Gut and Pancreatic Neuroendocrine Tumors in Pregnancy and Lactation

Chapter 24

Gut and Pancreatic Neuroendocrine Tumors in Pregnancy and Lactation Sahar Sherf and Run Yu Division of Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, CA, United States

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Neuroendocrine tumors (NETs) of the gut and pancreas are heterogeneous tumors with distinct clinical and pathologic features. Appendiceal carcinoid and pancreatic NETs are relatively more common in young women. Women with history of appendiceal carcinoids with benign features, or benign insulinoma, are assumed to have unchanged baseline fertility after surgical removal of the tumors. Most women with active gut or pancreatic NETs that require treatment are advised against pregnancy, with some exceptions. Management of NETs in pregnancy should be multidisciplinary; medical therapy with somatostatin analog is the mainstay of treatment.

24.1 INTRODUCTION Neuroendocrine tumors (NETs) can arise from most organs, but those from the gut and pancreas are most common and include heterogeneous tumors with distinct clinical and pathologic features.1–4 The incidence of gut NETs is 2.5 cases per 100,000 per year.5, 6 Gut NETs are solid masses of neuroendocrine cells containing secretory granules that release various peptide hormones, including serotonin, kinins, histamine, and kallikreins. Gut NETs include gastrin-producing duodenal NETs, somatostatin-producing ampullary NETs, somatostatin-producing gangliocytic paragangliomas, serotonin-producing jejunal and ileal NETs, appendiceal NETs, and colorectal NETs.1, 2 According to the Surveillance Epidemiology End Results database, gut NETs in the United States are most commonly found in the small intestine (at 38%).5, 6 Appendiceal NETs can be classified into typical carcinoids and goblet cell carcinoids, and they comprise only about 5% of gut NETs.7, 8 Pancreatic NETs (incidence of 0.32 cases per 100,000 per year5) are classified in multiple ways.4, 9 Pancreatic NETs are classified as functioning or nonfunctioning based on whether they cause hormonal hypersecretion syndromes or not. Most functioning pancreatic NETs secrete insulin, gastrin, vasoactive intestinal peptide (VIP), glucagon, or somatostatin. In addition, both gut and pancreatic NETs are divided into subgroups according to tumor grade and stage.1–4 Although most gut and pancreatic NETs exhibit indolent behaviors, some of them can metastasize to the lymph nodes, liver, and other organs. In both women and men, gut and pancreatic NETs are usually diseases that strike in late middle age; thus, in women, most gut and pancreatic NETs are diagnosed at postreproductive age.5, 9 Appendiceal carcinoid and some pancreatic NETs can occur during childhood and young adulthood. Appendiceal carcinoids are usually an incidental finding in young women with a clinical diagnosis of appendicitis who undergo appendectomy.7, 8, 10 Most appendiceal carcinoids are small (<1 cm) and noninvasive in otherwise healthy young women; appendiceal carcinoids with those benign features have an excellent prognosis and do not require further surgical intervention or surveillance. Rarely, appendiceal carcinoids can be large (>2 cm), invasive, or metastatic to lymph nodes or remote organs. Appendiceal carcinoids with those unfavorable features require right hemicolectomy, lymph node dissection, liver-directed therapies, and systemic therapies. Pancreatic NETs affect a significant number of young people, including women.4, 9 In a large series of pancreatic NETs, of the 539 female participants, 143 (26.5%) were under 40 years old at diagnosis of pancreatic NET, including 14 (2.6%) under 20, 48 (8.9%) between 20 and 29, and 81 (15.0%) between 30 and 39.9 Insulinoma is the most common (38.9%), and gastrinoma the second most common (7.4%) functioning pancreatic NET in female patients younger than 40, whereas nonfunctioning tumors are as common as insulinomas.9 Benign insulinoma carries an excellent prognosis after surgical resection in general, and in young women in particular.3, 4, 9 Other pancreatic NETs carry various prognoses depending Maternal-Fetal and Neonatal Endocrinology. https://doi.org/10.1016/B978-0-12-814823-5.00024-6 Copyright © 2020 Elsevier Inc. All rights reserved.

