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Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours
Best Practice & Research Clinical Endocrinology & Metabolism Vol. 19, No. 2, pp. 229–239, 2005 doi:10.1016/j.beem.2004.10.002 available online at http://www.sciencedirect.com
4 Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours James E. Jackson*
MRCP, FRCR Department of Imaging, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
Insulin- and gastrin-secreting neuroendocrine tumours of the pancreas are often very small at presentation because of the potent effects of their hormonal outputs, and they may therefore prove difficult to localize preoperatively. This is despite the advances made in recent years in cross-sectional imaging techniques, especially multidetector-row computed tomography and endoscopic ultrasound. In this chapter the techniques of angiography and arterial stimulation venous sampling used for the localization of these neoplasms are described; a combination of these two modalities provides both anatomical and functional data that are not available with other localization techniques, thereby improving operative outcome. Key words: neuroendocrine tumours; gastrinoma; insulinoma; pancreas; angiography; calcium; secretin.
Insulinomas and gastrinomas present when small with characteristic clinical symptoms. Both may be cured by surgery but can be difficult to find at operation because of their small size. Preoperative imaging is therefore aimed at documenting the site of the primary tumour or tumours and excluding metastatic disease. This chapter focuses on the techniques of visceral angiography and arterial stimulation venous sampling (ASVS).
INSULINOMA More than 90% of insulinomas are single, benign neoplasms, and surgical excision is curative. Practically all are intrapancreatic, and an experienced surgeon using direct palpation of the pancreas together with intraoperative ultrasound scanning will be able to find the majority of these tumours, supporting the argument by some authors that * Corresponding author. Tel.: C44 2083834939; Fax: C44 2083833121. E-mail addresses: [email protected] (J.E. Jackson), [email protected] (J.E. Jackson). 1521-690X/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
230 J. E. Jackson
their preoperative localization is unnecessary.1,2 It is agreed by the majority, however, that knowledge of the site of the tumour before surgery is helpful in that it allows one to determine not only whether enucleation of the neoplasm or pancreatic resection is likely to be required but also whether the tumour is amenable to removal via a laparoscopic approach.3–6 It should also mean that the operation itself can be performed more rapidly, thereby reducing its reported morbidity and mortality. There are many publications documenting the imaging investigations most commonly used for the preoperative detection of insulinomas, and what is clear from a review of these is that there is no single investigation that consistently outperforms the others.7–11 The three most useful modalities, however, are contrastenhanced computed tomography (CT), endoscopic ultrasound and angiography performed with ASVS, although it is striking how widely discrepant the results for localization are between different centres for each of these techniques (except ASVS), a fact which presumably simply reflects the specialist expertise and equipment (e.g. multidetector-row CT) available in the separate institutions. There can be little doubt that angiography combined with ASVS should not precede the non-invasive investigations of CT and MRI, but it remains a highly sensitive investigation for the precise localization of this tumour and will usually provide more information than endoscopic ultrasound, which is itself an invasive investigation. As with many procedures which require specialist expertise, the choice between these two modalities will depend upon the facilities available at any particular institution, but one of the advantages of the angiographic technique is that it combines both anatomic localization of a tumour with functional information provided by the ASVS which can confirm that a visualized angiographic abnormality is an insulin-secreting neuroendocrine tumour. Additionally, in the unusual instance in which the angiogram fails to demonstrate the tumour, ASVS will still be able to localize the tumour to a particular region of the pancreas.
Angiography Technique Angiography is undertaken via a common femoral artery approach. A selective coeliac axis arteriogram using a digital subtraction technique should be performed initially as this will usually demonstrate most of the pancreas; it is not unusual for an insulinoma to be identified on this first run and thereby guide further selective catheterization in order to delineate its anatomy in greater detail (Figure 1a). A meticulous technique is absolutely essential; bowel movement must be completely abolished by the liberal use of appropriate antiperistaltic agents, and complete immobility of the patient during breath-holding must be achieved. Selective splenic arteriograms in left anterior oblique projections (sometimes accompanied by cranio-caudal and/or caudo-cranial angulations as well in order to project the pancreas clear of the splenic artery) and common hepatic, gastroduodenal and superior mesenteric angiograms are subsequently performed. In many instances the dorsal pancreatic and inferior pancreatico-duodenal arteries will also require catheterization in order to interrogate further a possible angiographic abnormality; occasionally a tumour blush will only be identified on these superselective studies. Insulinomas are seen as well-defined, round or oval vascular blushes that are of increased vascularity when compared with the surrounding normal pancreatic
Angiography and ASVS for pancreatic neuroendocrine tumours 231
(c) 700 600 Hepatic Insulin mU/l
500 400
GDA Insulin mU/l
300
Splenic Insulin mU/l
200
SMA Insulin mU/l
100 0 –120
–20
80
180
280
Figure 1. Female patient with biochemical evidence of an insulinoma but failed localization on CT. (a) Coeliac axis angiogram demonstrates a rounded vascular blush 8 mm diameter in the distal pancreatic body consistent with a neuroendocrine tumour (arrow). (b) Selective splenic arteriogram (left anterior oblique projection) demonstrates the tumour in greater detail (arrow). (c) Graph showing the result of ASVS, with marked elevation of insulin after injection of calcium gluconate into the splenic artery and no response when the same agent is injected into the other visceral artery branches, thus confirming that the visualized tumour is the insulinoma.
