This may occur from maternal disease (e.g., CAH, adrenal and ovarian tumors) or use of andr ogenic medication in pregnancy or, rarely, placental aromatase de \201 ciency. 46XY DSD Disorders of testis development XY gonadal dysgenesis can be caused by mutations i n a number of genes controlling male sexual differentiation, including SRY, SF-1, WT-1, and SOX , and can present with normal external genitalia. There is early testicular failure resulting from torsion or infarction. Biochemical defects of androgen synthesis Rare de \201 ciencies of the enzymes 5 A -reduct ase, 17 -hydroxysteroid dehydrogenase, or 3 B -hydroxysteroid dehydrogenase, which are a lso associated with glucocorticoid and mineralocorticoid de \201 ciencies, are autosomal r ecessively inherited and may result in variable degrees of undervirilization. Androgen receptor insensitivity syndrome b Also see Androgen insensitivity syndrome (p. 335 ). Defects of the androgen receptor gene on the X chromosome, or auto- somal post-receptor sig naling genes, may result in complete or partial androgen insensitivity. Complete androgen insensitivity results in normal female external geni- talia and usually o nly presents with testicular prolapse in childhood or primary amenorrhea in adolescence. In partial androgen insensitivity, presentation may vary from mild virilization to micropen is, hypospadias, undescended testes, or only d spermatogenesis. 77-Draznin-Chap77.indd 457 3/31/2011 8:46:55 PM CHAPTER 77 Sexual differentiation 458 Gonadotropin defects Gonadotropin de \201 ciency may occur in hypopituitarism or may be as soci- ated with anosmia (Kallmann syndrome). It usually presents with delayed puberty but i s an occasional cause of micropenis and undescended testes. LH receptor gene defects are rare and result in complete absence of virilization, as the testes are unable to respond to placental hCG. Anti-M llerian hormone de \201 ciency or insensitivity Testes are usually undescended and uterus and fallopian tubes are present. Management of ambiguous genitalia In the newborn period, the infant should be monitored in the hospital for the following: \200 Hypoglycemia (until hypopituitarism is excluded) \200 Salt-wasting (until CAH is excluded) Explain to the parents that the infant appears t o be healthy but has a defect that interferes with determining sex. It is helpful to show t he par- ents the physical \201 ndings as you explain this. Advise them to postpone the re gistration of the birth until after further investigations, and discuss what they will say to relatives and friends. Sex assignment Decision on the sex of rearing should be based on the optimal expected outco me in terms of psychosexual and reproductive function. Parents should be allowed discussion with an endocrinologist, a surgeon specializ- ing in urogenital reconstruction, a psycholo gist, and a social worker. Following the necessary investigations and discussions, early gender assignment is thought to optimize the psychosexual outcome, but further research into this area is still required . Further management \200 If female sex is assigned, any testicular tissue should be remove d. \200 Reconstructive surgery may include clitoral reduction, gonadectomy, and vaginopla sty in girls, and phallus enlargement, hypospadias repair, and orchidopexy in boys. In both sexes, multiple-stage procedures may be required. Testosterone may enhance phallus size in male infants and a trial of therapy is sometimes useful before sex assignment. Hormone replacement therapy may also be required from puberty into adulthood. Continuing psychological support for the parents and child is very important. 77-Draznin-Chap77.indd 458 3/31/2011 8:46:55 PM CONGENITAL ADRENAL HYPERPLASIA 459 Congenital adrenal hyperplasia b Also see Chapter 47, Congenital adrenal hyperplasia in adu lts (p. 239). A number of autosomally inherited enzyme de \201 ciencies result in cor- tis ol de \201 ciency, excess pituitary ACTH secretion, and adrenal gland hyperplasia. 