Localization of Occult Insulin Secreting Tumors of the Pancreas H. KALLIO, M.D., H. SUORANTA, M.D.
Percutaneous transhepatic portal venography (PTP) and selective portal blood sample collection for immunoreactive insulin (IRI) analyses was done in four patients who had clinical evidence of the presence of an insulin secreting tumor, but selective arteriography of the pancreas did not visualize any insulinomas. In all patients the clinical diagnosis was confirmed and the localization of the tumors could be calculated with the aid of the PTP and the IRI values detected in different parts of the portal trees. Because no tumor was found at the operation in two patients, despite careful exploration of the pancreas, blind distal pancreatectomy was performed to the point suggested with the help of the investigations, and insulinomas were found close to the resection lines. In the two other patients the proposed localization of the tumor preoperatively was confirmed. There have been no postoperative hypoglycemic symptoms.
is essential for permanent cure of patients who have insulin secreting B-cell tumors of the pancreas causing hypoglycemic attacks.2 9'10 Ten per cent of the benign tumors are multiple1 and two-thirds of them are located in the head and the body while one-third are found in the tail of the pancreas.14 The tumor may occur outside the pancreas and is usually in the wall of duodenum or near it.7 Preoperative angiography of the pancreas provides useful information about the number and localization of the tumors, but in approximately 10% cannot be found at operation3'14 and symptoms of hyperinsulinism persist. Recently, percutaneous transhepatic portal venography (PTP) with collection of blood samples for hormone analysis has been proposed as a useful approach for investigation ofpancreatic disease.6'8 This study comprises the first report of this method for localization of occult insulinomas. S URGICAL REMOVAL OF INSULINOMAS
Clinical Data During the past two years several patients have been investigated for suspected insulinomas mainly because Reprint requests: Harri Kallio, M.D., Second Department of Surgery, Meilahti Hospital, Haartmaninkatu 4, 00290 Helsinki 29, Finland.
From the Second Department of Surgery and the Department of Radiology, Meilahti Hospital, Helsinki, Finland
of neurological symptoms associated with a low fasting blood glucose level. Among them were four patients aged 40-64 years in whom selective pancreatic angiography had not demonstrated an insulinoma (Table 1.) None of the patients had signs of liver impairment or other demonstrable cause of hypoglycemia. Previously, three of the patients had had a duodenal ulcer and one of them had been treated by partial gastrectomy while the others had had medical treatment only. Methods
Prior to surgical exploration, PTP was performed on each patient using an angiographic table and local anesthesia. The portal vein was punctured with a 250 mm long Teflon® cannula with a steel mandrin (Surgimed) (outer diameter was 1.6 mm and the inner diameter was 1.0 mm.) With the patient in the supine position the needle was inserted through the eighth, ninth, or tenth intercostal space in the middle axillary line and directed towards the center of the liver by aiming at the twelfth thoracic vertebral body. The patients held their breaths in mild expiration during the puncture to avoid perforation of the lung. The cannula was withdrawn slowly after removal of the mandrin, and when blood appeared a small amount of contrast material (Angiografin 60, Schering Co.,) was injected manually to identify the vessel. The cannula was guided by a Teflon coated J-shaped guide wire to the splenic and the superior mesenteric veins and 40 ml of the constrast material was injected at a flow rate of 12 ml/second. This series lasted 12-16 seconds showing both these venous systems. Sampling was started from the hilus of the spleen and successive samples were withdrawn every 2-3 cm along the splenic vein. Samples were also withdrawn from the superior mesenteric vein. Peripheral blood
0003-4932/79/0100/0049 $00.70 X J. B. Lippincott Company
49
Ann. Surg. a January 1979
KALLIO AND SUORANTA
50
TABLE 1. Clinical Series
Patient
Age (years)
Sex
Duration of Symptoms (months)
L.A. A.S. A.L. A. K.
