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New Diagnostic Criteria for the Localization of Insulinomas with the Selective Arterial Calcium Injection Test: Decision Tree Analysis
CLINICAL STUDY
New Diagnostic Criteria for the Localization of Insulinomas with the Selective Arterial Calcium Injection Test: Decision Tree Analysis Kenji Kajiwara, MD, PhD, Takuji Yamagami, MD, PhD, Naoyuki Toyota, MD, PhD, Hideaki Kakizawa, MD, PhD, Masaki Urashima, MD, Masashi Hieda, MD, PhD, Yasutaka Baba, MD, PhD, Tomoyuki Akita, PhD, Junko Tanaka, PhD, and Kazuo Awai, MD, PhD ABSTRACT Purpose: To explore optimal diagnostic criteria for localizing insulinomas with the selective arterial calcium injection (SACI) test using decision tree analysis. Materials and Methods: A retrospective study included 86 vessels of 18 patients (5 men, 13 women; mean age 67 y; range, 49– 73 y) with insulinomas who underwent SACI test between June 2007 and May 2016. Of 27 insulinomas, 7 were found in the head, 13 in the body, and 7 in the tail of the pancreas. Two patients had multiple tumors. To identify optimal diagnostic criteria, decision tree analysis was performed, and sensitivity, specificity, and accuracy of the conventional and the proposed new diagnostic criteria (plasma insulin concentration after calcium injection [ICpost] > 2.0 plasma insulin concentration before calcium injection [ICpre]) were compared. Results: The proposed new diagnostic criteria for insulinoma obtained by decision tree analysis were (i) ICpost > 2.7 ICpre and maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre and maximum insulin concentration < 60.3 μIU/mL with ICpre being 7.5 μIU/mL. Sensitivity, specificity, and accuracy of the new criteria for the SACI test were 100%, 91.4%, and 94.2; sensitivity, specificity, and accuracy of conventional criteria were 100%, 69.0%, and 79.1%. Conclusions: New diagnostic criteria for localization of insulinomas with the SACI test yielded higher diagnostic performance than conventional criteria.
ABBREVIATIONS ICpost ¼ plasma insulin concentration after calcium injection, ICpre ¼ plasma insulin concentration before calcium injection, SACI ¼ selective arterial calcium injection
From the Department of Radiology (K.K., T.Y.), Medical School, Kochi University, 185-1 Kohasu, Oko-cho, Nankoku 783-8505, Japan; Departments of Diagnostic Radiology (K.K., Y.B., K.A.) and Epidemiology, Infectious Disease Control and Prevention (T.A., J.T.), Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Department of Diagnostic Radiology (N.T.), National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; Department of Radiology (H.K.), Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan; and Department of Diagnostic Radiology (M.U., M.H.), Hiroshima City Hospital, Hiroshima, Japan. Received April 23, 2018; final revision received and accepted May 18, 2018. Address correspondence to K.K.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2018 J Vasc Interv Radiol 2018; ▪:1–5 https://doi.org/10.1016/j.jvir.2018.05.015
Insulinomas are the most common islet cell tumors. Diagnosis of insulinomas rests on establishing evidence of symptomatic hypoglycemia accompanied by inappropriate insulin and/or proinsulin levels after a period of prolonged fasting. When these tumors come to clinical attention, they are usually small, solitary, and intrapancreatic. Their location is determined by imaging studies, including ultrasound (US), computed tomography (CT), magnetic resonance imaging, and endoscopic US (1,2). Preoperative localization in the work-up for insulinoma increases the chance for curative surgical resection (3,4). The selective arterial calcium injection (SACI) test with hepatic venous sampling for insulin was developed to localize discrete insulin-secreting islet cell tumors to regions of the pancreas (5). A > 2-fold increase after stimulation in the serum insulin concentration over its baseline
2 ▪ Localization of Insulinomas with SACI Test
EDITORS’ RESEARCH HIGHLIGHTS New diagnostic criteria for localization of insulinomas using the selective arterial calcium injection test provided both higher specificity and higher accuracy compared with conventional criteria in a study of 86 visceral arteries in 18 patients. Plasma insulin concentration increases of > 2.7-fold after calcium and new values for insulin concentration changes are proposed. The small number of patients precludes larger or controlled studies, and this study bears further validation. Nevertheless, these criteria may enhance surgical confidence and planning for surgical exposure and resection.
value is considered to be positive for pancreatic insulinoma. Although the documented sensitivity of the SACI test for localizing insulinomas is 84%–100%, its specificity is poor, and no case-control studies have been reported (6). In some of our cases, the test results may have been falsepositive (Fig 1a–c). Consequently, the purpose of this study was to identify optimal diagnostic criteria for localizing insulinomas with the SACI test and perform decision tree analysis.
