ACTA
Acta Diabetol 29: 38-40, 1992
DIABETOLOGICA 9 Springer-Verlag 1992
Letter to the editor
Familial insulinoma: description of two cases M. Maioli 1, M. Ciccarese 1, A. Pacifico 1, G. Tonolo 1, A. Ganau 1, S. Cossn 2, E Tanda 2, and G. Realdi 1 Institute of Clinical Medicine, and z Institute of Pathological Anatomy, University of Sassari, Italy
Abstract. We describe cases o f isolated functioning insulin o m a occurring in two members o f the same family (father and daughter). The father h a d a first encapsulated insulinoma diagnosed at 14 years o f age and at the age o f 33 years he was operated o n for a second insulinoma infiltrating the exocrine pancreas with l y m p h n o d e metastases. The d a u g h t e r was o p e r a t e d on for an encapsulated insulinoma in the tail o f the pancreas w h e n she was 6 years old. N o clinical and l a b o r a t o r y signs o f other endocrine disturbances have so far been detected in either care or in any other m e m b e r s o f the family. O u r report suggests the possibility o f multiple familial insulinoma, although this is an extremely rare condition. O u r d a t a also indicate that insulinomas, even if well controlled by medical treatment, should always be r e m o v e d by surgery because m a l i g n a n c y c a n n o t be excluded with certainty. M o r e o v e r , patients should be closely followed up, as recurrence m a y develop up to 15 years after surgery. Key words: H y p o g l y c a e m i a - Islet cell a d e n o m a - Islet cell c a r c i n o m a
Introduction Insulinoma is an u n c o m m o n t u m o u r [1], but less rare than multiple endocrine neoplasia ( M E N type I) [2]. A t least 10% o f all insulinomas are m a l i g n a n t [3] and in 10% o f cases, two or m o r e t u m o u r s are found, sometimes with different histology and appearing m a n y years a p a r t [4]. Tragl and M a y r [5] were the first to describe familial multiple a d e n o m a s o f pancreatic beta cell occurring in two m e m b e r s o f the same family, not associated with M E N type I, and to o u r knowledge this association still remains extremely rare. We report here apparently isolated functioning insulin o m a s occurring in two m e m b e r s o f the same family (father and daughter). Offprint requests to: M. Maioli, Istituto di Clinica Medica, viale S. Pietro 8, 1-07100 Sassari, Italy
Case reports In 1967, at 10 years of age, MM, (a male now aged 34 years) developed loss of consciousness and sweating with neurological symptoms, suggesting hypoglycaemia. At 13 years of age in 1970, he had a subcutaneous lipoma of the left shoulder removed. One year later, following several hypoglycaemic crises, a clinical diagnosis of insulinoma was made (fasting glucose/insulin ratio < 3) and an encapsulated tumour (histologically an insulinoma) localized to the tail of the pancreas, was removed. His father had died at 54 o f multiple duodenal and stomach ulcers, his mother suffered from high blood pressure and an uncle from type 2 diabetes mellitus. After surgery, he did well until January 1985 when he had another hypoglycaemic episode after physical effort. Ultrasound scan of the upper abdomen was negative at that time. After 2 years the crises became a daily occurrence and the patient took food very frequently, with a marked increase of weight. In September 1989, the patient entered our department, where blood samples showed low fasting plasma glucose, and high insulin levels with a glucose/insulin ratio of less than 3. The 72 h fasting test was interrupted after 11 hours (Table 1). Ultrasound scan, computerized tomography and digital subtractive angiography of the coeliac axis and superior mesenteric artery showed an adenoma 1 cm in diameter in the tail of the pancreas. Other endocrine diseases had been excluded. The patient refused operation, and diazoxide 200 rag/day was started, with good results. At the end of October 1990, the patient consented to surgery. Partial pancreatectomy with resection of lymph nodes and hepatic biopsies was performed. Macroscopically, the specimen was 5 x 4 cm, and greyish in colour. Sections showed a poorly circumscribed, 1.5 cm yellow nodule. Histology showed an unencapsulated tumour infiltrating the exocrine pancreas and blood vessels, with neoplastic thrombi. Immunohistochemical staining using PAP and