62 64 45 40
Female Male Male Female
16 14 8 48
sample were collected at the same time. Insulin concentrations were analyzed by radioimmunoassay method (Phadebas insulin test). Results The PTP was successful in all four patients and the portal vascular bed could be completely visualized so that exact sites of blood sampling for hormone analyses could be defined and the venograms showed normal drainage patterns in all patients. A photograph of the PTP from patient L.A. is shown in Figure 1, and both the portal system and the pancreatic veins are visualized. Figure 2 presents the venous diagram for the same patient and shows the results of hormone analyses and the site of the insulinoma found at operation. The results of the other three patients are shown in Figures 3-6. High insulin concentrations were measured near the tumor sites and varied between 99 and 440 AtU/ml. Thus they were one and one-half to ten times higher than in the surrounding samples and the samples taken from seven patients without pancreatic tumor whose insulin concentration in the splenic vein was 28.0 + 10.0 ,uU/ml. The insulin concentrations were also five to 22 times higher than normal plasma concentrations as the reference area with the used method is 8.0-20.0 AU/ml.
Symptoms Convulsions Convulsions Convulsions Convulsions Psychiatric symptoms
Preoperative Angiography Finding
Operative Finding
Negative Negative Negative Negative
Insulinoma Insulinoma Insulinoma Insulinoma
No correlation was found between the sizes of the tumor (4-18 mm in diameter) and the detected insulin values. Caudal pancreatectomies were performed in all the patients according to the results of PTP and hormone analyses. The tumors in patients L.A. and A.K. could not be palpated during operation and distal blind pancreatectomy was performed up to the point proposed by the hormone studies. When the pancreatic tails were cut into thin slices the tumors were, however, located. They lay in pancreatic tissue, 0.5-1.0 cm from the lines of resection. Three patients had mild hyperglycemic episodes postoperatively for one to three weeks but did not require insulin therapy. All patients have now been symptom free postoperatively for five to 18 months and 36-hour fasting tests have all been normal.
Discussion
The number and the localization of insulinomas is important when surgical procedures are planned.
C~~~~~~~~~~~~~~~~~j/v 2
8
FIG. 1. Normal percutaneous transhepatic portal venography in patient L.A.
FIG. 2. Patient L.A.: sampling sites and insulin concentrations in various parts of the portal system. The tumor was 4 mm in diameter and was found in the tail of the pancreas (the units for insulin concentrations are AU/ml. Normal values in the peripheral blood vary between 2 and 20 ,AU/ml). (1) V. lienalis-8.5, (2) v. lienalis-151.2, (3) v. lienalis-34.5, (4) v. portae-15.2, (5) v. mes superior-4.6, (6) v. mes superior-3.2, (7) v. portae-4.8, (8) v. mes superior-6.0.
Vol. 189
o
No. I
INSULIN SECRETING PANCREATIC TUMORS
51
5
FIG. 3. Patient A.A.: sampling sites and insulin concentrations in various parts of the portal system. The tumor was 8 mm in diameter and was found in the tail of the pancreas. (I) V. lienalis-246.6, (2) v. lienalis- 130.0, (3) v. lienalis-87.0, (4) v. mes sup-76.3, (5) v. portae-80.6.
Subtotal distal pancreatectomy3'12 and pancreaticoduodenectomy4' I are the operative procedures recommended when occult insulinomas are treated. Both methods have a high incidence of surgical complications and can lead to permanent pancreatic insufficiency or diabetes. At present, the angiographic methods are considered to give the best information on the localization of insulinomas. Depending mainly on the
1g
FIG. 4. Patient A. L.: sampling sites and insulin concentrations in various parts of the portal venous system. The tumor was 18 mm in diameter and was found in the body of the pancreas (1) V. lienalis-36.4 (2) v. lienalis-87.4, (3) v. lienalis-27.6, (4) v. lienalis-38.5, (5) v. mes sup-12.3, (6) v. mes inf-440.9, (7) v. portae- 1 16.8.