MATERIALS AND METHODS This study was approved by the institutional ethics committee. The principles of the Declaration of Helsinki were applied, and informed consent for the procedures was obtained from all patients.
Patients Between June 2007 and May 2016, 18 patients (5 men, 13 women; mean age 67 y; range, 49–73 y) underwent the SACI test at our institution and affiliated hospitals (Table 1). The SACI test with hepatic venous sampling of the insulin level was performed for preoperative localization of pancreatic insulinoma. All patients manifested hypoglycemia in the presence of an inappropriately elevated insulin level. All patients whose pancreatic insulinoma was histologically confirmed and who underwent surgery were reviewed retrospectively. Before the SACI test, all patients had undergone other preoperative tumor localization procedures (dynamic CT and endoscopic US). The SACI test results were compared with dynamic CT and endoscopic US findings and surgery results. In clinical and imaging followup studies, patient symptoms, hemoglobin A1c level, and dynamic CT findings were assessed.
Technique For selective arterial calcium injection, a 5-F catheter was introduced in the right hepatic vein via femoral venous puncture. A 4-F catheter was placed in the celiac artery and
Kajiwara et al ▪ JVIR
superior mesenteric artery via femoral artery puncture, followed by insertion of a 1.9-F microcatheter. After catheterization, the gastroduodenal, superior mesenteric, splenic (proximal and distal segments), and hepatic arteries were selectively cannulated in turn. The interval between each calcium injection was at least 5 minutes. Calcium gluconate (10% solution) at a dose of 0.025 mEq Caþþ/kg was diluted to a 5-mL bolus and injected rapidly into each artery. Blood samples for insulin determination were obtained from the right hepatic vein 0, 20, 40, 60, 90, and 120 seconds or 0, 30, 60, and 120 seconds after the calcium injection. Sampling results from the right hepatic vein were plotted for each patient. Calcium gluconate was delivered to 86 vessels (18 gastroduodenal, 18 superior mesenteric, 18 proximal splenic, 14 distal splenic, and 18 hepatic arteries). When a positive response was elicited on calcium injection into the splenic artery, the tumor was localized to the body or tail of the pancreas; when it was identified on injection into the duodenal and/or superior mesenteric arteries, the tumor was localized to the pancreatic head or neck.
Statistical Analysis Hemoglobin A1c levels before and after injection were compared with the paired t test. Differences of P < .05 were considered statistically significant. Data analysis was performed with JMP Version 11 (SAS Japan, Tokyo, Japan). Variables were entered into partition modeling analysis in JMP for decision tree analysis. The sensitivity, specificity, and accuracy of the new diagnostic criteria determined with decision tree analysis was compared with conventional diagnostic criteria (plasma insulin concentration after calcium injection [ICpost] > 2.0 plasma insulin concentration before calcium injection [ICpre]).
RESULTS The median maximal increase in insulin concentration over the baseline in the dominant artery was 14.8-fold (range, 2.7-fold to 207.3-fold); it was 3.4-fold (range, 2.0-fold to 39.3-fold) over the baseline in the artery suspected as falsepositive. Of 27 insulinomas, 7 were found in the head, 13 in the body, and 7 in the tail of the pancreas at surgery. Two patients had multiple tumors. Mean tumor size was 13 mm ± 6.9. Surgery identified the pathologic source of excessive insulin secretion in all 18 patients. Euglycemia was obtained by surgery in all 18 patients. During follow-up (mean 68.5 months; range, 10–117 months), none of the operated patients experienced further hypoglycemic episodes; dynamic CT detected no new tumors. The mean hemoglobin A1c level increased from 4.7% ± 0.44 to 5.3% ± 0.47 in 17 patients after surgery (P < .01, paired t test); postoperative hemoglobin was not assessed in the other patient. Sensitivity, specificity, accuracy, and positive predictive value for the conventional criteria (ICpost > 2.0 ICpre) were 100%, 69.0%, 79.1%, and 60.9% (Table 2). Comparison with endoscopic US and dynamic CT
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Figure 1. A 68-year-old woman with insulinoma. (a) CT image showing a hypervascular nodule (arrowhead) in the pancreatic body. (b) Celiac angiogram showing a hypervascular tumor (arrowhead), 10 mm in diameter, in the body of the pancreas. The right hepatic artery arises from a branch of the celiac artery. (c) A 19.8-fold increase in insulin level in the proximal splenic artery suggested insulinoma in the pancreatic body. The 2.2-fold increase in insulin level in the right hepatic artery was suspected to be a false-positive finding. GDA ¼ gastroduodenal artery; RHA ¼ right hepatic artery; SMA ¼ superior mesenteric artery; SpA (d) ¼ distal splenic artery; SpA (p) ¼ proximal splenic artery.
