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Best Practice & Research Clinical Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem
BEST
Clinical Endocrinology & Metabolism
Endocrine oncology in pregnancy
A. Lansdown, MB BCh, MRCP, Clinical Research Fellowª, D.A. Rees, FRCP, PhD, Senior Lecturer *
Centre for Endocrine and Diabetes Sciences, School of Medicine, Cardiff University, Cardiff, UK
Keywords:
pregnancy thyroid cancer adrenocortical carcinoma Cushing’s syndrome phaeochromocytoma paraganglioma neuroendocrine tumour carcinoid octreotide
Endocrine tumours occur rarely in pregnant women but present clinicians with unique challenges. A high index of suspicion is often required to make a diagnosis since the symptoms and signs associated with many of these tumours, including insulinoma, adrenocortical carcinoma and phaeochromocytoma, mimic those of normal pregnancy or its complications, such as pre-eclampsia. The evidence base which informs management is very limited hence decisions on investigation and therapy must be individu- alised and undertaken jointly by the multidisciplinary medical team and the patient. The optimal strategy will depend on the nature and stage of the endocrine tumour, gestational stage, treatments available and patient wishes. Thus, surgical interven- tion, appropriately timed, may be considered in pregnancy for resectable adrenocortical carcinoma or phaeochromocytoma, but delayed until the postpartum period for well-differentiated thyroid cancer. Medical therapy may be required to reduce the drive to tumour growth, control symptoms of hormone excess and to minimise the risks of surgery, anaesthesia or labour.
@ 2011 Elsevier Ltd. All rights reserved.
Introduction
Endocrine cancer diagnosed during pregnancy poses challenges for the clinician and patient, not only with respect to the choice of investigation and therapy but also in relation to timing of inter- ventions according to gestational stage. The risks to maternal and foetal health must be carefully weighed-up in management; almost invariably this leads to a conflict between optimal treatment of
* Corresponding author. Tel .: +44 02920 742341; Fax: +44 02920 744671. E-mail addresses: lansdownaj@doctors.org.uk (A. Lansdown), reesda@cf.ac.uk (D.A. Rees).
ª Tel .: +44 02920 742341; Fax: +44 02920 744671.
the mother and the well-being of the foetus.1 Management decisions should ideally be based upon the best evidence but well-designed randomised-controlled trials have not been undertaken in pregnant women with endocrine cancer hence treatment decisions must be individualised, taking into account patient wishes, tumour characteristics, and gestational stage.
Thyroid cancer
Background
Thyroid cancer is the commonest endocrine malignancy, affecting three times as many women as men. Ten percent of papillary thyroid cancers are diagnosed in pregnancy or the early postpartum period. Smith et al. identified 5000 women with invasive malignancy over a 9-year period of almost 5 million obstetric births in California. Thyroid cancer was detected at a rate of 14 cases per 100,000, with approximately one-quarter of cases identified prenatally, 2% at delivery, and 75% in the postpartum period.2 In contrast, new thyroid nodules are detected during pregnancy in up to 15% of women.3,4 Kung et al. performed a prospective study of 221 healthy pregnant women in Southern China, an area of borderline iodine sufficiency, and reported an appearance of new thyroid nodules in 11.3% of subjects. All 21 women with a thyroid nodule greater than 5 mm underwent fine-needle aspiration biopsy (FNAB) and no cases of thyroid malignancy were detected.4 Whilst these data suggest that the onset of new thyroid malignancy may be relatively uncommon in pregnancy, the prevalence of benign and malignant nodular thyroid disease is quite high, thus endocrinologists managing thyroid disease in pregnancy are likely to encounter such cases in their clinics with comparative regularity.
Causal factors relating to pregnancy
Since oestrogen and human chorionic gonadotrophin (HCG) are known to have stimulatory actions on thyroid hormone secretion at different phases of pregnancy, they might also be viewed as potential drivers for thyroid malignancy. The thyroid stimulating activity of HCG in the first trimester of preg- nancy is well recognised due to its structural homology with TSH.5 Whereas oestradiol has been shown to stimulate thyroglobulin gene expression but not expression of the c-myc proto-oncogene.6 More recently, oestradiol was shown to promote KAT5 human papillary thyroid cancer cell proliferation, an effect that was attenuated by tamoxifen, and accompanied by increased expression of the anti- apoptotic protein, Bcl-xL.7 Furthermore, a recent study of PTEN knockout mice established a direct role for oestrogens in regulating thyrocyte proliferation and subsequent development of follicular carcinoma.8 Epidemiological studies may also support a potential role for oestrogen in thyroid cancer development. A case-control study of female residents in Washington State aged 18-80 with a diag- nosis of thyroid cancer showed that women who had taken exogenous oestrogens or with a history of one or more previous pregnancies were found to have a slight but significant increased risk of thyroid carcinoma compared with women who had never used oestrogens or nulliparous women.9 Conversely, the Japanese Collaborative Cohort found no association between thyroid cancer and previous preg- nancy or hormone use10 in keeping with observations by Mack et al. in their study of 292 pairs of female thyroid cancer patients in Los Angeles County.11 Therefore, although experimental data may support a potential role of oestrogen in thyroid cancer development and/or progression, the epide- miological data are at present inconclusive.
