Acta Oncologica
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Genetic and Clinical Characteristics OF Multiple Endocrine Neoplasia Type 1 B. Skogseid, C. Larsson & K. Öberg To cite this article: B. Skogseid, C. Larsson & K. Öberg (1991) Genetic and Clinical Characteristics OF Multiple Endocrine Neoplasia Type 1, Acta Oncologica, 30:4, 485-488, DOI: 10.3109/02841869109092405 To link to this article: http://dx.doi.org/10.3109/02841869109092405
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 35
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Citing articles: 6 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20 Download by: [Australian Catholic University]
Date: 31 July 2017, At: 08:11
Acia Oncologica Vol. 30 No. 4 1991
FROM THE DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY HOSPITAL, LUDWIG INSTITUTE FOR CANCER RESEARCH, UPPSALA, AND THE DEPARTMENT OF CLINICAL GENETICS, KAROLINSKA HOSPITAL, STOCKHOLM, SWEDEN.
GENETIC AND CLINICAL CHARACTERISTICS OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 B. SKOGSEID. C. LARSSONand K.
Abstract Multiple endocrine neoplasia type 1 (MEN 1) is an inherited disorder of autosomal-dominant type encompassing tumors of the parathyroid glands, anterior pituitary and endocrine pancreas. The genetic defect responsible for MEN 1 maps to the long arm of chromosome 1I ( 1 lq13). Constitutional heterozygosity for the MEN 1 region is lost in proliferating pancreatic endocrine and parathyroid tissue, which suggests that the MEN 1 gene belongs to the group of tumor suppressor genes (antioncogenes).Genetic screening by linkage analysis using RFLP markers allows selection of gene carriers with high degree of accuracy and makes it possible to concentrate the laborious biochemical screening efforts to family members at risk of developing the MEN 1 syndrome. Biochemical screening of the MEN 1 lesions in young asymptomatic individuals decreases the age at diagnosis with many years (decades) and therapeutic intervention can be instituted early. Although it still remains to be established whether early intervention will have an impact on mortality, our long-term experience with 20 MEN 1 kindreds suggests a reduced morbidity as a result of thorough biochemical screening. Key w o r h ; Multiple endocrine neoplasia type 1, gene mapping, screening, pancreatic endocrine tumors, meal stimulation test.
Background The first allusion to the M E N 1 gene was presented in 1954 ( 1) and subsequently several extensive predigrees (2, 3) have provided evidence of a dominant autosomal gene, with high penetrance, in control of the trait. In 1971, Knudson (4) proposed the two-mutation model of oncogenesis inheritable neoplastic diseases, based on epidemiological analyses of retinoblastoma. In heritable retinoblastoma the first mutation is germinal and thus present in all cells, which therefore are predisposed to tumor development. The tumor, after a second mutation, occurs in a somatic cell and represents an elimination of the normal allele (the wild type). Even if the frequency of
BERG
the somatic mutation is low the cells are so abundant that the probability of this second event occurring is very high. The finding that the length of D N A fragments generated upon digestion with restriction enzymes will vary among individuals ( RFLPs), permits identification of the parental origin of an allele. Comparison of constitutional and tumor D N A from patients with inherited retinoblastoma revealed losses of chromosome 13 alleles in tumor tissue. The lost alleles always represented the chromosome derived from the unaffected parent, while the remaining chromosome was found to carry the mutated retinoblastoma gene, i.e. originated from the affected parent. Unmasking of the mutated retinoblastoma gene results in tumor growth and consequently introduction of the cloned antioncogene into retinoblastoma cells via a retroviral vector suppresses the malignant phenotype (5).
MEN 1 gene
mapping
In order to detect a presumptive M E N 1 locus, constitutional and tumor genotypes in two brothers with pancreatic endocrine tumors were compared (Figure) and showed loss of constitutional heterozygosity for all informative loci on chromsome 11 (6). Furthermore, the R F L P analysis revealed that the retained chromosome 11 was transmitted from the MEN 1 affected mother. This finding of chromosome rearrangements in M E N 1 phenotype tissue was interpreted as a n indication of the chromosome harboring the M E N 1 gene. Subsequently, linkage studies in four
Presented at the Meeting on Recent Advances in Diagnosis and Treatment of Neuroendocrine Gut and Pancreatic Tumors held in Kebnekaise, Sweden, June 13-16, 1990. Accepted for publication 13 December 1990. 485
486
B. SKOGSEID ET AL
Figure. Autoradiogram showing hybridization to the calcitonin probe. Pancreatic endocrine tumor tissue (Tu) from two MEN 1-atfected brothers displayed loss of constitutional heterozygosity (third and sixth lane). The lost allele originated from the unaffected father (right lane), whereas the retained allele was transmitted from the MEN I-affected mother (left lane).