findings suggested that 18 of 86 vessels (20.9%) in 12 of 18 patients were false-positive results (6 gastroduodenal, 3 superior mesenteric, 3 proper hepatic, 4 proximal splenic, and 2 distal splenic arteries). The proposed new diagnostic criteria for insulinoma obtained by decision tree analysis were (i) ICpost > 2.7 ICpre and maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre and maximum insulin concentration < 60.3 μIU/mL with ICpre 7.5 μIU/mL (Fig 2). Sensitivity, specificity, accuracy, and positive predictive value of the new criteria for the SACI test were 100%, 91.4%, 94.2%, and 84.8% (Table 3). Comparison with endoscopic US and dynamic CT findings suggested that 5 of 86 vessels (5.8%) in 3 of 8 patients were falsepositive (gastroduodenal, hepatic, and proximal splenic arteries, n ¼ 1 each; distal splenic arteries, n ¼ 2). No technical errors or anatomic variants were apparent on review of angiograms. There were no immediate, short-term, or long-term complications resulting from the SACI test
procedure, and there were no hypoglycemic episodes after calcium injection during the SACI test.
DISCUSSION Initial reports claimed that with the SACI test, insulinomas were accurately localized (7) with a sensitivity of 84%– 100% (4,8–10). However, specificity was suboptimal. In a study comprising 45 cases, Guettier et al (10) obtained a positive response in a single vessel in 16 cases (35.6%) and a positive response in 2 vessels in 24 cases (53.3%). They suggested that an overlap in arterial territory, tumor behavior, or problems related to the specificity of the test were implicated. They also found that in 2 false-positive cases, the test failed to detect the true insulinoma. Thompson et al (11) reported a positive response in a single vessel in 31 of 42 cases (73.8%) and a positive response in 2 vessels in 11 of 42 cases (26.2%). They cited significant variations in the pancreatic arterial anatomy and suggested
4 ▪ Localization of Insulinomas with SACI Test
Kajiwara et al ▪ JVIR
Table 1. Demographic and Clinical Data of 18 Patients Who Underwent Selective Arterial Calcium Injection Test for Preoperative Localization of Insulinoma Characteristics
N (%)
Sex Male
5 (27.8)
Female
13 (72.2)
Age, y
67
Hypoglycemic episodes
18 (100) 4.7% ± 6.9%
Hemoglobin A1c Total number of tumors Tumor size, mm, mean ± SD
27 13 ± 6.9
Pancreas location Head
7 (25.9)
Body
13 (48.1)
Tail
7 (25.9) Figure 2. Decision tree demonstrating optimal cutoff value for localizing insulinomas. JMP was used for the analysis. The proposed new diagnostic criteria were (i) ICpost > 2.7 ICpre and maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre and maximum insulin concentration < 60.3 μIU/mL with ICpre 7.5 μIU/mL.
Table 2. Diagnosis with Conventional Criteria Final Diagnosis Diagnosis with SACI test
Positive
Negative
Positive
28
18
Negative
0
40
Sensitivity 100% (28/28)
Specificity 69.0% (40/58)
PPV 60.9% (28/46) NPV 100% (40/40) Accuracy 79.1% (68/86)
NPV ¼ negative predictive value; PPV ¼ positive predictive value; SACI ¼ selective arterial calcium injection.
that the major pancreatic arteries may perfuse overlapping distributions, resulting in a 2-fold increase in the hepatic venous insulin concentration after different arterial calcium stimulations in the presence of a single insulinoma. Hayashi et al (12) reported that among 6 patients (17 vessels), the SACI test returned questionable false-positive results in 4 patients. They attributed the false-positive results to the influx of calcium via branches of intrapancreatic anastomoses and proposed a maximum insulin concentration > 150 μIU/mL and a > 2-fold increase in the insulin concentration as new criteria for the localization of insulinomas. In the present study, in all 18 consecutive patients with hypoglycemia, the SACI test correctly localized the source of excessive insulin (sensitivity 100%) based on conventional criteria. Among the 18 patients (86 vessels), 12 were suspected to have false-positive results when endoscopic US and CT findings were compared with conventional criteria. False-positive localizations are particularly problematic because they mislead surgical exploration. The cutoff level, based on conventional diagnostic criteria of a 2-fold increase in the insulin concentration, may be too low for the localization of insulinomas. Therefore, decision tree analysis was applied in this study to discover optimal new diagnostic criteria for localizing insulinomas with the SACI test.
