Paraganglioma in pregnancy: A case series and literature review

Abstract

Paragangliomas are rare neuroendocrine neoplasms which are often catecholamine-secreting and associated with familial syndromes. Described here are three women with a variety of pathology: isolated secretory paraganglioma diagnosed in pregnancy, secretory metastatic paraganglioma in pregnancy and non-secretory metastatic paraganglioma in pregnancy. Whilst paragangliomas are associated with morbidity and mortality during pregnancy, good maternal and fetal outcomes can be achieved through individualised care within the context of a multidisciplinary team. Although paragangliomas are associated with morbidity and mortality in pregnancy, good maternal and fetal outcomes can be achieved through individualised care within the context of a multidisciplinary team.

Introduction

Paragangliomas are neuroendocrine neoplasms arising from chromaffin cells throughout the sympathetic and parasympathetic nervous systems. ¹ Like phaeochromocytomas, their intra-adrenal counterparts, paragangliomas can secrete catecholamines: adrenaline, noradrenaline and dopamine.^1,2 Although the majority of paragangliomas occur sporadically, up to one-third are associated with familial syndromes,^1,3,4 and up to 33% of paragangliomas are malignant. ¹ , ⁵

Pregnancies complicated by paraganglioma are very rare, with a reported incidence of catecholamine-secreting tumours during pregnancy of 0.002–0.07%.^6–11 Though there is limited reported evidence, the maternal and fetal mortality rates for paraganglioma are estimated to be up to 3.6 and 12% which is slightly lower than that for pheochromocytoma at 9.8 and 17%, respectively.^6,12 With appropriate recognition and management, fetal mortality decreases, and maternal mortality almost approximates that of the background population.^6,12

The diagnosis of paraganglioma in pregnancy remains a clinical challenge. Functional paragangliomas commonly present with the features of catecholamine excess, including paroxysmal hypertension, headache, tachycardia, diaphoresis and flushing.^1,13,14 The hypertension associated with catecholamine excess can be severe and labile, ¹⁵ with possible precipitants of hypertensive crises including parturition and surgery. ¹⁶ In pregnancy, some of these clinical features may be attributed to physiological changes of pregnancy, pre-eclampsia or other pregnancy-related causes of hypertension.^17–19 Therefore, clinicians must maintain a high level of clinical suspicion in the case of pregnant women with severe hypertension or other features of catecholamine excess. ¹² Women with both pre-existing and newly diagnosed secretory paragangliomas require timely multi-disciplinary care through all phases of care from pre-pregnancy to the post-partum period.^6,19,20

Head and neck paragangliomas often present with palpable masses or with symptoms related to mass effect. ²¹ Non hormonally functional paragangliomas most commonly arise from the parasympathetic chain in the head and neck. ¹ Though non-functional paragangliomas have similar familial and malignant risks to their functional counterparts, there is much less morbidity and mortality related to catecholamine excess. ¹⁴ Despite this, there have been reports of perioperative haemodynamic instability, and women with non-functional paragangliomas are still likely to benefit from multidisciplinary care akin to their functional counterparts.^1,21

We present our experience of three women with paraganglioma during pregnancy (Table 1). In addition, we discuss the current evidence and recommendations for management of this potentially life-threatening condition.

Table 1.

Case demographics.

Case	Secretory	Metastatic	Medical treatment	Gestation at delivery (weeks)	Birth weight and %	Mode of delivery	Fetal outcome	Genetic mutation
1	Yes	No	PhenoxybenzaminePropranolol	31 + 3	1900g 25%	El CS	Healthy	NT
2	Yes	Yes	Perioperative MgSO4	38 + 3	3880g 99%	El CS	Healthy	NA
3	No	Yes	Nil	39	3444g 75%	NVD	Healthy	SDHB

NT: not tested; El CS: elective caesarean section; MgSO₄: magnesium sulfate; SDHB: succinate dehydrogenase complex subunits B; NA: not available; NVD: normal vaginal delivery.