MEN 1 families were performed. These families had been subjected to a thorough biochemical and radiological screening program for ten years. Individuals older than 35 years and repeatedly negative for MEN 1 biochemical screening were designated as unaffected, while MEN 1 offspring who were ‘biochemically healthy’ and under 35 years of age were excluded. The disease was found to be closely linked to the PYGM locus at llq13 (6) and these results were later confirmed in studies of other MEN 1 families (7, 8). A genetic linkage map of markers in the vicinity of the MEN 1 locus was constructed permitting identification of carriers of the predisposition of MEN 1 with a high degree of accuracy (9). In MEN 1 parathyroid lesions allele losses on chromosome 1 1 could be detected and deletion mapping further restricted the MEN 1 region (10). About one-third of sporadic parathyroid adenomas showed loss of constitutional heterozygosity for the MEN 1 region (8, 10, 1 I ) indicating that tumorigenesis of host sporadic parathyroid adenomas involves mechanisms similar to the heritable counterparts. Only 2 of 27 informative cases of sporadic pituitary adenomas displayed allele losses for chromosome 11 (10). Neurosurgery in MEN 1 patients is rarely indicated and therefore pituitary tumor specimens are practically not available for RFLP analysis. It is still unclear whether MEN 1 pituitary tumorigenesis differs from that of the parathyroids and the endocrine pancreas, i.e. inactivation of both 1 Iql3 alleles. Chromosome 11 allele losses have recently been reported in a case of sporadic insulinoma ( 12).
Clinical features Primary hyperparathyroidism is the most common manifestation of the MEN 1 syndrome and has been designated to be the presenting lesion (13). However, data from
our ten-year prospective screening study (unpublished) indicate that any of the MEN 1 lesions could well be the first one to become clinically detectable. The diagnosis hyperparathyroidism is confirmed by findings of hypercalcemia associated with an inappropriately elevated serum parathyroid hormone level. Treatment involves surgical ablation of all glands with immediate autotransplantation of 50-60 mg parathyroid tissue (14). Reported prevalence of lesions in the anterior pituitary are largely determined from reviewing MEN 1 necropsy cases in the literature; these range from 50 to 60% (3, 15, 16). In screening studies the frequencies are lower (16,27 and 42%) (13, 17, 18). In a retrospective study from the Mayo Clinic 27% of MEN 1 pituitary tumors subjected to surgery were microadenomas while the remaining 73% were macroadenomas (19).Furthermore, it was concluded that the MEN I-associated pituitary adneomas are more often endocrinologically functional, displaying multiple hormone production in comparison with pituitary adenomas occurring in the general population. Clinically prolactinomas are most common ( 13, 18). Diagnosis depends on endocrine assessment and detection of tumor mass. Magnetic resonance tomography and computed tomography (CT) may be advantageous methods for the latter diagnostic criterion. The management policies of MEN 1 pituitary lesions have largely been the same as for sporadic pituitary adenomas, although no systematic evaluation of these issues has been reported. The reported prevalence of pancreatic involvement in MEN 1-affected individuals varies between 30°h (screening material) and 82% (necropsy material) (3, 15, 16, 20). The pancreatic lesion is multicentric and consists of different stages of endocrine cell proliferation; ‘hyperplasia’ or microadenomas, adenomas and carcinomas ( l, 3,21,22). The clinical symptoms are dependant on the particular hormone production in the lesions. Even though the pancreatic endocrine tumor may secrete several peptides, one of them is usually predominant and associated with a specific syndrome. The most frequent of the classical endocrine syndromes seen in MEN 1 pancreatic tumor patients are the Zollinger-Ellison syndrome due to gastrin-producing tumors and hypoglycemic symptoms due to insulinomas (3,23). Other peptides involved in different combinations are vasoactive intestinal polypeptide, pancreatic polypeptide (PP), glucagon, somatostatin and calcitonin (24). Neuroendocrine tumors (carcinoids) of the duodenum responsible for a Zollinger-Ellison syndrome concomitant with pancreatic endocrine tumors have recently been reported (25). The reported ages at onset of the MEN 1 pancreatic endocrine lesion range from 6 to 81 years (16,26) but averages are outlined to the fourth or fifth decade of life (18,27). There has not yet been any systematic assessment of the actual onset age of the pancreatic endocrine dysfunction in MEN 1 but our experience with a prospective
487
MEN I . GENETIC AND CLINICAL CHARACTER
Table 1 Biochemical Screening for M E N I pancreatic endocrine tumors
Serum insulin Serum proinsulin Serum C-peptide Serum pancreatic polypeptide Serum gastrin Serum calcitonin Plasma glucagon Plasma somatostatin Plasma vasoactive intestinal polypeptide Serum human chorionic gonadotrophin subunits a and p Meal stimulation test with measurement of serum PP and gastrin response