Table 3. Diagnosis with New Diagnostic Criteria Final Diagnosis Diagnosis with SACI test
Positive
Negative
Positive
28
5
Negative
0
53
Sensitivity 100% (28/28)
Specificity 91.4% (53/58)
PPV 84.8% (28/33) NPV 100% (53/53) Accuracy 94.2% (81/86)
NPV ¼ negative predictive value; PPV ¼ positive predictive value; SACI ¼ selective arterial calcium injection.
The sensitivity, specificity, and accuracy of the new criteria for the SACI test were 100%, 91.4%, and 94.2%. Sensitivity, specificity, and accuracy were 100%, 69.0%, and 79.1% with conventional criteria (Tables 2 and 3) Although sensitivity was 100% based on the conventional and the new criteria, with the latter, specificity and accuracy were remarkably greater. If there are many false-positive results, the surgeon may question the presence of occult tumors, and the extent of the operation may insufficient. As the new criteria decrease the number of false-positive findings, the surgeon can be confident of the presence of tumors. In the past, insulinomas < 2.0 cm in diameter were considered to be occult tumors. Owing to advances in imaging techniques and the development of new localization procedures, it became possible to detect such small tumors. Because combined dynamic CT and endoscopic US studies are almost 100% sensitive for the localization of insulinomas (13–16), these were applied as the gold standard. The possibility that small occult insulinomas were missed cannot
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be ruled out. However, postoperative dynamic CT detected no new insulinomas, and none of 18 patients presented with hypoglycemia symptoms during postoperative follow-up. Therefore, we do not think that insulinomas were missed with clinical repercussions in this study population. This retrospective study has some limitations. As the SACI test is invasive, ethical considerations prohibit its performance in normal control subjects without endogenous hyperinsulinemic hypoglycemia, and these biochemical results remain unknown. Consequently, there was no control group, and the true specificity of the SACI as a diagnostic test cannot be determined (6). To confirm the usefulness of the proposed criteria, additional studies in larger populations are needed. In conclusion, these findings suggest that the optimal cutoff value for the SACI test is (i) ICpost > 2.7 ICpre with maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre with maximum insulin concentration < 60.3 μIU/mL and ICpre 7.5 μIU/mL. The diagnostic performance of the proposed criteria for localization of insulinomas with the SACI test was higher than of the conventional criteria. Consequently, the new criteria improve the surgeon’s ability to address these tumors and may lead to better treatment outcomes.
REFERENCES 1. Doi R, Komoto I, Nakamura Y, et al. Pancreatic endocrine tumor in Japan. Pancreas 2004; 28:247–252. 2. Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol 2013; 19:829–837. 3. Morganstein DL, Lewis DH, Jackson J, et al. The role of arterial stimulation and simultaneous venous sampling in addition to cross-sectional imaging for localisation of biochemically proven insulinoma. Eur Radiol 2009; 19:2467–2473.