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on the tumor grade and stage, and they may require abdominal surgery, liver-directed therapy, somatostatin analog treatment, and other systemic therapies, which may decrease female fertility.3, 4, 9 It needs to be emphasized that due to the low prevalence of gut and pancreatic NETs, there have been no systematic studies on the consequences of those tumors on pregnancy and lactation, or vice versa. Relatively more cases are reported on appendiceal carcinoid and insulinoma before or during pregnancy. The following sections are based on the relationship between pregnancy and lactation and other more common cancers or tumors, case reports, and the authors’ clinical experience. General guidelines and reviews on managing cancers in general, and endocrine tumors in particular, related to pregnancy are available.11, 12

24.2 PREGNANCY PLANNING AND PROSPECTIVE MANAGEMENT OF GUT AND PANCREATIC NETs IN WOMEN WITH HISTORY OF SUCH TUMORS 24.2.1

Women with no Current Evidence of NETs

Although the topic has never been directly addressed, there has been no clinical or experimental evidence that hormones secreted by gut and pancreatic NETs have specific, long-lasting effects on female fertility. Once the functioning NETs are completely removed surgically, female patients gradually resume their baseline health status. Women with a history of appendiceal carcinoids with benign features are usually assumed to have preserved baseline fertility and general health. Anecdotally, spontaneous pregnancy may happen soon after the removal of appendiceal carcinoids.13 A successful pregnancy has been reported in a young woman with aggressive appendiceal carcinoids; several years after tumor debulking and intraperitoneal chemotherapy, she became pregnant twice through assisted reproductive methods and delivered a healthy term baby each time.14 In the authors’ clinical experience, most young female patients with benign insulinomas can be fertile after tumor removal. In patients with history of NETs of higher grade and stage, extensive abdominal surgical operation may result in adhesions, and systemic targeted therapy or chemotherapy may result in irregular menstruation or even secondary amenorrhea, resulting in decreased fertility. There are also no systematic studies on the effects of pregnancy on the recurrence of gut or pancreatic NETs. In our clinical experience, recurrence of gut or pancreatic NETs during or right after pregnancy is exceedingly rare, if it happens at all. Thus, women with a history of appendiceal carcinoids with benign features or benign insulinomas are assumed to have unchanged baseline fertility after surgical removal of the tumors. There are no specific precautions to be taken before, during, or after pregnancy. If a woman with a history of NET of higher grade and stage wants to become pregnant, she needs to be counseled on her current fertility status and the uncertainty of pregnancy on the risk of recurrence of her previous NETs. In the absence of evidence of higher risk of NET recurrence during pregnancy, we believe that having a history of NET itself is not a contraindication of pregnancy.

24.2.2

Women with Active Gut or Pancreatic NETs

Female patients with small, nonfunctioning pancreatic NETs, often in the background of multiple endocrine neoplasia syndrome type 1 (MEN1)15 may require only surveillance and do not require any active treatment, especially after the removal of hyperplastic parathyroid glands or parathyroid adenomas and treatment of pituitary tumors if they have MEN1.16 There are no clear contraindications of pregnancy in those women. If the female MEN1 patients have active pituitary tumors or primary hyperparathyroidism, these issues need to be addressed before considering pregnancy (see Chapters 18 and 21, respectively, for further discussion).16 In our experience, most women with active gut or pancreatic NETs that require ongoing treatment don’t desire pregnancy due to the burden of the disease, may have irregular menstruation due to their treatments, and are generally advised against pregnancy by their physicians. Several factors make pregnancy a challenging issue. Surgical debulking may cause miscarriages, liver-directed therapies often use radioactive pharmaceuticals or chemotherapeutic agents, systemic therapies with targeted agents such as everolimus and sunitinib may be teratogenic, and peptide receptor radionuclide therapy (PRRT) also uses radiopharmaceuticals.1–4 Monitoring response to therapies by imaging may be limited in pregnancy, as computed tomography (CT) and nuclear imaging should be used with caution during pregnancy.17 The only exceptions may be patients with stable gut or pancreatic NETs who require only somatostatin analog or proton pump inhibitor treatments. We are not aware of any case reports on conception while on somatostatin analog treatment for gut or pancreatic NETs, but females treated with somatostatin analog for acromegaly can be pregnant with no adverse fetal consequences.18, 19

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There are two case reports of pregnancy in women with known and active gastrinomas treated with proton pump inhibitors; a healthy baby was delivered in each case.20, 21 If a patient with active gut or pancreatic NETs exhibits a satisfactory treatment response but still has a clear disease burden, and she strongly desires pregnancy, then pausing treatment may be tried to see if the tumor burden remains stable. If the tumor is stable, pregnancy should be possible. A case report describes such a scenario.22 A young woman with pancreatic NETs with liver metastases was diagnosed 6 years prior to pregnancy. The patient received multiple treatment modalities with a stable disease burden. Pregnancy ensued after pausing all treatment for a year. She underwent induced labor at 38 weeks’ gestation; octreotide was not needed. She delivered a healthy baby via uncomplicated vaginal delivery. There is no clear evidence that gut or pancreatic NETs progress more rapidly in pregnancy. Instead, case reports generally show no tumor progression during pregnancy,20–22 while other case reports show spontaneous regression of pelvic NETs and bronchial carcinoids after pregnancy in the absence of any treatment.23–25 It is postulated that pregnancy contributes to tumor regression by immunological response and activation of proapoptotic pathways, cytokines, T and B cells, and growth factors in pregnancy. The presence of metastatic carcinoid disease in pregnancy, particularly with carcinoid syndrome, may increase the risk of fetal demise. In a review of pregnant patients with carcinoid tumor in 1983, 4 of 18 patients developed carcinoid syndrome; 2 of these patients had successful pregnancies, but the others resulted in fetal death.26 Hypoglycemia caused by insulinoma during pregnancy may also cause fetal demise.27