Diagnostic approach
Although only 5-20% of thyroid nodules are malignant, in most pregnant women FNAB of single or throughout pregnancy regarding surgery and also in the postpartum period where breastfeeding may be considered and adjunctive radioiodine treatment may be necessary. The Endocrine Society has proposed that, as in the non-pregnant state, thyroid ultrasonography can be useful in determining the nature of a nodule, monitoring its growth, aiding in the FNAB and in identifying the location of any suspicious lymph nodes. Radioiodine scanning of the thyroid is, of course, contraindicated.15
Surgery
The need for, and timing of thyroid surgery for cancer during pregnancy has been the subject of much debate, balancing the need for timely intervention to deal with the tumour on the one hand and risks to the foetus and mother of operative intervention on the other. Surgery undertaken during the first trimester may be associated with increased foetal loss and possible teratogenicity.16 Furthermore, in the third trimester, any surgery is associated with the risk of preterm labour. Surgery undertaken for thyroid disease in pregnancy, including thyroid cancer, may also be associ- ated with increased complications. Kuy et al. compared surgical outcomes for thyroid and para- thyroid surgery in 201 pregnant women with 31,155 non-pregnant women and found that pregnancy independently predicted a higher rate of surgical complications, hospital stay and costs.17 The Endocrine Society recommends that women with thyroid nodules found to be malignant in early pregnancy may be considered for surgery in the second trimester15 when surgery is at its safest.12,18 Alternatively, they suggest that patients with well-differentiated tumours without advanced disease may prefer to delay surgery until the postpartum period. Such an approach does not appear to be associated with a worse outcome.12,19-22 In contrast, patients with advanced, undifferentiated, medullary, Hurthle cell or anaplastic carcinomas may be considered for surgery during pregnancy since the prognosis is worse for these tumours, although the data are very limited.15 A decision to proceed with surgery in pregnancy or not should thus be undertaken in consultation with the patient and will need to factor in the patient’s attitude to managing risk in addition to tumour-related factors.
Radioiodine therapy (131I)
Radioiodine therapy may be required post-surgery for remnant ablation but this must be delayed until after pregnancy due to its adverse effects on the foetus.23 Breastfeeding must also stop, ideally 1- 2 months prior to treatment.15 To date, the evidence is reassuring with respect to future fertility and outcomes of subsequent pregnancies, which do not appear to be affected by 131I therapy. A systematic review in women who received radioiodine therapy showed up to 27% had irregular menses in the year following treatment but there was no increase in miscarriages, preterm births, stillbirths or congenital abnormalities.24 Nevertheless, the Endocrine Society guidelines recommend that further pregnancy should be avoided for 6 months to 1 year following therapeutic radioiodine, both to confirm cancer remission and to ensure stability of thyroid function.15
Men treated with radioiodine may demonstrate a transient rise in follicle-stimulating hormone (FSH), luteinizing hormone (LH) and inhibin in the months following treatment, indicating a degree of testicular dysfunction. A reduction in sperm count may also occur, such that sperm banking may be considered in advance of treatment, but the available data do not support any increased infertility, miscarriages or congenital malformations.25,26
Thyroid function testing and thyroglobulin monitoring
Pregnancy can pose a challenge for monitoring of thyroid status due to a paucity of normative data for serum TSH and T4 adjusted for gestational stage. However, some studies have reported trimester- specific reference ranges for TSH and T4.27-29 Thyroglobulin levels can also be difficult to interpret because concentrations may fluctuate during pregnancy.30-33 Although there is considerable inconsistency in the findings of these studies which have variably demonstrated a progressive thyroglobulin rise throughout pregnancy, a rise in the third trimester only or even a fall in late pregnancy. Furthermore, changes in thyroglobulin levels may be influenced by ethnicity and iodine status.33 Mazzaferri concludes that serum thyroglobulin levels may be altered by the changes in T4 and TSH which accompany pregnancy, and that monitoring by serial neck ultrasonography and thyroid function provides a more specific and sensitive method of follow-up than thyroglobulin measurement.34
Thyroid replacement and TSH suppression
Exogenous administration of thyroid hormone is recommended to achieve a suppressed but detectable TSH level when surgical treatment of thyroid cancer is delayed until the postpartum period or in those pregnant women with pre-existing thyroid cancer.15,18 Subclinical hyperthyroidism has not been shown to affect foetal development.35 The free T4 should be maintained in the upper non- pregnant normal range to minimise maternal and foetal complications.15 Patients who undergo thyroidectomy must be replaced with adequate doses of thyroxine in view of the risks of even minor hypothyroidism to foetal development.
