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10.1245/s10434-007-9398-4
Annals of Surgical Oncology 14:2121-2127 (2007)
© 2007 Society of Surgical Oncology
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Original Article

The Role of Intra-Arterial Calcium Stimulation Test with Hepatic Venous Sampling (IACS) in the Management of Occult Insulinomas

Ling-Ming Tseng, MD1,5, Jui-Yu Chen, MD1,5, Justin Ging-Shing Won, MD2,5, Hsiao-Shan Tseng, MD3,5, An-Han Yang, MD, PhD4,5, Sine-E. Wang, MD1,5 and Chen-Hsen Lee, MD1,5

1 Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
2 Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
3 Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
4 Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
5 National Yang-Ming University, Taipei, Taiwan

Correspondence: Address correspondence and reprint requests to: Chen-Hsen Lee, MD; E-mail: chlee{at}vghtpe.gov.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 OPERATION STRATEGY
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Occult insulinomas remain a clinical challenge. Specifically designed protocols are necessary to aid detection and facilitate a focused pancreatic exploration.

Methods: Seventeen non-multiple endocrine neoplasia (non-MEN) patients referred to this medical center in the past 10 years because of equivocal diagnosis, failure of previous operation or difficulty in localization for insulinomas were studied. A routine intra-arterial calcium stimulation test with venous sampling (IACS test) was done for lesion localization. An exploratory laparotomy with intraoperative ultrasound (IOUS) examinations was performed.

Results: Preoperative imaging (sonography, high-resolution computed tomography scan, and magnetic resonance imaging) found six insulinomas, and IOUS found an additional six in the pancreatic regions; all were compatibly indicated by the IACS test. The remaining five patients with occult lesions by IOUS were treated by 40% (1) or 60–70% (4) distal pancreatectomies when insulin gradients were demonstrated on calcium stimulation to the splenic or to the superior mesenteric artery, respectively, and nesidioblastosis was found in each pathology examination. There were no complications related to the arterial stimulation and venous sampling (ASVS) test. No patient had recurrent hyperinsulinism, permanent morbidity, or mortality from surgery.

Conclusions: IACS test helps in the diagnosis of equivocal pancreatogenous hypoglycemia, indicating the pancreatic region of priority exploration and guiding a pancreatic resection.

Key Words: Occult insulinoma • Intra-arterial calcium stimulation test with hepatic venous sampling • Nesidioblastosis • Guided distal pancreatectomy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 OPERATION STRATEGY
 RESULTS
 DISCUSSION
 REFERENCES
 
Hypoglycemia is one of the major causes of altered mental status commonly encountered in the emergency room. It is characterized by quick recovery of consciousness on intravenous infusion of glucose. Pancreatogenous hyperinsulinism is a rare cause of hypoglycemia and is caused by autonomous hypersecretion of insulin by B cell tumors (insulinomas) or less commonly by hyperplasia (nesidioblastosis). Surgery is the only potentially curative treatment because long-term medicinal therapy is unsatisfactory. As insulinomas are generally benign and intrapancreatic solitary small neoplasmas, a simple enucleation of the tumor with preservation of the normal pancreas and adjacent tissue is the goal. However, conventional imaging studies such as ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) often fail to reveal the majority of insulinomas smaller than 2 cm in diameter.1 Failure to resect a tumor because of the inability to localize it before or during surgery occurs in up to 10% of patients.2 Localization of these nondiagnostic conventional imaging cases (occult lesions) can be challenging. Many investigators reported that the best way to localize these occult lesions intraoperatively is to mobilize the entire pancreas and explore by palpation and intraoperative ultrasonography (IOUS).3–8 Problems remain, however, in the management of patients with occult insulinomas and for those with previous negative pancreatic explorations.

A safe, sensitive preoperative localization procedure may facilitate a focused pancreatic exploration by an experienced surgeon. It facilitates a successful surgical therapy and minimizes the risk of complications that may be associated with blind pancreatic resections. The intra-arterial calcium stimulation test with hepatic venous sampling (IACS) technique has been reported to be the most sensitive and powerful preoperative localization tool.2 It could provide further information on the anatomic region of a tumor. The aim of our study was to assess the stimulation test in regionalizing insulin-secreting occult tumors in 17 consecutive patients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
OPERATION STRATEGY
 RESULTS
 DISCUSSION
 REFERENCES
 
Seventeen patients with a provisional diagnosis of insulinoma were referred because of difficulty in diagnosis (seven patients) or for management after a failed operation (two patients) in the past 10 years (1996–2006). The 17 patients all had failure of image studies such as sonography, CT scan, and/or MRI to localize the insulinomas at the referring hospitals and were referred as occult insulinomas. There were 6 men and 11 women aged between 29 and 78 years old (mean 57). All underwent careful history review and diagnostic tests, including a supervised 72-hour fasting and measurements of serum level of immunoreactive insulin (IRI), C-peptide, and insulin antibodies. An IACS test for tumor localization was performed on all patients.