21-hydroxylase de \201 ciency (>90%) The most common cause of CAH results in cortisol and mineralocor- ticoid de \201 ciency, while the build-up of precursor steroids is channeled toward excess adrenal androgen synthesis. Different gene defects in the 21-hydroxylase gene (e.g., deletion, splice site, or point mutation) result in different degrees of enzyme dys function and thus wide variation in phenotypes. Clinical features Virilization of female fetuses may result in clitoromegaly and labial fus ion at birth. 75% have suf \201 cient mineralocorticoid de \201 ciency to cause renal sal t-wasting. Because males have normal genitalia at birth, they may present acutely ill in the neonatal period with vomiting, dehydration, collapse, hyponatremia, and hyperkalemia. Non-salt-wasti ng boys present with early genital enlargement, pubarche, and rapid growth. If untreated or poorly treated, both sexes may develop pubic hair, acne, rapid height veloc ity, advanced bone maturation, and precocious puberty that may result in very short \201 nal height. Nonclassic CAH is due to milder 21-hydroxylase de \201 ciency, and affected girls present in later childhood or adulthood with hirsutism, acne, prema- ture or exaggerated adrenarche , menstrual irregularities, and infertility. 11 BB -hydroxylase de \201 ciency ( 5%) This enzyme, which converts 11-deoxycortisol to cortisol, is the \201 nal step in cortisol syn thesis. In addition to excess adrenal androgens, the overpro- duced precursor corticosteron e has mineralocorticoid activity. Thus, in contrast to salt-wasting in 21-hydroxylase de \201 ciency, these subjects may have hypernatremia and hypokalemia. Hypertension is rarely seen in infancy but may develop during childhood and affects 50 \200\22360% of adults. Speci \201 c investigations for CAH b See also Assessment of ambiguous genitalia (p. 456). \200 Plasma 17A OH progesterone: An elevated level indicates 21-hydroxylase de \201 ciency. It may be dif \201 cult to distinguish this from the physi ological hormonal surge that occurs in the \201 rst 2 days of life. This test should ther efore be repeated (together with 11-deoxycortisol) after 48 hours of age. An ACTH stimulation test may be required to discriminate between the different enzyme de \201 ciencies. Plasma electrolytes may need to be monitored over the \201 rst 2 weeks. \200 Plasma ren in level is also useful to con \201 rm salt-wasting in those with normal serum sodium and relatively mild 21-hydroxylase de \201 ciency. 77-Draznin-Chap77.indd 459 3/31/2011 8:46:55 PM CHAPTER 77 Sexual differentiation 460 Other rare enzyme de \201 ciencies 17AA -Hydrolxylase de \201 ciency This impairs cortiso l, androgen, and estrogen synthesis, but overproduc- tion of mineralocorticoids leads to hy pokalemia and hypertension. 3 B -Hydroxysteroid dehydrogenase de \201 ciency This impairs cortisol, mineralocorticoid, and androgen biosynthesis. Males have hypospadias and undescen ded testes. However, excess DHEA, a weak androgen, may cause mild virilization in females. Steroid acute regulatory protein \200 STAR mutation: 46XY sex reversal and severe adrenal failure. Heterozygous defect. Extremely rare CYPIIAI (P450: side-chain cleavage cytochrome enzyme): 46XY sex reversal and severe adrenal failure. Heterozygous defect. Extremely rare P450 oxidoreductase de \201 ciency: Biochemical picture of combined 21-hydroxylase/17A - hydrolxylase/17, 20 Lyase de \201 ciencies. Spectrum of presentation from children with ambiguous genitalia, adrenal failure, and the Antley \200\223Bixler skel etal dysplasia through to mildly affected individuals with polycystic ovarian syndrome Management \200 Hydrocortisone (10 \200\22320 mg/m 2 per day orally in 3 divided doses). In older patients, prednisone or dexamethasone can also be employed. In addition to treating c ortisol de \201 ciency, this therapy suppresses ACTH and thereby limits excessive producti on of adrenal androgens. Occasionally, higher doses are required to achieve adequate androg en suppression, however overtreatment may suppress growth. Box 77.1 De \201 nitions Disorders of chromosomes These include the following: \200 45X Turner