Henry Ford Hospital Medical Journal

Volume 32 Number 4 First International Workshop on Article 3 MEN-2

12-1984

Multiple Endocrine Neoplasia Type 2 Syndromes: Historical Perspectives

John H. Sipple

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Recommended Citation Sipple, John H. (1984) "Multiple Endocrine Neoplasia Type 2 Syndromes: Historical Perspectives," Henry Ford Hospital Medical Journal : Vol. 32 : No. 4 , 219-222. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol32/iss4/3

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp Med J Vol 32, No 4, 1984

Multiple Endocrine Neoplasia Type 2 Syndromes: Historical Perspectives

John H. Sipple, MD='

bponyms are flattering, sometimes embarrassing, and So i dug deeper in the library stacks and was able to find certainly not descriptive. When I was asked to give the five other cases of of the thyroid in patients historical perspective on the Sipple syndrome at this with pheochromocytoma. All were quite similar to the conference, I was flattered. The paper 1 wrote in 1959 case I had seen, mainly young adults with bilateral was my oniy venture into endocrinology, and 1 have pheochromocytomas and anaplastic-appearing car­ worked in the field of pulmonary disease for the last 25 cinomas of the thyroid. All five cases had been reported years. So much outstanding work has been done by so because of some interesting medical or surgical aspect many investigators in this fieid, and my contribution of pheochromocytoma and not because of the presence was so minimal, that remembering the name MEN-2 is of thyroid carcinoma. At that time, there were slightly more meaningful to a medical student than remem­ more than 500 cases of pheochromocytoma in the litera­ bering an eponym. ture. The six cases of carcinoma of the thyroid were somewhere between 14 and 40 times the expected inci­ dence if it were a chance occurrence. No familial history Discovery of the Sipple Syndrome of pheochromocytoma or carcinoma of the thyroid was i was a medical resident in 1959 when i was asked bythe reported in any of the six cases, although a few cases of neurosurgical service to consult on the case of a 33-year- familial pheochromocytoma had been reported by that old man who was hypertensive after he had surgery for time, it was well known that 5% of the patients with arteriovenous malformation of the brain with cerebral pheochromocytoma had neurofibromatosis. Pheo­ hemorrhage. I thought his hypertension was due to chromocytoma had also been described in some of the increased intracranial pressure; but, as I stood at the inherited neurocutaneous syndromes in which vascular autopsy tabie, 1 was amazed when I saw large, bilateral malformations in the brain occurred. The clue which pheochromocytomas and a 2 cm pale tan mass in each should have led me to suspect that my patient's prob­ lobe of the thyroid and nodular enlargement of lem was hereditary was that he had an arteriovenous the oniy parathyroid gland we could find. Micro­ malformation in the brain. It seemed reasonable that scopically, the thyroid tumors, called follicular pheochromocytoma and neurofibromatosis might be (1), were invasive and pooriy differ­ an inherited condition because both tissues arise from entiated. Since this was the same year in which Hazard neuroectoderm, but I could not understand how car­ first described medullary carcinoma (2), it was no won­ cinoma of the thyroid gland would fit into that scheme. der that our pathologists did not recognize it as such. The pheochromocytomas had high levels of epi­ In my literature search I found experimental data to nephrine and norepinephrine, so there was no doubt suggest that fluctuating levels of catecholamines might that they were functional. Since we did not have serum cause fluctuating levels of thyroid-stimulating hormone calcium or phosphorus determinations, we did not (TSH), which might cause alternating hyperplasia and know whether the patient had had hyperpara­ involution of thyroid follicular cells, which in turn, thyroidism. might result in carcinoma of the thyroid gland. So I wrote a three-page paper entitied "The Association of As I stood at the autopsy table, I knew 1 was looking at Pheochromocytoma with Carcinoma of the Thyroid something special although I did not understand it. I Gland," submitted it to the American Journal of Med­ doubted very much that it was a chance occurrence. icine, and it was published in 1961 (1). When i went to the literature, I found oniy a 1952 book by DeCourcy and DeCourcy entitled Pheochro­ mocytoma and the General Practitioner (3). They stated Submitted for publication: July 24, 1984 that "a considerable and, we beiieve, a significantly Accepted for publication: December 3, 1984 high percentage of patients with pheochromocytoma •Department of Medicine, State University of New York, Upstate Medical have had coexistent diffuse or nodular goiter or thyroid Center, Syracuse carcinoma." That was interesting, but it provided no Address reprint requests to Dr. J.H. Sipple, Department of Medicine, State University of New York, Upstate Medical Center, 766 Irving Avenue, Syracuse, facts. New York 13210,