parenchyma (Figure 1a and b). They are visualized during the early arterial phase and persist for a variable length of time into the venous phase of the run. Early and prominent venous drainage from the tumour is common. Differentiation between benign and malignant tumours based upon the angiographic appearance of the primary
232 J. E. Jackson
neoplasm is generally not possible, although the demonstration of multiple vascular liver nodules consistent with metastases would obviously support the latter. ASVS8–15 The localization of an insulinoma by ASVS relies upon the fact that a hyperosmolar concentration of calcium in the vessels supplying the tumour will cause degranulation of cells within the neoplasm and release of insulin (and any other hormone secreted by that tumour) into the portal venous system, resulting in a detectable rise in insulin in venous samples obtained from the hepatic veins. This is achieved by injecting 1 mL of 10% calcium gluconate (0.225 mmol) selectively into the vessels supplying the pancreas, which will cause a temporary several-fold increase in molar concentration of calcium within the injected vessels. The splenic, gastroduodenal, superior mesenteric and proper hepatic (i.e. beyond the origin of the gastroduodenal) arteries are those vessels most commonly studied during this technique; an appropriate rise in the level of insulin in the hepatic vein (sampled through a second catheter introduced via a femoral venous approach) will localize the insulinoma to the pancreatic body/tail, antero-superior portion of the pancreatic head and postero-inferior portion of the pancreatic head, respectively. A rise in insulin after injection into the proper hepatic artery suggests the presence of hepatic metastases. Technique Immediately after the diagnostic angiogram, a venous catheter is introduced into the right or middle hepatic vein close to their point of drainage into the inferior vena cava; 1 mL of 10% calcium gluconate is diluted with normal saline to a volume of 4 mL and is injected into each of the vessels supplying the pancreas in turn. The rate of injection of this agent will need to be varied depending upon the size of vessel which has been catheterized and the flow within it as judged by the preliminary injection of a small amount of contrast medium; it is essential that the calcium does not spill into adjacent branches supplying other portions of the pancreas and thus potentially localize the insulinoma to an incorrect site. Venous samples are obtained from the hepatic vein catheter before and 30, 60, 90, 120 and 180 seconds after the calcium injection. A twofold or greater rise in insulin above baseline is considered a diagnostic elevation (Figure 1c). The injection of calcium into subsequent vessels should be performed no sooner than 2 minutes after the final venous sample (5 minutes after the previous calcium injection). This is to allow any rise in insulin concentration that may have occurred after the previous injection to return to baseline levels (or close to them) in order to avoid problems with subsequent interpretation of the results. For the same reason, it is advisable to obtain two venous samples separated by 1 minute before each subsequent calcium injection. If a tumour blush has been demonstrated angiographically, then the vessel supplying this area is usually studied last. Depending upon the results of the selective angiogram performed immediately prior to ASVS, further injections may be made into other vessels supplying an area of angiographic abnormality, most commonly the inferior pancreatico-duodenal or dorsal pancreatic arteries. Results When reviewing the published literature on the preoperative imaging of insulinomas it is important to realize that, because of the rarity of the tumour, most series reporting
Angiography and ASVS for pancreatic neuroendocrine tumours 233
on any more than one or two patients are likely to be from a tertiary referral centre. There may, therefore, be a bias towards insulinomas that are more difficult to localizeso-called ‘occult’ tumours-since those that are easily identified on cross-sectional imaging studies, in particular CT, are less likely to be referred on to a specialist centre. The extent of this bias will obviously depend upon referral practices; in those countries where all pancreatic neuroendocrine tumours are referred on to a specialist centre the bias will be much less than those in which only occult neoplasms are referred. While this may go some way to explain the widely discrepant results reported for the various imaging techniques it is obviously not the whole story, and scanning techniques, equipment and the particular radiological expertise in different centres are probably more important factors. Endoscopic ultrasound (EUS) and angiography, in particular, are very operator-dependent, and this is likely to account almost entirely for the variation in localization results for these two modalities seen from different centres. Angiographic localization, for example, varies from as low as 43% to as high as 94%, with most centres demonstrating a vascular tumour blush in approximately 70% of patients.2,8,10,11,16 ASVS, however, successfully localizes insulinomas in over 90% of individuals in all series because it is much less reliant on operator expertise; it requires only an ability to successfully catheterize the main visceral vessels supplying the pancreas.
Complications Hypoglycaemia occurring as a result of ASVS is possible but is unlikely given the small quantity of calcium gluconate that is injected.15 It is worthwhile, however, checking blood glucose regularly during the procedure and commencing a dextrose infusion only if this falls below 2.2 mmol/L. A dextrose infusion is otherwise not recommended as this may stimulate the normal pancreas to produce insulin, thereby reducing the insulin gradient obtained during ASVS. Other possible complications relate to the angiographic procedure itself and include groin haematoma, allergy to iodinated contrast medium and contrast-medium-induced nephrotoxicity. Transhepatic portal venous sampling17–19 This invasive investigation involves the direct percutaneous transhepatic puncture of the right portal vein and the selective catheterization via this route of the portal venous tributaries. Venous samples are then obtained from the splenic, pancreatic, pancreatico-duodenal and superior mesenteric veins, the site of each sample being recorded on a ‘map’ of the portal venous system. Tumour localization is based upon demonstrating a rise in hormone concentration from a specific region of the pancreas. While the reported sensitivity of this technique is high at approximately 84%, serious complications, which mainly relate to the transhepatic portal vein catheterization, are not infrequent.18 For these reasons, together with the development of the less invasive technique of ASVS described above, the indications for this investigation have practically disappeared. Needless to say, it should never be performed unless other less invasive investigations, including ASVS, have failed to localize the neoplasm. There may still be a role for this investigation in the condition of persistent hypoglycaemia of infancy.20
234 J. E. Jackson
