The laparoscopic approach toward hyperinsulinism in children

Seminars in Pediatric Surgery (2007) 16, 245-251

The laparoscopic approach toward hyperinsulinism in children Klaas (N) M. A. Bax, MD, PhD, FRCS(ED),a D. C. van der Zeeb a

From the Sophia Children’s Hospital, Erasmus Medical Centre, Rotterdam, The Netherlands; and the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, The Netherlands.

b

KEYWORDS Hyperinsulinism; Insulinoma; Laparoscopy; Pancreatectomy; Children

Hyperinsulinemic hypoglycemia (HH) in children requiring surgery is rare. Early HH can be the result of focal or diffuse pancreatic pathology. A number of genetic abnormalities in early HH have been identified, but in the majority of patients no abnormality is found. The sporadic focal and diffuse forms as well the autosomal recessive form are particularly therapy-resistant and demand for early surgery. Preoperative discrimination between focal and diffuse disease in early HH is difficult. 18 F DOPA PET in combination with CT is promising as is laparoscopic exploration of the pancreas. Frozen section biopsy analysis has not been uniformly beneficial. If macroscopically no focal lesion is found, limited laparoscopic distal pancreatectomy provides tissue for definitive pathologic examination. Subsequent near total laparoscopic spleen-saving pancreatectomy surgery is not particularly difficult. Later HH may occur in the context of the MEN-1 syndrome and is then multifocal in nature. In MEN-1 patients, a distal spleen-saving pancreatectomy with enucleation of lesions in the head seems justified. Insulinproducing lesions in non-MEN-1 patients should be enucleated. There should always be a suspicion of malignancy. Also, in older children, surgery for hyperinsulinism should be performed laparoscopically. © 2007 Elsevier Inc. All rights reserved.

Hyperinsulinism in children may have several causes. It can be differentiated in normo- or hyperglycemic hyperinsulinism or hypoglycemic hyperinsulinism (Table 1). The treatment of normo- or hyperglycemic hyperinsulinism is basically nonsurgical and the same applies for temporary congenital and iatrogenic hyperinsulinism. Surgery comes into view in the treatment of congenital persistent or recurrent hyperinsulinism and later onset hypoglycemic hyperinsulinism. This paper will deal with those forms of hyperinsulinism that are of surgical interest.

Address reprint requests and correspondence: Klaas (N) M. A. Bax, MD, PhD, FRCS(Ed), Department of Pediatric Surgery, Sophia Children’s Hospital, Erasmus Medical Center Rotterdam, PO Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: [email protected].

1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.06.006

Persistent hyperinsulinemic hypoglycemia in infancy (PHHI) PHHI is characterized by an elevated serum insulin level despite low blood sugar level. In addition, the free fatty acid and ketone body levels in the blood are low. This means that no alternative fuel is left for the brain and that brain damage is likely to occur.8 To understand the pathology and treatment of PHHI, the glucose-stimulated insulin production is briefly discussed.5,9 When glucose in the blood rises, glucose transport into the ␤ cell is facilitated by GLUT-2 glucose transporter. In the cell, glucose is converted by glucokinase into glucose-6-phosphate. Glucose-6-phosphate is metabolized, which generates energy, thereby increasing the ratio ATP/ADP. As a result, the K⫹ ATP channel closes, inhibiting potassium efflux and promoting potassium accumulation in the cell. As a result, the cell membrane depolarizes, which opens the

246 Table 1

Seminars in Pediatric Surgery, Vol 16, No 4, November 2007 Classification of hyperinsulinism

Normo- or hyperglyemic hyperinsulinism: 1. Obesity1-3 2. Critical illness4 Hypoglycemic hyperinsulinism5: 1. Congenital hyperinsulinism a. Temporary i. Maternal diabetes ii. Perinatal asphyxia iii. Small for gestational age b. Persistent or recurrent 2. Later onset hyperinsulinism a. Non syndromatic insulinoma b. Syndromatic insulinoma 3. Iatrogenic hyperinsulinism (Munchausen Syndrome by proxy)6,7