219 Sipple

Medullary Carcinoma of the Thyroid proven and 15 probable cases of pheochromocytoma, The association I reported in 1961 was developed into a five cases of MTC, and two cases with parathyroid chief- well-defined syndrome by Cushman from Rochester, cell hyperplasia. The mix of cases differed somewhat in New York, in 1962 when he reported a family in which the 256-person kindred reported by a group from the the father had pheochromocytoma, medullary car­ National institutes of Health in 1973 (7). They found 25 cinoma of the thyroid, and parathyroid ; the cases of MTC, 16 cases of parathyroid disease, and 11 son had pheochromocytoma and medullary carcinoma cases of pheochromocytoma. The increased number of of the thyroid; and the granddaughter had medullary MTC cases is a result of better detection through the use carcinoma of the thyroid gland (4). Cushman correctly of serum calcitonin as a marker for MTC. concluded that the syndrome was a Mendelian domi­ nantly inherited disorder and that the carcinoma of the The fascinating work of defining the nature of MTC thyroid gland was medullary (MTC), not a carcinoma of began in 1959 when Hazard described this entity as a the follicular cells. solid and nonfollicular carcinoma (2). Amyloid couid be In our case, the pathology had been reviewed by Dr. identified consistentiy in the stroma. The incidence of Schimke, and the carcinoma was medullary (5), as it was lymph node metastases is high, and the carcinoma in ail subsequent reports. appears undifferentiated under the microscope but is not highly malignant. Usually called papillary or an­ Dr. Anton Joachimpalli and Dr. Phillip Speller in aplastic carcinoma before Hazard's description, MTC Syracuse are the endocrinologists who studied the rela­ accounts for only about 5% of thyroid . tives of the patient i reported. The family pedigree was About 20% of cases are familial, and most of the familial prepared by Dr. Joachimpalli (Figure). Both children of cases occur in MEN-2 kindreds (8). the propositus had pheochromocytoma and MTC, as did one of his brothers. Two of the brother's children had MTC, and one had C-ceii hyperplasia. A seven-year- old grandchild has elevated calcitonin levels and is awaiting thyroid surgery. Discovery of Serum Calcitonin as a Marker for MTC [pt84 (j)t78 [pt83 (pt3 In 1966, Williams reported thatthe parafollicular cells in the thyroid are the cells of origin of medullary car­ cinoma (9). in his studies, Pearse (10) found evidence Dt38 itis itas A* n that, in response to elevated serum calcium, these cells secreted a serum calcium-lowering hormone which he 65 /-N 063 called thyrocalcitonin. In 1968, three reports confirmed calcitonin secretion by MTC (11-13), and by the early 1970s, Tashjian and associates developed a radio­ immunoassay for the hormone in serum (14-16). Serum |i]i6 (^14 is 07 calcitonin was measured before and after calcium in­ fusion in 170 members of kindreds with MEN-2. In 47 subjects whose calcitonin tests were positive, 42 had Figure thyroidectomies, and ali had C-ceil abnormalities; Pedigree of Sipple's original case of pheochromocytoma and medullary 35, medullary carcinoma; and 7, C-ceil hyperplasia. carcinoma of the thyroid (courtesy of Dr. Anton Joachimpalli). Thyroid nodules or palpable lymph nodes couid be demonstrated in only half of the cases. Thereafter, Medullary Thyroid Carcinoma and Pheochromocytoma other families with MEN-2 were discovered by cal­ W\ Medullary Thyroid Carcinoma citonin tests performed on relatives of patients thought ^ C-cell Hyperplasia of Thyroid to have sporadic MTC or sporadic or familial pheo­ r*1 Tested and No Disease chromocytoma. Thus was discovered a very sensitive t Died and specific tumor marker. 33 Age in 1984 or at time of deatn ? Possible cases Calcitonin testing and thyroidectomy in patients with ^ Propositus MEN-2 disclosed that the C-cell abnormality is a rather diffuse process. The carcinomas are almost always bi­ By 1968, 41 cases of pheochromocytoma and MTC had lateral, and areas of C-ceil hyperplasia are frequently been reported in the literature, as reviewed by Steiner, adjacent to areas of carcinoma. Occasionally, in Goodman, and Powers in Medicine (6). They also re­ younger patients, oniy C-cell hyperplasia is present, ported a kindred of 186 persons, which included 10 indicating that it is a precursor of medullary carcinoma.