Non-insulinoma pancreatogenous hypoglycaemia syndrome In infancy, hyperinsulinaemic hypoglycaemia is caused by generalized pancreatic b-cell dysfunction which histologically is characterized by nesidioblastosis (the neodifferentiation of islet of Langerhans cells from pancreatic exocrine duct epithelium) and islet hypertrophy.20,21 Similar histological findings in adults with hyperinsulinaemic hypoglycaemia—in whom an insulinoma has not been identified by imaging, at surgery or in the subsequent resected pancreas—have been reported very rarely and have led to the description of a separate clinical entity: the non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS).22–24 Patients with this condition tend to differ clinically from those with an insulinoma in that neuroglycopenic episodes due to hyperinsulinaemic hypoglycaemia tend to occur within 4 hours of a meal and subsequent 72-hour fasts are negative. ASVS is a useful investigation in this group of individuals in that it not only confirms pancreatic b-cell hyperfunction when positive (normal b-cells will not release insulin after the injection of calcium), but also guides the extent of pancreatic resection required for relief of symptoms. This investigation appears less useful in persistent hypoglycaemia of infancy.20 A diagnosis of NIPHS should always be made with extreme caution. It must be remembered that endogenous hyperinsulaemic hypoglycaemia in adults is almost invariably due to an insulinoma, and it is important that a patient is not misdiagnosed as having nesidioblastosis on the basis of negative imaging studies and surgery, as has been reported previously4, particularly as the histological features of this condition may coexist with islet cell tumours.22
GASTRINOMAS Gastrin-secreting tumours are the cause of Zollinger–Ellison syndrome (ZES) and, in approximately one third of cases, occur in the setting of type 1 multiple endocrine neoplasia (MEN-1) with the remainder being so-called sporadic neoplasms. The latter are malignant in 60–90 and up to 50% are extrapancreatic, most commonly within the duodenum, although primary lymph-node gastrinomas occur in approximately 10%.25–27 Gastrinomas associated with MEN-1 are commonly multicentric, particularly within the duodenum, but may be more indolent than sporadic tumours. Current medical therapy can successfully control symptoms due to gastric acid hypersecretion in almost every patient but, despite this, most experts agree that sporadic cases of localized gastrinoma should be excised; operative resection of primary tumours, and of metastatic lymph node deposits if present, remains the only chance of cure which can be achieved in 30–50% of individuals.25,28–30 The role of surgery in patients with associated MEN-1 is more controversial as it is unclear whether this offers survival or disease-free benefit in this population. It has been suggested by some, however, that a primary tumour O2.5 cm in size should be resected in an effort to reduce the risk of development of hepatic metastases31, although this strategy has not been documented as being successful by others.27 Preoperative imaging in both groups is aimed, therefore, at demonstrating the number and location of primary tumours and the presence or absence of local and distant metastases in order to determine which patients might benefit from surgery. It is useful to remember when attempting to localize gastrinomas that 90% occur within what is termed the ‘gastrinoma triangle’, an area bounded by the junction of
Angiography and ASVS for pancreatic neuroendocrine tumours 235
the neck and body of the pancreas medially, the junction of the second and third parts of the duodenum inferiorly, and the junction of the cystic and common bile ducts superiorly. Somatostatin receptor scintigraphy (SRS) is the initial localization study of choice, and this investigation, together with endoscopic ultrasound, will detect more than 90% of gastrinomas. The role of angiography and ASVS is less clearcut, although both should undoubtedly be performed in those patients in whom other investigations have failed to localize a gastrinoma.32 Not all centres would proceed with these studies, however, in a patient with a sporadic gastrinoma shown to have localized disease on SRS and/or EUS, although there is a good argument based upon reports in the literature that they should be performed.33 As is the case with insulinomas, angiography and ASVS provide both anatomical and functional information about the site of neoplasia which is not available from other investigations. In the case of sporadic duodenal gastrinomas, for example, which are often !5 mm in diameter and are notoriously difficult to localize preoperatively, the poor resolution of SRS will not allow differentiation between a duodenal, pancreatic head or primary lymph-node primary. Endoscopic ultrasound in the same individual will often not demonstrate the duodenal primary tumour and may incorrectly localize the primary to normal or metastatic peripancreatic lymph nodes. There is more agreement on the need for angiography and ASVS in patients with MEN-1-associated gastrinomas who are surgical candidates as these tumours are more commonly multicentric. These individuals may also have incidental non-functioning pancreatic tumours, and ASVS is very useful in determining the source of gastrin secretion if localized resection is being considered. Angiography The technique of visceral angiography is almost identical to that used for the localization of pancreatic insulinomas, although selective catheterization of the gastroduodenal and inferior pancreatico-duodenal arteries is more frequently required in order to try and visualize duodenal primaries. Gastrinomas tend to be less intensely vascular than insulinomas (Figure 2), and they may only be identified on superselective studies, especially when involving peripancreatic lymph nodes or duodenum. In addition, there is usually marked thickening of the gastric and duodenal mucosal folds due to acid hypersecretion, which can produce focal blushes that may be confused with hypervascular tumours. The use of angled projections will, however, usually allow differentiation between a mucosal fold and a gastrinoma in that the latter will be seen as a rounded blush on all obliquities (Figure 2b). Hepatic metastases are usually well demonstrated. ASVS32–35 The technique of ASVS is identical to that used for insulinomas. In the original publications describing the technique, secretin was used as the secretagogue, but a more recent publication describes good results using the same dose of calcium gluconate as that used for the localization of insulinomas.33 It is possible that calcium gluconate is the better agent to use: when the conventional stimulatory dose of 30 U of secretin (equivalent to 2.8 nmol) is injected, this produces a rise in secretin concentration by several orders of magnitude in the circulation as a whole, since this is normally only 3.2 pmol/L. This in turn causes gastrin release from the tumour due to
236 J. E. Jackson
Figure 2. Male patient with biochemical evidence of gastrinoma. Endoscopic ultrasound had demonstrated a tumour in the pancreatic neck. (a) Arterial phase of selective inferior pancreatico-duodenal arteriogram demonstrates a 10 mm vascular tumour blush in the region of the pancreatic neck consistent with a neuroendocrine tumour. (b) Late arterial, early capillary phase of the same arteriogram demonstrates multiple small vascular tumour blushes in the first and second parts of the duodenum consistent with neuroendocrine tumours (arrow), confirmed at subsequent surgery.