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4. Abboud B, Boujaoude J. Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol 2008; 14:657–665. 5. Doppman JL, Miller DL, Chang R, Shawker TH, Gorden P, Norton JA. Insulinomas: localization with selective intraarterial injection of calcium. Radiology 1991; 178:237–241. 6. Baba Y, Hayashi S, Senokuchi T, Nakajo M. Which indexes are appropriate among those derived from selective arterial calcium stimulation and venous sampling (ASVS) for diagnosing pancreatic insulinomas? Evaluation using receiver operating characteristic analyses. Pancreas 2011; 40: 308–310. 7. Doppman JL, Miller DL, Chang R, Gorden P, Eastman RC, Norton JA. Intraarterial calcium stimulation test for detection of insulinomas. World J Surg 1993; 17:439–443. 8. Wiesli P, Brandle M, Schmid C, et al. Selective arterial calcium stimulation and hepatic venous sampling in the evaluation of hyperinsulinemic hypoglycemia: potential and limitations. J Vasc Interv Radiol 2004; 15: 1251–1256. 9. Lo CY, Chan FL, Tam SC, Cheng PW, Fan ST, Lam KS. Value of intraarterial calcium stimulated venous sampling for regionalization of pancreatic insulinomas. Surgery 2000; 128:903–909. 10. Guettier JM, Kam A, Chang R, et al. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab 2009; 94:1074–1080. 11. Thompson SM, Vella A, Service FJ, Grant CS, Thompson GB, Andrews JC. Impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selective arterial calcium stimulation with hepatic venous sampling for preoperative localization of occult insulinoma. Surgery 2015; 158:162–172. 12. Hayashi T, Honda H, Yasumori K, et al. [Selective intra-arterial injection of calcium for localization of insulinomas: proposed new criteria]. Nihon Igaku Hoshasen Gakkai Zasshi 1995; 55:952–956. [in Japanese]. 13. Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc 2011; 73:691–696. 14. Ardengh JC, Rosenbaum P, Ganc AJ, et al. Role of EUS in the preoperative localization of insulinomas compared with spiral CT. Gastrointest Endosc 2000; 51:552–555. 15. Rappeport ED, Hansen CP, Kjaer A, Knigge U. Multidetector computed tomography and neuroendocrine pancreaticoduodenal tumors. Acta Radiol 2006; 47:248–256. 16. Alsohaibani F, Bigam D, Kneteman N, Shapiro AM, Sandha GS. The impact of preoperative endoscopic ultrasound on the surgical management of pancreatic neuroendocrine tumours. Can J Gastroenterol 2008; 22:817–820.
New Diagnostic Criteria for the Localization of Insulinomas with the Selective Arterial Calcium Injection Test: Decision Tree Analysis Kenji Kajiwara, MD, PhD, Takuji Yamagami, MD, PhD, Naoyuki Toyota, MD, PhD, Hideaki Kakizawa, MD, PhD, Masaki Urashima, MD, Masashi Hieda, MD, PhD, Yasutaka Baba, MD, PhD, Tomoyuki Akita, PhD, Junko Tanaka, PhD, and Kazuo Awai, MD, PhD ABSTRACT Purpose: To explore optimal diagnostic criteria for localizing insulinomas with the selective arterial calcium injection (SACI) test using decision tree analysis. Materials and Methods: A retrospective study included 86 vessels of 18 patients (5 men, 13 women; mean age 67 y; range, 49– 73 y) with insulinomas who underwent SACI test between June 2007 and May 2016. Of 27 insulinomas, 7 were found in the head, 13 in the body, and 7 in the tail of the pancreas. Two patients had multiple tumors. To identify optimal diagnostic criteria, decision tree analysis was performed, and sensitivity, specificity, and accuracy of the conventional and the proposed new diagnostic criteria (plasma insulin concentration after calcium injection [ICpost] > 2.0 plasma insulin concentration before calcium injection [ICpre]) were compared. Results: The proposed new diagnostic criteria for insulinoma obtained by decision tree analysis were (i) ICpost > 2.7 ICpre and maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre and maximum insulin concentration < 60.3 μIU/mL with ICpre being 7.5 μIU/mL. Sensitivity, specificity, and accuracy of the new criteria for the SACI test were 100%, 91.4%, and 94.2; sensitivity, specificity, and accuracy of conventional criteria were 100%, 69.0%, and 79.1%. Conclusions: New diagnostic criteria for localization of insulinomas with the SACI test yielded higher diagnostic performance than conventional criteria.