Table 1. 72-h fasting test Time(h)
8.00 8.30 9.00 9.30
10.00 10.30 i1.00 11.30"
Glycaemia 2.6 2.8 2.3 2.2 2.0 (mmol/1) IRI 0.11 0.14 0.12 0.14 0.12 (gmol/l) C-peptide 0.6 0.7 0.7 0.6 0.6 (nmol/1)
1.8
1.7
1.4
0.14
0.14
0.14
0.8
0.9
0.9
" The test was interrupted at 11.30 because of the onset of headache, confusion, tachycardia, tremors and sweating
M. Maioli et al.: Familial insulinoma: description of two cases
39
Fig. 1. A lymph node shows a metastatic tumor in the subcapsular sinuses (H & E x 144)
the avidin-biotin immunoperoxidase system (ABC method) [6], showed marked diffuse positivity for monoclonal (M) or polyclonal (P) antibodies against insulin (P) and synaptophysin (M), while glucagon (P) and gastrin (P) antibodies gave negative results. Four out of seven lymph nodes from the peripancreatic tissue showed metastases (Fig. 1). The liver biopsy showed non-neoplastic infiltration. A diagnosis of pancreatic insulinoma with lymph node metastases was made. Review of the slides and the immunohistochemical investigation carried out on the tumour removed in 1971 confirmed the original diagnosis. After surgery, the patient did not have any cytostatic treatment and 1 year later all hormonal values and blood glucose were normal. M. R. is the youngest daughter of M. M. At the age of 6, in July 1985, she first developed vertigo, which lasted for about 1 h and spontaneously subsided. In April 1987, a diagnosis of insulinoma was made after surgical removal of a nodule of i cm in diameter from the tail of the pancreas [7]. After discharge, the patient was followed up in our institution and so far, after 4 years, both clinical and laboratory evidence of endocrine disturbances are still absent and there are no signs of recurrence. The other members of the family have been investigated, but symptoms and biochemical evidence of hyperinsulinism or other endocrine disturbances were absent.
Discussion The cases we report here are certainly insulinomas according to clinical, laboratory, histological and immunohistochemical criteria. Both cases occurred at very young ages, and one had two different tumours appearing 14 years apart, the second of which showed aggressiveness indicated by vascular invasion and lymph node metastases. The patients are first degree relatives (father and daughter). Neither has developed any other endocrine neoplasia, after, respectively, 20 and 4 years after the first diagnosis of insulinoma. This suggests that these two cases might be considered as familial insulinomas not associated with multiple endocrine neoplasia. Evidence in support of our conclusion includes the presence of diabetes mellitus in one m e m b e r of the family and the absence of
other endocrine abnormalities. Diabetes has been reported to be more frequent in families of patients with insulin o m a than in the general population [8]. Moreover, Like et al. [9] described a strain of hereditary diabetic mice, which has a propensity to develop insulinomas. Conversely, diabetes does not appear as frequently in M E N type 1. Familial insulinoma is extremely rare [5], while families with other endocrine tumors have been reported [10, 11]. O f course, another possibility to be kept in mind is that presence o f the two insulinomas in the same family might occur by chance and without any genetic involvement. However, the very early onset of the t u m o r (both in childhood) and the fact that the two patients are first degree relatives (father and daughter) suggest that this is familial insulinoma. Since so far, 20 and 4 years after the diagnosis of insulinoma, neither patient nor any other family members have developed other endocrine diseases, these cases might be considered as isolated familial insulinomas, even if we cannot exclude that the father o f M . M. might have had Zollinger-Ellison syndrome. In conclusion our cases confirm the Tragl and M a y r [5] observation that insulinomas, though very rarely, can occur in families, unassociated with M E N type I. One of the tumours showed aggressive behaviour, confirming that, notwithstanding good control by medical treatment, these tumours should always be brought to surgery because of the possibility of vascular invasion and metastases. Finally, these patients should be closely followed up as recurrence m a y develop up to 15 years after surgery.