uremia (18). Invasive growth of or bleeding in pituitary tumors constitutes other potential causes of death among MEN I-affected individuals. Whether or not screening and early intervention in the M E N 1 trait is benefical for survival has not yet been clarified. Case report
biochemical screening program (Table) suggests a considerable lower onset age (unpublished data). The biochemical diagnosis of pancreatic endocrine lesions in MEN 1 preceded the radiological signs of pancreatic involvement with a mean of 3.5 years. A standardized meal stimulation test with measurement of serum PP and gastrin responses attained the highest sensitivity among the biochemical screening markers applied (28). Other effective markers for early pancreatic tumor diagnosis in asymptomatic individuals were basal insulin and proinsulin (23). Due to the multiplicity of the pancreatic endocrine lesion in MEN 1 the only curative treatment available, albeit rarely indicated, is total pancreatectomy (21). Instead a surgical procedure, encompassing distal pancreatic resection (corpus-cauda) in combination with enucleation of lesions in the pancreatic head seems to be widely applied ( 2 1,29). Symptomatic therapy by medication comprises histamine receptor blocking agents or inhibitors of the proton pump of parietal cells for the Zollinger-Ellison syndrome, diazoxide in hypoglycemic patients, and a longacting somatostatin analogue (30). For malignant and/or recurrent pancreatic disease, chemotherapy with streptozotocin or treatment with interferons has been applied with promising results (30).
A 22-year-old male, member of a MEN 1 family with a pronounced ability to develop highly malignant proinsulinomas at young age, was designated healthy at first screening. At the age of 19, serum calcium was 2.73 mmol/l and parathyroidectomy was performed. Furthermore, basal serum proinsulin was 65 pmol/l (reference limit < 8.9) and the meal test indicated pancreatic endocrine tumor (abnormal serum PP response to the meal). The patient had severe hypoglycemic symptoms after a 24-h fasting, but CT, ultrasonography, and angiography could not detect a pancreatic tumor. Transhepatic portal catheterization with sampling showed high levels of serum proinsulin (221 pmol/l) in the splenic vein with a marked gradient towards veins draining the pancreatic head. At exploration three tumors, sized 0.5 to I .5 cm were found in the distal part. Intraoperative ultrasonography detected another four tumors about 3 mm in diameter in the tail of the pancreas. No tumor was found in the pancreatic head. A distal resection was performed. The operative specimen also contained five microadenomas. Postoperatively proinsulin levels normalized and a 72-h fasting test could be performed without hypoglycemia. However, six months later the meal stimulation test indicated relapse with an abnormally high serum PP response and basal serum proinsulin increased to 27 pmol/l. The fasting test was negative with an appropriate decrease of proinsulin to 4.4 pmol/l after 72 h. Radiology failed to demonstrate tumors in the remaining proximal part of the pancreas. These biochemical findings indicated proliferation of the endocrine pancreas but the normal regulation of the proinsulin-insulin secretion during fasting was interpreted as an early state of tumor development, which could be designated preneoplasia. Low dose of interferon treatment (Introna, 3 MU three times a week subcutaneously) was instituted as an attempt to reduce further mitogen activity and proliferation and finally tumor development. After three months of treatment the serum PP response to the meal was again normal, basal serum proinsulin levels were almost normal (12pmol/l) and the 72-h fasting test remained negative with an inhibition of proinsulin secretion to levels under detection limit ( ~ 2 . pmol/l). 5
Prognosis
ACKNOWLEDGEMENTS
The prognosis of MEN 1 is dependant on several factors but could generally be denoted as good in comparison with other potentially malignant dieases. An assessment of survival rates in patients with sporadic pancreatic endocrine tumors compared to those as part of the M E N 1 trait showed a significantly longer survival for the MEN 1 patients and averaged 15 years from diagnosis (30). The cause of death in MEN 1 patients with pancreatic endocrine tumors could either be due to hypersecretion of peptides accompanied by syndromes with pronounced morbidity o r to tumor progression, o r a combination of both, leading to a life-threatening clinical deterioration of the patients' condition. The parathyroid lesion may, left undiagnosed, lead to nephrolithiasis but rarely to fatal
This work was supported by grants from the King Gustav V's Jubilee Fund and the Swedish Cancer Society. Corresponding aufhor: Dr Bntt Skogseid, Department of Internal Medicine, University Hospital, s-75 I 85 Uppsala, Sweden.