ABBREVIATIONS ICpost ¼ plasma insulin concentration after calcium injection, ICpre ¼ plasma insulin concentration before calcium injection, SACI ¼ selective arterial calcium injection
From the Department of Radiology (K.K., T.Y.), Medical School, Kochi University, 185-1 Kohasu, Oko-cho, Nankoku 783-8505, Japan; Departments of Diagnostic Radiology (K.K., Y.B., K.A.) and Epidemiology, Infectious Disease Control and Prevention (T.A., J.T.), Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Department of Diagnostic Radiology (N.T.), National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; Department of Radiology (H.K.), Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan; and Department of Diagnostic Radiology (M.U., M.H.), Hiroshima City Hospital, Hiroshima, Japan. Received April 23, 2018; final revision received and accepted May 18, 2018. Address correspondence to K.K.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2018 J Vasc Interv Radiol 2018; ▪:1–5 https://doi.org/10.1016/j.jvir.2018.05.015
Insulinomas are the most common islet cell tumors. Diagnosis of insulinomas rests on establishing evidence of symptomatic hypoglycemia accompanied by inappropriate insulin and/or proinsulin levels after a period of prolonged fasting. When these tumors come to clinical attention, they are usually small, solitary, and intrapancreatic. Their location is determined by imaging studies, including ultrasound (US), computed tomography (CT), magnetic resonance imaging, and endoscopic US (1,2). Preoperative localization in the work-up for insulinoma increases the chance for curative surgical resection (3,4). The selective arterial calcium injection (SACI) test with hepatic venous sampling for insulin was developed to localize discrete insulin-secreting islet cell tumors to regions of the pancreas (5). A > 2-fold increase after stimulation in the serum insulin concentration over its baseline
2 ▪ Localization of Insulinomas with SACI Test
EDITORS’ RESEARCH HIGHLIGHTS New diagnostic criteria for localization of insulinomas using the selective arterial calcium injection test provided both higher specificity and higher accuracy compared with conventional criteria in a study of 86 visceral arteries in 18 patients. Plasma insulin concentration increases of > 2.7-fold after calcium and new values for insulin concentration changes are proposed. The small number of patients precludes larger or controlled studies, and this study bears further validation. Nevertheless, these criteria may enhance surgical confidence and planning for surgical exposure and resection.
value is considered to be positive for pancreatic insulinoma. Although the documented sensitivity of the SACI test for localizing insulinomas is 84%–100%, its specificity is poor, and no case-control studies have been reported (6). In some of our cases, the test results may have been falsepositive (Fig 1a–c). Consequently, the purpose of this study was to identify optimal diagnostic criteria for localizing insulinomas with the SACI test and perform decision tree analysis.
MATERIALS AND METHODS This study was approved by the institutional ethics committee. The principles of the Declaration of Helsinki were applied, and informed consent for the procedures was obtained from all patients.
Patients Between June 2007 and May 2016, 18 patients (5 men, 13 women; mean age 67 y; range, 49–73 y) underwent the SACI test at our institution and affiliated hospitals (Table 1). The SACI test with hepatic venous sampling of the insulin level was performed for preoperative localization of pancreatic insulinoma. All patients manifested hypoglycemia in the presence of an inappropriately elevated insulin level. All patients whose pancreatic insulinoma was histologically confirmed and who underwent surgery were reviewed retrospectively. Before the SACI test, all patients had undergone other preoperative tumor localization procedures (dynamic CT and endoscopic US). The SACI test results were compared with dynamic CT and endoscopic US findings and surgery results. In clinical and imaging followup studies, patient symptoms, hemoglobin A1c level, and dynamic CT findings were assessed.
Technique For selective arterial calcium injection, a 5-F catheter was introduced in the right hepatic vein via femoral venous puncture. A 4-F catheter was placed in the celiac artery and
Kajiwara et al ▪ JVIR
superior mesenteric artery via femoral artery puncture, followed by insertion of a 1.9-F microcatheter. After catheterization, the gastroduodenal, superior mesenteric, splenic (proximal and distal segments), and hepatic arteries were selectively cannulated in turn. The interval between each calcium injection was at least 5 minutes. Calcium gluconate (10% solution) at a dose of 0.025 mEq Caþþ/kg was diluted to a 5-mL bolus and injected rapidly into each artery. Blood samples for insulin determination were obtained from the right hepatic vein 0, 20, 40, 60, 90, and 120 seconds or 0, 30, 60, and 120 seconds after the calcium injection. Sampling results from the right hepatic vein were plotted for each patient. Calcium gluconate was delivered to 86 vessels (18 gastroduodenal, 18 superior mesenteric, 18 proximal splenic, 14 distal splenic, and 18 hepatic arteries). When a positive response was elicited on calcium injection into the splenic artery, the tumor was localized to the body or tail of the pancreas; when it was identified on injection into the duodenal and/or superior mesenteric arteries, the tumor was localized to the pancreatic head or neck.
Statistical Analysis Hemoglobin A1c levels before and after injection were compared with the paired t test. Differences of P < .05 were considered statistically significant. Data analysis was performed with JMP Version 11 (SAS Japan, Tokyo, Japan). Variables were entered into partition modeling analysis in JMP for decision tree analysis. The sensitivity, specificity, and accuracy of the new diagnostic criteria determined with decision tree analysis was compared with conventional diagnostic criteria (plasma insulin concentration after calcium injection [ICpost] > 2.0 plasma insulin concentration before calcium injection [ICpre]).
