. Tumor grade and receptor status will guide management. Chest x-ray and liver ultrasound are safe in pregnancy and may be used for staging. MRI may be another useful imaging modality. The risks and benefits of ionizing imaging such as CT and PET should be assessed on an individual case basis and discussed within the multidisciplinary team, but are generally avoided during pregnancy. CA15–3 used as a tumor marker in breast cancer outside pregnancy, is physiologically elevated during pregnancy.⁴⁹

Treatment

Management options should be fully discussed with the woman and her family following MDT discussion. These will depend on stage, grade and receptor status. Loco-regional clearance can be performed in all trimesters. Modified radical mastectomy with axillary staging is the surgical management of choice if treatment is necessary in the first trimester. Either breast preserving surgery or mastectomy with axillary node dissection can be performed in the second and third trimesters.² Breast reconstructive surgery should be postponed avoiding prolonged anesthesia and allow optimization of symmetrization of breasts after delivery.⁶⁸ Adjuvant chemotherapy can be started in the second trimester and should be stopped by around 34 weeks. Anthracycline-based regimens are most studied during pregnancy and no increased risk of fetal cardiotoxicity has been described.⁶⁹ However, many chemotherapeutic drugs can be used safely after the first trimester.² Tamoxifen is a selective estrogen receptor modulator, that acts as an antagonist in breast tissue. There are very limited data on the use of tamoxifen in human pregnancy. Animal studies suggest an association with fetal malformations. Guidelines recommend tamoxifen is contraindicated during pregnancy.^2,68,69 However, no causal relationship has been established and patients should be counseled regarding risks versus benefits.⁷⁰ Trastuzumab is a recombinant monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). There are very limited data on the use of trastuzumab in human pregnancy. Oligohydramnios, anhydramnios and fetal lung hypoplasia have been reported.⁷¹ Trastuzumab is generally avoided during pregnancy, but if deemed necessary, enhanced monitoring of amniotic fluid is required. Trastuzumab also poses a risk of maternal cardiotoxicity and maternal cardiac function should be closely monitored.⁷²

Timing of delivery

Continuation of pregnancy versus termination should be sensitively discussed with the woman and her family, including information on prognosis, treatment and future fertility. Timing of delivery, if pregnancy is continuing, should be an individualized decision. Chemotherapy should be discontinued 3 weeks prior to elective delivery to allow the maternal bone marrow to recover and reduce risk of complications associated with neutropenia.

Breastfeeding

• There are limited data on the safety of trastuzumab and tamoxifen and breastfeeding. The current advice is to avoid use during breastfeeding;⁶⁸
• Breastfeeding during ongoing chemotherapy is contraindicated;
• There is no evidence that previous chemotherapy affects the safety of breastfeeding;
• Previous radiotherapy may cause fibrosis and reduces the risk of lactation from the affected breast;
• There is no evidence to suggest that breastfeeding increases the risk of recurrence in women who have completed treatment for breast cancer. Women should be reassured and offered support to breastfeed from the unaffected breast if they wish;
• Women who wish to breastfeed should be offered support by a lactation specialist.

Ongoing care

• Non-hormonal contraceptives should be offered to women with breast cancer;
• Advice on the postponement of pregnancy should be individualized. Generally, a period of at least 2 years following completion of treatment is advised, when the risk of recurrence is highest.

MANAGEMENT IN LOW-RESOURCE SETTINGS

• Management of malignancy in pregnancy in low resources may be extremely challenging due to a lack of diagnostic services, relevant expertise and resources for appropriate surgical management.
• Surgico-pathological staging of disease may be challenge due to potential lack of access the minimally invasive surgery including equipment or training.
• Management may need to focus on resuscitation, management of anemia and provision of adequate analgesia. Symptom management and keeping women comfortable should be a priority where cases are considered palliative.
• Open and honest discussions with the woman and her family regarding likely diagnosis, prognosis and available treatments are key. Consideration of referral to higher levels of care may be appropriate after full discussion and ensuring joint decision-making is enacted.
• Consider should be given to the management of any comorbidities such as HIV in cervical cancer cases in low-resource setting.

WOMAN-CENTERED CARE, BREAKING BAD NEWS AND SHARED DECISION-MAKING

The pregnant woman should always be at the center of care provided. Her individual needs and situation should be carefully considered throughout her care pathway both for pregnancy and cancer management. Pregnancy and cancer diagnoses are life changing events regardless of outcome.

The risks of stress, anxiety and depression should be considered, appropriate support and guidance should be offered. Inclusion of psychosocial support in the multidisciplinary care team will aid in ensuring continuous assessment and follow up is provided. Risks to the baby both in utero and longer-term outcomes may also contribute to the woman’s and her family’s concerns. Clear and comprehensive provision of information regarding the diagnosis, implications for both mother and the pregnancy and likely short- and longer-term outcomes can be useful in reducing stress for women. Other important considerations are the implications on both mother and child interactions and father–child relationships.

Implications for the woman on fertility, risk of early menopause, sexual dysfunction including dyspareunia, vaginal stenosis or loss of sexual desire may contribute to anxiety and depression. Both the physical and psychosocial impacts on the woman should be considered and ameliorated where possible.

Clear communication regarding individual risks and current evidence may help alleviate anxiety. Peer support may also be a useful to women and families affected by cancer during pregnancy.

Breaking bad news

Well-developed communication skills are essential to providing quality care to women during pregnancy. Various guidelines are available to aid clinicians in delivering bad news with empathy and professionalism. Ensuring privacy, adequate time and being open and honest are some basic principles that should be observed. Arranging for a family member or other support person to be present is good practice.

The SPIKES (Setting up, Perception, Invitation, Knowledge, Emotions with Empathy and Strategy or Summary) protocol involves six practical steps to assist clinicians and has been used to train oncologists:^73,74

• Establish an appropriate setting;
• Assess the patient’s perception of the situation: “What is your understanding of the reasons we did the MRI?”
• Obtain the patient’s invitation. Determine the amount of information they know and how much information is desired: “How would you like me to give you the information about the test results? Would you like me to give you all the information or sketch out the results and spend more time discussing the treatment options?”
• Know the medical facts and their implications before initiating the conversation. Giving information to the patient, particularly bad news, can be difficult. Warning the patient bad news is coming may lessen the shock: “Unfortunately, I have some bad news to tell you.” Avoidance of technical language and giving information is small chunks and checking understanding is often useful.
• Address the patient’s emotions with empathic responses. Emotional reactions may vary from silence to crying to denial or anger.
  • Observe their response;
  • Identify the emotion experienced by the patient by naming to oneself. If they appear sad but are silent, use open questions to see how they are feeling;
  • Identify the reason for the emotion. Usually this is connected to the bad news. However, if you are unsure, ask the patient;
  • Give the patient time to express their feelings.
• Establish a strategy for support.

Shared decision-making involves pregnant women (and their families) and healthcare professionals communicating and working together to achieve person-center care. Shared decision-making should be integral to providing care for malignancy during pregnancy. It should be facilitated by a trusting relationship between the woman and care provider and equality in discourse supporting self-determination.⁷⁵ Emphasizing the importance of the woman’s views, explaining evidence-based treatment options and providing recommendations can be part of the shared decision-making process.

PRACTICE RECOMMENDATIONS

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