recirculation of the secretin and is therefore not specific to the artery being injected. This is in contrast to the administration of 1 mL of 10% calcium gluconate (0.225 mmol) which represents less than 1% of the circulating calcium pool and produces no appreciable rise in plasma calcium concentrations and therefore no stimulation of a gastrinoma during recirculation. When injected into the vessel supplying a gastrinoma, both of these secretagogues will produce a significant rise in gastrin concentration in the hepatic vein of at least 25% at 20 seconds or 50% at 30 seconds after administration; a similar rise does not occur when the injection is made into a vessel supplying normal territory. H2-antagonists and proton pump inhibitors, drugs prescribed to patients with gastrinomas, increase fasting gastrin levels since they reduce acid secretion, and there have been concerns that this secondary hypergastrinaemia may interfere with the results of ASVS. However, withdrawal of these agents prior to this investigation for 3 days and 2 weeks, respectively, to ensure that fasting gastrin levels are back to baseline increases the risk of gastrointestinal bleeding and perforation, presenting features of gastrinomas in up to a quarter of patients. Work in the author’s own institution has demonstrated that discontinuation of these drugs is not necessary as it is still possible to localize gastrinomas by ASVS despite higher basal gastrin levels than would be present following withdrawal of therapy. Results Gastrinomas are less commonly demonstrated angiographically than insulinomas and reported sensitivities are as low as 30–40%.34 Like insulinomas, however, the results may be improved by the use of ASVS. There are relatively few data available regarding the usefulness of the combination of angiography and ASVS for localizing primary
Angiography and ASVS for pancreatic neuroendocrine tumours 237
gastrinomas, but a few small series report sensitivities of between 77 and 100%.32–36 A single paper37 has evaluated the technique’s ability to detect hepatic metastases and documents a low sensitivity of 41% but high specificity (a positive result was only seen in 2% of patients without liver deposits). Summary Visceral angiography combined with ASVS is a highly sensitive investigation for the localization of insulinomas and gastrinomas. Its major advantage over other investigations is that the venous sampling provides functional data, which confirm that a visualized abnormality is a functioning neoplasm. The rarity of these tumours means that reports of ASVS are limited to case studies and relatively small series, but these suggest that the technique is extremely useful in patients with insulinomas and gastrinomas. There are good arguments for its performance in all patients being considered for curative surgical resection.
Practice points † visceral angiography combined with ASVS is a highly sensitive technique for the localization of insulinomas and gastrinomas † the angiographic demonstration of small pancreatic neuroendocrine tumours requires a meticulous technique; superselective catheterization of vessels supplying the pancreas and duodenum is often necessary † calcium gluconate may be used as the secretagogue during ASVS when localizing both insulinomas and gastrinomas † ASVS provides functional information about the site of tumours which is not available from other investigations
Research agenda † the true usefulness of ASVS for the detection of hepatic metastases that are not visible on other imaging modalities needs to be studied † the response of other functioning pancreatic neuroendocrine tumours to ASVS using calcium gluconate should be investigated
REFERENCES 1. Huai JC, Zhang W, Niu HO et al. Localization and surgical treatment of pancreatic insulinomas guided by intraoperative ultrasound. Am J Surg 1998; 175: 18–21. 2. Machado MC, da Cunha JI, Jukemura J et al. Insulinoma: diagnostic strategies and surgical treatment. A 22year experience. Hepatogastroenterology 2001; 48: 854–858. 3. Jaroszewski DE, Schlinkert RT, Thompson GB & Schlinkert DK. Laparoscopic localization and resection of insulinomas. Arch Surg 2004; 139: 270–274. 4. Hirshberg B, Libutti SK, Alexander HR et al. Blind distal pancreatectomy for occult insulinoma, an inadvisable procedure. J Am Coll Surg 2002; 194: 761–764.
238 J. E. Jackson 5. Mahon D, Allen E & Rhodes M. Laparoscopic distal pancreatectomy. Three cases of insulinoma. Surg Endosc 2002; 16: 700–702. 6. Hiramoto JS, Feldstein VA, LaBerge JM & Norton JA. Intraoperative ultrasound and preoperative localization detects all occult insulinomas. Arch Surg 2001; 136: 1020–1025. *7. Gouya H, Vignaux O, Augui J et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. Am J Roentgenol 2003; 181: 987–992. *8. Brandle M, Pfammatter T, Spinas GA et al. Assessment of selective arterial calcium stimulation and hepatic venous sampling to localize insulin-secreting tumours. Clin Endocrinol (Oxf) 2001; 55: 357–362. *9. Lo CY, Chan FL, Tam SC et al. Value of intra-arterial calcium stimulated venous sampling for regionalization of pancreatic insulinomas. Surgery 2000; 128: 903–909. 10. Chavan A, Kirchhoff TD, Brabant G et al. Role of intra-arterial calcium stimulation test in the preoperative localization of insulinomas. Eur Radiol 2000; 10: 1582–1586. 11. Brown CK, Bartlett DL, Doppman JL et al. Intraarterial calcium stimulation and intraoperative ultrasonography in the localization and resection of insulinomas. Surgery 1997; 122: 1189–1193. *12. Won JG, Tseng HS & Yang AH. Intra-arterial stimulation test for detection of insulinomas: detection rate, responses of pancreatic peptides, and its relationship to differentiation of tumour cells. Metabolism 2003; 52: 1320–1329. 13. Sung YM, Do YS, Lee MK et al. Selective intra-arterial calcium stimulation with hepatic venous sampling for preoperative localization of insulinomas. Korean J Radiol 2003; 4: 101–108. 14. Pereira PL, Roche AJ, Maier GW et al. Insulinoma and islet cell hyperplasia: value of the calcium intraarterial stimulation test when findings of other preoperative studies are negative. Radiology 1998; 206: 703–709. 15. O’Shea D, Rohrer-Theurs AW, Lynn JA et al. Localization of insulinomas by selective intraarterial calcium injection. J Clin Endocrinol Metab 1996; 81: 1623–1627. 16. Geoghegan JG, Jackson JE, Lewis MP et al. Localization and surgical management of insulinoma. Br J Surg 1994; 81: 1025–1028. 17. Suzuki K, Takahashi S, Aiura K et al. Evaluation of the usefulness of percutaneous transhepatic portal catheterization for preoperatively diagnosing the localization of insulinomas. Pancreas 2002; 24: 96–102. 18. Miller DL, Doppman JL, Metz DC et al. Zollinger–Ellison syndrome: technique, results and complications of portal venous sampling. Radiology 1992; 182: 235–241. 19. Vinik AI, Delbridge L, Moattari R et al. Transhepatic portal vein catheterization for localization of insulinomas: a ten-year experience. Surgery 1991; 109: 1–11. 20. Chigot V, de Lonlay P, Nassogne MC et al. Pancreatic arterial calcium stimulation in the diagnosis and localization of persistent hyperinsulinaemic hypoglycaemia of infancy. Pediatr Radiol 2001; 31: 650–655. 