In the patient with established thyroid cancer who becomes pregnant, already on thyroid replacement therapy, suppressive doses of levothyroxine should be continued, increasing the pre- pregnancy dose by at least 25% as soon as pregnancy is confirmed, with close monitoring of thyroid function throughout pregnancy.36,37 The recent Thyroid Hormone Early Adjustment in Pregnancy (THERAPY) Trial showed that a two-tablet per week increase in levothyroxine on confirmation of pregnancy reduced the risk of maternal hypothyroidism during the first trimester.38 Athyreotic patients and those with pre-pregnancy TSH levels below 1.5 mIU/1 or taking more than 100 ug/day of levothyroxine were more likely to attain suppressed TSH levels, although only a small minority required dose reduction if a trimester-specific TSH cut-off of 0.1 mIU/l was used. The study also demonstrated that a 4-weekly TSH test schedule identified 92% of abnormal values. Pregnant women should also be alerted to the potential for reduced bioavailability of levothyroxine when commonly prescribed drugs in pregnancy, such as iron supplements, antacids or calcium are taken.34
Prognosis
Most studies demonstrate that the outcome of differentiated thyroid cancer for women diagnosed during pregnancy or in the postpartum period is generally good and similar to their non-pregnant counterparts.12,19-22,39 Moosa and Mazzaferri compared the outcomes of 61 pregnant women with thyroid cancer with 528 matched non-pregnant controls.19 Tumour stage, history of prior irradiation, percentage of patients with papillary thyroid cancer as a diagnosis, and therapeutic management did not differ between groups, although pregnant women were more likely to have their thyroid nodule discovered incidentally at neck examination. There were no differences in outcomes with respect to cancer recurrences, distant recurrences or cancer deaths between the two groups. Furthermore, outcome was not affected by delaying surgery until the postpartum period, suggesting that treatment of thyroid cancer identified during pregnancy can safely be delayed until after delivery for most patients.19
In contrast, Vannucchi et al. compared outcomes in 123 women with differentiated thyroid cancer according to whether the diagnosis and treatment had occurred >1 year after delivery, during preg- nancy or the first year after delivery, or in nulliparous women or prior to pregnancy.40 They found that thyroid cancer diagnosed during pregnancy was associated with a poorer prognosis and was the most significant indicator of persistent disease. However, a greater proportion of women diagnosed during pregnancy had a follicular thyroid cancer variant hence the findings from this study must be put in context alongside previous data.
Adrenocortical carcinoma
Background
Adrenocortical carcinoma (ACC) is a very rare tumour with an estimated annual incidence of one to two cases per million, roughly 60% of whom are women.41 Due to this rarity, and because the hyper- androgenism and hypercortisolism which typically accompanies ACC renders women infertile, presentation in pregnancy is exceedingly uncommon with only 12 such cases published in the liter- ature prior to 200542 and a further 12 added to this total since.43 The evidence base which informs management in pregnancy is thus very limited and based on case reports and case series only.
Clinical presentation
ACCs in pregnancy tend to secrete cortisol alone or in combination with androgens. Patients thus commonly present with endocrine symptoms and signs, including hypertension, diabetes, oedema, weight gain, muscle wasting, virilisation, acne and depression, or with symptoms relating to local extension of the tumour. 43 Rarer presentations include a case of a maternal ACC with LH/hCG receptor overexpression, causing virilisation of a female infant,44 and hypoglycaemia, thought to be related to pro-insulin-like growth factor 2 hypersecretion.43
Abiven-Lepage et al. compared 12 patients diagnosed with ACC during pregnancy or the post- partum period with a cohort of 98 non-pregnant women under the age of 50.43 They found that patients with pregnancy-associated ACC presented with larger tumours and at a more advanced stage than their non-pregnant counterparts. Two-thirds of the pregnancy group had evidence of local or metastatic extension, in contrast to the non-pregnant group, in which stage 3 or 4 disease was present in only 40%. These differences were considered to be most likely due to diagnostic delay although more rapid tumour growth during pregnancy could not be excluded. A trend towards a higher frequency of cortisol hypersecretion was also noted in the pregnancy-associated ACCs, which is surprising in view of the increased rates of miscarriage and subfertility associated with cortisol excess.
