Tohoku J. exp. Med., 1975, 115, 15-19 High Epinephrine Content in the Adrenal Tumors from Sipple's Syndrome TATSUO SATO, KIYOSHI KOBAY ASHI, YUKIO MIURA, HISAICHI SAKUMA, KAORU YOSHINAGA and KATSUHIRO NAKAMURA* Department of Internal Medicine and Department of Pathology,* Tohoku University Schol of Medicine, Sendai SATO, T., KOBAYASHI, K., MIURA, Y., SAKIIMA, H., YOSHINAGA, K. and NAKAMURA, K. High Epinephrine Content in the Adrenal Tumors from Sipple's Syndrome. Tohoku J. exp. Med., 1975, 115 (1), 15-19 Ÿ Percent of epine phrine content to total catecholamine is low in pheochromocytomas irrespective of unilateral or bilateral adrenal origin when they have no medullary carcinoma of the thyroid. However, epinephrine content higher than norepinephrine has been noted in the adrenal tumors from the patients with Sipple's syndrome. Although an exact reason for this remained unknown, our data could suggest that the adrenal tumors in Sipple's syndrome are primarily different from other types of pheochromocytoma, and thorough examinations for detecting the thyroid carcinoma should be necessary when the adrenal tumor is rich in epinephrine. Ÿ pheochromocytoma; tumor catecholamine content; Sipple's syndrome; medullary thyroid carcinoma In normal human adrenal Inedulla, epinephrine (E) makes up 85% of the total catecholamine. However, it has been known that the percentage of E is frequently reversed in the adrenal pheochromocytoma (Neville 1969). During the course of study on catecholamine analysis in this neoplasma, an interesting finding hitherto not reported has been observed, particularly in the adrenal tumors obtained from patients with Sipple's syndrome. It is the purpose of this paper to present these analytical data and to discuss their clinical significances. MATERIALS AND METHODS Thirty-four adrenal pheochromocytomas were subjected to the present study. They consisted of 15 tumors obtained from patients with unilateral adrenal pheochromocytoma, 6 from 3 siblings of a family, each having bilateral adrenal tumors without medullary carcinoma of the thyroid gland, and 13 from 5 cases of Sipple's syndrome. All patients with Sipple's syndrome had bilateral and/or multiple adrenal pheochromocytomas. Three out of 34 tumors were autopsy materials (2 to 6 hr postmortem) and the remaining 31 were surgical specimens. Diagnoses of pheochromocytomand medullary carcinoma were confirmed by histological examinations. The tumors were placed on dry-ice immediately after removal and kept frozen until assay (within 48 hr). Small pieces of the tumor excluding connective tissues and necrotic portions were chopped and homogenized with 0.1 N hydrochloric acid by a motor-driven Received for publication, November 5, 1974. 15
16 T. Sato et al. TABLE 1. Catecholamine contents with various types of pheochromocytoma * g; fi mg/g of wet tissue ; E, epinephrine; NE, norepinephrine; M, male; F, female; P, paroxysmal; S, sustained; R, right; L, left.
Epinephrine Content in Adrenal Tumors 17 glass homogenizer. This was then centrifuged at 12,000 rpm for 30 min at 4?C. Cate cholamines in the supernatant were measured fluorimetrically by the method of Euler and Lushajko (1961). None of the patients were given norepinephrine (NE) before removal of the tumor. RESULTS The concentrations of E and NE in mg/g and percent of E in each tumor are given in Table 1 together with clinical data, site and weight of the tumor. As can be seen, percent of E content in the unilateral tumor cases without thyroid carci noma ranged from 1.5 to 42.3%. All tumors in this type contained more excessive amounts of NE than E and normal ratio of E to NE content was completely reversed. Six tumors obtained from bilateral adrenal pheochromocytomas which occurred in 3 members in a single family, but had no thyroid carcinoma, showed a similar pattern of catecholamine content, NE being higher than E. On the other hand, all 13 tumors came from Sipple's syndrome were consistently rich in E content. Percent of E to total catecholamine contents was higher than 50%. The percent of E in the tumors was not related to the patient's age, sex, size of tumor or type of hypertension. We found that unilateral DISCUSSION adrenal pheochromocytoma has much greater quantities of NE than E. In normal adrenal glands, the blood from the cortex passes through the medulla and the chromaffin tissue is therefore exposed to high concentrations of steroid hormones. It has been shown that the enzymatic conversion of NE to E depends on the presence of glucocorticoids (Wurtman and Axelrod 1966). Pheochromocytoma developed in the adrenal gland, which is no longer enclosed by sufficient amounts of cortical tissue, must be exposed to lower concentrations of glucocorticoids. This is why the adrenal pheochromocytoma contains less E than does the normal adrenals. However, this plausible explana tion seems unlikely for the following reasons. If the tumor is small and the adrenal cortex remains intact in most part, it can be expected