Intra-Arterial Calcium Stimulation Test with Hepatic Venous Sampling Technique
All IACS tests were performed by one experienced radiologist. A 5 Fr. catheter with a side-hole at the tip was positioned through right femoral vein into the right hepatic vein. After catheterization of the right femoral artery with a 4 Fr. catheter, standard pancreatic arteriography was performed with selective injections of nonionic contrast agent into the superior mesenteric (SMA), gastroduodenal artery (GDA), proper hepatic (PHA), and splenic arteries (SA). Following each selective arteriogram, 10% calcium gluconate (Lyphomed, Rosemont, IL, USA), at a dose of 0.01–0.025 meq Ca2+/kg, was diluted with normal saline to a 5mL bolus and injected into the selectively catheterized artery. The injection rate was as rapid as possible, but note that regurgitation should be avoided to prevent contamination. For example, when the catheter was put in the proper hepatic artery, regurgitation of calcium would leak into the gastroduodenal artery that the result would include the hepatic and gastroduodenal artery perfusing region. Blood samples were then obtained through the right hepatic vein catheter. Five-milliliter samples of blood were obtained just prior to the injection and then at intervals of 30, 60, 90, 120, and 180 seconds after the injection of calcium for insulin levels. At least 10 minutes were left between two different sets of sampling. Samples were frozen and stored until the insulin assay was performed. A significant gradient was defined as an increase of 2 folds or more of IRI levels from baseline. A positive test in the SA, SMA, or GDA suggested an insulinoma in the pancreatic tail, body, or head.

Algorithm of Approach
High-resolution localization studies were routinely repeated, including MRI or spiral CT scans of the abdomen, according to a pancreatic protocol (Fig. 1Go). An IACS was done to regionalize the tumors in all patients, regardless of the findings of other localization studies. If the IACS was concordant with the findings of other localization studies, a focused pancreatic exploration was performed for treatment. When the tumor was not localized by other studies, we performed an exploratory laparotomy with IOUS examinations and palpation. IOUS was performed with 7.5-MHz real-time high-resolution transducer. The pancreas was routinely scanned in the longitudinal plane by passing the probe from the pancreatic head, body, and to the tail. Intraoperative ultrasound was considered positive for an insulinoma if a discrete sonolucent mass lesion was well demarcated from the surrounding pancreas. In addition, verification of mass lesion was confirmed with transverse and longitudinal imaging planes.


Figure 1
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  		FIG. 1. An algorithm for the management of 17 patients with pancreatogenous hypoglycemia due to occult origin.

 

   OPERATION STRATEGY
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 OPERATION STRATEGY
RESULTS
 DISCUSSION
 REFERENCES
 
During laparotomy, the pancreatic head or tail was mobilized as the priority exploratory region for careful inspection and palpation according to the results suggested by the calcium stimulation tests. An IOUS was employed in all cases. IOUS was used to confirm the existence of the tumor and to detect the relative position of the main pancreatic duct. Superficial insulinomas in the tail or body and all those in the head and uncinate process were enucleated. Deep-seated insulinomas in the tail or body were removed by distal pancreatectomy. When no lesion was palpable or visualized by IOUS, a distal pancreatectomy was performed, guided by the findings of the IACS. If a significant insulin gradient was found in the SA, a 40% distal pancreatectomy was performed; if a gradient was also found in SMA, a 60–70% distal pancreatectomy was performed (Fig. 1Go). Findings of intraoperative localization procedures (palpation and IOUS) were compared with those of the preoperative invasive localization studies as well as with the final pathological result of the insulinoma. All operations were done by one experienced surgeon (CH.L.).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 OPERATION STRATEGY
 RESULTS
DISCUSSION
 REFERENCES
 
We confirmed that none of the patients were taking oral hypoglycemic agents and all had episodes of hypoglycemic attack and Whipple’s triad. Some had extremely low blood glucose levels, below 20 mg/dL, on their visits to the emergency rooms. In five patients (patients 4, 6, 7, 8, and 10), the diagnosis of insulinoma was equivocal. The other 12 had a definitive biochemical diagnosis of insulinomas. One patient (patient 14) had an 8-hour exploratory laparotomy that failed to find the insulinoma and had postoperative pancreatitis previously (Table 1Go).