REFERENCES Wermer P. Genetic aspects of adenomatosis of endocrine glands. Am J Med 1954; 16: 363-71. Wermer P. Endocrine adenomatosis and peptic ulcer in a large kindred: inherited multiple tumors and mosaic pleitropism in man. Am J Med 1963; 35: 205-12. Ballard HS, Frame B, Hartsock RJ. Familial multiple endocrine adenoma-peptic ulcer complex. Medicine (Baltimore) 1964; 43: 481-516.
488
B. SKOGSEID ET AL.
4. Knudson AG. Mutation and cancer. Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820-3. 5. Huang H-JS, Yee J-K, Shew J-Y, et al. Suppression of the neoplastic phenotype by replacement of the Rb gene in human cancer cells. Science 1988; 242: 1563-6. 6. Larsson C, Skogseid B, b e r g K, Nakamura Y,Nordenskiold M. Multiple endocrine neoplasia type 1 gene maps to chromosome I I and is lost in insulinoma. Nature 1988; 332: 85-7. 7. Bale SJ, Bale AE, Stewart K, et al. Linkage analysis of multiple endocrine neoplasia type 1 with INT 2 and other markers on chromosome 1 1 . Genomics 1989; 4: 320-2. 8. Thakker RV, Bouloux P, Wooding C, et al. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 1 1 . N Engl J Med 1989; 321: 218-24. 9. Nakamura Y, Larsson C, Julier C, et al. Localization of the genetic defect in multiple endocrine neoplasia type 1 within a small region of chromosome 11. Am J Hum Genet 1989; 44: 751 - 5 . 10. Bystrom C, Larsson C, Blomberg C, et al. Localization of the gene for multiple endocrine neoplasia type 1 to small region within chromosome Ilq 13 by deletion mapping in tumors. Proc Natl Acad Sci USA 1990; 87: 1968-72. 1 1 . Friedman E, Sakaguchi K, Bale AE, et al. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type I . N Engl J Med 1989; 321: 213-8. 12. Patel P, ORahilly S, Buckle V, Nakamura Y, Turner RC, Wainscoat JS. Chromosome 1 1 allele loss in sporadic insulinoma. J Clin Pathol 1990; 43: 377-8. 13. Benson L, Ljunghall S, Akerstrom G, oberg K. Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type I . Am J Med 1987; 82: 731-7. 14. Malmaus J, Benson L, Johansson H, et al. Parathyroid surgery in the multiple endocrine neoplasia type 1 syndrome: Choice of surgical procedure. World J Surg 1986; 10: 668 -72. 15. Croisier JC, Azerad E, Lubetzki J. L’adenomatose polyendocrinienne. A propos d’une observation personelle et revenue de la litterature. Sem Hop Paris 1971; 47: 494-525. 16. Eberle F, Griin R. Multiple endocrine neoplasia, type 1 (MEN 1). Ergeb Inn Med Kinderheilkd 1981; 46: 75-149. 17. Marx SJ, Spiegel AM, Brown EM, Aurbach GD. Family studies in patients with primary parathyroid hyperplasia. Am J Med 1977; 62: 698-706. 18. Vasen HFA, Lamers CBHW, Lips CJM. Screening for the multiple endocrine neoplasia syndrome type I . A study of 11
