ANNUAL REVIEWS
Further
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Copyright 1976. All rights reserved
Annu. Rev. Med. 1976.27:263-268. Downloaded from www.annualreviews.org Access provided by Auburn University on 02/02/15. For personal use only.
MULTIPLE ENDOCRINE
+7197
NEOPLASIA TYPE IP Samuel A. Wells, Jr., MD. Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710
David A. Ontjes, MD. Department of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27514
INTRODUCTION The syndromes characterized by the occurrence of several tumors involving various endocrine organs are referred to as multiple endocrine neoplasias. Generally, two types occur clinically, and both appear to be inherited as Mendelian dominant traits. In the first, termed multiple endocrine neoplasia type I (MEN-I) (I), there is an association of tumors involving the parathyroids, pancreatic islets, and pituitary gland. This syndrome is frequently accompanied by a fulminant peptic ulcer diathe sis (Zollinger-Ellison syndrome). In multiple endocrine neoplasia type II (MEN-II) (2), medullary carcinoma of the thyroid gland (MCT), pheochromocytoma(s), and parathyroid hyperplasia are associated. It has been suggested (3) that the MEN-II syndrome can be attributed to a defect in a single-cell system, originating in the neural crest and representing a familial chromaffinomatosis. Medullary carcinoma of the thyroid gland was described as a distinct clinical and pathological entity by Hazard (4) in 1959. As first proposed by Williams (5), this tumor arises from the parafollicular or C-cells of the thyroid gland. Several investi gators (6-8) have demonstrated that MCT synthesizes and secretes the hormone thyrocalcitonin (TCT). In addition to the secretion of TCT, MCT has on occasion been shown to secrete a variety of other substances including ACTH (9), histami nase (10), prostaglandins (II), and serotonin (12). Approximately 30% of patients with MCT have an associated diarrhea. Seroto nin prostaglandins, and TCT have all been proposed as agents that provoke this ,
ISupported in part by a Grant (RR-30) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health, Bethesda, Maryland. 263
264
WELLS & ONTJES
symptom; however, its etiology remains uncertain. TCT has been shown to increase the intestinal secretion of water and electrolytes when administered to normal subjects. The dosages of TCT required for this effect produce plasma TCT levels equivalent to those seen in many patients with MCT (13).
Annu. Rev. Med. 1976.27:263-268. Downloaded from www.annualreviews.org Access provided by Auburn University on 02/02/15. For personal use only.
CLINICAL PRESENTAnON Usually in MEN-II, the MCT is diagnosed first. Patients seek medical advice because of a lump in the neck or, less frequently, because of hoarseness or symptoms related to metastatic disease. Occasionally patients are symptomatic from functional pheochromocytomas, and a diagnosis of MCT is made subsequently. It is unusual for signs or symptoms of hyperparathyroidism to initiate the diagnosis. A genetic variant of MEN-II has been described in which patients with MCT and pheochromocytomas have associated multiple mucosal neuromas or neurofibromas, intestinal ganglioneuromatosis, characteristic facies, and a Marfanoid habitus (14). Patients with this variant can often be diagnosed in childhood because the character istic facies and mucosal neuromatosis are apparent at a very early age.