21. Abernethy LJ, Davidson DC, Lamont GL et al. Intra-arterial calcium stimulation test in the investigation of hyperinsulinaemic hypoglycaemia. Arch Dis Child 1998; 78: 359–363. *22. Kaczirek K, Soleiman A, Schindl M et al. Nesidioblastosis in adults: a challenging cause of organic hypersinsulinism. Eur J Clin Invest 2003; 33: 488–492. 23. Thompson GB, Service FJ, Andrews JC et al. Non-insulinoma pancreatogenous hypoglycaemic syndrome: an update in 10 surgically treated patients. Surgery 2000; 128: 937–944. *24. Service FJ, Natt N, Thompson GB et al. Noninsulinoma pancreatogenous hypoglycaemia: a novel syndrome of hyperinsulinaemic hypoglycaemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab 1999; 84: 1582–1589. 25. Norton JA, Alexander HR, Fraker DL et al. Possible primary lymph node gastrinoma: occurrence, natural history and predictive factors: a prospective study. Ann Surg 2003; 237: 650–657. *26. Norton JA & Jensen RT. Current surgical management of Zollinger–Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1). Surg Oncol 2003; 12: 145–151. *27. Mignon M. Diagnostic and therapeutic strategies in Zollinger–Ellison syndrome associated with multiple endocrine neoplasia type 1 (MEN-1): experience of the Zollinger–Ellison syndrome research group: Bichat, 1958–1999. Bull Acad Natl Med 2003; 187: 1249–1258. *28. Norton JA, Alexander HR, Fraker DL et al. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases or survival in patients with Zollinger–Ellison syndrome? Ann Surg 2004; 239: 617–625. 29. Zogakis TG, Gibril F, Libutti SK et al. Management and outcome of patients with sporadic gastrinoma arising in the duodenum. Ann Surg 2003; 238: 42–48.
Angiography and ASVS for pancreatic neuroendocrine tumours 239 30. Hung PD, Schubert ML & Mihas AA. Zollinger–Ellison syndrome. Curr Treat Options Gastroenterol 2003; 6: 163–170. 31. Li ML & Norton JA. Gastrinoma. Curr Treat Options Oncol 2001; 2: 337–346. 32. Imamura M, Takahashi K, Adachi H et al. Usefulness of selective arterial injection test for localization of gastrinoma in the Zollinger–Ellison syndrome. Ann Surg 1987; 205: 230–239. *33. Turner JJ, Wren AM, Jackson JE et al. Localization of gastrinomas by selective intra-arterial calcium injection. Clin Endocrinol (Oxf) 2002; 57: 821–825. 34. Doppman JL, Miller DL, Chang R et al. Gastrinomas: localization by means of selective intraarterial injection of secretin. Radiology 1990; 174: 25–29. 35. Rosato FE, Bonn J, Shapiro M et al. Selective arterial stimulation of secretin in localization of gastrinomas. Surg Gynecol Obstet 1990; 171: 196–200. 36. Cohen MS, Picus D, Lairmore TC et al. Prospective study of provocative angiograms to localize functional islet cell tumours of the pancreas. Surgery 1997; 122: 1091–1100. 37. Gibril F, Doppman JL, Chang R et al. Metastatic gastrinomas: localization with selective arterial injection of secretin. Radiology 1996; 198: 77–84.
4 Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours James E. Jackson*
MRCP, FRCR Department of Imaging, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
Insulin- and gastrin-secreting neuroendocrine tumours of the pancreas are often very small at presentation because of the potent effects of their hormonal outputs, and they may therefore prove difficult to localize preoperatively. This is despite the advances made in recent years in cross-sectional imaging techniques, especially multidetector-row computed tomography and endoscopic ultrasound. In this chapter the techniques of angiography and arterial stimulation venous sampling used for the localization of these neoplasms are described; a combination of these two modalities provides both anatomical and functional data that are not available with other localization techniques, thereby improving operative outcome. Key words: neuroendocrine tumours; gastrinoma; insulinoma; pancreas; angiography; calcium; secretin.
Insulinomas and gastrinomas present when small with characteristic clinical symptoms. Both may be cured by surgery but can be difficult to find at operation because of their small size. Preoperative imaging is therefore aimed at documenting the site of the primary tumour or tumours and excluding metastatic disease. This chapter focuses on the techniques of visceral angiography and arterial stimulation venous sampling (ASVS).
INSULINOMA More than 90% of insulinomas are single, benign neoplasms, and surgical excision is curative. Practically all are intrapancreatic, and an experienced surgeon using direct palpation of the pancreas together with intraoperative ultrasound scanning will be able to find the majority of these tumours, supporting the argument by some authors that * Corresponding author. Tel.: C44 2083834939; Fax: C44 2083833121. E-mail addresses: [email protected] (J.E. Jackson), [email protected] (J.E. Jackson). 1521-690X/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
230 J. E. Jackson
their preoperative localization is unnecessary.1,2 It is agreed by the majority, however, that knowledge of the site of the tumour before surgery is helpful in that it allows one to determine not only whether enucleation of the neoplasm or pancreatic resection is likely to be required but also whether the tumour is amenable to removal via a laparoscopic approach.3–6 It should also mean that the operation itself can be performed more rapidly, thereby reducing its reported morbidity and mortality. There are many publications documenting the imaging investigations most commonly used for the preoperative detection of insulinomas, and what is clear from a review of these is that there is no single investigation that consistently outperforms the others.7–11 The three most useful modalities, however, are contrastenhanced computed tomography (CT), endoscopic ultrasound and angiography performed with ASVS, although it is striking how widely discrepant the results for localization are between different centres for each of these techniques (except ASVS), a fact which presumably simply reflects the specialist expertise and equipment (e.g. multidetector-row CT) available in the separate institutions. There can be little doubt that angiography combined with ASVS should not precede the non-invasive investigations of CT and MRI, but it remains a highly sensitive investigation for the precise localization of this tumour and will usually provide more information than endoscopic ultrasound, which is itself an invasive investigation. As with many procedures which require specialist expertise, the choice between these two modalities will depend upon the facilities available at any particular institution, but one of the advantages of the angiographic technique is that it combines both anatomic localization of a tumour with functional information provided by the ASVS which can confirm that a visualized angiographic abnormality is an insulin-secreting neuroendocrine tumour. Additionally, in the unusual instance in which the angiogram fails to demonstrate the tumour, ASVS will still be able to localize the tumour to a particular region of the pancreas.