Diagnosis
Establishing a diagnosis of cortisol excess in pregnancy can be challenging due to the normal physiological changes that occur, resulting in increases in serum cortisol, urine free cortisol (UFC) and plasma adrenocorticotropic hormone (ACTH) levels.42,45-47 UFC excretion is normal in the first trimester but can increase up to three-fold by term, hence values greater than three times the upper limit of normal in the second and third trimesters are supportive of Cushing’s syndrome.42,45 In addition, suppression of serum cortisol by dexamethasone during pregnancy is blunted resulting in a higher rate of false-positive results.42,47 Plasma ACTH may also less reliably distinguish adrenal from non-adrenal sources of hypercortisolism in pregnancy: a case series showed that 50% of patients with adrenal Cushing’s syndrome had non-suppressed ACTH levels.42 Lindsay et al. therefore recommended that a combination of adrenal ultrasound imaging, high dose dexamethasone suppression test (HDDST), and plasma ACTH levels are a useful initial step in the differential diagnosis of pregnant patients with Cushing’s syndrome. Patients with borderline or low plasma ACTH who fail to suppress cortisol on HDDST are likely to have an adrenal aetiology. Ultrasonography identified adrenal lesions in 73% of their cases.42 Second-line imaging with MRI may be needed to localise an adrenal source in the event of a negative ultrasound scan and is recommended to accurately stage tumours in advance of treatment.
Management
Firm recommendations on treatment are difficult in view of the very limited experience with ACC in pregnancy but since surgery is the only treatment modality which has the potential to radically alter outcome in this devastating disease, this should be considered after magnetic resonance imaging (MRI) assessment at any stage of gestation. ACCs have been successfully resected during the third trimester and at the time of Caesarean section.43 There is a risk of inducing premature labour, especially in the third trimester.48 Hence close liaison with the obstetric and paediatric teams is mandatory. Adjuvant mitotane therapy should also be considered since this is known to prolong recurrence-free survival in radically resected tumours.49 However, since the drug crosses the placenta and is teratogenic, treat- ment should be delayed until as soon as possible after delivery.42,43,50 Breastfeeding is not recom- mended.43 Metyrapone, which is generally well tolerated in pregnancy, may be considered on a temporary basis for medical control of hypercortisolism, pending definitive treatment.42,51,52 Keto- conazole should be reserved for individuals who need medical therapy but cannot tolerate metyrapone since ketoconazole has been shown to cross the rat placenta and is both teratogenic and abortifa- cient.42,53 ACCs identified during the first trimester may also be considered for medical termination of pregnancy, especially in advanced stage disease.43
Outcome
Adrenocortical carcinoma presenting in pregnancy or the postpartum period is often associated with poor outcomes for the mother and foetus. Significant maternal morbidity, including diabetes mellitus, hypertension, heart failure and pre-eclampsia, is usually evident.42,43 Abiven-Lepage et al. found that diagnosis during pregnancy or in the postpartum period was associated with a shorter maternal survival compared with non-pregnant women, and a trend towards a shorter disease-free survival (Fig. 1).43 These findings could not be attributed to differences in age or tumour stage, which are known prognostic factors for survival in ACC, since cases were matched with controls for these variables. Surgical and medical therapies were also similar between groups, suggesting that delayed treatment due to pregnancy was not a factor in survival. Furthermore, cortisol excess was also
A
1.00
Survival:
— ACC in pregnancy/postpartum
0.75
- Matched controls
0.50
0.25
0.0
0
50
100
150
200
250
Months
B
1.00
Disease free survival:
— ACC in pregnancy/postpartum
0.75
- Matched controls
0.50
0.25
0.0
0
50
100
150
200
250
Months
not considered as a potential adverse factor in outcome since exclusion of the small number of non- secretory ACCs from the analysis did not affect the differences observed in survival. The authors thus speculate that tumour progression might be influenced in some way by pregnancy, although they were unable to obtain material for gene expression profiling which has been shown to identify distinct classes of ACC with different prognoses.54
Foetal morbidity and mortality is also high in pregnancy-associated ACC. This may relate to maternal cortisol excess since Cushing’s syndrome as a whole in pregnancy has been associated with a high frequency of intrauterine growth restriction, preterm births, stillbirths and intrauterine deaths. 42,43,55 Outcome can be improved by correction of the hypercortisolism.42 Hence early disease recognition is essential.
Phaeochromocytoma
Phaeochromocytoma presenting in pregnancy is rare with an estimated incidence of 1 in 50,000 pregnancies.56 Although uncommon, establishment of the diagnosis is critically important since unsuspected disease is associated with a poor maternal and foetal outcome which can be improved by early recognition: before 1970s an antenatal diagnosis rate of only 25% was associated with 50% maternal and foetal mortality, compared with only 2% maternal and 10% foetal mortality in recent series, where the diagnosis was made before delivery in 83%.57,58 In addition to a failure to detect the disease because of its rarity, other factors may also contribute to an increased mortality, including contraindications to certain imaging techniques such as radioisotope studies, precipitation of tumour catecholamine secretion by the enlarging uterus (Fig. 2) and the potential for pregnant women to undergo emergency surgical procedures without adequate opportunity for careful preoperative medical preparation.59 It is thus vital that clinicians managing patients with phaeochromocytoma familiarise themselves both with the clinical and biochemical features which distinguish phaeochro- mocytoma from other hypertensive disorders in pregnancy, and the intricacies of disease management once the diagnosis is established.