and variants \200 47XXY and variants \200 45X/46XY mixed gonadal dysgenesis \200 46XX/46XY gonadal chime ra 46XX DSD These include the following: \200 Disorders of gonadal (ovarian) development \200 Androgen excess \200 Structural disorders, e.g., cloacal extrophy, vaginal atresia 46XY DSD These include the following: \200 Disorders of gonadal (testicular) development \200 Disorders in androgen synthesis and action \200 Structural disorders, e.g., sever e hypospadias, cloacal extrophy 77-Draznin-Chap77.indd 460 3/31/2011 8:46:55 PM CONGENITAL ADRENAL HYPERPLASIA 461 In salt losers, initial IV \202 uid resuscitation (10 \200\22320 mL/kg normal saline) may be required to treat circulatory collapse. Long-term mineralocorticoid replacement ( \202 udrocortisone 0.05 \200\2230.3 mg/day) may have incomplete ef \201 cacy, particularly in infancy, and sodium chloride supplements are also needed. Up to 4 \200\2235 meq/kg/day spli t qid may be needed in infancy. Reconstructive surgery (clitoral reduction, vaginoplasty) is often performed in infancy and further procedures may be required during puberty. This requires a n experienced surgeon. \200 Warn of the need for extra steroid during stress. Monitoring of hormonal therapy Height velocity and bone age If hydrocortisone therapy is insuf \201 cient, the growth rat e will be above nor- mal and bone age will be advanced. Conversely, if hydrocortisone thera py is excessive, growth is suppressed. 17AOHP Blood levels should be assessed periodically, especially when clinical signs of rapi d growth or bone age advancement occur. Complete normalization of 17 AOHP levels should be avoided, as this often leads to overtreatment. In girls and prepubertal boys, androgen leve ls (testosterone and andros- tendione) can be measured if there is concern about poor contr ol and/ or virilization. Mineralocorticoid and sodium replacement This should be monitored by measuring plasma elect rolytes and renin lev- els and by regular blood pressure assessments. Genetic advice The inheritance of CAH is autosomal recessive, and parents should be informe d of a 25% risk of recurrence in future offspring. If the mutation is identi \201 able on DNA analysis in the child and parents, chorionic villus sampling may allow prenatal diagnosis. Maternal dexamethasone therapy from around 5 \200\2236 weeks of pregnancy can be used to prevent virilization of the female fetus. Further reading Brook CGD (Ed.) (1995). Clinical Pediatric Endocrinology , 3rd ed. Oxford: Blackwell Science. Fluck CE, Miller WL (2006). P450 oxidoreductase de \201 ciency: a new form of congenital a drenal hyperplasia. Curr Opin Paediatr 18:435 \200\223441. Hochberg Z (Ed.) (1998). Practical Algorithms in Pediatric Endocrinology . Basel: Karger Hughes IA (1989). Handbook of Endocrine Investigations in Children . Bristol, UK: John Wrig ht & Sons. Hughes IA, Houk C, Ahmed SF, et al. (2006). Consensus statement on management of intersex d isorders. Arch Dis Child 91:554 \200\223563. Joint LWPES/ESPE Working Group (2002). Consensus statement on 21 hydroxylene de \201 cienc y. J Clin Endocrinol Metab 87:4048 \200\2234053. Wilkins L (1994). In Kappy MS, Blizzard RM, Migeon CJ (Eds.), The Diagnosis and Treatment o f Endocrine Disorders in Childhood and Adolescence , 4th ed. Spring \201 eld, IL: Charles C Thomas. 77-Draznin-Chap77.indd 461 3/31/2011 8:46:55 PM This page intentionally left blank Part 8 Neuroendocrine disorders Emily Jane Gallagher and Dina Green 78 The neuroendocrine system 79 Carcinoid tumors 80 Insulinomas 81 Gastrinomas 82 Glucagono mas 83 VIPomas 84 Somatostatinomas 464 465 472 475 478 481 483 78-Draznin-Chap78.indd 463 3/31/2011 4:02:13 PM CHAPTER 78 The neuroendocrine system 464 The neuroendocrine system Introduction Neuroendocrine cells are found in many sites throughout the body. They are par ticularly prominent in the GI tract and pancreas and share a com- mon embryological origin. These cells have the ability to synthesize, store, and release peptide hormones. Given the prevalence of neuroendocrine cells, most neuroendocrine tumors occur within the g astroenteropancreatic axis. Of these tumors, >50% are traditionally termed carcinoid tumors and have been usually sub- classi \201 ed into foregut, midgut, and hindgut lesions, with the remainder largely comprising pancreatic islet cell tumors. Carcinoid and islet cell tumors are generally slow growing. Further reading Barakat MT, Meeran K, Bloom SR (2004). Neuroendocrine tumors. Endocr Relat Cancer 11(1):1 \200\22318. 