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  		TABLE 1. Clinical characteristics of patients
 
All 17 patients had elevated serum IRI levels, and none had multiple endocrine neoplastic syndrome or detectable insulin antibodies. Hypoglycemia was induced by 72-hour supervised fasting in all but four patients (patients 6, 7, 8, and 10). Their calcium stimulation tests all showed a significant gradient in one or two of the three arteries (SA, SMA, and GDA) (Table 2Go). Following the algorithm in Fig. 1Go, we found six insulinomas by preoperative localization studies using CT and/or MRI and IOUS as well. A 0.8-cm and a 0.5-cm insulinoma were found in two patients at the pancreatic head and neck. The other insulinomas were found in the uncinate process and tail. These six insulinomas were enucleated or resected. IOUS was performed in the remaining 11 patients, and an insulinoma was localized intraoperatively by IOUS in six patients. One was located at pancreatic tail, one was in the pancreatic head, and four were in the uncinate process; all were enucleated. These 12 patients all had a solitary insulinoma; each insulinoma was found in the pancreatic region, as suggested by the calcium stimulation tests.


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  		TABLE 2. Findings of preoperative studies and results of calcium stimulated arteriogram test versus surgical findings
 
In five patients, the tumors were intraoperatively neither palpable nor detectable by IOUS, and consequently the pancreatic resection area was governed by insulin gradient, as suggested by the stimulation tests. One patient underwent a 40% distal pancreatectomy, and four patients underwent a 60–70% distal pancreatectomy. All five were found to have nesidioblastosis on pathology examination of the pancreas. No tiny insulinomas were found. The postoperative fasting blood glucose levels in these 17 patients were 92–127 mg/dL during a follow-up period of 4–105 months. There was no operative mortality. Five patients had a pancreatic fistula that was successfully managed without operation. One patient had an incisional hernia. There were no complications related to the IACS. No patient became diabetic or had permanent morbidity or death from surgery. Thus far, none of our 17 patients have undergone resurgery for recurrent hyperinsulinism.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 OPERATION STRATEGY
 RESULTS
 DISCUSSION
REFERENCES
 
Insulinoma is a rare neoplasm characterized by frequent hypoglycemic attacks. Surgical resection is first considered to treat this disease, and therefore it is important to identify its localization. An exhaustive preoperative localization procedure is generally not informative. One reason is that insulinoma is often recognized as a small tumor, and conventional image studies often fail to localize it; another reason is the excellent outcome achieved by experienced surgeons when a policy of combination of bimanual palpation and IOUS is adopted.3–8 However, problems remain in the management of patients with occult insulinomas and for those with previous negative pancreatic explorations. Specifically designed protocols are necessary to aid detection. Occult insulinomas are those not localized by all preoperative image studies; some (about 10%) also may not be localized by IOUS.2 A blind distal pancreatectomy is not appropriate because it may not cure the disease and possible complications are still a risk.9–10 Recent studies indicated that the operation should be terminated under these circumstances and the patient referred to a specialist center.11 The intra-arterial calcium stimulation test with venous sampling (IACS), or arterial stimulation and venous sampling (ASVS) test for regionalizing insulinoma, is a procedure modified by Doppman from the selective arterial secretin injection (SASI) study of Imamura that was used to regionalize gastrinoma.12 It helps to regionalize the lesion pre-operatively with a 94% accuracy,13 and our experience found similar reliability.

Since all of our preoperatively localized insulinomas were visualized by high-resolution techniques as well as IOUS, it seemed unnecessary to repeat image studies for these referred occult insulinomas, retrospectively. In addition, when an insulinoma is localized by IOUS and is located in the region suggested by the calcium stimulation test, no extra tumor could be found in other unsuggested pancreatic regions. We, therefore, propose that a limited regional exploration of the pancreas guided by the calcium stimulation tests may be sufficient. Multiple insulinomas, which account for 10–15% of pancreatogenous hypoglycemia, were not found in the dissection of the pancreatic region, just as they were not suggested by the IACS in this study.14

In 5 of our 17 patients (28.8%), neither preoperative localization studies nor IOUS localized the tumor. These five patients all had positive calcium stimulated arteriogram in the splenic artery, and two had additional positive tests in the SMAs. Distal pancreatectomies in these patients were guided by the calcium stimulation tests. Pathology examinations showed nesidioblastosis in all five patients, but none had a solitary insulinoma. The concept of adult nesidioblastosis15,16 (so-called noninsulinoma pancreatogenous hypoglycemia17) versus a tiny insulinoma missed by ultrathin-sliced pathology examinations is controversial because of the lack of objective pathologic criteria for the diagnosis of nesidioblastosis.18,19 In addition, this diffuse islet cell growth can be found in 40% of autopsy population who did not have any evidence of glucose metabolic disorders.20

Patients who had previous negative pancreatic explorations are challenges. Many have had excessive manipulation of pancreas and biopsies with negative frozen section, which poses an increased risk of postoperative pancreatitis. For example, patient 14 was hospitalized for 1 month for pancreatitis in her previous operation and was medicated for 4 years with Diazoxide without good control of hypoglycemia, leading to morbid obesity. Her repeat imaging studies were negative, but her IACS test was positive in the GDA and strongly positive in the SMA (Fig. 2Go). We re-explored only the pancreatic head and neck without mobilizing the body and tail because of dense adhesion caused by previous operation. A 2.5-cm insulinoma was found in the uncinate process and enucleated. The patient was cured without complications. As surgical morbidity is higher in cases undergoing re-operation, the major goal should be the successful removal during the first operation. Limited surgical exploration with less surgical morbidity can be expected if precise localization is completed prior to surgery.