Isolated secretory infra-renal paraganglioma diagnosed in pregnancy

A 15-year-old woman in her first pregnancy was admitted at 23 weeks’ gestation with a blood pressure of 185/85 mmHg without proteinuria (urine protein:creatinine 0.01 g/mmol) or other clinical features of pre-eclampsia. She was initially commenced on methyldopa 250 mg twice daily, and a screen for secondary causes of hypertension was performed. Non-fasting, seated plasma metanephrines were elevated, with a normetanephrine of 7196 pmol/L (normal <900 pmol/L), metanephrine of 84 pmol/L (normal <500 pmol/L) and 3-methoxytyramine <90 pmol/L (normal < 100). Abdominal magnetic resonance imaging (MRI) demonstrated a 4.6 × 3.8 × 5.7 cm left infrarenal mass posterior to the gravid uterus with T2 enhancement. Chromogranin A levels were 752 μg/L (27–94 μg/L) in the absence of a proton pump inhibitor. Antihypertensives were rationalised to prazosin 1 mg three times a day and subsequently changed to phenoxybenzamine, which was increased to 20mg/10 mg/20 mg. Propranolol was added later for reflex tachycardia. At 28 weeks’ gestation, she was diagnosed with gestational diabetes (75 g OGTT with fasting plasma glucose 6.6 mmol/L and 2-h post-prandial glucose 8.1 mmol/L). Her body mass index (BMI) was 33 kg/m²_, and she required a maximum total daily dose of insulin of 184 units subcutaneously.

Surgical resection was considered; however, the location of the paraganglioma behind the gravid uterus made post-partum resection more favourable. Inpatient care was required from 23 weeks’ gestation due to markedly labile blood pressure, though escalation of alpha blockade was limited by postural hypotension. She also developed paroxysms of chest discomfort, headache and dizziness. The severity of her symptoms and lability of her blood pressure led to a decision for early delivery. An elective caesarean section was performed at 31 weeks and 3 days of gestation under combined spinal-epidural anaesthesia with ropivacaine and fentanyl. A magnesium sulphate 5 g bolus at induction followed by a 24-h 2 g/h infusion was used for additional perioperative blood pressure control. A vertical midline skin incision was made for ease of access should the paraganglioma require urgent simultaneous removal. Intrapartum blood pressure ranged from 95/60 mmHg to 150/70 mmHg without rapid variation, and heart rate ranged from 80 to 100 bpm. Oxytocin was used post-delivery. A female infant was delivered, weighing 1900 g with Apgar scores of 7 at 1 min and 8 at 5 min.

The woman was discharged on phenoxybenzamine (20 mg/10 mg/20 mg) and propranolol 10 mg both three times daily. An Implanon® (68 mg etongestrel) implant was inserted before discharge as her preferred contraception. A post-partum Ga-68 DOTA-octreotate positron emission tomography (PET) scan showed no evidence of metastases, and she subsequently underwent an uncomplicated surgical resection of the paraganglioma. Histopathology demonstrated a 52 mm paraganglioma with no mitoses, no lymphovascular or perineural invasion and an intact tumour capsule. Immunohistochemistry was positive for chromogranin and synaptophysin, s100 sustentacular cell topoisomerase proliferation index <1%. Succinate dehydrogenase complex B (SDHB) and succinate dehydrogenase complex A (SDHA) staining were both positive.

The woman returned for antenatal care three years later with no new medical issues but complex social and mental health issues. Though her BMI remained elevated at 41.8 kg/m², the results of her early and routine 75 g oral glucose tolerance tests were normal. She remained normotensive for the duration of her pregnancy and postpartum, An elective repeat caesarean section at 39 weeks’ gestation was performed, and a healthy male infant was delivered, weighing 3720g with Apgar scores of 9 and 9 at 1 and 5 min respectively. with Apgar scores of 9 and 9 was delivered. Blood remains stored for genetic investigations; however, she has not attended further follow-up appointments.

Secretory metastatic paraganglioma in pregnancy

A 32-year-old woman in her third pregnancy with metastatic right jugulotympanic noradrenaline- and dopamine-secreting paraganglioma was referred for antenatal care. She had been diagnosed eight years prior with a locally invasive right jugulotympanic paraganglioma with 2/4 lymph nodes involved, which was treated with surgery and adjuvant external beam radiotherapy. Initial Ga-68 DOTA-octreotate PET with computed tomography (CT) demonstrated local uptake only. A repeat Ga-68 DOTA-octreotate PET/CT five years later demonstrated metastatic bone disease. Immunohistochemistry of the original paraganglioma was SDHB negative, SDHA positive, Ki 67: 1–5%. Her previous obstetric history included two post-term inductions resulting in normal vaginal deliveries. The second neonate was born one year after the initial diagnosis. She had rising catecholamines (normetanephrine 5839 pmol/L (<900), metanephrine 121 pmol/L (<500), 3-methoxytyramine 1331 pmol/L (<110), chromogranin A 133 μg/L (27–94)) and evidence of disease progression on imaging, so systemic peptide receptor radionuclide therapy (PRRT) was planned. During the preparation for PRRT, she unexpectedly conceived and chose to continue the pregnancy; thus, the therapy was delayed.