78-Draznin-Chap78.indd 464 3/31/2011 4:02:13 PM INCIDENCE 465 Carcinoid tumors De \201 nition and classi \201 cation Historically, these tumors have been divided into t hose arising in the foregut, midgut, or hindgut. Strictly speaking, carcinoid tumors are serotonin secreting and argen- taf \201 n positive (take up silver stain), so the term should be reserved for those tumors that ful \201 ll these criteria. Increasingly, the remainder are being classi \201 ed as neuroendocrine tum ors together with their tissue of origin. About 85% of carcinoid tumors develop in the GI tract, 10% in the lung, and the rest in various organs such as the thymus or ovary. In 30% of patients, carcinoid tumors are multiple, and associations with other malignancies such as adenocarcinomas of the GI tract and prostate are recognized. Incidence The annual incidence of carcinoid tumors is approximately 2.5 per 100,000 populat ion, although postmortem studies suggest that this may be a sig- ni \201 cant underestimat e. 79-Draznin-Chap79.indd 465 3/31/2011 4:02:41 PM CHAPTER 79 Carcinoid tumors 466 Carcinoid syndrome This syndrome only occurs in a subset of patients with carcinoid tumors (<10%). It occurs when suf \201 cient vasoactive substances (e.g., serotonin, histamine, t achykinins, kallikrein, and prostaglandins) are released into the systemic circulation. For this reason, almost all patients with the carcinoid syndrome due to GI tumors have hepatic metastases. In contrast, some bronchial carcinoids may present with classical fea- tures of the syndrome without metastatic disease. The original description of the syndrome includes \202 ushing, diarrhea, asthma, right heart valvular lesions, and pellagra-like skin lesions. In a published series of patients from Sweden with known GI carcinoids, 84% presented with diarrhea, 75% with \202 ushing, and 44% with intestinal obstruction. During the course of the illness, it was noted that 33% of the patients had carcinoid heart disease and 15% com plained of symptoms of wheezing. 1 The carcinoid \202 ush may be precipitated by spicy food, hot drinks, alco- hol, exercise , and postural changes. The cause of \202 ushing is heterogeneous and results from the re lease of a variety of vasoactive substances. Acute attacks typically cause a diffuse erythe matous \202 ush affecting the face and upper thorax, whereas long-standing carcinoid may be associated with a violacious \202 ush and facial telangiectasia. A life-threatening carcinoid crisis ( \202 ushing, BP \202 uctuations, bronchoc- onstric tion, arrhythmias, altered mental status) can be provoked in these patients as a result of anesthesia or surgical manipulation of the tumor. Box 79.1 Carcinoid heart disease \200 Occurs in up to two-thirds of patients with the car cinoid syndrome \200 The mechanism is poorly understood although is thought to be related to serotonin. Pathologically, the lesions are characterized by \201 brous thickening of the endocardium in plaques. The right side of the heart is typically involved. Thickening and retraction of the tricusp id and pulmonary valve lea \202 ets lead to tricuspid regurgitation in nearly all cases an d, less commonly, to pulmonary regurgitation, tricuspid stenosis, and pulmonary stenosis. T he left side of the heart is involved in <10% of cases. Valve replacement can be bene \201 cial, but surgery may be associated with signi \201 cant morbidity and mortality. 1 Norheim I, berg K, Theodorsson \200\223Norheim E, etal. (1987). Malignant carcinoid tumor s: an analy- sis of 103 patients with regard to tumor localization, hormone production, and survival. Ann Surg 206(2):115 \200\223125. 