Figure 2
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  		FIG. 2. Calcium stimulated arteriogram in a 63-year-old female with a 2.5-cm occult insulinoma in the uncinate process of the pancreas that failed to be found in previous laparotomy (case 14).

 
Six of the 17 patients (35.3%) in this series had their tumors located in the uncinate process. Of these six patients, four had a significant insulin gradient in the SMA (cases 2, 3, 15, and 16), one in the GDA (case 11), and one in both (case 14). This suggested that the uncinate process may have a dual arterial supply, from SMA and GDA. This observation helps in interpreting the results of calcium stimulation test. Others have also reported that pancreatic head and uncinate process are the most frequent locations of an occult insulinoma.18,21 Therefore, blind distal and progressive pancreatectomy are no longer justified. We suggest that, with the guidance of a suggesting calcium stimulation test, the uncinate process should be the region of priority to search for an occult insulinoma.

Most patients with an insulinoma have intermittent attacks, so physicians may not directly observe an episode; however, 98% of patients with insulinoma have demonstrable Whipple’s triad after a 72-hour supervised fasting.22 On a rare occasion when the fasting test failed, some clinicians may resort to using image studies to make/confirm the diagnosis of insulinoma. If the lesions are occult, then physicians might hesitate to refer and surgeons would hesitate to operate due to uncertain diagnosis. In this situation, the calcium infusion test can be used both as a diagnostic test and as a regionalizing study for insulinomas.23,24 For example, four of the patients in this series had negative supervised 72-hour fasting test and negative preoperative localization studies (Table 1Go) despite a clear history of Whipple’s triad. The lowest plasma glucose levels on ER records were 15–40 mg/dL. Because of the negative fasting test and negative image localization studies, the diagnosis of insulinoma was delayed for years until a calcium stimulated arteriogram study was done. Thus, our experience suggests that a IACS test may be used to confirm the diagnosis for those patients with a highly suspicious pancreatogenous hypoglycemia but a negative supervised prolonged fasting test.

Although the cure rate for occult insulinomas was 100% in this study, this calcium stimulation test is not without limitations. Factors that may affect its accuracy include anatomical variations of the pancreatic arterial supplies, backflow of the calcium test fluid, and probably lack of calcium receptors in the insulinomas. Failure to acknowledge these pitfalls could lead to misinterpretation of test results. Careful reading of the arteriogram obtained before the calcium stimulation test would help to prevent mistakes. Occasionally, the arteriogram could visualize insulinomas (patients 9 and 12). In this study, exploration of the priority region directed by the calcium tests still needed the IOUS to verify the lesion sites. If an insulinoma was not found in the priority region, it was necessary to explore the entire pancreas before the decision was made to resect part of the pancreas according to the calcium stimulation test.

Our study confirms that IACS test is a very sensitive technique for preoperative localization of insulin-secreting lesion. The complication rate is negligible. IACS is useful in the management of patients with occult insulinomas. It is a diagnostic aid for patients with equivocal pancreatogenous hypoglycemia, especially when a supervised 72-hour fasting test is negative. It helps the surgeon to select the region of priority for pancreatic exploration and thus reduces morbidity. Although it is reported that even ASVS may not be able to distinguish insulinoma from islet hypertrophy or nesidioblastosis,17 our experience supports that it enables regionalization of the hormonally active area and guides pancreatic resection when no lesion is seen by IOUS. Today, with advances in laparoscopic techniques, laparoscopic pancreatic surgery of insulinoma has been shown to be feasible and safe in selected patients.25–27 Since palpation would not be available in these cases, the use of IACS is a good option besides the laparoscopic IOUS and is valuable both for accurate localization and for decision making concerning the most appropriate surgical procedure for laparoscopic approach.28

In conclusion, IACS is helpful in the evaluation, management, and planning of the therapeutic strategy. It is effective and less laborious for occult lesion identification. We recommend that it be considered in all adult patients with pancreatogenous hyperinsulinemic hypoglycemia prior to the surgical exploration.


   ACKNOWLEDGMENTS
 
The authors thank Ms Wen-Lin Chung for assistance in data collection.

Received for publication November 1, 2006. Accepted for publication February 17, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 OPERATION STRATEGY
 RESULTS
 DISCUSSION
 REFERENCES
 

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