FIG. 5. Patient A. K.: sampling sites and insulin concentrations in the portal venous system. The tumor was 10 mm in diameter and was found in the rail of the pancreas. (1) v. lienalis-56.8, (2) v. lienalis-86.4, (3) v. lienalis-94.7, (4) v. lienalis-99.0, (5) v. mes sup-66.6, (6) v. portae-27.0.
size of the tumor's definitive localization can be achieved in about 20-90% of cases.5,12,13 In the patients presented here, the angiography was negative. PTP and selective blood sampling from the portal venous system has been proposed as a valuable method in the diagnosis of a pancreatic disease.12 We have used this method and selectively collected blood samples from the portal tree for hormone analyses in order to localize insulinomas. In these four patients the correct localization of the insulinomas was deduced from the hormone concentrations measured in different parts of the portal tree. The venogram was useful in blood sampling and assessment of the results of hormone assay because the direction of blood flow as
FIG. 6. Photograph of the excised pancreatic tail on patient A. K. The insulinoma is seen in the pancreatic tissue and is darker in color than the surrounding tissue (indicated by arrow).
KALLIO AND SUORANTA
52
well as venous anatomy were defined. The value of this method was especially evident in two patients (A.L. and A.K.) in whom blind distal pancreatectomy was performed to the extent suggested by the selected venous insulin levels. A single insulinoma was found in the excised tail in each patient. In the other two patients, the localization of the tumors suggested preoperatively was confirmed at operation. Technically, this investigation is relatively easy to perform. The main difficulty is getting the needle into the portal venous system. We have however failed five times in 75 attempts in 72 patients when performing the procedure of either PTP or PTP with selective venous sampling. There have been no major complications. Only one patient sustained a mild pneumothorax, the difficulty being poor cooperation in breath holding. The method appears to be very useful in the localization of hormone secreting tumors of the pancreas. Other tumors secreting biologically active substances in the splanchnic region might also be localized by this method.
3. 4. 5.
6. 7.
8.
9.
10. 1 1.
12.
References
13.
1. Breidahl, H. D., Priestley, J. T. and Rynearson, E. H.: Hyperinsulinism: Surgical Aspects and Results. Ann. Surg.,
14.
142:698, 1955. 2. Clarke, M., Crofford, 0. B., Graves, H. A. and Scott, H. W.:
Ann. Surg. * January 1979
Functioning Beta Cell Tumors (Insulinomas) of the Pancreas. Ann. Surg., 175:956, 1972. Clayton, H. S. and Grage, T. B.: Diagnosis and Surgical Aspects of Insulinoma. Am. J. Surg., 127:174, 1974. Fonkalsrud, E. W., Dilley, R. B. and Longmire, W. P.: Insulin Secreting Tumors of the Pancreas. Ann. Surg., 159:730, 1964. Gray, R., Rosch, J. and Grollman, J. H.: Arteriography in the Diagnosis of Islet Cell Tumors. Radiology, 97:39, 1970. Gothlin, J., Lunderquist, A. and Tylen, U.: Selective Phlebography of the Pancreas. Acta Radiol. Diagn., 15:474, 1974. Harrison, T. S., Child, C. G., Fry, W. J., et al.: Current Surgical Management of Functioning Islet Cell Tumors of the Pancreas. Ann. Surg., 178:485, 1973. Ingemansson, S., Lunderquist, A., Lundquist, et al.: Portal and Pancreatic Vein Catheterization with Radioimmunologic Determination of Insulin, Surg. Gynecol. Obstet., 141:705, 1975. Kavlie, H. and White, T. T.: Pancreatic Islet Beta Cell Tumors and Hyperplasia: Experience in 14 Seattle Hospitals. Ann. Surg., 175:326, 1972. Laroche, G. P., Ferris, D. 0. Priestley, J. T., et al.: Hyperinsulinism. Arch. Surg., 96:763, 1968. Mengoli, L. and Le Quesne, L. P.: Blind Pancreatic Resection for Suspected Insulinoma: A Review of the Problem. Br. J. Surg., 54:749, 1967. Moss, N. H. and Rhoads, J. E.: Hyperinsulinism and islet cell tumors of the pancreas. In Howar, J. M. and Jordan, G. L. (eds.): Surgical Diseases of the Pancreas. Philadelphia, J. B. Lippincott Co., 1960, pp. 321-441. Robins, J. M., Bookstein, J. J., Oberman, H. A. and Fajans, S. S.: Selective Angiography in Localizing Islet Cell Tumors of the Pancreas. Radiology, 106:525, 1973. Stefanini, P., Carboni, M., Patrassi, N. and Basoli, A.: Beta Islet Cell Tumors ofthe Pancreas: Results of a Study on 1067 Cases. Surgery, 75:597, 1974.