References 1. Marks V, Salmons E, Insulinoma: natural history and diagnosis. Clin Gastroenterol 3: 559-573, 1974 2. Snyder N, Scurry MT, Deiss WP, Five families with multiple endocrine adenomatosis. Ann Intern Med 76: 53-58, 1972
M. Maioli et al,: Familial insulinoma: description of two cases
40 3. Wirsching R, Speisbero F, Landgraf R, Islet cell cancer with organic hyperinsulinism. Clinical aspects, diagnosis and therapy. Klin Wochenschr 60: 815-822, 1982 4. Stefanini P, Carboni M, Patrassi M, Basoli A, Beta-islet cell. Tumors of the pancreas: Results of a study on 1067 cases. Surgery 75: 597-609, 1974 5. Tragl KH, Mayr WR, Familial islet cell-adenomatosis. Lancet II: 426-428, 1977 6. Hsu SM, Raine L, Fanger H, Use of avloubiotin paraxodase complex (ABC) in immunoperoxidase technique. A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577-580, 1981 7. Radillo O, Tedesco F, Zweyer M, Englaro E, Citt/t A, Pocecco M, Bussani R, Radovich F, Unusual occurrence of insulinoma
8. 9. 10. 11.
in two members of the same family. Acta Oncologica rot. 11, no. 2, 1990 Shatney CH, Grace TB, Diagnostic and surgical aspects of insulinoma. A review of twenty-seven cases. Am J Surg 127:174-184, 1974 Like AA, Stelnke J, Jones EE, Oahill OF, Pancreatic studies in mice with spontaneous diabetes. Am J Pathol 46:621-644, 1965 Sandler LM, Moncrieff MW, Familial hyperparathyroidism. Arch Dis Child 55:146-147, 1980 Tisherman SE, Gregg F J, Danowski TS, Familial pheochromocytoma. JAMA 182: 152-156, 1962
Acta Diabetol 29: 38-40, 1992
DIABETOLOGICA 9 Springer-Verlag 1992
Letter to the editor
Familial insulinoma: description of two cases M. Maioli 1, M. Ciccarese 1, A. Pacifico 1, G. Tonolo 1, A. Ganau 1, S. Cossn 2, E Tanda 2, and G. Realdi 1 Institute of Clinical Medicine, and z Institute of Pathological Anatomy, University of Sassari, Italy
Abstract. We describe cases o f isolated functioning insulin o m a occurring in two members o f the same family (father and daughter). The father h a d a first encapsulated insulinoma diagnosed at 14 years o f age and at the age o f 33 years he was operated o n for a second insulinoma infiltrating the exocrine pancreas with l y m p h n o d e metastases. The d a u g h t e r was o p e r a t e d on for an encapsulated insulinoma in the tail o f the pancreas w h e n she was 6 years old. N o clinical and l a b o r a t o r y signs o f other endocrine disturbances have so far been detected in either care or in any other m e m b e r s o f the family. O u r report suggests the possibility o f multiple familial insulinoma, although this is an extremely rare condition. O u r d a t a also indicate that insulinomas, even if well controlled by medical treatment, should always be r e m o v e d by surgery because m a l i g n a n c y c a n n o t be excluded with certainty. M o r e o v e r , patients should be closely followed up, as recurrence m a y develop up to 15 years after surgery. Key words: H y p o g l y c a e m i a - Islet cell a d e n o m a - Islet cell c a r c i n o m a
Introduction Insulinoma is an u n c o m m o n t u m o u r [1], but less rare than multiple endocrine neoplasia ( M E N type I) [2]. A t least 10% o f all insulinomas are m a l i g n a n t [3] and in 10% o f cases, two or m o r e t u m o u r s are found, sometimes with different histology and appearing m a n y years a p a r t [4]. Tragl and M a y r [5] were the first to describe familial multiple a d e n o m a s o f pancreatic beta cell occurring in two m e m b e r s o f the same family, not associated with M E N type I, and to o u r knowledge this association still remains extremely rare. We report here apparently isolated functioning insulin o m a s occurring in two m e m b e r s o f the same family (father and daughter). Offprint requests to: M. Maioli, Istituto di Clinica Medica, viale S. Pietro 8, 1-07100 Sassari, Italy