Throughout her pregnancy, she remained asymptomatic. Her blood pressures were consistently below 110/60 mmHg, and she became markedly hypotensive with trials of alpha-blockade. Her plasma normetanephrines and 3-methoxytyramine levels continued to increase and reached seven to nine times the upper limit of normal as seen in Table 2. She was electively admitted at 37 weeks’ gestation for medical optimisation prior to delivery; again, alpha blockade was not tolerated. Numerous trials of low dose phenoxybenzamine or prazosin caused acute symptomatic hypotension despite liberal salt ingestion and intravenous normal saline.

Table 2.

Summary of case series.

Case	Pregnancy	Lesion	CA excess	NMN (pmol/L)	MN (pmol/L)	3MT (pmol/L)	CgA	Alpha-blocker	Delivery	Fetal outcome
1	20152018	PGLNil	YesNo	7196NA	84NA	<90NA	ug/L	PhenoxyNil	El CS El CS	HealthyHealthy
2	200220092015	NAPGLPGL	NANAYes	NANA9466	NANA97	NANA1828	NANA133	NilNilNil	NVDNVDEl CS	HealthyHealthyHealthy
3	20112015	PGLPGL	NoNo	NA308	NA127	NA<90	NANT	NilNil	NVDNVD	HealthyHealthy

CA: catecholamine excess; PGL: paraganglioma; NT: not tested; NA: not available; NVD: normal vaginal delivery; El CS: elective caesarean section; CgA: chromogranin A; NMA: normetanephrine; MA: metanephrine; 3MT: 3-methoxytyramine.

Caesarean section was selected as the mode of delivery. Intravenous magnesium sulphate infused at 1 g/h, preceded by a 1 g loading dose and labetalol 1–2mg/h infusion were commenced 24 h prior to delivery. She underwent a caesarean section with combined spinal-epidural anaesthesia with bupivacaine and fentanyl. She had labile blood pressure during the caesarean section with a peak of 200/110 mmHg managed with phentolamine, ephedrine and metaraminol. She delivered a healthy female 3880 g infant with Apgar scores of 9 at both 1 and 5 min.

The woman tolerated a re-challenge with phenoxybenzamine 10 mg twice daily with addition of propranolol 10 mg twice daily post-partum. She successfully established breastfeeding, and an Implanon® was inserted prior to discharge for contraception. She has subsequently completed three cycles of PRRT as well as further genetic counselling.

Non-secretory metastatic paraganglioma in pregnancy

A 33-year-old multigravid woman with known SDHB-related metastatic paraganglioma was referred for antenatal care. Six years prior, she underwent extensive resection of a locally invasive carotid body tumour, complicated by a recurrent laryngeal nerve palsy. Metastatic disease was confirmed on imaging, including occipital skull metastases, pulmonary and osseous metastases. Plasma-free metanephrines and 24-h urinary fractionated metanephrines were repeatedly normal, suggesting non-secretory metastatic paraganglioma. Her unplanned but desired pregnancy occurred during planning for PRRT and further local therapy for her skull lesion.

The woman’s antenatal care involved a multi-disciplinary team approach across two tertiary health services. Serial MRI scans demonstrated minimal growth of the 2.7 cm occipital skull lesion, and she did not have any symptoms related to mass effect. Stereotactic radiosurgery was delayed until post-partum. Her blood pressures throughout pregnancy remained stable. Induction of labour with vaginal delivery, an early epidural and shortened second stage were planned.

The woman underwent induction of labour at 39 weeks’ gestation and delivered a female neonate at 3444 g complicated by a 700 mL post-partum haemorrhage. She remained normotensive throughout delivery and post-partum. She continued follow-up with her local specialist teams.

Discussion

Given the rarity of paraganglioma in pregnancy, there is limited evidence to guide optimal antenatal treatment, timing of definitive surgery and mode of delivery. Therefore, recommendations regarding management are primarily derived from expert opinion, case studies and small case series. We discuss the current available evidence for management of women with paraganglioma in pregnancy.