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kindreds in the Netherlands. Arch Intern Med 1989; 149: 271 7-22. Scheithauer BW, Laws ER, Kovacs K, Horvath E, Randall RV, Carney JA. Pituitary adenomas of the multiple endocrine neoplasia type 1 syndrome. Semin Diagn Pathol 1987; 4: 205- 1 1. Brandi ML, Marx SJ, Aurbach GD, Fitzpatrick LA. Familial multiple endocrine neoplasia type 1: A new look at pathophysiology. Endocr Rev 1987; 8: 391-405. Thompson NW, Lloyd RV, Nishiyama RH, et al. MEN 1 pancreas. A histological and immunohistochemical study. World J Surg 1984; 8: 561-74. Klopper G, Willemer S, Stamm B, H k k i WH, Heitz PU. Pancreatic lesions and hormonal profile of pancreatic tumors in multiple endocrine neoplasia type 1. Cancer 1986; 57: 1824-32. 6berg K, Wilinder 0, Bostrom H, Lundqvist G, Wide L. Peptide hormone markers in screening for endocrine tumors in multiple endocrine adenomatosis type I . Am J Med 1982; 73: 619-30. Eriksson B, Arnberg H, Lindgren PG, et al. Neuroendocrine pancreatic tumours: clinical presentation, biochemical and histopathological findings in 84 patients. J Intern Med 1990; 228: 103-13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med 1990; 322: 723-7. Lips CJM, Lamers CBHW, Vasen HFA. Multiple endocrine neoplasia syndromes. Crit Rev Oncol 1984; 2: 117-84. Marx SJ, Winik AI, Santen RJ, Floyd JC, Mills JL, Green J. Multiple endocrine neoplasia type 1: Assessment of laboratory tests to screen for the gene in a large kindred. Medicine 1986; 65: 226-41. Skogseid B, 6berg K, Benson L, et al. A standardized meal stimulation test of the endocrine pancreas for early detection of pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome. Five years’ experience. J Clin Endocrinol Metab 1987; 64: 1233-40. Norton JA, Cromack DT, Shawker TH, et al. Intraoperative ultrasonographic localization of islet cell tumors. A prospective comparison to palpation. Ann Surg 1988; 207: 160-8. Eriksson B, Skogseid B, Lundqvist G, Wide L, Wilander E, ()berg K. Medical treatment and long-term survival in a prospective study of 84 patients with endocrine tumors. Cancer 1990; 65: 1883-90.
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Genetic and Clinical Characteristics OF Multiple Endocrine Neoplasia Type 1 B. Skogseid, C. Larsson & K. Öberg To cite this article: B. Skogseid, C. Larsson & K. Öberg (1991) Genetic and Clinical Characteristics OF Multiple Endocrine Neoplasia Type 1, Acta Oncologica, 30:4, 485-488, DOI: 10.3109/02841869109092405 To link to this article: http://dx.doi.org/10.3109/02841869109092405
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 35
View related articles
Citing articles: 6 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20 Download by: [Australian Catholic University]
Date: 31 July 2017, At: 08:11
Acia Oncologica Vol. 30 No. 4 1991
FROM THE DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY HOSPITAL, LUDWIG INSTITUTE FOR CANCER RESEARCH, UPPSALA, AND THE DEPARTMENT OF CLINICAL GENETICS, KAROLINSKA HOSPITAL, STOCKHOLM, SWEDEN.
GENETIC AND CLINICAL CHARACTERISTICS OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 B. SKOGSEID. C. LARSSONand K.
