Multiple Endocrine Adenomatosis: in Support of the Common Origin Theories

0022-534 7/78/ 1192-0161$02. 00/0

Vol. 119, February

THE JOURNAL OF UROLOGY

Printed in U.S .A

Copyright© 1978 by The Williams & Wilkins Co.

Original Articles MULTIPLE ENDOCRINE ADENOMATOSIS: IN SUPPORT OF THE COMMON ORIGIN THEORIES KENNETH L. JANSON,* JAMES A. ROBERTS

AND

MARIA VARELA

From the Section of Urology, Department of Anatomy and Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana

ABSTRACT

Herein we give clinical support to the theory of a common ongm of multiple endocrine adenornatosis. Accurate clinical evaluation of a patient suspected to have endocrine neoplasia requires the search for a much wider range of potential endocrine tumors. Such an approach is now made possible by the radioimmunoassay. Chromosome patterns and histocompatibility antigens are reviewed in a family with the disease. We have found 2 patients whose twnors provide new clinical support to the theories of a common etiologic origin in multiple endocrine adenomatosis. The new data demonstrate that classification of the disease into rigid subcategories may cause a physician to overlook other tumors caused by the genetic condition. Several investigators have proposed a common etiologic origin to explain the concept of multiple endocrine neoplasia." 2 Pearse, who was the first to suggest that various hormone-secreting endocrine glands share a common neuroectodermal origin (fig. 1), advanced the theory that these tumors were related closely in their ability to demonstrate the property of amine precursor uptake and decarboxy lation." :i, 4 However, Jesseph and Zollinger suggested that pancreatic islet cells may have a central role in the multiglandular syndromes. 5 Later, Vance and associates proposed that the basic genetic defect in multiple endocrine adenomatosis involves hyperplasia of the primordial islet cells of Langerhans (nesidioblastosis), with a consequent chronic oversecretion of islet cell hormones. 6 Hormone-producing tumors are not always multiple or familial. However, in the familial type several syndromes have been described. Wermer's syndrome, multiple endocrine adenomatosis type 1, describes a combination of pituitary, parathyroid and pancreatic tumors. 7 Sipple's syndrome, or multiple endocrine adenomatosis type 2, consists of familial patterns of pheochromocytoma, medullary thyroid carcinoma and parathyroid tumors. 8 Even more categories have been proposed. Khairi and associates labeled the coexistence of familial pheochromocytoma with medullary thyroid carcinoma and mucosal neuromas as multiple endocrine adenomatosis type 3. 9 Block and associates then suggested that pheochromocytoma, in combination with medullary thyroid carcinoma, parathyroid tumors, mucosal neuromas and hyperplastic corneal nerves, be called multiple endocrine adenomatosis type 2b. '° Herein we present a family that shares features of multiple endocrine adenomatosis types 1 and 2. This family demonstrates that tumor associations of the multiple endocrine adenomatosis syndrome can be more variable than

would be expected from the usual subcategorization described in the literature. Each of the common origin concepts remains speculative. However, if a common etiologic origin exists we should to find other patients with overlap between tumor as was identified in this family. Consideration of this disease as a single unified process could, perhaps, allow for a more complete and accurate diagnosis. Although multiple endocrine adenomatosis syndromes are known to be inherited as autosomal dominants no chromosomal abnormalities have been described. 1 1-1 4 However, we have found a marker chromosome in this family that may be pertinent to the etiology of the disease.

Accepted for publication April 7, 1977. Read at annual meeting of Southeastern Section, American Urological Association, Hollywood, Florida, April 4-8, 1976. * Current address: 1228 West Fork Ave., Lake Forest, Illinois 60045. 161

CLINICAL MATERIAL

The case histories presented herein include 3 successive generations of patients with pheochromocytoma. These tumors occurred with other neoplasms not previously ra,,nrrari in association with this disease. Steiner and associates recently indicated that "there have been no cases of pheochromocytoma .... in association with pituitary or pancreatic tumors". 14 However, members of the family we studied showed associated pituitary and pancreatic tumors, revealing that tumors from the supposedly distinct syndromes, multiple endocrine adenomatosis types 1 and 2, can occur together. Peripheral leukocytes were used for chromosome studies and determination of histocompatibility antigen phenotypes in the living members of the family that we studied. CASE REPORTS