24.3 GUT AND PANCREATIC NETs FOUND DE NOVO DURING PREGNANCY It is exceedingly rare that gut or pancreatic NETs are diagnosed de novo during pregnancy. Functioning NETs are usually diagnosed during pregnancy via severe hormonal hypersecretion syndromes, but diagnosis can be particularly challenging because the symptoms of functioning NETs can mimic the physiologic changes or complications of pregnancy. Carcinoid syndrome is seen in patients with small bowel NET with metastases to the liver as a result of bypassing the hepatic clearance of serotonin from the portal circulation.1, 2 Carcinoid syndrome is characterized by flushing, diarrhea, abdominal cramps, and (less commonly) right heart valvular lesions (i.e., carcinoid heart disease). Carcinoid crisis is characterized by hemodynamic instability due to the sudden release of large amounts of vasoactive peptides in the circulation, often elicited by anesthesia or invasive procedures. We are not aware of cases of de novo diagnosis of carcinoid syndrome in pregnancy. Insulinoma is a relatively common functioning NET in pregnancy, and it causes hypoglycemia.27–30 Pancreatic NET may also secrete parathyroid hormone (PTH)-related protein (PTHrp), which causes hypercalcemia.31 We are not aware of other functioning pancreatic NETs diagnosed de novo during pregnancy. Nonfunctioning gut and pancreatic NETs present with mass effects, such as gastrointestinal bleeding, abdominal pain, vomiting, or incidental findings.32–35 The most common nonfunctioning NETs diagnosed de novo in pregnancy is appendiceal carcinoids.33, 34, 36, 37 Diagnosis of gut and pancreatic NETs in pregnancy requires a high index of suspicion. As blood glucose levels are often lower during pregnancy and insulinoma is a rare cause of hypoglycemia, hypoglycemia caused by insulinoma is often missed until a profound level is reached.27–30 It is key to document insulin and proinsulin levels at the time of hypoglycemia to ascertain whether hypoglycemia is caused by insulinoma. High proinsulin levels suggest malignant insulinoma.30 Magnetic resonance imaging (MRI) usually localizes an insulinoma in the pancreas. Appendiceal carcinoids most commonly present as appendiceal masses found by imaging for abdominal pain in pregnancy, presumably caused by appendicitis; carcinoids are then found in the surgical specimen.33, 34, 36, 37

24.4 MANAGEMENT OF GUT AND PANCREATIC NETs DURING PREGNANCY AND PERIPARTUM The management of gut and pancreatic NETs in pregnancy and peripartum should be individualized based on the tumor grade, stage, hormonal secretion status, and comorbidities. As the care of pregnant patients with NETs is complicated, they should seek care at an institution with a multidisciplinary team of specialists on NETs, including obstetricians and anesthesiologists.38 We agree with the conclusions of a recent review on management of NETs in pregnancy.39 Asymptomatic NETs may be best monitored closely, with no intervention. Given the procedural risk and the possibility of disease regression, surgical resection of NETs, which is recommended in nonpregnant patients with localized disease, should be postponed until after delivery if possible. While hepatic artery embolization and radiofrequency ablation have been used in pregnancy, they too should be avoided during organogenesis. Finally, medical therapy with somatostatin analogs also should be deferred in asymptomatic disease or in the absence of carcinoid syndrome, hypoglycemia, other hormonal

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hypersecretion syndromes, and disease progression.39 Other systemic therapies such as everolimus, sunitinib, telotristat, and PRRT should mostly be deferred until after pregnancy for their potential fetal risk. Close monitoring for development of symptoms and evidence of tumor progression is nevertheless necessary.