that smaller the tumor, higher the E content. We did not find that the size of tumor is related to E content. Bilateral adrenal tumors from the familial cases without thyroid carcinoma showed the same NE dominant pattern as found in the unilateral pheochromocytoma group. So far as tested, only the tumors from Sipple's syn drome had E more than 50%, despite its adrenal origin. Since these data have been accumulated over 15 years or more, we believed that such unity is not mere accidental. More than 50 cases of Sipple's syndrome have been appeared in English literatures. In Japan, 12 cases in total including our 5 have been reported up to date. Unfortunately, the tumor catecholamine has been analyzed in only 10 cases excluding ours, as shown in Table 2 (Muntz et al. 1947; DeGraeff et al. 1959; Sipple 1961; Grunstein and Finkelstein 1962; Nourok 1964; Sapira et al. 1965;
18 T. Sato et al. TABLE 2. Percent of epinephrine content to total catecholamine in the adrenal tumors from Sipple's syndrome (published cases) Falck et al. 1968; Brown et al. 1972). Sipple's original patient had also high E (Sipple 1961). Assay methods used varied with investigators, but here again higher E content than 50% are found in two thirds of these cases. Since extradre nal pheochromocytoma has no phenylethanolamine-n-methyltransferase (PNMT), we are waiting a case who has both medullary carcinoma of the thyroid and ectopic pheochromocytoma, if present. Does that case have high E or not? We are not aware of Sipple's syndrome in which pheochromocytoma occurs in a site other than the adrenal gland. Biochemically, pheochromocytoma in Sipple's syndrome seems to differ from other types of pheochromocytoma, particularly in E synthesis, storage and release. O ur knowledges about these points are not yet complete, but we could say that PNMT is active enough to produce much more amounts of E than NE in most of this type of tumors. Although high E content in the tumor does not always result in an increase in urinary E excretion, we found that metanephrine output tends to be higher than normetanephrine, indicating that synthesis of E and production of its o-methylated metabolites are actually high in Sipple's syndrome. More study should be required to evaluate the difference between Sipple's sy ndrome and other pheochromocytoma along with enzymatic or genetic factors.cli nically, the present study indicates that tumor analysis for their catechol amine contents is an important procedure. It could prospectively suggest that when the adrenal tumor contains E more than 50%, the patient may have the carcinoma of the thyroid gland with higher possibility. Therefore, further exami-
Epinephrine Content in Adrenal Tumors 19 nations for the neck should be necessary. Pheochromocytoma is relatively easily diagnosed as compared with the thyroid carcinoma because laboratory tests for catecholamine are readily available. Recent advance in thyrocalcitonin radio immunoassay would be valuable for detecting the medullary carcinoma of the thyroid, but this is difficult to carried out routinely as yet (Tashjian and Melvin 1968). References 1) Brown, W.J., Barajas, J., Waisman, J. & DeQuattro, V. (1972) Ultrastructural and biochemical correlates of adrenal and extradrenal pheochromocytoma. Cancer, 29, 744-759. 2) DeGraeff, J., Huller, H. & Moolenaar, A.J. (1959) Pheochromocytoma. A report of seven cases. Acta med. stand., 164, 419-430. 3) Euler, von U.S. & Lushajko, F. (1961) Improved technique for the fluorimetric estimation of catecholamines. Acta physiol. stand., 51, 348-355. 4) Falck, B., Ljungberg, 0. & Rosengren, E. (1968) On the occurrence of monoamines and related substances in familial medullary thyroid carcinoma with pheochromocy toma. Acta path. microbiol. stand., 74, 1-10. 5) Grunstein, I. & Finkelstein, W. (1962) Pregnancy complicated by bilateral pheo chromocytoma with fatal outcome. Amer. J. Obstet. Gynec., 83, 508-514. 6) Muntz, H.H., Ritchey, J.O. & Gatch, W.D. (1947) Adrenalin producing tumor (pheochromocytoma) containing 2300 mg of adrenalin. Ann. intern. Med., 26, 133-147. 7) Neville, A.M. (1969) The adrenal medulla. In: Functional Pathology of the Human Adrenal Gland, edited by T. Symington, E.S. Livingston, Ltd., Edinburgh and London, p. 270. 8) Nourok, D.S. (1964) Familial pheochromocytoma and thyroid carcinoma. Ann. intern. Med., 60, 1028-1040. 9) Sapira, J.D., Altman, M., Vandyk, K. & Shapiro, A.P. (1965) Bilateral adrenal pheochromocytoma and medullary thyroid carcinoma. New Engl. J. Med., 273, 140-143. 10) Sipple, J.H. (1961) The association of pheochromocytoma with carcinoma of the thyroid gland. Amer. J. Med., 31, 163-166. 11) Tashjian, A.H. & Melvin, K.E.W. (1968) Medullary carcinoma of the thyroid gland. Studies of thyrocalcitonin in plasma and tumor extracts. New Engl. J. Med., 279, 279-283. 12) Wurtman, R.J. & Axelrod, J. (1966) Control of enzymatic synthesis of adrenaline in the adrenal medulla by adrenal cortical steroid. J. biol. Chem., 241, 2301-2305.