Percutaneous transhepatic portal venography (PTP) and selective portal blood sample collection for immunoreactive insulin (IRI) analyses was done in four patients who had clinical evidence of the presence of an insulin secreting tumor, but selective arteriography of the pancreas did not visualize any insulinomas. In all patients the clinical diagnosis was confirmed and the localization of the tumors could be calculated with the aid of the PTP and the IRI values detected in different parts of the portal trees. Because no tumor was found at the operation in two patients, despite careful exploration of the pancreas, blind distal pancreatectomy was performed to the point suggested with the help of the investigations, and insulinomas were found close to the resection lines. In the two other patients the proposed localization of the tumor preoperatively was confirmed. There have been no postoperative hypoglycemic symptoms.
is essential for permanent cure of patients who have insulin secreting B-cell tumors of the pancreas causing hypoglycemic attacks.2 9'10 Ten per cent of the benign tumors are multiple1 and two-thirds of them are located in the head and the body while one-third are found in the tail of the pancreas.14 The tumor may occur outside the pancreas and is usually in the wall of duodenum or near it.7 Preoperative angiography of the pancreas provides useful information about the number and localization of the tumors, but in approximately 10% cannot be found at operation3'14 and symptoms of hyperinsulinism persist. Recently, percutaneous transhepatic portal venography (PTP) with collection of blood samples for hormone analysis has been proposed as a useful approach for investigation ofpancreatic disease.6'8 This study comprises the first report of this method for localization of occult insulinomas. S URGICAL REMOVAL OF INSULINOMAS
Clinical Data During the past two years several patients have been investigated for suspected insulinomas mainly because Reprint requests: Harri Kallio, M.D., Second Department of Surgery, Meilahti Hospital, Haartmaninkatu 4, 00290 Helsinki 29, Finland.
From the Second Department of Surgery and the Department of Radiology, Meilahti Hospital, Helsinki, Finland
of neurological symptoms associated with a low fasting blood glucose level. Among them were four patients aged 40-64 years in whom selective pancreatic angiography had not demonstrated an insulinoma (Table 1.) None of the patients had signs of liver impairment or other demonstrable cause of hypoglycemia. Previously, three of the patients had had a duodenal ulcer and one of them had been treated by partial gastrectomy while the others had had medical treatment only. Methods
Prior to surgical exploration, PTP was performed on each patient using an angiographic table and local anesthesia. The portal vein was punctured with a 250 mm long Teflon® cannula with a steel mandrin (Surgimed) (outer diameter was 1.6 mm and the inner diameter was 1.0 mm.) With the patient in the supine position the needle was inserted through the eighth, ninth, or tenth intercostal space in the middle axillary line and directed towards the center of the liver by aiming at the twelfth thoracic vertebral body. The patients held their breaths in mild expiration during the puncture to avoid perforation of the lung. The cannula was withdrawn slowly after removal of the mandrin, and when blood appeared a small amount of contrast material (Angiografin 60, Schering Co.,) was injected manually to identify the vessel. The cannula was guided by a Teflon coated J-shaped guide wire to the splenic and the superior mesenteric veins and 40 ml of the constrast material was injected at a flow rate of 12 ml/second. This series lasted 12-16 seconds showing both these venous systems. Sampling was started from the hilus of the spleen and successive samples were withdrawn every 2-3 cm along the splenic vein. Samples were also withdrawn from the superior mesenteric vein. Peripheral blood
0003-4932/79/0100/0049 $00.70 X J. B. Lippincott Company
49
Ann. Surg. a January 1979
KALLIO AND SUORANTA
50
TABLE 1. Clinical Series
Patient
Age (years)
Sex
Duration of Symptoms (months)
L.A. A.S. A.L. A. K.