Ca2⫹ channel and causes Ca2⫹ influx, resulting in insulin secretion via exocytosis. Genetic mutations in KCNJ11(formerly KIR 6.2) or ABCC8 (formerly SUR 1) causes the K⫹ ATP channel to close. These genes are located close together on the short arm of chromosome 11. Other pathways for increased insulin production are mutations leading to overactivation of glucokinase (GK) or glutamate dehydrogenase (GLUD1). In the latter event, there is also hyperammonia. In a large proportion of patients, no genetic defect, however, can be demonstrated. The initial treatment of hyperinsulinism is aimed at avoiding hypoglycemia by administration of glucose: 15 to 20 mg/Kg/min as needed. Glucagon, which mobilizes liver glycogen, can also be given, but glucagon is a strong insulin secretagogue.10 Whereas sulfonylureas increase insulin secretion by reacting with their receptor (SUR) to close the K⫹ ATP channel, diaxozide inhibits this process. Chlorothiazide activates the potassium channels by a different mechanism. Somatostatin and its analoge octreotide open the K⫹ 2⫹ influx. Calcium entry blockers ATP channel and inhibit Ca like nifedipin may be effective.5,9 All of these therapeutic modalities have their side effects (Table 2). Surgical therapy comes into view when medical therapy fails (Table 3). The criteria for successful medical management are a feeding regimen acceptable to the family, with normal blood glucose concentrations during reasonable periods of fasting. How long the trial period should be has not been firmly established, but it is the feeling of experts that children should be subjected to surgery sooner rather than later.10 The incidence of neurological impairment is high even when managed in specialized centers,11,12 but the timing of the initial surgery has been quite late. Absolute indications for surgery are: 1. Focal hyperplasia unresponsive to medical treatment; and 2. Glucose infusion dependency despite maximum doses of diazoxide, chlorothiazide, nifedipine, glucagon, and somatostatin.

The morbidity of more than 95% or more pancreatectomy is considerable. The immediate surgical morbidity is high.13 The bile duct is especially at risk. There is a high risk of developing diabetes later on in childhood. There is evidence that the exocrine function is impaired as well, but malnutrition sufficient to cause growth failure may not be apparent for a variable period.10,13,14 So extended pancreatectomy should only be performed in diffuse forms that do not respond sufficiently to medical treatment. The differentiation between focal and diffuse forms has not been easy. Genetic studies are often not helpful as there are many mutations while the founder mutation is often not known. Classic imaging studies using ultrasound, CT, and MRI have not been very helpful either. Cumbersome techniques such as transhepatic venous imaging and sampling as well as hepatic venous sampling after intraarterial calcium infusion have been performed.15,16 Radiation is a concern. Moreover, during transhepatic venous sampling, a controlled hypoglycemia to below 3 mmol/L is mandatory, which is potentially dangerous. Recently, the use of 18 F dehydroxyphenylalanine positron emission tomography (18F DOPA PET) has been used for the detection of focal lesions.17 Five of 14 patients had a focal lesion which was confirmed at surgery and by histology. Of the 9 remaining patients, 4 had surgery, and diffuse disease was confirmed histologically. Intraoperative frozen section biopsy analysis has also been used to differentiate between focal and diffuse disease.18,19 In true focal disease, however, the condition should be cured when the lesion has been taken out, and extensive pancreatectomy should not be necessary. This has not been uniformly the case, and the value of peroperative frozen section biopsy has been queried.20,21 The peroperative yield of focal lesions has been increased by the use of 3.5⫻ magnifying glasses.22 Féketé could see a focal lesion in 31 of 45 cases. The degree of magnification during laparoscopy is much higher, and a higher yield of focal lesions may be expected. We started, therefore, to approach therapy-resistant congenital hyperinsulinism laparoscopically and have used it so far in 4 children. All 4 were around 1 month of age. The first 2 did not have an 18 F DOPA PET, but the last 2 had. The PET was

Table 2

Side effects of treatment of hyperinsulinism

Glucose: organomegaly, central venous line complications for its administration Glucagon: nausea, vomiting, GH release, increased myocardial contractility, decreased secretion of gastric and pancreatic enzymes Diazoxide: fluid retention, cardiac failure, hypertrichosis, hyperurecemia, hypotension, leucopenia, thrombocytopenia Chlorothiazide: hyponatremia, hypokalemia Nifedipin: hypotension Somatostatin or octreotide: suppression of GH, TSH, ACTH; ileus, cholelithiasis, steatorrhea