220 MEN-2 Flistoricai Perspectives

Pheochromocytoma (8) suggested the subset MEN-2B to distinguish these The chromaffin cells in the adrenal medulla are the cases from those kindreds without mucosal neuromas precursors of pheochromocytoma. Although the very (MEN-2A). The Table, slightly modified from a 1975 high incidence of bilateral pheochromocytoma in article by Block, et ai (21), uses Sizemore's suggested MEN-2 had been appreciated since the early 1960s, it ciassification and the currently accepted terminology, was not until 1975 tliat adrenal medullary hyperplasia in 1981 Carney, et al reported 21 cases of MEN-2B (22). was reported as a precursor to pheochromocytoma in Ali had MTC, and six had pheochromocytoma. Twenty MEN-2 (16,17). Apparently MEN-2 is characterized first had typical facial characteristics with big lips, elongated by hyperplasia and then by neoplasia of C-cells of the face, wide-eyed expression, and broad-based nose; thyroid gland and of the chromaffin cells of the adrenal and 16 were marfanoid and asthenic. Ail had some medulla. skeletal abnormality, most commonly, pes cavus, kyphoscoliosis or lordosis. Apparently no overlap Ljungberg's demonstration of a positive chromaffin re­ occurs between MEN-2A and MEN-2B kindreds. action to chromate by MTC ceils prompted speculation that C-cells may have the same embryological origin as the chromaffin cells of the adrenal medulla, ie, from the TABLE neuroectoderm (18). However, C-cells arise from the Multiple Endocrine Neoplasia Syndromes ultimobranchial body (6th branchial pouch), which is endoderm. it has been suggested that some neuro- Type 1 (Wermer syndrome) blastic ceils may migrate to the ultimobranchial body Pituitary tumors (19) . Pancreatic islet tumors Zollinger-Ellison syndrome Two other topics merit attention; One is the para­ thyroid gland and the relationship of MEN-1 to MEN-2; Parathyroid tumors the other is the patients with MEN-2 who also have mucosal neuromas but hardly ever have parathyroid Type 2 disease (MEN-2B). 2A 2B (Sipple syndrome) Medullary thyroid Parathyroid Hyperplasia Medullary thyroid carcinoma (MTC) carcinoma (MTC) Pheochromocytomas Parathyroid hyperplasia or adenoma with or without Pheochromocytoma Rarely parathyroid disorders hyperparathyroidism is a definite feature of MEN-2, Hyperparathyroidism Other associated abnormalities although not generally very important clinically, i thinl< Mucosal neuromas it is an independent part of the inherited disease and Hyperplastic corneal nerves not a result of hypercaicitoninemia, because a number skeletal anomalies of cases with hypercalcemia have been reported, and one case with normal calcitonin had parathyroid hyper­ plasia (7). The common denominators of MEN-1 and Conclusion MEN-2 are parathyroid disease and Mendelian Since my original case report in 1961, so many indi­ dominant inheritance. viduais have contributed to our understanding of MEN-2 that it is impossible to recognize them ail in this short historical overview. It is gratifying that my name MEN-2 Patients with Mucosal Neuromas has been associated with this synd rome, but it is even in 1965, Williams reported two patients with pheo­ more rewarding to participate in a workshop like this. chromocytoma and MTC who had mucosal neuromas This First international Workshop on MEN-2 illustrates (20) . Other similar cases were described, some with that observations in one case can lead to the con­ skeletal abnormalities; and in 1975, Sizemore's group tributions of many workers in the fieid.