Clinical presentation
Establishing the diagnosis of a phaeochromocytoma can be difficult because of the similarity of presentation to other hypertensive syndromes which develop commonly in pregnancy such as gestational hypertension and pre-eclampsia. A high index of suspicion is therefore required for the
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diagnosis, especially when the presentation is atypical for these common disorders. A previous report from the Confidential Enquiries into Maternal Deaths in the United Kingdom states that the diagnosis should be considered in the presence of glycosuria and in multigravid women who have severe hypertension but no prior history of pre-eclampsia.60 Other useful signals to the presence of a phaeochromocytoma may include the absence of weight gain, oedema, coagulopathy and deranged liver function tests, which are hallmarks of pre-eclampsia but which develop rarely in phaeochro- mocytoma, and the development of hypertension at any stage of pregnancy, including the first trimester when pre-eclampsia is uncommon (Table 1). The presence of the classic signs and symptoms of phaeochromocytoma, namely sweating, palpitations, headache, orthostatic hypotension and paroxysmal hypertension should also alert the clinician to the diagnosis, although only a minority of patients present in this manner in pregnancy.59 The onset of symptoms on standing accompanied by an orthostatic fall in blood pressure (due to the relative hypovolaemia which accompanies phaeochro- mocytoma) may serve as a particularly useful differentiator from pre-eclampsia.59,61
Establishing the diagnosis
The diagnosis should be confirmed by the demonstration of elevated fractionated metanephrines in a 24-h urine collection as in the non-pregnant state; catecholamine levels do not appear to be affected by pregnancy or pre-eclampsia.62 In contrast, whilst measurement of plasma-free metanephrines has been advocated as a simpler alternative to timed urine collections outside of pregnancy, there is compara- tively little experience in pregnancy at present to support its use as a first-line test. The tumour should be localised using MRI as the preferred imaging modality, since this avoids the radiation exposure asso- ciated with computed tomography (CT) and identifies adrenal and extra-adrenal (paraganglioma) sites of disease. Clinicians should be especially alert to the potential for a non-adrenal source when there is an underlying inherited endocrine cancer syndrome predisposing to paragangliomas, such as Von Hippel Lindau (VHL) syndrome or mutations in the succinate dehydrogenase B or D genes (SDHB/D).63-66 They should also consider an extra-adrenal source when there is preferential secretion of normetanephrine, since extra-adrenal tumours typically lack expression of phenylethanolamine-N-methyltransferase, which catalyses the conversion of norepinephrine to epinephrine. Radioisotope imaging studies, such as 131I-metaiodobenzylguanidine (MIBG) scans, or positron emission tomography (PET) studies are often used in non-pregnant patients to localise tumours not identified on CT or MRI, but these are contra- indicated in pregnancy due to the radiation exposure. However, such scans may be considered in the postpartum period provided the patient is not breastfeeding.
Management
The definitive treatment for phaeochromocytoma is surgery but it is essential that this is preceded by adequate alpha- and, if needed, subsequent beta-adrenergic blockade in order to prevent hypertensive
| Characteristics | Phaeochromocytoma | Pre-eclampsia |
|---|---|---|
| Onset | Any stage of pregnancy | Second or third trimester |
| Prior history of pre-eclampsia in multigravid woman | Absent | Usually present |
| Weight gain | Absent | Present |
| Oedema | Absent | Often present |
| Palpitations | Often present | Absent |
| Sweating | Often present | Absent |
| Episodes of anxiety | May be present | Uncommon |
| Hypertension | May be paroxysmal or sustained | Sustained |
| Postural hypotension | Often present | Absent |
| Glycosuria | Often present | Absent |
| Proteinuria | Usually absent | Present |
| Hepatic transaminases | Normal | Raised |
| Thrombocytopaenia | None | Often present |
crisis and consequent risks to the mother and foetus. Phenoxybenzamine is the alpha-blocker of choice and should be started as soon as the diagnosis is made. Although it crosses the placenta and may briefly cause hypotension in the neonate and perinatal depression in the mother,67 such concerns are out- weighed by the pressing need for treatment in a potentially life-threatening condition. The dose of phenoxybenzamine should be titrated to achieve adequate control of the blood pressure or until side effects, such as nasal stuffiness or postural hypotension, become dose-limiting. Labetalol, which combines both alpha- and beta-blocking properties, is not recommended since the ratio of alpha- to beta-blockade is inflexible. Doxazosin, a selective alpha1 blocker, has been used in pregnancy-associated phaeochro- mocytoma61 but its effects can be overcome by high circulating catecholamine concentrations since it acts as a competitive antagonist. Beta-blockers, such as propranolol, may be needed to oppose catecholamine- driven arrhythmias and reflex tachycardia often associated with alpha blockade. These must never be commenced before alpha blockade since this would run the risk of hypertensive crisis secondary to unopposed alpha-adrenergic stimulation. Concerns related to intrauterine growth restriction from beta blockade are usually outweighed by the need for adequate tumour control. Rate-limiting calcium channel antagonists may offer an alternative to beta blockade in situations where the latter are contraindicated.