Abstract Multiple endocrine neoplasia type 1 (MEN 1) is an inherited disorder of autosomal-dominant type encompassing tumors of the parathyroid glands, anterior pituitary and endocrine pancreas. The genetic defect responsible for MEN 1 maps to the long arm of chromosome 1I ( 1 lq13). Constitutional heterozygosity for the MEN 1 region is lost in proliferating pancreatic endocrine and parathyroid tissue, which suggests that the MEN 1 gene belongs to the group of tumor suppressor genes (antioncogenes).Genetic screening by linkage analysis using RFLP markers allows selection of gene carriers with high degree of accuracy and makes it possible to concentrate the laborious biochemical screening efforts to family members at risk of developing the MEN 1 syndrome. Biochemical screening of the MEN 1 lesions in young asymptomatic individuals decreases the age at diagnosis with many years (decades) and therapeutic intervention can be instituted early. Although it still remains to be established whether early intervention will have an impact on mortality, our long-term experience with 20 MEN 1 kindreds suggests a reduced morbidity as a result of thorough biochemical screening. Key w o r h ; Multiple endocrine neoplasia type 1, gene mapping, screening, pancreatic endocrine tumors, meal stimulation test.
Background The first allusion to the M E N 1 gene was presented in 1954 ( 1) and subsequently several extensive predigrees (2, 3) have provided evidence of a dominant autosomal gene, with high penetrance, in control of the trait. In 1971, Knudson (4) proposed the two-mutation model of oncogenesis inheritable neoplastic diseases, based on epidemiological analyses of retinoblastoma. In heritable retinoblastoma the first mutation is germinal and thus present in all cells, which therefore are predisposed to tumor development. The tumor, after a second mutation, occurs in a somatic cell and represents an elimination of the normal allele (the wild type). Even if the frequency of
BERG
the somatic mutation is low the cells are so abundant that the probability of this second event occurring is very high. The finding that the length of D N A fragments generated upon digestion with restriction enzymes will vary among individuals ( RFLPs), permits identification of the parental origin of an allele. Comparison of constitutional and tumor D N A from patients with inherited retinoblastoma revealed losses of chromosome 13 alleles in tumor tissue. The lost alleles always represented the chromosome derived from the unaffected parent, while the remaining chromosome was found to carry the mutated retinoblastoma gene, i.e. originated from the affected parent. Unmasking of the mutated retinoblastoma gene results in tumor growth and consequently introduction of the cloned antioncogene into retinoblastoma cells via a retroviral vector suppresses the malignant phenotype (5).
MEN 1 gene
mapping
In order to detect a presumptive M E N 1 locus, constitutional and tumor genotypes in two brothers with pancreatic endocrine tumors were compared (Figure) and showed loss of constitutional heterozygosity for all informative loci on chromsome 11 (6). Furthermore, the R F L P analysis revealed that the retained chromosome 11 was transmitted from the MEN 1 affected mother. This finding of chromosome rearrangements in M E N 1 phenotype tissue was interpreted as a n indication of the chromosome harboring the M E N 1 gene. Subsequently, linkage studies in four
Presented at the Meeting on Recent Advances in Diagnosis and Treatment of Neuroendocrine Gut and Pancreatic Tumors held in Kebnekaise, Sweden, June 13-16, 1990. Accepted for publication 13 December 1990. 485
486
B. SKOGSEID ET AL
Figure. Autoradiogram showing hybridization to the calcitonin probe. Pancreatic endocrine tumor tissue (Tu) from two MEN 1-atfected brothers displayed loss of constitutional heterozygosity (third and sixth lane). The lost allele originated from the unaffected father (right lane), whereas the retained allele was transmitted from the MEN I-affected mother (left lane).
MEN 1 families were performed. These families had been subjected to a thorough biochemical and radiological screening program for ten years. Individuals older than 35 years and repeatedly negative for MEN 1 biochemical screening were designated as unaffected, while MEN 1 offspring who were ‘biochemically healthy’ and under 35 years of age were excluded. The disease was found to be closely linked to the PYGM locus at llq13 (6) and these results were later confirmed in studies of other MEN 1 families (7, 8). A genetic linkage map of markers in the vicinity of the MEN 1 locus was constructed permitting identification of carriers of the predisposition of MEN 1 with a high degree of accuracy (9). In MEN 1 parathyroid lesions allele losses on chromosome 1 1 could be detected and deletion mapping further restricted the MEN 1 region (10). About one-third of sporadic parathyroid adenomas showed loss of constitutional heterozygosity for the MEN 1 region (8, 10, 1 I ) indicating that tumorigenesis of host sporadic parathyroid adenomas involves mechanisms similar to the heritable counterparts. Only 2 of 27 informative cases of sporadic pituitary adenomas displayed allele losses for chromosome 11 (10). Neurosurgery in MEN 1 patients is rarely indicated and therefore pituitary tumor specimens are practically not available for RFLP analysis. It is still unclear whether MEN 1 pituitary tumorigenesis differs from that of the parathyroids and the endocrine pancreas, i.e. inactivation of both 1 Iql3 alleles. Chromosome 11 allele losses have recently been reported in a case of sporadic insulinoma ( 12).