Bax and van der Zee Table 3

Laparoscopic Approach Toward Hyperinsulinism in Children

247

PHHI form, molecular defect, response to medical treatment, and surgical therapy5

Sporadic form Focal Diffuse Autosomal recessive form Autosomal dominant form Autosomal dominant form Beckwith Wiedemann chromosome 11p15.1 Glycosylation disorders

Molecular defect

Response

? SUR1/Kir6.2

poor

Surgery

SUR1/Kir6.2 glucokinase (activating) glutamate dehydrogenase (activating) duplication/imprinting

poor excellent excellent good

enucleation ⬎95% pancreatectomy ⬎95% pancreatectomy no no ?

phosphomannose isomerase

good

no deficiency

negative in the third patient but positive in the fourth one, in which it seemed located at the inferior border of the pancreas close to the uncinate process (Figure 1A and B).

The laparoscopic technique The laparoscopic technique is rather simple; the child is placed supine with the legs in frog-like position at the lower end of a short operating table, which is tilted in reverse Trendelenburg. The surgeon stays at the lower end of the table with the camera person to his left and the scrub nurse to his right. Two screens are used, one at each side of the head of the patient. The first port is inserted in an open way through the inferior umbilical fold for a 5-mm 30° telescope. The CO2 pneumoperitoneum pressure is at 8 mm Hg and flow at 2 L/min. Pararectally at umbilical level, 3.5-mm ports are inserted for 3-mm working instruments (Figure 2).

The greater curvature of the stomach is suspended with two transabdominal stay sutures (Figure 3). Next the gastrocolic ligament is opened transversally, thus exposing the pancreas (Figure 4). It is amazing how easy the pancreas in the organomegalic newborn child is exposed. In the first, second, and fourth child, a focal lesion could be seen at the angle between the uncinate process and the lower border of the tail of the pancreas (Figure 5). The blood supply looked somewhat different and the lesion looked “hard” at probing, much the same like a cube of ice is touched in a glass of water. If a lesion is not seen or palpated, the lower border of the pancreas is easily mobilized. Care is taken not to open the mesentery of the transverse colon. When a focal lesion is present, it should be enucleated, and if removed completely, the patient is cured as was the case in the first two patients. The last patient remained hypoglycemic and was reoperated a few weeks later under the diagnosis that the focal lesion had not been completely removed. At repeat surgery, it was clear that the focal lesion had been insuffi-

Figure 1 PHHI. Focal lesion in the uncinate process. (A) Positive 18 F DOPA PET. In front of the left kidney a hot spot is seen. (B) Concomitant CT scan showing a lesion in the same spot. (Color version of figure is available online.)

248

Figure 2 Postoperative picture of the abdomen after laparoscopic exploration for PHHI. Infraumbilically a 6-mm port for the telescope had been inserted. The two 3.5-mm Ø ports for the working instruments had been positioned pararectally at umbilical level. In the left hypochondrium, skin marks can be seen as leftovers from the transabdominal wall suspension of the greater curvature of the stomach. (Color version of figure is available online.)

ciently removed. The suspicious area of the first exploration was now removed together with the tail of the pancreas, which resulted in cure as well. The re-exploration was surprisingly easy in contrast to what is usually the case in open surgery. The spleen was left in situ. In the third patient, no focal lesion could be detected and a distal pancreatectomy was performed (Figure 6). Histology as well as the clinic was compatible with diffuse disease. Two months later, the patient had a repeat laparoscopic exploration, and again, the repeat surgery was surprisingly easy. The head of the pancreas as well as the uncinate process were removed, leaving just a little nubbin

Figure 3 The greater curvature of the stomach has been suspended with two transabdominal stay sutures. (Color version of figure is available online.)