Surgery is the definitive treatment for phaeochromocytoma but its timing in relation to pregnancy is a matter of debate. A number of factors influence decision making, including gestational age, presence or absence of foetal distress, and surgical accessibility. If the phaeochromocytoma is diagnosed in early pregnancy, provided medical blockade is optimised, adrenalectomy before 24 weeks’ gestation usually results in a good outcome.58,63 This may be achieved laparoscopically where the tumour size allows. After 24 weeks’ gestation, problems with tumour accessibility may delay surgery until foetal maturity is reached, at 34 weeks’ gestation or beyond. In such circumstances, surgery may be combined with elective Caesarean section 61,68 or performed at a later date63,69 to reduce vascularity and improve access. Although a good outcome has been reported in selected cases with vaginal delivery,63 Caesarean section, which must always be undertaken in liaison with an experienced anaesthetist, is generally considered the preferred mode of delivery because of concerns of inducing a pressor crisis from uterine contractions.
Genetic testing
Germline mutations in disease susceptibility genes giving rise to VHL syndrome, multiple endocrine neoplasia types 2A and 2B, type 1 neurofibromatosis, or the more recently characterised inherited phaeochromocytoma/paraganglioma syndromes due to mutations in the SDHB or SDHD genes, account for one-quarter of pheochromocytomas.7º Since these conditions are commonly associated with young onset disease, it is not surprising that many patients reported with phaeochromocytoma in pregnancy have mutations in one of these genes. In pregnant women with phaeochromocytomas, genetic testing for one of these familial syndromes should thus always be considered in order to facilitate a tumour surveillance programme and case detection of asymptomatic carrier relatives.
Neuroendocrine tumours
Neuroendocrine tumours (NETs) arise from neuroendocrine cells which are distributed widely in the body hence the spectrum of tumours which fall into this classification, and their modes of presentation and biological behaviour is diverse. NETs are rare but are increasing in incidence, with recent data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registry and Norwegian Registry of Cancer (NCR) providing an estimated annual incidence of 4-5/ 100,000 and prevalence of 35/100,000 across all tumour sites.71,72 NETs affect men and women in roughly equal numbers with a peak incidence in middle age. For this reason, and because many patients may choose not to become pregnant when a diagnosis of metastatic NET is made, experience of NETs in pregnancy is very limited and largely restricted to isolated case reports or case series only.
Clinical presentation and natural history
Most cases which describe NETs presenting in pregnancy relate to incidentally discovered NETs found at appendectomy undertaken for suspected appendicitis.73-75 This is perhaps not surprising in
view of the fact that appendiceal carcinoids reach a peak incidence at a much younger age than other NETs. Islet cell tumours have also been described although fewer than 30 cases of insulinoma pre- senting in pregnancy have been reported, most of which appear during the first trimester with hypoglycemic episodes.76,77 Diagnosis is frequently delayed because mild hypoglycaemia is common in early pregnancy and the symptoms of nausea, weakness and hypotension are mistaken for those of normal pregnancy. Furthermore, symptoms may improve during the second and third trimesters with the rise in insulin resistance, such that the diagnosis is often only established in the postpartum period when a rebound in insulin sensitivity occurs.76,77 Fewer than 10 patients with gastrinoma causing Zollinger-Ellison syndrome in pregnancy have been described78,79 all of whom had symptoms of gastric acid hypersecretion. Other modes of presentation reported include major haemorrhage from a jejunal NET80 non-functioning pancreatic NETs discovered incidentally at ultrasound81 and vaginal bleeding from a NET arising within the uterine cervix.82 Only a few pregnant patients have been reported with carcinoid syndrome, and these have usually been known to the treating clinicians in advance of pregnancy.75,83 Durkin reviewed a series of 18 patients with carcinoid tumours involving 25 pregnancies75 four of whom had carcinoid syndrome. Successful pregnancies were achieved in 2 of the 4 whilst the other two resulted in foetal deaths. Whilst these outcomes may be of concern, it should be noted that this case series was reported in 1983 before somatostatin analogue therapy became widely available. Moreover, good foetal and maternal outcomes have been reported recently in 2 patients with metastatic NETs treated with intravenous octreotide during labour.83,84 Although NETs are known to express oestrogen receptors85 there are no data to suggest that pregnancy influences the natural history of NETs which appears, as in the non-pregnant setting, to depend largely on tumour differ- entiation and grade. Thus, well-differentiated tumours monitored during pregnancy may remain stable84,86 in contrast to high grade, poorly differentiated tumours which usually progress rapidly.