Angiography Technique Angiography is undertaken via a common femoral artery approach. A selective coeliac axis arteriogram using a digital subtraction technique should be performed initially as this will usually demonstrate most of the pancreas; it is not unusual for an insulinoma to be identified on this first run and thereby guide further selective catheterization in order to delineate its anatomy in greater detail (Figure 1a). A meticulous technique is absolutely essential; bowel movement must be completely abolished by the liberal use of appropriate antiperistaltic agents, and complete immobility of the patient during breath-holding must be achieved. Selective splenic arteriograms in left anterior oblique projections (sometimes accompanied by cranio-caudal and/or caudo-cranial angulations as well in order to project the pancreas clear of the splenic artery) and common hepatic, gastroduodenal and superior mesenteric angiograms are subsequently performed. In many instances the dorsal pancreatic and inferior pancreatico-duodenal arteries will also require catheterization in order to interrogate further a possible angiographic abnormality; occasionally a tumour blush will only be identified on these superselective studies. Insulinomas are seen as well-defined, round or oval vascular blushes that are of increased vascularity when compared with the surrounding normal pancreatic
Angiography and ASVS for pancreatic neuroendocrine tumours 231
(c) 700 600 Hepatic Insulin mU/l
500 400
GDA Insulin mU/l
300
Splenic Insulin mU/l
200
SMA Insulin mU/l
100 0 –120
–20
80
180
280
Figure 1. Female patient with biochemical evidence of an insulinoma but failed localization on CT. (a) Coeliac axis angiogram demonstrates a rounded vascular blush 8 mm diameter in the distal pancreatic body consistent with a neuroendocrine tumour (arrow). (b) Selective splenic arteriogram (left anterior oblique projection) demonstrates the tumour in greater detail (arrow). (c) Graph showing the result of ASVS, with marked elevation of insulin after injection of calcium gluconate into the splenic artery and no response when the same agent is injected into the other visceral artery branches, thus confirming that the visualized tumour is the insulinoma.
parenchyma (Figure 1a and b). They are visualized during the early arterial phase and persist for a variable length of time into the venous phase of the run. Early and prominent venous drainage from the tumour is common. Differentiation between benign and malignant tumours based upon the angiographic appearance of the primary
232 J. E. Jackson
neoplasm is generally not possible, although the demonstration of multiple vascular liver nodules consistent with metastases would obviously support the latter. ASVS8–15 The localization of an insulinoma by ASVS relies upon the fact that a hyperosmolar concentration of calcium in the vessels supplying the tumour will cause degranulation of cells within the neoplasm and release of insulin (and any other hormone secreted by that tumour) into the portal venous system, resulting in a detectable rise in insulin in venous samples obtained from the hepatic veins. This is achieved by injecting 1 mL of 10% calcium gluconate (0.225 mmol) selectively into the vessels supplying the pancreas, which will cause a temporary several-fold increase in molar concentration of calcium within the injected vessels. The splenic, gastroduodenal, superior mesenteric and proper hepatic (i.e. beyond the origin of the gastroduodenal) arteries are those vessels most commonly studied during this technique; an appropriate rise in the level of insulin in the hepatic vein (sampled through a second catheter introduced via a femoral venous approach) will localize the insulinoma to the pancreatic body/tail, antero-superior portion of the pancreatic head and postero-inferior portion of the pancreatic head, respectively. A rise in insulin after injection into the proper hepatic artery suggests the presence of hepatic metastases. Technique Immediately after the diagnostic angiogram, a venous catheter is introduced into the right or middle hepatic vein close to their point of drainage into the inferior vena cava; 1 mL of 10% calcium gluconate is diluted with normal saline to a volume of 4 mL and is injected into each of the vessels supplying the pancreas in turn. The rate of injection of this agent will need to be varied depending upon the size of vessel which has been catheterized and the flow within it as judged by the preliminary injection of a small amount of contrast medium; it is essential that the calcium does not spill into adjacent branches supplying other portions of the pancreas and thus potentially localize the insulinoma to an incorrect site. Venous samples are obtained from the hepatic vein catheter before and 30, 60, 90, 120 and 180 seconds after the calcium injection. A twofold or greater rise in insulin above baseline is considered a diagnostic elevation (Figure 1c). The injection of calcium into subsequent vessels should be performed no sooner than 2 minutes after the final venous sample (5 minutes after the previous calcium injection). This is to allow any rise in insulin concentration that may have occurred after the previous injection to return to baseline levels (or close to them) in order to avoid problems with subsequent interpretation of the results. For the same reason, it is advisable to obtain two venous samples separated by 1 minute before each subsequent calcium injection. If a tumour blush has been demonstrated angiographically, then the vessel supplying this area is usually studied last. Depending upon the results of the selective angiogram performed immediately prior to ASVS, further injections may be made into other vessels supplying an area of angiographic abnormality, most commonly the inferior pancreatico-duodenal or dorsal pancreatic arteries. Results When reviewing the published literature on the preoperative imaging of insulinomas it is important to realize that, because of the rarity of the tumour, most series reporting
Angiography and ASVS for pancreatic neuroendocrine tumours 233
on any more than one or two patients are likely to be from a tertiary referral centre. There may, therefore, be a bias towards insulinomas that are more difficult to localizeso-called ‘occult’ tumours-since those that are easily identified on cross-sectional imaging studies, in particular CT, are less likely to be referred on to a specialist centre. The extent of this bias will obviously depend upon referral practices; in those countries where all pancreatic neuroendocrine tumours are referred on to a specialist centre the bias will be much less than those in which only occult neoplasms are referred. While this may go some way to explain the widely discrepant results reported for the various imaging techniques it is obviously not the whole story, and scanning techniques, equipment and the particular radiological expertise in different centres are probably more important factors. Endoscopic ultrasound (EUS) and angiography, in particular, are very operator-dependent, and this is likely to account almost entirely for the variation in localization results for these two modalities seen from different centres. Angiographic localization, for example, varies from as low as 43% to as high as 94%, with most centres demonstrating a vascular tumour blush in approximately 70% of patients.2,8,10,11,16 ASVS, however, successfully localizes insulinomas in over 90% of individuals in all series because it is much less reliant on operator expertise; it requires only an ability to successfully catheterize the main visceral vessels supplying the pancreas.