Seminars in Pediatric Surgery, Vol 16, No 4, November 2007

Figure 4 The greater omentum is transected using electrocautery. (Color version of figure is available online.)

of pancreas just below the distal end of the choledochal duct (Figure 7). Hypoglycemia persisted. The spleen was left in situ. Surprisingly little literature is available on the use of laparoscopy in the diagnosis and treatment of congenital hyperinsulinism and its relative simplicity even when used for repetitive surgery. The first two patients were reported before.23,24

Later onset hyperinsulinism Later onset hyperinsulinism in children is rare. When searching in the literature for insulinoma in children, it is often not clear whether the focal form of congenital hypersinsulinism is taken together with late-onset hyperinsulinism.

Figure 5 A focal lesion has been identified in the uncinate process. A stay suture has been inserted for traction. (Color version of figure is available online.)

Bax and van der Zee

Laparoscopic Approach Toward Hyperinsulinism in Children

Figure 6 Diffuse PHHI. The distal pancreas has been dissected free from the surrounding structures, leaving the spleen and its vessels intact. (Color version of figure is available online.)

Rickham in 1975 reported on the rarity of islet cell tumors in childhood. He described 3 patients: 1 neonate and 2 older children.25 Vane and coworkers reported on a series of 69 children with a neoplastic metabolic or medical disease seen in the period 1977 to 1987.26 Five had insulinomas and 4 nesiodioblastosis. From the same institute, the experience with pancreatic disorders in the period 1992 to 2004 was reviewed.27 There were 62 patients. Five had nesiodioblastosis. None had late onset insulinoma. A 1971 to 1991 review of pediatric pancreatic tumors at the Hospital for Sick Children in Toronto revealed 6 tumors: 3 solid cystic carcinoma, 1 pancreaticoblastoma, 1 malignant islet tumor, and 1 benign insulinoma.28 Insulinomas are part of the MEN-1 syndrome, and these insulinomas account for 10% to 15% of large series

249

of insulinomas in adults.29 Pancreatic endocrine tumors occur in at least 50% of the patients with MEN-1 syndrome.30 Roughly two-thirds of these tumors are functioning tumors, and pancreatic endocrine tumors in MEN-1 have a tendency to be or to become malignant. Pancreatic disease in MEN-1 patients is multifocal, and enucleation alone results in a high incidence of recurrent disease in the residual pancreas.30 When searching the literature, one is struck by the high frequency of malignancy in children with insulinoma-like manifestations.31-33 The rarity of benign endocrine tumors in the pancreas and especially of insulinomas at any age has been observed before.32,34 In children presenting with insuloma-like symptoms, malignancy should therefore always be suspected. The usual histological pattern of malignant neoplasms, such as nuclear polymorphism, mitotic activity, and infiltration to the surrounding tissues, is often not reliable, the diagnosis being provided by local invasion and metastasis.35 Factitious hyperinsulinism leading to pancreatectomy has been described, and its existence should always be kept in mind.6 An increased plasma insulin/C peptide ratio is useful in identifying factitious hyperinsulinism but is not inevitably present. When the hyperinsulinism is caused by administration of oral antidiabetics, there is no increased ratio. Under such circumstances, plasma level determination of the expected agent should be performed.7 The preoperative localization of insulinomas even in adults has been a problem in the past. The diagnostic yield by dual-phase helical CT with thin section has been reported to be 94.4% accurate,36 by MRI of 88.8%,37 and by roughly 50% by scintigraphic techniques.38 The yield of 18 F DOPA PET seems promising.17,39 The operative yield for inspection in one series was 62.5% and for palpation 96.4%.36 Using laparoscopy and endoscopic ultrasonography, the

Figure 7 Repeat pancreatic exploration for ongoing symptoms in PHHI after distal pancreatectomy. (A) The pancreatic head is still in situ but easily approachable. (B) All but some pancreatic tissue around the distal end of the common bile duct has been removed. (Color version of figure is available online.)