Case reports In 1967, at 10 years of age, MM, (a male now aged 34 years) developed loss of consciousness and sweating with neurological symptoms, suggesting hypoglycaemia. At 13 years of age in 1970, he had a subcutaneous lipoma of the left shoulder removed. One year later, following several hypoglycaemic crises, a clinical diagnosis of insulinoma was made (fasting glucose/insulin ratio < 3) and an encapsulated tumour (histologically an insulinoma) localized to the tail of the pancreas, was removed. His father had died at 54 o f multiple duodenal and stomach ulcers, his mother suffered from high blood pressure and an uncle from type 2 diabetes mellitus. After surgery, he did well until January 1985 when he had another hypoglycaemic episode after physical effort. Ultrasound scan of the upper abdomen was negative at that time. After 2 years the crises became a daily occurrence and the patient took food very frequently, with a marked increase of weight. In September 1989, the patient entered our department, where blood samples showed low fasting plasma glucose, and high insulin levels with a glucose/insulin ratio of less than 3. The 72 h fasting test was interrupted after 11 hours (Table 1). Ultrasound scan, computerized tomography and digital subtractive angiography of the coeliac axis and superior mesenteric artery showed an adenoma 1 cm in diameter in the tail of the pancreas. Other endocrine diseases had been excluded. The patient refused operation, and diazoxide 200 rag/day was started, with good results. At the end of October 1990, the patient consented to surgery. Partial pancreatectomy with resection of lymph nodes and hepatic biopsies was performed. Macroscopically, the specimen was 5 x 4 cm, and greyish in colour. Sections showed a poorly circumscribed, 1.5 cm yellow nodule. Histology showed an unencapsulated tumour infiltrating the exocrine pancreas and blood vessels, with neoplastic thrombi. Immunohistochemical staining using PAP and
Table 1. 72-h fasting test Time(h)
8.00 8.30 9.00 9.30
10.00 10.30 i1.00 11.30"
Glycaemia 2.6 2.8 2.3 2.2 2.0 (mmol/1) IRI 0.11 0.14 0.12 0.14 0.12 (gmol/l) C-peptide 0.6 0.7 0.7 0.6 0.6 (nmol/1)
1.8
1.7
1.4
0.14
0.14
0.14
0.8
0.9
0.9
" The test was interrupted at 11.30 because of the onset of headache, confusion, tachycardia, tremors and sweating
M. Maioli et al.: Familial insulinoma: description of two cases
39
Fig. 1. A lymph node shows a metastatic tumor in the subcapsular sinuses (H & E x 144)
the avidin-biotin immunoperoxidase system (ABC method) [6], showed marked diffuse positivity for monoclonal (M) or polyclonal (P) antibodies against insulin (P) and synaptophysin (M), while glucagon (P) and gastrin (P) antibodies gave negative results. Four out of seven lymph nodes from the peripancreatic tissue showed metastases (Fig. 1). The liver biopsy showed non-neoplastic infiltration. A diagnosis of pancreatic insulinoma with lymph node metastases was made. Review of the slides and the immunohistochemical investigation carried out on the tumour removed in 1971 confirmed the original diagnosis. After surgery, the patient did not have any cytostatic treatment and 1 year later all hormonal values and blood glucose were normal. M. R. is the youngest daughter of M. M. At the age of 6, in July 1985, she first developed vertigo, which lasted for about 1 h and spontaneously subsided. In April 1987, a diagnosis of insulinoma was made after surgical removal of a nodule of i cm in diameter from the tail of the pancreas [7]. After discharge, the patient was followed up in our institution and so far, after 4 years, both clinical and laboratory evidence of endocrine disturbances are still absent and there are no signs of recurrence. The other members of the family have been investigated, but symptoms and biochemical evidence of hyperinsulinism or other endocrine disturbances were absent.