Complications Hypoglycaemia occurring as a result of ASVS is possible but is unlikely given the small quantity of calcium gluconate that is injected.15 It is worthwhile, however, checking blood glucose regularly during the procedure and commencing a dextrose infusion only if this falls below 2.2 mmol/L. A dextrose infusion is otherwise not recommended as this may stimulate the normal pancreas to produce insulin, thereby reducing the insulin gradient obtained during ASVS. Other possible complications relate to the angiographic procedure itself and include groin haematoma, allergy to iodinated contrast medium and contrast-medium-induced nephrotoxicity. Transhepatic portal venous sampling17–19 This invasive investigation involves the direct percutaneous transhepatic puncture of the right portal vein and the selective catheterization via this route of the portal venous tributaries. Venous samples are then obtained from the splenic, pancreatic, pancreatico-duodenal and superior mesenteric veins, the site of each sample being recorded on a ‘map’ of the portal venous system. Tumour localization is based upon demonstrating a rise in hormone concentration from a specific region of the pancreas. While the reported sensitivity of this technique is high at approximately 84%, serious complications, which mainly relate to the transhepatic portal vein catheterization, are not infrequent.18 For these reasons, together with the development of the less invasive technique of ASVS described above, the indications for this investigation have practically disappeared. Needless to say, it should never be performed unless other less invasive investigations, including ASVS, have failed to localize the neoplasm. There may still be a role for this investigation in the condition of persistent hypoglycaemia of infancy.20
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Non-insulinoma pancreatogenous hypoglycaemia syndrome In infancy, hyperinsulinaemic hypoglycaemia is caused by generalized pancreatic b-cell dysfunction which histologically is characterized by nesidioblastosis (the neodifferentiation of islet of Langerhans cells from pancreatic exocrine duct epithelium) and islet hypertrophy.20,21 Similar histological findings in adults with hyperinsulinaemic hypoglycaemia—in whom an insulinoma has not been identified by imaging, at surgery or in the subsequent resected pancreas—have been reported very rarely and have led to the description of a separate clinical entity: the non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS).22–24 Patients with this condition tend to differ clinically from those with an insulinoma in that neuroglycopenic episodes due to hyperinsulinaemic hypoglycaemia tend to occur within 4 hours of a meal and subsequent 72-hour fasts are negative. ASVS is a useful investigation in this group of individuals in that it not only confirms pancreatic b-cell hyperfunction when positive (normal b-cells will not release insulin after the injection of calcium), but also guides the extent of pancreatic resection required for relief of symptoms. This investigation appears less useful in persistent hypoglycaemia of infancy.20 A diagnosis of NIPHS should always be made with extreme caution. It must be remembered that endogenous hyperinsulaemic hypoglycaemia in adults is almost invariably due to an insulinoma, and it is important that a patient is not misdiagnosed as having nesidioblastosis on the basis of negative imaging studies and surgery, as has been reported previously4, particularly as the histological features of this condition may coexist with islet cell tumours.22
GASTRINOMAS Gastrin-secreting tumours are the cause of Zollinger–Ellison syndrome (ZES) and, in approximately one third of cases, occur in the setting of type 1 multiple endocrine neoplasia (MEN-1) with the remainder being so-called sporadic neoplasms. The latter are malignant in 60–90 and up to 50% are extrapancreatic, most commonly within the duodenum, although primary lymph-node gastrinomas occur in approximately 10%.25–27 Gastrinomas associated with MEN-1 are commonly multicentric, particularly within the duodenum, but may be more indolent than sporadic tumours. Current medical therapy can successfully control symptoms due to gastric acid hypersecretion in almost every patient but, despite this, most experts agree that sporadic cases of localized gastrinoma should be excised; operative resection of primary tumours, and of metastatic lymph node deposits if present, remains the only chance of cure which can be achieved in 30–50% of individuals.25,28–30 The role of surgery in patients with associated MEN-1 is more controversial as it is unclear whether this offers survival or disease-free benefit in this population. It has been suggested by some, however, that a primary tumour O2.5 cm in size should be resected in an effort to reduce the risk of development of hepatic metastases31, although this strategy has not been documented as being successful by others.27 Preoperative imaging in both groups is aimed, therefore, at demonstrating the number and location of primary tumours and the presence or absence of local and distant metastases in order to determine which patients might benefit from surgery. It is useful to remember when attempting to localize gastrinomas that 90% occur within what is termed the ‘gastrinoma triangle’, an area bounded by the junction of
Angiography and ASVS for pancreatic neuroendocrine tumours 235
the neck and body of the pancreas medially, the junction of the second and third parts of the duodenum inferiorly, and the junction of the cystic and common bile ducts superiorly. Somatostatin receptor scintigraphy (SRS) is the initial localization study of choice, and this investigation, together with endoscopic ultrasound, will detect more than 90% of gastrinomas. The role of angiography and ASVS is less clearcut, although both should undoubtedly be performed in those patients in whom other investigations have failed to localize a gastrinoma.32 Not all centres would proceed with these studies, however, in a patient with a sporadic gastrinoma shown to have localized disease on SRS and/or EUS, although there is a good argument based upon reports in the literature that they should be performed.33 As is the case with insulinomas, angiography and ASVS provide both anatomical and functional information about the site of neoplasia which is not available from other investigations. In the case of sporadic duodenal gastrinomas, for example, which are often !5 mm in diameter and are notoriously difficult to localize preoperatively, the poor resolution of SRS will not allow