Case 1. A 9-year-old girl was evaluated in 1973 for enuresis and was found to have a blood pressure of 200/180 mm. The patient had an atrophic right kidney and right vesicoureteral reflux. The 24-hour urinary vanillyl mandelic acid was 18.6 mg. After adrenergic blockage with phenoxybenzamine hydrochloride and propranolol hydrochloride the right kidney and adrenal, containing a pheochromocytoma, were resected. Right and left renal vein renin concentrations were equal. No other tumor was identified. The child is now normotensive and urinary vanillyl mandelic acid is normal. Chromosomal analysis revealed a marker on the 15th chromosomal (fig. 2). Histocompatibility phenotype (HL-A) was the same as her mother (case 2) (see table). Case 2. The 31-year-old mother of the girl in case l was

162

JANSON, ROBERTS AND VARELA Adenoma Medullary carcinoma of thyroid

Thyroid, parafollicular cell

Adenorna

~ Ultimobranchial body

Neuroectoderm

Islet cell tumor and odenocorcinoma

Adenomo and carcinoma

Pheochromocyloma Carcinoid

Extra-adrenal pheochromocytoma (paragangliama)

Fm. 1. Neural crest origin of cells producing polypeptides or amine hormones

later evaluated for intermittent episodes of hypertension associated with tachycardia and headaches. Diagnostic evaluation when the woman was normotensive revealed a normal urinary vanillyl mandelic acid and catecholamines. Because of the family history and identification of 2 renal mass lesions on excretory urography, angiography was done. Bilateral adrenal and extra-adrenal tumors were noted in addition to bilateral renal masses. These were adrenal pheochromocytomas and an accessory pheochromocytoma in a para-aortic position. In addition to a right renal cystadenoma with renal cysts and a left renal adenoma the patient had 3 islet cell tumors of the pancreas. A small 1 cm. nodule was palpated in the tail of the pancreas, with a 2 cm. nodule slightly more proximal. These nodules were excised with the tail of the pancreas. A larger 3 cm. nodule palpated in the head of the pancreas was not disturbed. The tumors were well encapsulated and yellowish-brown on cross section. Sections stained with hematoxylin and eosin revealed small prismatic cells arranged in an alveolar pattern with fibrosis between alveoli (fig. 3). All tumors, except for the tumor in the head of the pancreas, were removed and the patient is now normotensive and without symptoms. Recent evaluation has shown normal serum calcium and calcitonin levels before and after calcium infusion, as well as normal parathormone, gastrin, insulin and luteinizing hormone levels. Chromosomal studies revealed a marker on the 15th chromosomal pair identical to that of her 9-year-old daughter, and the same HL-A haplotype.

Case 3. The grandmother of the girl in case 1 and mother of the woman in case 2 had visual difficulties when she was 22 years old. The patient had bitemporal hemianopia, consistent with pituitary tumor. A craniotomy was done in 1938 with resection of a pituitary tumor (pathologic diagnosis not known). She was then well until 1944 when hypertension developed. The patient was found to have bilateral pheochromocytomas, which were resected, but she died in shock. REVIEW OF THE LITERATURE

The new diagnostic technique, radioimmunoassay, enables more complete and accurate endocrinologic evaluations. Biochemical endocrinologic interrelationships are complex and a single tumor may produce multiple active hormonal substances. 15 Thus, although an elevated hormone level in the blood does not necessarily indicate the presence of another tumor responsible for that particular hormone, this possibility should nevertheless be considered. There may be more overlap between multiple endocrine adenomatosis syndromes than is acknowledged generally and the presence of multiple tumors may exist even though not detected clinically. Other observations seem relevant. 1) Multiple endocrine adenomatosis types 1, 2, 2b and 3 are all familial syndromes. All are inherited as autosomal dominants and parathyroid hyperplasia can be a feature of each. 7- 10, 14 2) Adrenal and thyroid tumors are categorized with multiple endocrine adenomatosis type 2. However, several reports have shown that adrenal cortical adenomas and thyroid adenomas may occur

163

MULTIPLE ENDOCRINE ADENOMATOSIS

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5

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A stud)'. of_ the chromosomal patterns of additional family members mdicates that a 50-year-old sister of case 3 who has not had multiple endocrine adenomatosis, also has ~ marker on the 15th chromosomal pair. A younger sister and brother of case 1 show the same chromosome marker but have no evident disease. These children have a different father from case 1 and sh~re a d_ifferent HL-A haplot:ype with their mother (case 2). This findmg shows a phenotypic difference in those members of the family with tumor and those without. It raises the quest~on as _to whe~her they also may lack the phenotype associated with multiple endocrine adenomatosis (fig. 4). More data are needed in patients with this disorder to determine the incidence and significance of chromosomal patterns. DISCUSSION

Fm. 2. Trypsin Giemsa banding technique ofkaryotype from case 1 shows marker (15 p+ ).