Diagnosis

Screening for catecholamine excess should be considered in pregnant women with hypertension, which may be paroxysmal or sustained. A paraganglioma may manifest during pregnancy due to mass effect, uterine contractions, physical or emotional stress and medications including metoclopramide, morphine and high dose corticosteroids.^1,17 Increased oestrogen levels may also have a role in potentiating tumour enlargement. ²²

The recommended screening test during pregnancy is plasma-free metanephrines which has high diagnostic sensitivity.^1,23 This blood sample should be drawn after the woman has been resting in the supine position for at least 20 min.^1,23 Clinically significant elevations of more than two-three times the upper limit of normal require consideration of localisation with imaging. The pattern of biochemical results can be a diagnostic clue, with paragangliomas almost invariably resulting in an isolated elevation of normetanephrine, whilst elevation of both normetanephrine and metanephrine is more consistent with an adrenal aetiology.^1,2 Ultrasonography may be performed initially, though its sensitivity for small tumours is limited. ²³ Therefore, MRI is the imaging test of choice in pregnant women. CT is usually avoided due to concerns for the risks associated with fetal exposure to ionising radiation. ⁶ Following a confirmed diagnosis of paraganglioma, women should be offered genetic counselling, and investigations as up to one-third of paragangliomas are related to inherited syndromes, susceptible genes include succinate dehydrogenase subunits, neurofibromatosis 1, RET and MAX (Table 3).^1,24

Table 3.

Succinate dehydrogenase mutations associated with paraganglioma.

Mutation	Risk
Succinate dehydrogenase A (SDHA)	Up to 5% lifetime risk of paraganglioma or phaeochromocytoma
Succinate dehydrogenase B (SDHB)	Up to 30% lifetime risk of paraganglioma or phaeochromocytoma
Succinate dehydrogenase C (SDHC)	Up to 20% lifetime risk of paraganglioma or phaeochromocytoma
Succinate dehydrogenase D (SDHD)	Up to 60% lifetime risk of paraganglioma or phaeochromocytoma
Succinate dehydrogenase AF2 (SDHFA2)	Inheritance from father associated with unknown risk

Adapted from eviQ from the Cancer Institute New South Wales.

False-positive elevations in catecholamines and metanephrines have been observed in the setting of severe pre-eclampsia, acute illness, stimulant use, alcohol withdrawal and medications such as paracetamol, methyldopa and tricyclic anti-depressants.^1,25 This rise is typically less than three times the upper limit of normal. ¹ If distinguishing between a paraganglioma and alternate diagnoses is not possible due to inconclusive biochemistry and imaging, empiric treatment with alpha blockade for the duration of the pregnancy should be considered then allowing further investigations including localisation with functional imaging post-partum.

Medical management

The cornerstone of medical management for catecholamine excess in pregnancy is alpha-adrenergic blockade, which aims to prevent vasospasm and hypertension during times of catecholamine surge which can cause placental abruption and intrauterine hypoxia. ²³ There is no clear consensus regarding the optimal blood pressure target in the pregnant woman with a paraganglioma to prevent hypertension and vasospasm. Equally, overtreatment may result in maternal hypotension and uteroplacental insufficiency and intrauterine growth restriction; thus, systolic blood pressure targets between 130 and 140 mm Hg have been proposed. ²³ ,^26–28 Blood pressure and fetal wellbeing must be monitored meticulously throughout the pregnancy.

Phenoxybenzamine is often used as a first-line agent for alpha blockade. Phenoxybenzamine is an irreversible alpha-adrenergic antagonist which has a half-life of 24 h and may continue to exert an effect for up to one week after cessation. ²⁴ Whilst generally considered safe for the fetus, ²⁹ phenoxybenzamine has been shown to cross the placenta and may cause transient neonatal hypotension and respiratory depression. ³⁰ Therefore, it is recommended that the newborns of mothers who took phenoxybenzamine during pregnancy be monitored during the first few days of life. ³¹ Prazosin is an alternate selective alpha-adrenergic blocker which may be considered as a second-line agent. ⁶ There are case reports of prazosin use in paraganglioma in pregnancy without adverse effects. However, given its significantly shorter half-life of 2–3 h, it must be administered two to three times per day. ²⁵ A recent publication of over 249 pregnancies with functional paraganglioma and pheochromocytoma found improved maternal and fetal outcomes in women managed with alpha-adrenergic blockade though no preferred agent or dose could be concluded. ¹⁴ Calcium channel blockers may be trialled for women who are intolerant to alpha blockers. However, calcium channel blockers are more commonly used in addition to alpha blockers to optimise blood pressure control.^23,32

Reflex tachycardia following alpha blockade and tachyarrhythmias due to catecholamine excess may be managed with beta blockers. ²⁹ During pregnancy, beta blockers have been associated with lower birth weight, small for gestational age and intrauterine fetal growth restriction, so judicious use is required.^33–35 All beta blockers cross the placenta, and monitoring for neonatal bradycardia, hypotension and hypoglycaemia should be considered. ³⁶ It is essential that beta blockers are not be commenced until adequate alpha blockade has been achieved, as unopposed alpha-adrenergic receptor stimulation may precipitate a hypertensive crisis. ³⁷ Propranolol or metoprolol is considered suitable choices for this purpose. ³³ Labetalol is a used for hypertension in pregnancy which blocks both alpha and beta receptors and was previously suggested as a single therapeutic agent in catecholamine excess. ³⁵ However, labetalol is no longer recommended in this context due to its association with paroxysmal hypertension, thought to be due to its relatively weak alpha receptor antagonism.^1,6,36