Establishing the diagnosis
In the non-pregnant state, the diagnosis and staging of NETs relies upon a combination of clinical assessment, measurement of general and specific neuroendocrine hormonal markers, imaging and histological confirmation. Pursuit of a histological diagnosis is critical where this is not previously known, not only to confirm a neuroendocrine origin but also to determine tumour grade since this influences prognosis and choice of therapy.87 Plasma chromogranin A (CgA) is a useful general tumour marker since it displays good sensitivity in most types of NET, especially in metastatic carcinoid tumours, and correlates with tumour volume. Pregnancy appears to have only a modest stimulatory effect on circulating CgA levels: Syversen et al.88 noted a higher CgA level in maternal sera at term (median 469 pmol/l) than in the first trimester (median 286 pmol/l) or in non-pregnant women (median 306 pmol/l). NETs, especially metastatic NETs arising from the embryological midgut, may also secrete serotonin, although plasma measurement is usually replaced by urinary analysis of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAA levels may be modestly increased in late pregnancy and in women with pre-eclampsia.89 As in the non-pregnancy setting, insulinomas are diagnosed on the basis of inappropriate insulin secretion in the face of prevailing hypoglycaemia eli- cited during a 72-h fast. Pregnancy does not appear to influence the suppressive effect of hypo- glycaemia on insulin secretion,77 although a decision to undertake such a test during pregnancy should take into account maternal and foetal well-being in addition to clinical need since the test is not without risk and must be undertaken under close supervision. Serum gastrin concentrations appear to be unaffected by pregnancy90 and measurement is helpful in the diagnostic work-up for gastrinoma.
A radiological imaging strategy during pregnancy will require close liaison with radiologists but the choice of technique will depend partly upon whether the imaging is being undertaken to detect disease in newly presenting patients or in monitoring extent and progression of disease in those where the diagnosis is already established. Ultrasound may be useful in monitoring known liver metastases84 but lacks specificity when a new diagnosis is being pursued. CT and nuclear imaging techniques, such as indium-111 octreotide scintigraphy, should be avoided in view of the radiation associated with these studies but MRI may be useful. There is little experience of endoscopic ultrasound or capsule endos- copy in pregnancy but these may be of use in rare situations where the clinical situation mandates an urgent diagnosis of the primary tumour.80 Finally, echocardiography should be undertaken prior to
conception in all patients with known carcinoid syndrome and/or raised 5-HIAA in order to screen for carcinoid heart disease and to assess the severity of any valvular lesion, such that valve replacement surgery may be undertaken prior to pregnancy if clinically indicated. Patients who present during pregnancy with carcinoid syndrome should similarly undergo echocardiographic monitoring.
Management
Surgery
Patients found to have appendiceal NETs at appendectomy should be managed in line with guidelines established for appendiceal NETs outside pregnancy, namely to proceed to right hemi- colectomy if the tumour measures >2 cm, if there is deep mesoappendiceal invasion and/or there are positive surgical margins.91 However, depending on stage of gestation this may be deferred until the time of Caesarean section or the postpartum period.73 Surgical experience is very limited for NETs presenting at other sites, although Kamphues et al. recently reported the first 2 cases of well differ- entiated, localised pancreatic NETs which were successfully resected in the second trimester without consequence to the mother or foetus.81 Insulinomas may be surgically enucleated in the second trimester if the diagnosis is established in early pregnancy76,77 or managed medically by frequent meals and intravenous glucose infusions if diagnosed at later stages of pregnancy, with surgery being deferred to the postpartum period after appropriate localisation.