RESULTS The median maximal increase in insulin concentration over the baseline in the dominant artery was 14.8-fold (range, 2.7-fold to 207.3-fold); it was 3.4-fold (range, 2.0-fold to 39.3-fold) over the baseline in the artery suspected as falsepositive. Of 27 insulinomas, 7 were found in the head, 13 in the body, and 7 in the tail of the pancreas at surgery. Two patients had multiple tumors. Mean tumor size was 13 mm ± 6.9. Surgery identified the pathologic source of excessive insulin secretion in all 18 patients. Euglycemia was obtained by surgery in all 18 patients. During follow-up (mean 68.5 months; range, 10–117 months), none of the operated patients experienced further hypoglycemic episodes; dynamic CT detected no new tumors. The mean hemoglobin A1c level increased from 4.7% ± 0.44 to 5.3% ± 0.47 in 17 patients after surgery (P < .01, paired t test); postoperative hemoglobin was not assessed in the other patient. Sensitivity, specificity, accuracy, and positive predictive value for the conventional criteria (ICpost > 2.0 ICpre) were 100%, 69.0%, 79.1%, and 60.9% (Table 2). Comparison with endoscopic US and dynamic CT
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Figure 1. A 68-year-old woman with insulinoma. (a) CT image showing a hypervascular nodule (arrowhead) in the pancreatic body. (b) Celiac angiogram showing a hypervascular tumor (arrowhead), 10 mm in diameter, in the body of the pancreas. The right hepatic artery arises from a branch of the celiac artery. (c) A 19.8-fold increase in insulin level in the proximal splenic artery suggested insulinoma in the pancreatic body. The 2.2-fold increase in insulin level in the right hepatic artery was suspected to be a false-positive finding. GDA ¼ gastroduodenal artery; RHA ¼ right hepatic artery; SMA ¼ superior mesenteric artery; SpA (d) ¼ distal splenic artery; SpA (p) ¼ proximal splenic artery.
findings suggested that 18 of 86 vessels (20.9%) in 12 of 18 patients were false-positive results (6 gastroduodenal, 3 superior mesenteric, 3 proper hepatic, 4 proximal splenic, and 2 distal splenic arteries). The proposed new diagnostic criteria for insulinoma obtained by decision tree analysis were (i) ICpost > 2.7 ICpre and maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre and maximum insulin concentration < 60.3 μIU/mL with ICpre 7.5 μIU/mL (Fig 2). Sensitivity, specificity, accuracy, and positive predictive value of the new criteria for the SACI test were 100%, 91.4%, 94.2%, and 84.8% (Table 3). Comparison with endoscopic US and dynamic CT findings suggested that 5 of 86 vessels (5.8%) in 3 of 8 patients were falsepositive (gastroduodenal, hepatic, and proximal splenic arteries, n ¼ 1 each; distal splenic arteries, n ¼ 2). No technical errors or anatomic variants were apparent on review of angiograms. There were no immediate, short-term, or long-term complications resulting from the SACI test
procedure, and there were no hypoglycemic episodes after calcium injection during the SACI test.
DISCUSSION Initial reports claimed that with the SACI test, insulinomas were accurately localized (7) with a sensitivity of 84%– 100% (4,8–10). However, specificity was suboptimal. In a study comprising 45 cases, Guettier et al (10) obtained a positive response in a single vessel in 16 cases (35.6%) and a positive response in 2 vessels in 24 cases (53.3%). They suggested that an overlap in arterial territory, tumor behavior, or problems related to the specificity of the test were implicated. They also found that in 2 false-positive cases, the test failed to detect the true insulinoma. Thompson et al (11) reported a positive response in a single vessel in 31 of 42 cases (73.8%) and a positive response in 2 vessels in 11 of 42 cases (26.2%). They cited significant variations in the pancreatic arterial anatomy and suggested
4 ▪ Localization of Insulinomas with SACI Test
Kajiwara et al ▪ JVIR
Table 1. Demographic and Clinical Data of 18 Patients Who Underwent Selective Arterial Calcium Injection Test for Preoperative Localization of Insulinoma Characteristics
N (%)
Sex Male
5 (27.8)
Female
13 (72.2)
Age, y
67
Hypoglycemic episodes
18 (100) 4.7% ± 6.9%
Hemoglobin A1c Total number of tumors Tumor size, mm, mean ± SD
27 13 ± 6.9
Pancreas location Head
7 (25.9)
Body
13 (48.1)
Tail
7 (25.9) Figure 2. Decision tree demonstrating optimal cutoff value for localizing insulinomas. JMP was used for the analysis. The proposed new diagnostic criteria were (i) ICpost > 2.7 ICpre and maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre and maximum insulin concentration < 60.3 μIU/mL with ICpre 7.5 μIU/mL.