79-Draznin-Chap79.indd 466 3/31/2011 4:02:41 PM DIAGNOSTIC INVESTIGATIONS 467 Diagnostic investigations Pathology Historically, carcinoid tumors have been identi \201 e d by their reaction to silver stains (argentaf \201 n positive). Characterizing the tumor histpathologically is very important and cur- rently includes the use of speci \201 c immunohistochemical stains such as chromogranin A, synaptophysin, sero tonin, and gastrin. Ki67, a marker of cell proliferation, is also used by some centers to guide treatment. Biochemical investigations A 24-hour urinary 5HIAA (serotonin metabolite) assessment has tr adition- ally been the mainstay of both diagnosis and monitoring. The test offers a speci \201 city of nearly 100% and a sensitivity of 70%. Elevated levels are usually only associated with midgut tumors and only once they have meta stasized. Elevated levels correlate well with symp- toms of the carcinoid syndrome and are useful in monitoring response to treatment. False-positive tests may result from dietary sources of serotonin (e.g., bananas, avocados, tomatoes, walnuts, pecan nuts, caffeine, pineapples, and chocolate) and interference from drugs (e.g., acetaminophen, nicotine, phenobarbital, phenacetin). Plasma or platelet serotonin are alternatives to urine testing, although the speci \201 city is uncertain. The most sensitive biochemical marker for neuroendocrine tumors is plasma chromogranin A (f alse positive \200\224renal/liver failure, proton pump inhibitors [PPIs], gastritis, in \202 ammatory bowel disease; false negative \200\224 L-dopa, phenothiazines). For carcinoid tumors the sensitivity of the test is nearly 100%, but the speci \201 city is lower than for urinary 5HIAA as raised levels are found in most neuroendocrine tumors. A plasma gut hormone pro \201 le may also be useful for identi \201 cation of tumor marke rs such as gastrin, pancreatic polypeptide, and somatostatin. Liver biochemistry is an unre liable marker of hepatic involvement as the alkaline phosphatase may remain in the normal r ange despite extensive metastatic disease. Exclude associated inherited syndromes Carcinoid tumors may rarely be associated with multi ple endocrine neo- plasia syndrome type 1 (MEN1), von Hippel \200\223Lindau syndrome (VHL), type 1 neuro \201 bromatosis (NF1), and tuberous sclerosis. 79-Draznin-Chap79.indd 467 3/31/2011 4:02:41 PM CHAPTER 79 Carcinoid tumors 468 Tumor localization and staging The aim of imaging with abdominal US, CT, and MRI is to both localize the primary tumor and assess the extent of metastatic spread. On CT, hepatic carcinoid metastases are usually multifocal, showing enhancement after IV co ntrast and frequently with low-attenuation areas of necrosis. MRI is at least as sensitive as CT, with lesions being iso-intense on T1-weighted images but of high signal on T2-weight ed images. More than 80% of carcinod tumors have somatostatin receptors, and scanning with radiolabele d octreotide can provide very useful informa- tion about the localization and extent of met astatic disease. It frequently reveals previously unidenti \201 ed extrahepatic sites of d isease. PET scanning, where available, can be useful for tumor localization and staging in dif \201 cult cases. Box 79.2 Monitoring treatment \200 Urinary 5HIAA or serum chromogranin A can be useful to monitor response to therapy if these markers were elevated at diagnosis. Imaging modalities are also essential to monitor tumor bulk. 79-Draznin-Chap79.indd 468 3/31/2011 4:02:41 PM TREATMENT 469 Treatment A multidisciplinary approach to the treatment of these tumors is essential. Surgical treatment In patients with local disease, surgery can be curative, but most patien ts have metastatic disease by the time they seek treatment. Even in patients with widespread local disease or distant metastases, surgery may still be of bene \201 t by reducing overall tumor bulk and thereby affording a more favorable respo nse to subsequent nonsurgical therapies. Surgery may be required to alleviate obstructive i ntestinal disease. Liver transplantation may be