Clinical features Primary hyperparathyroidism is the most common manifestation of the MEN 1 syndrome and has been designated to be the presenting lesion (13). However, data from
our ten-year prospective screening study (unpublished) indicate that any of the MEN 1 lesions could well be the first one to become clinically detectable. The diagnosis hyperparathyroidism is confirmed by findings of hypercalcemia associated with an inappropriately elevated serum parathyroid hormone level. Treatment involves surgical ablation of all glands with immediate autotransplantation of 50-60 mg parathyroid tissue (14). Reported prevalence of lesions in the anterior pituitary are largely determined from reviewing MEN 1 necropsy cases in the literature; these range from 50 to 60% (3, 15, 16). In screening studies the frequencies are lower (16,27 and 42%) (13, 17, 18). In a retrospective study from the Mayo Clinic 27% of MEN 1 pituitary tumors subjected to surgery were microadenomas while the remaining 73% were macroadenomas (19).Furthermore, it was concluded that the MEN I-associated pituitary adneomas are more often endocrinologically functional, displaying multiple hormone production in comparison with pituitary adenomas occurring in the general population. Clinically prolactinomas are most common ( 13, 18). Diagnosis depends on endocrine assessment and detection of tumor mass. Magnetic resonance tomography and computed tomography (CT) may be advantageous methods for the latter diagnostic criterion. The management policies of MEN 1 pituitary lesions have largely been the same as for sporadic pituitary adenomas, although no systematic evaluation of these issues has been reported. The reported prevalence of pancreatic involvement in MEN 1-affected individuals varies between 30°h (screening material) and 82% (necropsy material) (3, 15, 16, 20). The pancreatic lesion is multicentric and consists of different stages of endocrine cell proliferation; ‘hyperplasia’ or microadenomas, adenomas and carcinomas ( l, 3,21,22). The clinical symptoms are dependant on the particular hormone production in the lesions. Even though the pancreatic endocrine tumor may secrete several peptides, one of them is usually predominant and associated with a specific syndrome. The most frequent of the classical endocrine syndromes seen in MEN 1 pancreatic tumor patients are the Zollinger-Ellison syndrome due to gastrin-producing tumors and hypoglycemic symptoms due to insulinomas (3,23). Other peptides involved in different combinations are vasoactive intestinal polypeptide, pancreatic polypeptide (PP), glucagon, somatostatin and calcitonin (24). Neuroendocrine tumors (carcinoids) of the duodenum responsible for a Zollinger-Ellison syndrome concomitant with pancreatic endocrine tumors have recently been reported (25). The reported ages at onset of the MEN 1 pancreatic endocrine lesion range from 6 to 81 years (16,26) but averages are outlined to the fourth or fifth decade of life (18,27). There has not yet been any systematic assessment of the actual onset age of the pancreatic endocrine dysfunction in MEN 1 but our experience with a prospective
487
MEN I . GENETIC AND CLINICAL CHARACTER
Table 1 Biochemical Screening for M E N I pancreatic endocrine tumors
Serum insulin Serum proinsulin Serum C-peptide Serum pancreatic polypeptide Serum gastrin Serum calcitonin Plasma glucagon Plasma somatostatin Plasma vasoactive intestinal polypeptide Serum human chorionic gonadotrophin subunits a and p Meal stimulation test with measurement of serum PP and gastrin response
uremia (18). Invasive growth of or bleeding in pituitary tumors constitutes other potential causes of death among MEN I-affected individuals. Whether or not screening and early intervention in the M E N 1 trait is benefical for survival has not yet been clarified. Case report
biochemical screening program (Table) suggests a considerable lower onset age (unpublished data). The biochemical diagnosis of pancreatic endocrine lesions in MEN 1 preceded the radiological signs of pancreatic involvement with a mean of 3.5 years. A standardized meal stimulation test with measurement of serum PP and gastrin responses attained the highest sensitivity among the biochemical screening markers applied (28). Other effective markers for early pancreatic tumor diagnosis in asymptomatic individuals were basal insulin and proinsulin (23). Due to the multiplicity of the pancreatic endocrine lesion in MEN 1 the only curative treatment available, albeit rarely indicated, is total pancreatectomy (21). Instead a surgical procedure, encompassing distal pancreatic resection (corpus-cauda) in combination with enucleation of lesions in the pancreatic head seems to be widely applied ( 2 1,29). Symptomatic therapy by medication comprises histamine receptor blocking agents or inhibitors of the proton pump of parietal cells for the Zollinger-Ellison syndrome, diazoxide in hypoglycemic patients, and a longacting somatostatin analogue (30). For malignant and/or recurrent pancreatic disease, chemotherapy with streptozotocin or treatment with interferons has been applied with promising results (30).