in combination with standard multiple endocrine adenomatosis type 1 tumors. 16 3) Carcinoid, as well as lipoma, brown fat tumor, gastric polyp and mediastinal thymic neoplasms, has been reported to occur in combination with the tumors of the standard multiple endocrine adenomatosis type 1 syndrome. 16' 17 4) Patients with tuberous sclerosis, a type of neuroectodermal dysplasia, incur not only renal and neural tumors but pancreatic tumors (multiple endocrine adenomatosis type 1) and pheochromocytomas (multiple endocrine adenomatosis type 2) as well. 18 5) Siegelman and associates reported that a patient with pheochromocytoma and papillary carcinoma of the thyroid (multiple endocrine adenomatosis type 2) also had a renal cell carcinoma. 19 This observation, as in our second patient, demonstrates the association of renal tumors with multiple endocrinopathy. Two peptide hormones may be produced by the kidney: renin and erythropoietin. 6) Patients with the multiple endocrine adenomatosis type 2 syndrome frequently have been reported to have gastrointestinal symptoms, including persistent diarrhea and abnormal gastric motility. 9 These symptoms potentially could result from an unrecognized functioning pancreatic tumor (multiple endocrine adenomatosis type 1). GENETIC STUDIES

It has been shown that each of the multiple endocrine adenomatosis syndromes follows an autosomal dominant type of inheritance. Demonstration of father-to-son transmission appears to have precluded an X-linked mode of inheritance. 14 There have been few reports of chromosomal studies on multiple endocrine adenomatosis patients but, in each case, chromosomes have been found to be normal. 11-14 Studies of the chromosomal patterns in members of the family described herein reveal an identical marker of the 15th chromosomal pair in both living patients (cases 1 and 2). The mother of case 3 (the grandmother of case 2 and greatgrandmother of case 1) is still living. Her chromosomal pattern is normal, correlating with the fact that she has never had the disease. Therefore, the disease was inherited from the husband of this 90-year-old woman or originated in her daughter, if the marker is the cause for the disease.

Accordi~g to Pearse, " ... it is probable that many APUD h_yperpl~sias go undetected, particularly those which give rise to s!lent hormones like calcitonin". 4 Our experience with ~he family _members presented in this report, plus the foregomg data m our review of the literature reinforces this contention. The possible tumor combinatidns appear to be much more variable than currently described by the standard syndromes (types 1 and 2). Pancreatic tumors in addition to producing gastri~ as ~escribed by Jesseph ~nd Zollinger, 5 also may pr?duce msulm or _gl_ucagon, thus further increasing the potential modes of chmcal presentation. 4 We believe, therefore, that any patient with 1 hormone-producing tumor should be considered at risk for all tumors in the spectrum of multiple endocrine neoplasia and not simply those tumors that are confined by the narrow categorization of multiple endocrine adenomatosis types 1, 2, 2b or 3. The endocrine glands that secrete peptide hormones are embryologically related. Pearse believed that the neural crest gives origin to a~l of th~ cells of the amine precursor uptake and decarboxylat10n series. 4 The basic characteristics of these cells are 1) fluorogenic amine content, 2) amine precursor uptake and 3) _th~ presence of amino acid decarboxylase. These characteristics are demonstrated by histochemical techniques and radionuclide tracer studies and are the basic cellular characteristics needed to synthesize low molecular weight polypeptide hormones. It is particularly important for the urologist to be aware of potential ~ndocri~e associations. He is often the first specialist to se~ patients with pheochromocytoma. Patients with parathyroid tumors are often found in the evaluation of recurrent st:one disease. Th~se patients, especially those with a family history of endocrmopathy, should be considered at risk not only for medullary thyroid carcinoma, as would be suggested by the _standard associations of the multiple endocrine adenomatosis type~ s)'.ndrome, but also for pancreatic, pituitary, renal and carcmoid tumors. When multiple tumors or endocrine abnormalities are found the immediate family also should be evaluated. Radioimmunoassay now makes this evaluation practical and patients should be studied for the possibility of other neoplasms. 20 Eve~ if complete diagnostic studies are performed multiple endocrme_adenomatosis will remain a difficult diagnostic and therapeutic problem. We hope, however, that earlier detection Histocompatibility antigen phenotype* _ _ _ _ _ _ _ _H_L_-_A_-_A___

HL-A - B

Patients with tumor Mother Daughter Daughter Son

24 24

31

7 11

14 12

7

No tumor (different father) 31 1 31 1

14 14

8 8

~ (_;ourtesy of W. E. Braun, Histocompatibility Laboratory, Cleveland Chmc, Cleveland, Ohio.