Table 2. Diagnosis with Conventional Criteria Final Diagnosis Diagnosis with SACI test
Positive
Negative
Positive
28
18
Negative
0
40
Sensitivity 100% (28/28)
Specificity 69.0% (40/58)
PPV 60.9% (28/46) NPV 100% (40/40) Accuracy 79.1% (68/86)
NPV ¼ negative predictive value; PPV ¼ positive predictive value; SACI ¼ selective arterial calcium injection.
that the major pancreatic arteries may perfuse overlapping distributions, resulting in a 2-fold increase in the hepatic venous insulin concentration after different arterial calcium stimulations in the presence of a single insulinoma. Hayashi et al (12) reported that among 6 patients (17 vessels), the SACI test returned questionable false-positive results in 4 patients. They attributed the false-positive results to the influx of calcium via branches of intrapancreatic anastomoses and proposed a maximum insulin concentration > 150 μIU/mL and a > 2-fold increase in the insulin concentration as new criteria for the localization of insulinomas. In the present study, in all 18 consecutive patients with hypoglycemia, the SACI test correctly localized the source of excessive insulin (sensitivity 100%) based on conventional criteria. Among the 18 patients (86 vessels), 12 were suspected to have false-positive results when endoscopic US and CT findings were compared with conventional criteria. False-positive localizations are particularly problematic because they mislead surgical exploration. The cutoff level, based on conventional diagnostic criteria of a 2-fold increase in the insulin concentration, may be too low for the localization of insulinomas. Therefore, decision tree analysis was applied in this study to discover optimal new diagnostic criteria for localizing insulinomas with the SACI test.
Table 3. Diagnosis with New Diagnostic Criteria Final Diagnosis Diagnosis with SACI test
Positive
Negative
Positive
28
5
Negative
0
53
Sensitivity 100% (28/28)
Specificity 91.4% (53/58)
PPV 84.8% (28/33) NPV 100% (53/53) Accuracy 94.2% (81/86)
NPV ¼ negative predictive value; PPV ¼ positive predictive value; SACI ¼ selective arterial calcium injection.
The sensitivity, specificity, and accuracy of the new criteria for the SACI test were 100%, 91.4%, and 94.2%. Sensitivity, specificity, and accuracy were 100%, 69.0%, and 79.1% with conventional criteria (Tables 2 and 3) Although sensitivity was 100% based on the conventional and the new criteria, with the latter, specificity and accuracy were remarkably greater. If there are many false-positive results, the surgeon may question the presence of occult tumors, and the extent of the operation may insufficient. As the new criteria decrease the number of false-positive findings, the surgeon can be confident of the presence of tumors. In the past, insulinomas < 2.0 cm in diameter were considered to be occult tumors. Owing to advances in imaging techniques and the development of new localization procedures, it became possible to detect such small tumors. Because combined dynamic CT and endoscopic US studies are almost 100% sensitive for the localization of insulinomas (13–16), these were applied as the gold standard. The possibility that small occult insulinomas were missed cannot
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be ruled out. However, postoperative dynamic CT detected no new insulinomas, and none of 18 patients presented with hypoglycemia symptoms during postoperative follow-up. Therefore, we do not think that insulinomas were missed with clinical repercussions in this study population. This retrospective study has some limitations. As the SACI test is invasive, ethical considerations prohibit its performance in normal control subjects without endogenous hyperinsulinemic hypoglycemia, and these biochemical results remain unknown. Consequently, there was no control group, and the true specificity of the SACI as a diagnostic test cannot be determined (6). To confirm the usefulness of the proposed criteria, additional studies in larger populations are needed. In conclusion, these findings suggest that the optimal cutoff value for the SACI test is (i) ICpost > 2.7 ICpre with maximum insulin concentration > 60.3 μIU/mL or (ii) ICpost > 2.7 ICpre with maximum insulin concentration < 60.3 μIU/mL and ICpre 7.5 μIU/mL. The diagnostic performance of the proposed criteria for localization of insulinomas with the SACI test was higher than of the conventional criteria. Consequently, the new criteria improve the surgeon’s ability to address these tumors and may lead to better treatment outcomes.
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