24.4.1

Management of Carcinoid Syndrome in Pregnancy and Peripartum

Although carcinoid syndrome is exceedingly rare in pregnancy, it poses a unique challenge to the treatment team.22, 26, 39 Contrast studies and biopsies are limited during pregnancy due to iodine exposure and procedural risks; therefore, laboratory testing and ultrasound surveillance are of paramount importance. We recommend frequent laboratory and diagnostic monitoring with serum chromogranin A and serotonin levels, liver function tests, urinary 5-hydroxyindoleacetic acid (5HIAA) level, transthoracic echocardiogram, and abdominal ultrasound every 3 months. Serial abdominal ultrasounds should assess for fetal anomalies and growth, particularly in symptomatic patients treated with octreotide. It is reasonable to increase the frequency of monitoring in patients with high-grade tumors, secretory tumors, and larger tumors, as well as in symptomatic patients. It should be noted, however, that chromogranin A levels can rise in pregnancy partly due to contributions from the placenta, which has neuroendocrine activity, as well as from stress, so that does not necessarily implicate an increase in tumor size.40, 41 As such, urinary 5HIAA and serotonin levels may be better indicators of disease stability or progression during pregnancy. In those patients with elevated prepregnancy urinary 5HIAA or evidence of carcinoid heart disease, extra precaution is warranted, as they are at higher risk of complications during labor and delivery. In contrast to asymptomatic tumors, pregnancies affected by carcinoid syndrome could place patients at higher risk for fetal demise.26 The management of carcinoid syndrome focuses on blocking the production and release of vasoactive mediators. Octreotide is a synthetic somatostatin analog used to treat carcinoid syndrome during pregnancy.39 Most circulating octreotide is bound by maternal proteins; the unbound fraction is thought to cross the placenta by passive diffusion and to bind to the placenta and umbilical cord tissues, albeit with low affinity.42–45 Both the long- and short-acting forms cross the placental barrier, although data indicate that short-acting octreotide is found in lower concentrations in umbilical cord serum, amniotic fluid, and newborn serum. Octreotide use in pregnancy remains somewhat controversial. Its use during pregnancy has been limited to a small population, most of whom had acromegaly, which showed that octreotide use appears to be largely safe in pregnancy.45 Fetal weight is normal, and no malformations or cases of abnormal development are noted in pregnancies with octreotide exposure. Over the course of 6 years, linear growth, weight, neuropsychological development, and pituitary function of the children exposed to octreotide in utero remained normal. In one patient, an acute decrease in uterine artery blood flow was seen after octreotide injections, with no effect on pregnancy course, delivery, or fetal development. Octreotide concentrations were high in maternal serum and colostrum, and lower in umbilical cord serum, amniotic fluid, and newborn serum.44, 45 We recommend the use of short-acting, subcutaneous octreotide injections for symptomatic carcinoid patients.22, 39, 42 Intravenous octreotide infusions should be available when anesthesia and surgery are planned or if any signs of carcinoid crisis develop, but they should be used only if truly warranted. In active carcinoid syndrome, an intravenous bolus of octreotide should be given 1–2 h before surgery. In the case of an operative carcinoid crisis, an intravenous bolus and infusion of octreotide should be administered. Appropriate anesthetic management is vital during labor and delivery to avoid a carcinoid crisis.22, 39, 42 Analgesics should be provided to blunt a hyperadrenergic stress response, and euvolemia should be maintained. If abdominal delivery becomes necessary, both neuraxial and general anesthesia should be given.22, 42 General anesthesia should avoid drug triggers of carcinoid crisis, and it should help to blunt the stress response. Some suggest epidural over spinal anesthesia for patients with carcinoid syndrome because spinal anesthesia is thought to have more profound effects on sympathetic innervation. However, this is controversial. Furthermore, epidural analgesia should be started before the induction of labor to minimize pain-induced catecholamine release and allow controlled hemodynamic stability.

24.4.2

Management of Insulinoma During Pregnancy and Peripartum

Surgical resection of insulinoma generally should be avoided during pregnancy.27–30 Medical therapies should be emphasized, including frequent feeding, diazoxide, calcium channel blockers, and subcutaneous octreotide. In patients with recalcitrant and dangerous hypoglycemia, surgical resection or mammalian target of rapamycin (mTOR) inhibitors such as everolimus may have to be used. Early induction of labor can be attempted if the fetus is already mature. Intravenous infusions of octreotide and glucose are important during labor to minimize the risk of severe hypoglycemia.30

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24.5 LACTATION IN WOMEN WITH GUT AND PANCREATIC NETs In women with no evidence of disease or with stable NET disease not requiring active treatments, there are no contraindications to breastfeeding. In patients with progressive disease requiring active treatments, breastfeeding is generally challenging due to concern about drug excretion into breast milk, radioactivity exposure, and logistics. Patients requiring only somatostatin analog treatment may breastfeed safely.19

24.6 CONCLUSIONS While gut and pancreatic NETs before or during pregnancy are rare, they present unique challenges to the patient and treatment team. In the absence of objective evidence from systematic studies, we have provided our opinion on the management of these tumors during pregnancy and in prepregnancy planning in patients with known tumors. We drew heavily on experience with other more common cancers or tumors during pregnancy and lactation, case reports, and our own clinical experience. Our main opinions are that (1) women with a history of appendiceal carcinoids with benign features or benign insulinomas are assumed to have unchanged baseline fertility after surgical removal of the tumor; (2) most women with active gut or pancreatic NETs are advised against pregnancy, with a few exceptions; (3) management of NETs in pregnancy should be multidisciplinary; and (4) medical therapy with somatostatin analog is the mainstay of treatment.

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