250

Figure 8 CT scan in an 8-year-old girl presenting with insulinoma like symptoms. A double lesion is seen in front of the upper pole of the left kidney.

yield has been quoted to be 96.2%.36 Preoperative imaging in combination with preoperative ultrasonography gives a 100% yield.36,37 When preoperative imaging studies do not localize the tumor, endosurgical ultrasonography should be performed. Not only the pancreas but also the liver should be sonographed. As far as therapy is concerned, well-defined lesions should be enucleated.35 One could argue about the best surgical option in the multicentric disease MEN-1. For lesions in the tail of the pancreas, distal pancreatectomy could be performed. For lesions elsewhere, enucleation together with a distal pancreatomy could be offered.30,35 The spleen, however, should be preserved. Laparoscopic removal of insulinomas in children has been described. In one child with MEN-1, the insulinoma was enucleated, whereas in another child a distal pancreatectomy was performed.40,41 We operated on an 8-year-old child with hyperinsulinemic hypoglycemic attacks with suspicious lesion in the pancreas. At laparoscopy, a double lesion was seen at the lower border of the tail of the pancreas. A spleen-saving distal pancreatectomy was performed. The lesion turned out to be a malignant glucagonoma. A few years later, she presented again with hyperinsulinemic hypoglycemic attacks and liver metastases, for which she received a liver transplant (Figure 8).42,43

References 1. Lee JM, Okumura MJ, Herman WH, et al. Prevalence and determinants of insulin resistance among U.S. adolescents: a population-based study. Diabetes Care 2006;29:2427-32. 2. Littlejohn EE, Weiss RE, Deplewski D, et al. Intractable early childhood obesity as the initial sign of insulin resistant hyperinsulinism and precursor of polycystic ovary syndrome. J Pediatr Endocrinol Metab 2007;20:41-51.

Seminars in Pediatric Surgery, Vol 16, No 4, November 2007 3. Krekoukia M, Nassis GP, Psarra G, et al. Elevated total and central adiposity and low physical activity are associated with insulin resistance in children. Metabolism 2007;56:206-13. 4. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-67. 5. Sperling MA. Hypoglycemia. In Behrman,Kliegman,Jenson, eds. Nelson Textbook of Pediatrics (17th ed., chapter 81). Philadelphia, PA: Saunders, Elsevier Science, 2004:505-18. 6. Giurgea I, Ulinski T, Touati G, et al. Factitious hyperinsulinism leading to pancreatectomy: severe forms of Munchausen syndrome by proxy. Pediatrics 2005;116:e145-e18. 7. Owen L, Ellis M, Shield J. Deliberate sulphonylurea poisoning mimicking hyperinsulinaemia of infancy. Pediatrics 2005;116:e145-e18. 8. Evans M, Amiel SA. Carbohydrates as a cerebral metabolic fuel. J Pediatr 1998;11:99-102. 9. Glaser B, Thornton P, Otonkoski T, et al. Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000;82:79-86. 10. Aynsley-Green A, Hussain K, Hall J, et al. Practical management pf hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000; 82:F98-F107. 11. Meissner T, Wendel U, Burgard P, et al. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 2003;149:4351. 12. Menni F, de Lonlay P, Sevin C, et al. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476-9. 13. McAndrew HF, Smith V, Spitz L. Surgical complications of pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr Surg 2003;38:13-6. 14. Cade A, Walters M, Puntis JWL, et al. Pancreatic exocrine and endoscrine function after pancreatetomy for persistent hyperinsulinaemic hypoglycaemia of infancy. Arch Dis Child 1998;79:435-9. 15. Dubois J, Brunelle F, Touati G, et al. Hyperinsulism in children: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcome in 25 cases. Pediatr Radiol 1995;25:512-6. 16. Abernethy LJ, Davidson DC, Lamont GL, et al. Intra-arterial calcium stimulation test in the investigation of hyperinsulinaemic hypoglycemia. Arch Dis Child 1998;78:359-63. 17. Otonkoski T, Nanto-Salonen K, Seppanen M, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006;55:13-8. 18. Rahier J, Sempoux C, Fournet JC, et al. Partial or near-total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycaemia: the pathologist’s role. Histopathology 1998;32:15-9. 19. Suchi M, Thornton PS, Adzick NS, et al. Congenital hyperinsulinism. Intraoperative biopsy interpretation can direct the extent of pancreatectomy. Am J Surg Pathol 2004;28:1326-35. 20. Jack MM, Walker RM, Thomsett MJ, et al. Histologic findings in persistent hyperinsulinemic hypoglycemia of infancy: Australian experience. Pediatr Dev Pathol 2000;3:532-47. 21. Smith VV, Malone M, Risdon RA. Focal or diffuse lesions in persistent hyperinsulinemic hypoglycemia of infancy: concerns about interpretation of intraoperative frozen sections. Pediatr Dev Pathol 2001;4:138-43. 22. Cretolle C, Fekete CN, Jan D, et al. Partial elective pancreatectomy is curative in focal form of permanent hyperinsulinemic hypoglycaemia in infancy: a report of 45 cases from 1983 to 2000. J Pediatr Surg 2002;37:155-8. 23. Bax NM, van der Zee DC, de Vroede M, et al. Laparoscopic identification and removal of focal lesions in persistent hyperinsulinemic hypoglycemia of infancy. Surg Endosc 2003;17:833. 24. De Vroede M, Bax NM, Brusgaard B, et al. Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy. Pediatrics 2003;114:e520-e522. 25. Rickham PP. Islet cell tumors in childhood. J Pediatr Surg 1975;10:83-6. 26. Vane DW, Grosfeld JL, West KW, et al. Pancreatic disorders in infancy and childhood: experience with 92 cases. J Pediatr Surg 1989;24:771-6.