62 64 45 40
Female Male Male Female
16 14 8 48
sample were collected at the same time. Insulin concentrations were analyzed by radioimmunoassay method (Phadebas insulin test). Results The PTP was successful in all four patients and the portal vascular bed could be completely visualized so that exact sites of blood sampling for hormone analyses could be defined and the venograms showed normal drainage patterns in all patients. A photograph of the PTP from patient L.A. is shown in Figure 1, and both the portal system and the pancreatic veins are visualized. Figure 2 presents the venous diagram for the same patient and shows the results of hormone analyses and the site of the insulinoma found at operation. The results of the other three patients are shown in Figures 3-6. High insulin concentrations were measured near the tumor sites and varied between 99 and 440 AtU/ml. Thus they were one and one-half to ten times higher than in the surrounding samples and the samples taken from seven patients without pancreatic tumor whose insulin concentration in the splenic vein was 28.0 + 10.0 ,uU/ml. The insulin concentrations were also five to 22 times higher than normal plasma concentrations as the reference area with the used method is 8.0-20.0 AU/ml.
Symptoms Convulsions Convulsions Convulsions Convulsions Psychiatric symptoms
Preoperative Angiography Finding
Operative Finding
Negative Negative Negative Negative
Insulinoma Insulinoma Insulinoma Insulinoma
No correlation was found between the sizes of the tumor (4-18 mm in diameter) and the detected insulin values. Caudal pancreatectomies were performed in all the patients according to the results of PTP and hormone analyses. The tumors in patients L.A. and A.K. could not be palpated during operation and distal blind pancreatectomy was performed up to the point proposed by the hormone studies. When the pancreatic tails were cut into thin slices the tumors were, however, located. They lay in pancreatic tissue, 0.5-1.0 cm from the lines of resection. Three patients had mild hyperglycemic episodes postoperatively for one to three weeks but did not require insulin therapy. All patients have now been symptom free postoperatively for five to 18 months and 36-hour fasting tests have all been normal.
Discussion
The number and the localization of insulinomas is important when surgical procedures are planned.
C~~~~~~~~~~~~~~~~~j/v 2
8
FIG. 1. Normal percutaneous transhepatic portal venography in patient L.A.
FIG. 2. Patient L.A.: sampling sites and insulin concentrations in various parts of the portal system. The tumor was 4 mm in diameter and was found in the tail of the pancreas (the units for insulin concentrations are AU/ml. Normal values in the peripheral blood vary between 2 and 20 ,AU/ml). (1) V. lienalis-8.5, (2) v. lienalis-151.2, (3) v. lienalis-34.5, (4) v. portae-15.2, (5) v. mes superior-4.6, (6) v. mes superior-3.2, (7) v. portae-4.8, (8) v. mes superior-6.0.
Vol. 189
o
No. I
INSULIN SECRETING PANCREATIC TUMORS
51
5
FIG. 3. Patient A.A.: sampling sites and insulin concentrations in various parts of the portal system. The tumor was 8 mm in diameter and was found in the tail of the pancreas. (I) V. lienalis-246.6, (2) v. lienalis- 130.0, (3) v. lienalis-87.0, (4) v. mes sup-76.3, (5) v. portae-80.6.
Subtotal distal pancreatectomy3'12 and pancreaticoduodenectomy4' I are the operative procedures recommended when occult insulinomas are treated. Both methods have a high incidence of surgical complications and can lead to permanent pancreatic insufficiency or diabetes. At present, the angiographic methods are considered to give the best information on the localization of insulinomas. Depending mainly on the
1g
FIG. 4. Patient A. L.: sampling sites and insulin concentrations in various parts of the portal venous system. The tumor was 18 mm in diameter and was found in the body of the pancreas (1) V. lienalis-36.4 (2) v. lienalis-87.4, (3) v. lienalis-27.6, (4) v. lienalis-38.5, (5) v. mes sup-12.3, (6) v. mes inf-440.9, (7) v. portae- 1 16.8.
FIG. 5. Patient A. K.: sampling sites and insulin concentrations in the portal venous system. The tumor was 10 mm in diameter and was found in the rail of the pancreas. (1) v. lienalis-56.8, (2) v. lienalis-86.4, (3) v. lienalis-94.7, (4) v. lienalis-99.0, (5) v. mes sup-66.6, (6) v. portae-27.0.
size of the tumor's definitive localization can be achieved in about 20-90% of cases.5,12,13 In the patients presented here, the angiography was negative. PTP and selective blood sampling from the portal venous system has been proposed as a valuable method in the diagnosis of a pancreatic disease.12 We have used this method and selectively collected blood samples from the portal tree for hormone analyses in order to localize insulinomas. In these four patients the correct localization of the insulinomas was deduced from the hormone concentrations measured in different parts of the portal tree. The venogram was useful in blood sampling and assessment of the results of hormone assay because the direction of blood flow as
FIG. 6. Photograph of the excised pancreatic tail on patient A. K. The insulinoma is seen in the pancreatic tissue and is darker in color than the surrounding tissue (indicated by arrow).