Somatostatin analogue therapy
The somatostatin analogues lanreotide and octreotide are widely used in the management of NETs. They bind with high affinity to 2 of the 5 somatostatin receptor subtypes (SSTRs 2 and 5) and are effective in improving symptoms of carcinoid syndrome and other hormonally active NETs. They are generally very well tolerated with the gastrointestinal side effects which develop at the start of therapy typically subsiding after the first few weeks of treatment. Furthermore, recent data from the PROMID study confirm an anti-proliferative action of Octreotide LAR in metastatic midgut NETs, such that patients randomised to active drug in this study displayed an improved time to tumour progression (median 14.3 months) compared to those treated with placebo (median 6 months).92 Somatostatin analogues are thus often used first line in the management of metastatic, well-differentiated NETs. Octreotide is roughly two-thirds bound by maternal protein93 with the remaining unbound fraction able to cross the placenta by passive diffusion.94 Somatostatin receptors are expressed in the placenta95 and foetal tissues, including the pituitary gland.96 Initial reports of prolonged octreotide use in preg- nancy had raised possible concerns in relation to intrauterine growth restriction although more recent evidence from patients treated for acromegaly in pregnancy has not demonstrated any effects on maternal complications or congenital anomalies.96,97 Furthermore, long-term treatment with octreo- tide in 2 pregnant women with acromegaly and nesidioblastosis found that neonatal pituitary function was normal at delivery, and that the children displayed normal post-natal growth and weight.97,98 Whilst these data appear reassuring, experience with somatostatin analogue therapy in pregnancy is still very limited hence it would seem prudent that they are used judiciously in pregnant patients with NETs, taking into account patient symptoms, presence or absence of progressive disease prior to pregnancy, tumour grade and stage. It may be particularly important to consider treatment in patients with carcinoid syndrome, and essential to treat with intravenous octreotide infusion during labour or Caesarean section in order to minimise the risk of carcinoid crisis.83
Other therapy
Symptoms arising from gastrinomas causing Zollinger-Ellison syndrome may be usefully controlled by the use of gastric antisecretory drugs in pregnancy, either in the form of H2-receptor antagonists or proton pump inhibitors.78,79 A recent meta-analysis has confirmed that proton pump inhibitor use in pregnancy is not associated with an increased risk for congenital birth defects, preterm delivery or spontaneous abortions.99 Tumours identified in advance of pregnancy should be considered for surgical resection where this is feasible. Interferon alfa, everolimus and sunitinib should be avoided since toxicity has been demonstrated in animal studies. Radionuclide therapy is contraindicated in pregnant patients and breastfeeding mothers in view of the radiation involved. Chemotherapy is rarely
used in the management of NETs but may be indicated in patients with poorly differentiated high- grade tumours; consideration may need to be given to termination of the pregnancy in such cases in order to facilitate maximally effective treatment.82
Practice points
· Management of endocrine tumours in pregnancy must take into account both maternal and foetal well-being.
· Oestrogens may play a role in thyroid cancer development although epidemiological data are inconclusive.
· Pregnancy has not been shown to affect the prognosis of differentiated thyroid cancer.
· Thyroid surgery for differentiated thyroid cancer can often be safely delayed until after pregnancy, without any adverse effects on cancer outcomes, although if surgery is considered this should be undertaken in the second trimester.
· Radioiodine therapy is contraindicated during pregnancy and breastfeeding but has not been shown to affect future fertility or pregnancy outcomes.
· Thyroid replacement hormone dose should be increased in pregnancy to achieve appropriate, and suppressed, TSH levels throughout gestation.
· Adrenocortical carcinoma in pregnancy is extremely rare but is associated with high maternal and foetal morbidity and mortality.
· Adrenalectomy offers the only potential for cure and should be considered at any stage of pregnancy.
· Mitotane can be used as an adjuvant in the postpartum period.
· Early recognition of phaeochromocytoma presenting in pregnancy is critical since this improves maternal and foetal outcome.
· Adrenalectomy should be considered, after appropriate alpha blockade, for phaeochromo- cytoma diagnosed in early pregnancy (<24 weeks) but may be delayed until Caesarean section or the postpartum period for tumours discovered after 24 weeks’ gestation.
· Caesarean section is generally the preferred mode of delivery for phaeochromocytoma in pregnancy.
· Genetic testing for mutations in the RET, VHL, SDHB or SDHD genes should be considered in all patients presenting with phaeochromocytoma in pregnancy.
· Somatostatin analogues may be considered for symptomatic control of carcinoid syndrome in pregnancy, and prevention of carcinoid crisis in patients undergoing labour or general anaesthesia, but the safety data in relation to foetal outcomes are very limited.
Research agenda
· Further studies are needed to establish whether pregnancy affects the natural history and biological behaviour of thyroid cancer, adrenocortical carcinoma and neuroendocrine tumours.
· Large, prospective, multicentre studies are needed to establish optimal diagnostic, treatment and outcome issues for endocrine tumours presenting in pregnancy.
. Further data are needed on the safety of somatostatin analogue therapy in pregnancy.
Summary
Endocrine tumours presenting in pregnancy present unique challenges to the clinician, not least because the optimum treatment needed for the mother may compromise foetal well-being. The rarity
of presentation demands a high index of suspicion for the diagnosis of an endocrine tumour, since early recognition can improve maternal and foetal outcome. However, the evidence base which informs management is poorly developed and restricted to case series and retrospective cohort studies only. Further studies are thus needed to establish optimal investigational and treatment strategies. In the meantime, treatment decisions must be made on a case-by-case basis, not only taking into account the best available evidence but also disease-associated factors such as tumour grade and stage, gestational age of the pregnancy and patient preferences. In view of these complexities, decisions on management should not be made in isolation but should be undertaken on an interdisciplinary basis with involvement of obstetricians, neonatologists, oncologists, surgeons and other disciplines as needed, in addition to the endocrine team.
Conflict of interest
None.
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