Bax and van der Zee

Laparoscopic Approach Toward Hyperinsulinism in Children

27. Rabinovitch A, Rescorla FJ, Howard TJ, et al. Pancreatic disorders in children: relationship of postoperative morbidity and the indication for surgery. Am Surg 2006;72:641-3. 28. Jaksic T, Yaman M, Thorner P, et al. A 20-year review of pediatric pancreatic tumors. J Pediatr Surg 1992;27:1315-7. 29. Boukhman MP, Karam JH, Shaver J. Insulinoma: experience from 1950 to 1995. West J Med 1998;169:98-104. 30. Kouvaraki MA, Shapiro SE, Cote GJ, et al. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg 2006;30:643-53. 31. Vossen S, Goretzki PE, Goebel U, et al. Therapeutic management of rare malignant pancreatic tumors in children. World J Surg 1998;22: 879-82. 32. Shorter NA, Glick RD, Klimstra DS, et al. Malignant pancreatic tumors in childhood and adolescence: The Memorial Sloan-Kettering experience, 1967 to present. J Pediatr Surg 2002;37:887-92. 33. Karachaliou F, Vlachopapadopoulou E, Kaldrymidis P, et al. Malignant insulinoma in childhood. J Pediatr Endocrinol Metab 2006;19:757-60. 34. Kissane JM. Tumors of the exocrine pancreas in childhood. Cancer Treat Res 1982;8:99-129. 35. Fernandez-Cruz L, Herrera M, Saenz A, et al. Laparoscopic pancreatic surgery in patients with neuroendocrine tumours: indications and limits. Best Pract Res Clin Endocrinol Metab 2005;19:213-27.

251

36. Gouya H, Vignaux O, Augui J, et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. Surg Gynecol Obstet 1989;168:107-11. 37. Van Nieuwenhove Y, Vandaele S, Op de Beeck B, et al. Neuroendocrine tumors of the pancreas. Surg Endosc 2003;17:1658-62. 38. Virgolini I, Traub-Weidinger T, Decristoforo C. Nuclear medicine in the detection and management of pancreatic islet-cell tumours. Am J Roentgenol 2003;181:987-92. 39. Becherer A, Szabo M, Karanikas G, et al. Imaging of advanced neuroendocrine tumors with (18)F-FDOPA PET. J Nucl Med 2004; 45:1161-7. 40. Lo CY, Tam PK. Laparoscopic pancreatic resection of an insulinoma in a child. Asian J Surg 2003;26:43-5. 41. De Vogelaere K, De Schepper J, Vanhoeij M, et al. Laparoscopic management of insulinoma in a child with multiple endocrine neoplasia type 1. J Laparoendosc Adv Surg Tech A 2006;16:335-8. 42. Ahlman H, Friman S, Cahlin C, et al. Liver transplantation for treatment of metastatic neuroendocrine tumors. Arch Dis Child 2000;82: 392-3. 43. Makowka L, Tzakis AG, Mazzaferro F, et al. Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas. Ann N Y Acad Sci 2004;1014:265-9.