Pre-operative medical management with alpha-blockade remains the current international recommendation for catecholamine secreting pheochromocytoma and paraganglioma; however, literature regarding primary surgery in pheochromocytoma without medical management is emerging in the non-pregnant population. ³⁸

Operative management

Current evidence relating to surgical treatment of paragangliomas suggests that resection for lesions identified in the first 24 weeks of pregnancy should be considered if adequate alpha blockade can be achieved.^7,8,39 The second trimester is considered the optimal period during pregnancy to undertake an operative approach, given the risk of miscarriage in the first trimester and the effect of the gravid uterus in the third trimester.^23,40 Careful patient selection for surgical management is required with reported adverse maternal and fetal outcomes in up to 8% of women who underwent surgical management of functional paraganglioma and pheochromocytoma between 10 and 35 weeks of gestation. ¹⁴ Surgery for women diagnosed after 24 weeks’ gestation should be delayed until after delivery if clinically possible. ²³ Delaying surgery until the postpartum period allows for uterine involution, thus optimising surgical access if intra-abdominal. It also allows appropriate imaging to be undertaken to assess for synchronous or metastatic disease.

Timing and mode of delivery

Vaginal delivery was previously deemed too high risk in women with catecholamine-secreting tumours, as labour can stimulate massive catecholamine release and trigger a hypertensive crisis.^41,42 However, there is increasing literature of successful vaginal delivery with adequate alpha blockade.^6,14,43–47 Should vaginal delivery be attempted, a passive second stage is recommended to minimise the risk of tumour stimulation from raised intra-abdominal pressure associated with maternal pushing. ¹⁹ An elective epidural is recommended for those in whom a vaginal delivery is considered a feasible option. ³⁶

Caesarean section remains the preferred mode of delivery for most women. This is primarily due to historical data reflecting lower maternal and fetal mortality rates when compared to vaginal delivery.^39,41,42 Ideal pre-surgical planning includes at least 7–14 days of alpha-blockade and consideration of an intra-operative magnesium sulphate infusion. Magnesium reduces catecholamine release from the adrenal medulla and peripheral adrenergic nerve terminals. ⁴⁸ It is also an alpha-adrenergic antagonist and antiarrhythmic and is routinely used in the management of hypertension and cardiac arrhythmias during surgery.^45,49 Caesarean section was performed with combined spinal-epidurals in this case series. This enabled the women to be awake for the procedure, minimised the risk of hypoxia and aspiration associated with general anaesthesia and assisted with analgesia postoperatively. Regional or spinal anaesthetics also reduce stimulation of the adrenal gland and sympathetic chain if the block is high enough, typically necessitating blockade of T5–T12. ^6,45

The importance of pre-operative medical optimisation is demonstrated in this case series. In case 1, the woman with isolated secretory paraganglioma had markedly labile hypertension and significant symptomatology prior to delivery. However, effective alpha and beta blockade enabled a relatively uneventful course through anaesthesia and surgical delivery. This was in marked contrast to the woman with secretory metastatic paraganglioma, who was unable to tolerate even low dose alpha blockade pre-delivery, and who required intensive medical intervention immediately prior to, and during, anaesthesia and delivery to manage extreme blood pressure lability.

As described in case 3, a known paraganglioma which is clinically and biochemically silent also requires specialised monitoring and management. The literature demonstrates that women with this presentation may develop a hypertensive crisis during times of physiological stress such as parturition and surgery.^16,45 Delivery should therefore take place in an experienced centre with close monitoring of blood pressure and capacity to escalate intravenous alpha blockade and epidural sympathetic blockade as required. ⁴⁵

Conclusion

We present a case series of three women with paraganglioma in pregnancy which were managed within our tertiary maternity centre. These cases differed in regard to tumour burden, biochemical pattern, clinical challenges, and management but without significant maternal or fetal morbidity. Although morbidity and mortality rates are higher than the general pregnant population, we achieved good maternal and fetal outcomes in pregnancy through individualised care within the context of a multidisciplinary team which is consistent with emerging literature of improving maternal and fetal outcomes in women with paraganglioma in pregnancy. ¹⁴