221 Sipple

References

1. Sipple JH, The association of pheochromocytoma with carcinoma 13. Cunliffe WJ, Black MM, Hall R, et al. A calcitonin-secreting thy­ of the thyroid gland. Am J Med 1961;31:163-6. roid carcinoma. Lancet 1968;2:63-6.

2. Hazard JD, Hawk WA, Crile C Jr. Medullary (solid) carcinoma of 14. Tashjian AH Jr, Howland BC, Melvin KEW, Hill CS. Immunoassay the thyroid: A clinicopathologic entity. J Clin Endocrinol 1959; of human calcitonin. Clinical measurement, relation to serum 19:152-61. calcium and studies in patients with medullary carcinoma. N Engl J Med 1970;283:890-5. 3. DeCourcy JL, DeCourcy CB. Pheochromocytoma and the general practitioner. Cincinnati: Barclay Newman, 1952:90. 15. Melvin KEW, Miller HH, Tashjian AH Jr. Early diagnosis of med­ ullary carcinoma of the thyroid gland by means of calcitonin 4. Cushman P Jr. Familial endocrine tumors. Report of two unre­ assay. N Engl J Med 1971;285:1115-20. lated kindred affected with pheochromocytomas, one also with multiple thyroid carcinomas. Am J Med 1962;32:352-60. 16. Gagel RF, Melvin KEW, Tashjian AH Jr, et al. Natural history of familial medullary thyroid carcinoma: Pheochromocytoma syn­ 5. Schimke RN, Hartmann WH, Prout TE, Rimoin DL. Syndrome of drome and identification of preneoplastic stage by screening bilateral pheochromocytoma, medullary thyroid carcinoma and studies. Trans Assoc Am Physicians 1975;88:177-91. multiple neuromas. N Engl J Med 1968;279:1-7. 17. Carney JA, Sizemore GW, Tyce GM. Bilateral adrenal medullary 6. Steiner AL, Goodman AD, Powers SR. Study of a kindred with hyperplasia in multiple endocrine neoplasia type 2: Precursor of pheochromocytoma, medullary thyroid carcinoma, hyper­ bilateral pheochromocytoma. Mayo Clin Proc 1975;50:3-10, parathyroidism and Cushing's disease; multiple endocrine neo­ plasia type 2. Medicine 1968;47:371-409. 18. Ljungberg O, Cederquist E, Studnitz W. Medullary thyroid car­ cinoma and pheochromocytoma: A familial chromaffinomatosis. 7. Keiser HR, Beaven MA, Doppman J, Wells S, Buja LM. Sipple's Br Med J 1967;1:279-81. syndrome: Medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Ann Intern Med 1973;78:561-79. 19. Weichert RF. The neural ectodermal origin of the peptide- secreting endocrine . Am J Med 1970;49:232-41. 8. Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary carcinoma of the thyroid gland. 1975;35:695-704. 20. Williams ED. A review of 17 cases of carcinoma of the thyroid and pheochromocytoma. J Clin Pathol 1965;18:288-92. 9. Williams ED. Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 1966;19:114-8. 21. Block MB, Roberts JP, Kadair RC, Seyfer AE, Hull SF, Nofeldt FD. Multiple endocrine adenomatosis type Mb. JAMA 1975;234;710-4, 10. Pearse ACE. The cytochemistry of the thyroid C cells and their relationship to calcitonin. Proc R Soc Lond (Biol) 1966;164:478-87. 22. Carney JA, Bianco AJ Jr, Sizemore CW, Hayles AB, Multiple endocrine neoplasia with skeletal manifestations, J Bone Joint 11 Meyers JS, Abdel-Bard W, Granules and thyrocalcitonin-like ac­ Surg (Am) 1981 ;63A:405-10. tivity in medullary carcinoma of the thyroid gland, N Engl J Med 1968;278:323-9,

12, Melvin KEW, Tashjian AH Jr, The syndrome of excessive thy­ rocalcitonin produced by medullary carcinoma of the thyroid, Proc Natl Acad Sci USA 1968;59:1216-22,

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