considered in a very few selected patients in whom extrahepati c tumor spread and primary tumor recurrence has been excluded. Box 79.3 Perioperative management of carcinoid tumors It may be useful to give IV octreotide in the perioperative period, as anesthesia, surgery, and embolization may be associated with the release of various vasoactive peptides that ca n result in hypotension and bron- chospasm, leading to a potentially fatal carcinoid crisis . Medical treatment Certain symptom speci \201 c medical agents can be useful, such as loper amide or codeine for diarrhea. Somatostatin analogs Octreotide and its longer-acting analogs reduce the level of biochemic al tumor markers in the majority of patients and control symptoms in around 70% of cases. H owever, radiological evidence of tumor regression with these agents is rare. Patient resistance to somatostatin analogs is common after a few years. This potential for tachyphylaxis makes the early use of somatostatin ana- logs in asymptomatic patients contro versial. Patients are usually given a test dose of SC octreotide and then gener- ally started on the more convenient longer-acting analogs. Short-acting SC octreotide tid may be continued unt il cover with the longer-acting analog is complete. A continuous IV infusion of octreotide is the most effective treatment for a carcinoid crisis and is generally given at a rate of 50 \200\223100 mcg/h. A new somatostatin analog (SOM230 \200\224pasireotide) with high af \201 nity for receptor subtypes 1, 2, 3, and 5 is currently under evaluation in phase III trials. Hepatic embolization This can be performed by surgeons or, increasingly, by interventional radi- ologists. It is a palliative procedure offering symptom relief by decreasing tumor bu lk. 79-Draznin-Chap79.indd 469 3/31/2011 4:02:41 PM CHAPTER 79 Carcinoid tumors 470 The duration of improvement may be short-lived, and occasionally sig- ni \201 cant side effects such as the hepatorenal syndrome may occur. External beam radiotherapy This may provide palliation in those with symptomatic bone metas tases or spinal cord compression. Chemotherapy Cytotoxic chemotherapy may be considered in patients with advanced, progressiv e, or uncontrolled symptomatic disease. The bene \201 t is debatable. The most promising combination of streptozotocin and 5- \202 uorouracil (5-FU) produces on ly short-lasting responses in 10 \200\22330% of patients with carcinoid tumors, in contrast to the 50 \200\22360% response rate of pancreatic neuroendocrine tumors. Capecitabine (pro drug of 5-FU) can be adminis- tered orally, and it may offer a more speci \201 c antitumor effect. Side effects (e.g., \202 u-like symptoms, fatigue, weight loss, bone marrow suppression) are generally less severe than with conventional chemother- apy but are still the main limi tation to its use. Alpha2b -Interferon There is a good biochemical response rate (about 45%), with clinical im provement of the symptoms of carcinoid syndrome in 70% of patients. Tumor shrinkage has rar ely been described. A combination of octreotide and A 2b-interferon has been shown to produce biochemical and s ymptomatic improvement in some patients previously resistant to either drug alone. However, there is limited effect on tumor size. Radioactive isotope therapy These are relatively new modalities with few long-term data. There is increasing evidence to suggest that if a positive diagnostic uptake scan is obtain ed, therapeutic treatment with the relevant radionu- clide can offer at least signi \201 c ant symptomatic improvement. A few stud- ies have suggested tumor stabilization or regressi on may be achieved in some cases. Radiolabeled somatostatin analogs Radiolabeled somatostatin analogs, such as 111 InDTPA oct reotide, the newer 90 YDOTA octreotide, and 177 Lu octreotate, which have high af \201 nit y for type 2 somatostatin receptors, have been used as therapy. Because 111 InDTPA octreoti de has low tissue penetration, and a stable coupling of alpha- or beta-emitting isotopes to DTPA octreotide could not be achieved, newer compounds ( 90 YDOTA octreotide, 177 Lu octre otate) were developed. 