164

JANSON, ROBERTS AND VARELA

FIG. 3. Islet cell tumor from tail of pancreas. Normal pancreas in upper right section adjoins tumor cells surrounded by dense fibrosis. H & E, reduced from x425.

?

f'

,,o~'.;~ HLA Hoplotype 5 p+ Marker Tumor

~

.:.

,ot~

Female

Mole

FIG. 4. Tree of family with multiple endocrine adenomatosis shows individuals with tumors, chromosome marker 15 p+ and HL-A haplotypes.

of silent tumors will allow more prompt and effective surgical management. Study of apparently unaffected family members may detect further silent tumors. Family history should always be considered. Chromosome patterns and histocompatibility antigens should be studied not only in the patients with the disease but in their relatives as well. Significant information may be obtained about the etiology of the disease and those family members at risk of having the disease may be detected.

2.

3. 4.

REFERENCES

5.

1. Pearse, A. G. E.: The cytochemistry and ultrastructure of

polypeptide hormone producing cells (the APUD series), and

6.

the embryologic, physiologic, and pathologic implications of the concept. J. Histochem. Cytochem., 17: 303, 1969. Weichert, R. F., III: The neural ectodermal origin of the peptidesecreting endocrine glands. A unifying concept for the etiology of multiple endocrine adenomatosis and the inappropriate secretion of peptide hormones by nonendocrine tumors. Amer. J. Med., 49: 232, 1970. Pearse, A. G. E.: Common cytochemical properties of cells producing polypeptide hormones, with particular reference to calcitonin and thyroid C-cells. Vet. Rec., 79: 587, 1966. Pearse, A. G.: The APUD cell concept and its implications in pathology. Pathol. Annu., 9: 27, 1974. Jesseph, J. E. and Zollinger, R. M.: Surgical treatment of multiglandular syndromes. Mod. Trends Surg., 3: 150, 1971. Vance, J. E., Stoll, R. W., Kitabchi, A. E., Buchanan, K. D.,

MULTIPLE ENDOCRINE ADENOMATOSIS

7. 8. 9.

10. 11. I2.

13.

Hollander, D. and Williams, R. H.: Familial nesidioblastosis as the predominant manifestation of multiple endocrine adenomatosis. Amer. J. Med., 52: 211, 1972. Wermer, P.: Genetic aspects of adenomatosis of endocrine glands. Amer. J. Med., 16: 363, 1954. Sipple, J. H.: The association of pheochromocytoma with carcinoma of the thyroid gland. Amer. J. Med., 31: 163, 1961. Khairi, M. R., Dexter, R. N., Burzynski, N. J. and Johnson, C.: Mucosa! neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine, 54: 89, 1975. Block, M. B., Roberts, J.P., Kadair, R. G., Seyfer, A. E., Hull, S. F. and Nofeldt, F. D.: Multiple endocrine adenomatosis type Ub, diagnosis and treatment. J.A.M.A., 234: 710, 1975. Levan, G., Mitelman, F. and Telenius, M.: Chromosomes in Sipp!e's syndrome. Lancet, 1: 1510, 1973. Bartlett, R. C., Myall, R. W., Bean, L. R. and Mandelstam, P.: A neuropolyendocrine syndrome: mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma. Oral Surg., 31: 206, 1971. Nankin, H., Hydovitz, J. and Sapira, J.: Normal chromosomes in mucosa! neuroma variant of medullary thyroid carcinoma

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syndrome. J. Med. Genet., 7: 374, 1970. 14. Steiner, A. L., Goodman, A. D. and Powers, S. R.: Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type 2. Medicine, 47: 371, 1968. 15. Barreras, R. F.: Calcium and gastric secretion. Gastroenterology, 64: 1168, 1973. 16. Ballard, H. S., Fame, B. and Hartsock, R. J.: Familial endocrine adenoma-peptic ulcer complex. Medicine, 1964. 17. Rosai, J., Higa, E. and Davie, J.: Mediastinal endocrine neo·· plasm in patients with multiple endocrine adenomatosis. A previously unrecognized association. Cancer, 29: 1075, 1972. 18. Glushien, A. S., Mansuy, M. M. and Littman, D. S.: Pheochromocytoma: its relationship to the neurocutaneous syndromes. Amer. J. Med., 14: 318, 1953. 19. Siegelman, S. S., Zavod, R. and Hasson, J.: Hypernephroma, pheochromocytoma and thyroid carcinoma. J. Urol., J.02: 402, 1969. 20. Sizemore, G. W. and Go, V. L.: Stimulation tests for uu,15,m~,~ of medullary thyroid carcinoma. Mayo Clin. Proc., 1975.