A 22-year-old male, member of a MEN 1 family with a pronounced ability to develop highly malignant proinsulinomas at young age, was designated healthy at first screening. At the age of 19, serum calcium was 2.73 mmol/l and parathyroidectomy was performed. Furthermore, basal serum proinsulin was 65 pmol/l (reference limit < 8.9) and the meal test indicated pancreatic endocrine tumor (abnormal serum PP response to the meal). The patient had severe hypoglycemic symptoms after a 24-h fasting, but CT, ultrasonography, and angiography could not detect a pancreatic tumor. Transhepatic portal catheterization with sampling showed high levels of serum proinsulin (221 pmol/l) in the splenic vein with a marked gradient towards veins draining the pancreatic head. At exploration three tumors, sized 0.5 to I .5 cm were found in the distal part. Intraoperative ultrasonography detected another four tumors about 3 mm in diameter in the tail of the pancreas. No tumor was found in the pancreatic head. A distal resection was performed. The operative specimen also contained five microadenomas. Postoperatively proinsulin levels normalized and a 72-h fasting test could be performed without hypoglycemia. However, six months later the meal stimulation test indicated relapse with an abnormally high serum PP response and basal serum proinsulin increased to 27 pmol/l. The fasting test was negative with an appropriate decrease of proinsulin to 4.4 pmol/l after 72 h. Radiology failed to demonstrate tumors in the remaining proximal part of the pancreas. These biochemical findings indicated proliferation of the endocrine pancreas but the normal regulation of the proinsulin-insulin secretion during fasting was interpreted as an early state of tumor development, which could be designated preneoplasia. Low dose of interferon treatment (Introna, 3 MU three times a week subcutaneously) was instituted as an attempt to reduce further mitogen activity and proliferation and finally tumor development. After three months of treatment the serum PP response to the meal was again normal, basal serum proinsulin levels were almost normal (12pmol/l) and the 72-h fasting test remained negative with an inhibition of proinsulin secretion to levels under detection limit ( ~ 2 . pmol/l). 5
Prognosis
ACKNOWLEDGEMENTS
The prognosis of MEN 1 is dependant on several factors but could generally be denoted as good in comparison with other potentially malignant dieases. An assessment of survival rates in patients with sporadic pancreatic endocrine tumors compared to those as part of the M E N 1 trait showed a significantly longer survival for the MEN 1 patients and averaged 15 years from diagnosis (30). The cause of death in MEN 1 patients with pancreatic endocrine tumors could either be due to hypersecretion of peptides accompanied by syndromes with pronounced morbidity o r to tumor progression, o r a combination of both, leading to a life-threatening clinical deterioration of the patients' condition. The parathyroid lesion may, left undiagnosed, lead to nephrolithiasis but rarely to fatal
This work was supported by grants from the King Gustav V's Jubilee Fund and the Swedish Cancer Society. Corresponding aufhor: Dr Bntt Skogseid, Department of Internal Medicine, University Hospital, s-75 I 85 Uppsala, Sweden.
REFERENCES Wermer P. Genetic aspects of adenomatosis of endocrine glands. Am J Med 1954; 16: 363-71. Wermer P. Endocrine adenomatosis and peptic ulcer in a large kindred: inherited multiple tumors and mosaic pleitropism in man. Am J Med 1963; 35: 205-12. Ballard HS, Frame B, Hartsock RJ. Familial multiple endocrine adenoma-peptic ulcer complex. Medicine (Baltimore) 1964; 43: 481-516.
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