Discussion The cases we report here are certainly insulinomas according to clinical, laboratory, histological and immunohistochemical criteria. Both cases occurred at very young ages, and one had two different tumours appearing 14 years apart, the second of which showed aggressiveness indicated by vascular invasion and lymph node metastases. The patients are first degree relatives (father and daughter). Neither has developed any other endocrine neoplasia, after, respectively, 20 and 4 years after the first diagnosis of insulinoma. This suggests that these two cases might be considered as familial insulinomas not associated with multiple endocrine neoplasia. Evidence in support of our conclusion includes the presence of diabetes mellitus in one m e m b e r of the family and the absence of
other endocrine abnormalities. Diabetes has been reported to be more frequent in families of patients with insulin o m a than in the general population [8]. Moreover, Like et al. [9] described a strain of hereditary diabetic mice, which has a propensity to develop insulinomas. Conversely, diabetes does not appear as frequently in M E N type 1. Familial insulinoma is extremely rare [5], while families with other endocrine tumors have been reported [10, 11]. O f course, another possibility to be kept in mind is that presence o f the two insulinomas in the same family might occur by chance and without any genetic involvement. However, the very early onset of the t u m o r (both in childhood) and the fact that the two patients are first degree relatives (father and daughter) suggest that this is familial insulinoma. Since so far, 20 and 4 years after the diagnosis of insulinoma, neither patient nor any other family members have developed other endocrine diseases, these cases might be considered as isolated familial insulinomas, even if we cannot exclude that the father o f M . M. might have had Zollinger-Ellison syndrome. In conclusion our cases confirm the Tragl and M a y r [5] observation that insulinomas, though very rarely, can occur in families, unassociated with M E N type I. One of the tumours showed aggressive behaviour, confirming that, notwithstanding good control by medical treatment, these tumours should always be brought to surgery because of the possibility of vascular invasion and metastases. Finally, these patients should be closely followed up as recurrence m a y develop up to 15 years after surgery.
References 1. Marks V, Salmons E, Insulinoma: natural history and diagnosis. Clin Gastroenterol 3: 559-573, 1974 2. Snyder N, Scurry MT, Deiss WP, Five families with multiple endocrine adenomatosis. Ann Intern Med 76: 53-58, 1972
M. Maioli et al,: Familial insulinoma: description of two cases
40 3. Wirsching R, Speisbero F, Landgraf R, Islet cell cancer with organic hyperinsulinism. Clinical aspects, diagnosis and therapy. Klin Wochenschr 60: 815-822, 1982 4. Stefanini P, Carboni M, Patrassi M, Basoli A, Beta-islet cell. Tumors of the pancreas: Results of a study on 1067 cases. Surgery 75: 597-609, 1974 5. Tragl KH, Mayr WR, Familial islet cell-adenomatosis. Lancet II: 426-428, 1977 6. Hsu SM, Raine L, Fanger H, Use of avloubiotin paraxodase complex (ABC) in immunoperoxidase technique. A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577-580, 1981 7. Radillo O, Tedesco F, Zweyer M, Englaro E, Citt/t A, Pocecco M, Bussani R, Radovich F, Unusual occurrence of insulinoma
8. 9. 10. 11.
in two members of the same family. Acta Oncologica rot. 11, no. 2, 1990 Shatney CH, Grace TB, Diagnostic and surgical aspects of insulinoma. A review of twenty-seven cases. Am J Surg 127:174-184, 1974 Like AA, Stelnke J, Jones EE, Oahill OF, Pancreatic studies in mice with spontaneous diabetes. Am J Pathol 46:621-644, 1965 Sandler LM, Moncrieff MW, Familial hyperparathyroidism. Arch Dis Child 55:146-147, 1980 Tisherman SE, Gregg F J, Danowski TS, Familial pheochromocytoma. JAMA 182: 152-156, 1962