KALLIO AND SUORANTA
52
well as venous anatomy were defined. The value of this method was especially evident in two patients (A.L. and A.K.) in whom blind distal pancreatectomy was performed to the extent suggested by the selected venous insulin levels. A single insulinoma was found in the excised tail in each patient. In the other two patients, the localization of the tumors suggested preoperatively was confirmed at operation. Technically, this investigation is relatively easy to perform. The main difficulty is getting the needle into the portal venous system. We have however failed five times in 75 attempts in 72 patients when performing the procedure of either PTP or PTP with selective venous sampling. There have been no major complications. Only one patient sustained a mild pneumothorax, the difficulty being poor cooperation in breath holding. The method appears to be very useful in the localization of hormone secreting tumors of the pancreas. Other tumors secreting biologically active substances in the splanchnic region might also be localized by this method.
3. 4. 5.
6. 7.
8.
9.
10. 1 1.
12.
References
13.
1. Breidahl, H. D., Priestley, J. T. and Rynearson, E. H.: Hyperinsulinism: Surgical Aspects and Results. Ann. Surg.,
14.
142:698, 1955. 2. Clarke, M., Crofford, 0. B., Graves, H. A. and Scott, H. W.:
Ann. Surg. * January 1979
Functioning Beta Cell Tumors (Insulinomas) of the Pancreas. Ann. Surg., 175:956, 1972. Clayton, H. S. and Grage, T. B.: Diagnosis and Surgical Aspects of Insulinoma. Am. J. Surg., 127:174, 1974. Fonkalsrud, E. W., Dilley, R. B. and Longmire, W. P.: Insulin Secreting Tumors of the Pancreas. Ann. Surg., 159:730, 1964. Gray, R., Rosch, J. and Grollman, J. H.: Arteriography in the Diagnosis of Islet Cell Tumors. Radiology, 97:39, 1970. Gothlin, J., Lunderquist, A. and Tylen, U.: Selective Phlebography of the Pancreas. Acta Radiol. Diagn., 15:474, 1974. Harrison, T. S., Child, C. G., Fry, W. J., et al.: Current Surgical Management of Functioning Islet Cell Tumors of the Pancreas. Ann. Surg., 178:485, 1973. Ingemansson, S., Lunderquist, A., Lundquist, et al.: Portal and Pancreatic Vein Catheterization with Radioimmunologic Determination of Insulin, Surg. Gynecol. Obstet., 141:705, 1975. Kavlie, H. and White, T. T.: Pancreatic Islet Beta Cell Tumors and Hyperplasia: Experience in 14 Seattle Hospitals. Ann. Surg., 175:326, 1972. Laroche, G. P., Ferris, D. 0. Priestley, J. T., et al.: Hyperinsulinism. Arch. Surg., 96:763, 1968. Mengoli, L. and Le Quesne, L. P.: Blind Pancreatic Resection for Suspected Insulinoma: A Review of the Problem. Br. J. Surg., 54:749, 1967. Moss, N. H. and Rhoads, J. E.: Hyperinsulinism and islet cell tumors of the pancreas. In Howar, J. M. and Jordan, G. L. (eds.): Surgical Diseases of the Pancreas. Philadelphia, J. B. Lippincott Co., 1960, pp. 321-441. Robins, J. M., Bookstein, J. J., Oberman, H. A. and Fajans, S. S.: Selective Angiography in Localizing Islet Cell Tumors of the Pancreas. Radiology, 106:525, 1973. Stefanini, P., Carboni, M., Patrassi, N. and Basoli, A.: Beta Islet Cell Tumors ofthe Pancreas: Results of a Study on 1067 Cases. Surgery, 75:597, 1974.