90 YDOTA octreotide may result in partial remission in 10 \200\22325% of patients, while 17 7 Lu octreotate has proved very successful in achieving tumor regression in animal models w ith encouraging preliminary human studies (remission in 38% and stable disease in 4% at 3 m onths). 79-Draznin-Chap79.indd 470 3/31/2011 4:02:41 PM PROGNOSIS 471 Radiolabeled MIBG MIBG is structurally related to norepinephrine. After IV injection, up to 70% of carcinoid tumors concentrate signi \201 cant amounts of the compound. Limited published data suggest 65 \200\22380% of these patients treated with MIBG have pall iation of symptoms for varying lengths of time (6 \200\22324 months). Future treatments Antiangiogenic agents such as inhibitors of vascular endothelial growth f actor are currently being evaluated and may be of bene \201 t in preventing tumor progress ion. Pellagra Rarely, pellagra may develop due to nicotinamide de \201 ciency secondary to exce ssive tryptophan metabolism. Nicotinamide supplementation is therapeutic. Prognosis The site of origin and the size of the primary tumor, together with the extent of metastatic disease, largely determine the prognosis. Many carcinoid tumors are indolent and are frequently a postmortem \201 nding having caused no signi \201 cant symptoms during life. When the disease is con \201 ned locally to the region of the primary tumor, the 5-year survival is >90%. Individual patients have been reported to live 20 \200\22330 years after the diagnosis of m etastatic carcinoid tumor, but this should not be considered a benign disease. The 5-year s urvival rate when hepatic metastases are present is approximately 20 \200\22340% with a med ian survival time being about 2 years. Increasingly, evidence is suggesting that both survival time and quality of life for patien ts are improved by the use of more active and aggressive therapy. The prognosis is greatly in \202 uenced by the development of carcinoid heart disease and whether it is then amenable to treatment by heart valve replacement. Further reading Kaltsas G, Rockall A, Papadogias D, et al. (2004). Recent advances in radio logical and radionuclide imaging and therapy of neuroendocrine tumors. Eur J Endocrinol 151 (1):15 \200\22327. Oberg K (2002). Carcinoid tumors: molecular genetics, tumor biology, and update of diagnosi s and treatment. Curr Opin Oncol 14(1):38 \200\22345. 79-Draznin-Chap79.indd 471 3/31/2011 4:02:41 PM CHAPTER 80 Insulinomas 472 Insulinomas De \201 nition An insulinoma is a tumor of the endocrine pancreas that causes hypoglyc- em ia through its inappropriate secretion of insulin. Unlike other endocrine tumors of the pan creas, where malignancy is common, >90% of insulino- mas are benign. More than 80% of insulinomas are solitary, 10% are multiple and 10% are malignant. 50% of patients with multiple insulinomas have MEN1. Insulinomas are found with equal frequency throughout the head, body and tail of the pancreas. Incidence The annual incidence of insulinoma is of the order of 1 \200\2232 per million pop ulation. Clinical presentation Symptoms of hypoglycemia may include both adrenergic (e.g., pallor, s weating, tremor, and tachycardia) and neuroglycopenic (e.g., irritability, confusion, aggre ssion, seizures, and coma) symptoms. Patients typically give a history of relief of symptoms with food. Weight gain occurs in at least 30% of patients. Biochemical investigations The gold standard test remains the supervised 72 hour fast. More than 95% of cases can by diagnosed by the 72 hour fast. While fasting, the patient may con sume only caffeine-free beverages, must remain active and exercise normally. A laboratory g lucose measurement of <40 mg/dL should be found during symptoms in association with an inap propriately normal or elevated insulin and C-peptide level. An insulin/glucose ratio of >0. 3 is abnormal and consistent with organic hyperinsulinism. The presence of sulfonylurea metabolites in the urine or plasma should be excluded, and the abuse of exogenous insulin considered. 