differentiation between a duodenal, pancreatic head or primary lymph-node primary. Endoscopic ultrasound in the same individual will often not demonstrate the duodenal primary tumour and may incorrectly localize the primary to normal or metastatic peripancreatic lymph nodes. There is more agreement on the need for angiography and ASVS in patients with MEN-1-associated gastrinomas who are surgical candidates as these tumours are more commonly multicentric. These individuals may also have incidental non-functioning pancreatic tumours, and ASVS is very useful in determining the source of gastrin secretion if localized resection is being considered. Angiography The technique of visceral angiography is almost identical to that used for the localization of pancreatic insulinomas, although selective catheterization of the gastroduodenal and inferior pancreatico-duodenal arteries is more frequently required in order to try and visualize duodenal primaries. Gastrinomas tend to be less intensely vascular than insulinomas (Figure 2), and they may only be identified on superselective studies, especially when involving peripancreatic lymph nodes or duodenum. In addition, there is usually marked thickening of the gastric and duodenal mucosal folds due to acid hypersecretion, which can produce focal blushes that may be confused with hypervascular tumours. The use of angled projections will, however, usually allow differentiation between a mucosal fold and a gastrinoma in that the latter will be seen as a rounded blush on all obliquities (Figure 2b). Hepatic metastases are usually well demonstrated. ASVS32–35 The technique of ASVS is identical to that used for insulinomas. In the original publications describing the technique, secretin was used as the secretagogue, but a more recent publication describes good results using the same dose of calcium gluconate as that used for the localization of insulinomas.33 It is possible that calcium gluconate is the better agent to use: when the conventional stimulatory dose of 30 U of secretin (equivalent to 2.8 nmol) is injected, this produces a rise in secretin concentration by several orders of magnitude in the circulation as a whole, since this is normally only 3.2 pmol/L. This in turn causes gastrin release from the tumour due to
236 J. E. Jackson
Figure 2. Male patient with biochemical evidence of gastrinoma. Endoscopic ultrasound had demonstrated a tumour in the pancreatic neck. (a) Arterial phase of selective inferior pancreatico-duodenal arteriogram demonstrates a 10 mm vascular tumour blush in the region of the pancreatic neck consistent with a neuroendocrine tumour. (b) Late arterial, early capillary phase of the same arteriogram demonstrates multiple small vascular tumour blushes in the first and second parts of the duodenum consistent with neuroendocrine tumours (arrow), confirmed at subsequent surgery.
recirculation of the secretin and is therefore not specific to the artery being injected. This is in contrast to the administration of 1 mL of 10% calcium gluconate (0.225 mmol) which represents less than 1% of the circulating calcium pool and produces no appreciable rise in plasma calcium concentrations and therefore no stimulation of a gastrinoma during recirculation. When injected into the vessel supplying a gastrinoma, both of these secretagogues will produce a significant rise in gastrin concentration in the hepatic vein of at least 25% at 20 seconds or 50% at 30 seconds after administration; a similar rise does not occur when the injection is made into a vessel supplying normal territory. H2-antagonists and proton pump inhibitors, drugs prescribed to patients with gastrinomas, increase fasting gastrin levels since they reduce acid secretion, and there have been concerns that this secondary hypergastrinaemia may interfere with the results of ASVS. However, withdrawal of these agents prior to this investigation for 3 days and 2 weeks, respectively, to ensure that fasting gastrin levels are back to baseline increases the risk of gastrointestinal bleeding and perforation, presenting features of gastrinomas in up to a quarter of patients. Work in the author’s own institution has demonstrated that discontinuation of these drugs is not necessary as it is still possible to localize gastrinomas by ASVS despite higher basal gastrin levels than would be present following withdrawal of therapy. Results Gastrinomas are less commonly demonstrated angiographically than insulinomas and reported sensitivities are as low as 30–40%.34 Like insulinomas, however, the results may be improved by the use of ASVS. There are relatively few data available regarding the usefulness of the combination of angiography and ASVS for localizing primary
Angiography and ASVS for pancreatic neuroendocrine tumours 237
gastrinomas, but a few small series report sensitivities of between 77 and 100%.32–36 A single paper37 has evaluated the technique’s ability to detect hepatic metastases and documents a low sensitivity of 41% but high specificity (a positive result was only seen in 2% of patients without liver deposits). Summary Visceral angiography combined with ASVS is a highly sensitive investigation for the localization of insulinomas and gastrinomas. Its major advantage over other investigations is that the venous sampling provides functional data, which confirm that a visualized abnormality is a functioning neoplasm. The rarity of these tumours means that reports of ASVS are limited to case studies and relatively small series, but these suggest that the technique is extremely useful in patients with insulinomas and gastrinomas. There are good arguments for its performance in all patients being considered for curative surgical resection.
Practice points † visceral angiography combined with ASVS is a highly sensitive technique for the localization of insulinomas and gastrinomas † the angiographic demonstration of small pancreatic neuroendocrine tumours requires a meticulous technique; superselective catheterization of vessels supplying the pancreas and duodenum is often necessary † calcium gluconate may be used as the secretagogue during ASVS when localizing both insulinomas and gastrinomas † ASVS provides functional information about the site of tumours which is not available from other investigations
Research agenda † the true usefulness of ASVS for the detection of hepatic metastases that are not visible on other imaging modalities needs to be studied † the response of other functioning pancreatic neuroendocrine tumours to ASVS using calcium gluconate should be investigated
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