80-Draznin-Chap80.indd 472 3/31/2011 4:03:05 PM TUMOR LOCALIZATION 473 Tumor localization b See Table 80.1. Islet cell tumors are often small and may not be detected by any imag- ing technique. The a vailable radiological modalities have a wide reported range of sensitivity that is frequent ly dependent on the equipment and the operator. MRI or spiral CT correctly detects >60% of tumors, but preoperative localization can be dif \201 cult in tumors <1 cm in diameter. Arterial stimulation (with calcium or secretin) followed by venous sam- pling can localize approximately 90% of insulinomas but carries the risks of a more invasive technique. Endoscopic US, which requires specialized equipment and expertise, may identify tumors as s mall as 5 mm. The head of the pancreas is visual- ized with the probe in the duodenum and t he body and tail with it in the stomach. Intraoperative US using a transducer applied directly to the pancreas improves the sensitivity of US to over 90%. Experienced surgeons can frequently identify the lesions intraopera- tively by palpation al one. The risk of multiple tumors makes a thorough examination of the whole pancreas essenti al at operation. Somatostatin receptor scintigraphy has been shown to be useful in detecting insulinomas but it is dependent on somatostatin receptor sub- type expression by the tumor. Table 80.1 Radiological localization of pancreatic insulinomas Localization technique Reported sensitivity (%) Transabdominal US 30 \200\22361 Endoscopic US 80 Intraoperative US 90 CT 42 \200\22378 MRI 20 \200\223100 Octreotide scanning 68 \200\22386 Pancreatic arteriography 29 \200\22390 Venous sampling 84 80-Draznin-Chap80.indd 473 3/31/2011 4:03:05 PM CHAPTER 80 Insulinomas 474 Treatment The treatment of choice in all but very elderly or debilitated patients is surgic al removal. The perioperative mortality rates are <1% in the hands of an experienced surgeo n. The mortality is largely in \202 uenced by the inci- dence of acute pancreatitis and pe ritonitis. Postoperative hyperglycemia may occur even following partial pancreatectomy. Medical treatment to control symptoms may be achieved using a com- bination of diazoxide and octreotide. Radiolabeled somatostatin analog therapy may induce a biochemical and symptomatic response in patients with malignant insulinomas, and some small-scale studies report tumor regressio n. Prognosis Following removal of a solitary insulinoma, life expectancy is restored to normal . Malignant insulinomas, with metastases usually to the liver, have a natu- ral history of ye ars rather than months and symptoms may be controlled with medical therapy or speci \201 c antitumor therapy using streptozotocin and 5-FU. Average 5-year survival estimated to be approximately 35%. 80-Draznin-Chap80.indd 474 3/31/2011 4:03:05 PM CLINICAL PRESENTATION 475 Gastrinomas De \201 nition Gastrin, synthesized by the G cells situated predominantly in the gastric a ntrum, is the principal gut hormone stimulating gastric acid secretion. The Zollinger \200\223Ellison (gastrinoma) syndrome is due to the excessive release of gast rin by neuroendocrine tumors of the GI tract and pancreas. Gastrinomas most commonly arise in the duodenum (70%), with the remainder arising from the pancreas or adjacent lymph nodes . About 60% of patients have metastatic disease at the time of diagnosis. Prevalence The estimated prevalence is of the order of 1 per million population. Clinical presentation Patients typically present with peptic and/or esophageal ulcers that are multiple and refractory to standard medical treatment. Complications of peptic ulcer disease, such as perforation, hemorrhage, and pyloric stenosis, are frequently seen. Malabsorption and diarrhea may be the main presenting complaint in 10 \200\22320% of patien ts and is due to acid-related inactivation of enzymes and mucosal damage in the upper small bowel. Up to 25% of gastrinoma patients may have MEN1. In this context, the prevalence of multiple gastrinomas is higher than for sporadic tumors. 81-Draznin-Chap81.indd 475 3/31/2011 8:47:54 PM