DIAGNOSIS In 1968 several investigators (6-8) almost simultaneously demonstrated that MCT synthesizes and secretes TCT. This provided a rather unique clinical situation in which TCT was thought to serve as a marker for medullary thyroid carcinoma. Subsequently it has been shown that virtually all patients with MCT have elevated levels of TCT detectable in the peripheral blood. Other investigators have reported TCT to be elevated in various patients with disease states, including thyroiditis (15), the Zollinger-Ellison syndrome (16), oat cell carcinoma ( 17), and other non thyroid tumors (18). This does not, however, detract from the usefulness of TCT measure ment in patients suspected of having MCT, especially in kindreds with MEN-II where family members of an affected parent or sibling are at risk. It has been demonstrated in patients with MEN-II that an elevated level of TCT can often be detected before clinical disease is apparent. Several patients have been reported (19, 20) in whom an elevatedTCT was the only clue to diagnosis, there being no thyroid disease palpable clinically or demonstrable on radioactive thyroid scanning. Melvin & Tashjian ( 19) demonstrated that the infusion of calcium ion into MCT patients caused a marked elevation in TCT secretion, thus increasing the sensitivity of that hormonal measurement as a diagnostic test. Subsequently, Wolfe and asso ciates (21) described two sisters who had small but progressive increases of serum TCT in response to calcium infusion. The thyroid glands were removed and subse quent pathologic examination revealed C -cell hyperplasia, a supposedly premalig nant state. C ooper et al (22) had demonstrated in pigs that the infusion of pentagastrin markedly stimulated the release of TCT. Subsequently, Hennessy and associates (23) demonstrated that pentagastrin was a more potent stimulator of TCT release in MCT patients than was calcium infusion. Furthermore, the peak ofTCT response
Annu. Rev. Med. 1976.27:263-268. Downloaded from www.annualreviews.org Access provided by Auburn University on 02/02/15. For personal use only.
MULTIPL E ENDOCRINE NEOPL ASIA TYPE II
265
occurred 1-5 min following pentagastrin injection, as compared to 30 min following calcium infusion (Figure 1). In a subsequent study of a family with MEN-II, Hennessy et al (24) and Wells et al (25) demonstrated the superiority of pentagas trin stimulation in the early diagnosis of MCT. They described a total of five patients who had no elevated levels of TCT in response to calcium infusion [15 mg kg-I 4 hrl]. Four of the patients were children and all had elevated levels ofTCT in the peripheral blood following stimulation with pentagastrin (0.5 mg kg-I) (Figure 2). At surgery all of these children had very small tumors confined to the thyroid gland. The fifth patient was an adult who had no detectable elevation of TCT in the peripheral blood following calcium or pentagastrin stimulation. An elevated level of TCT, however, was detected in plasma sampled from a selectively catheterized inferior thyroid vein during pentagastrin stimulation. At subsequent surgery this patient was found to have C-cell hyperplasia. Selective venous catheterization with or without pentagastrin stimulation has also been described as a sensitive method of detecting foci of metastatic disease (25, 26). 1500
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PENTAGASTRIN INJECTION
5 1000
500
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� "=;:::::;'-�---� 100,..J.oo"l!"f--r-r-r 30 5 10 15 60 120 180 240 MINUTES
NO
Further
Quick links to online content
Copyright 1976. All rights reserved
Annu. Rev. Med. 1976.27:263-268. Downloaded from www.annualreviews.org Access provided by Auburn University on 02/02/15. For personal use only.
MULTIPLE ENDOCRINE
+7197
NEOPLASIA TYPE IP Samuel A. Wells, Jr., MD. Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710
David A. Ontjes, MD. Department of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27514
INTRODUCTION The syndromes characterized by the occurrence of several tumors involving various endocrine organs are referred to as multiple endocrine neoplasias. Generally, two types occur clinically, and both appear to be inherited as Mendelian dominant traits. In the first, termed multiple endocrine neoplasia type I (MEN-I) (I), there is an association of tumors involving the parathyroids, pancreatic islets, and pituitary gland. This syndrome is frequently accompanied by a fulminant peptic ulcer diathe sis (Zollinger-Ellison syndrome). In multiple endocrine neoplasia type II (MEN-II) (2), medullary carcinoma of the thyroid gland (MCT), pheochromocytoma(s), and parathyroid hyperplasia are associated. It has been suggested (3) that the MEN-II syndrome can be attributed to a defect in a single-cell system, originating in the neural crest and representing a familial chromaffinomatosis. Medullary carcinoma of the thyroid gland was described as a distinct clinical and pathological entity by Hazard (4) in 1959. As first proposed by Williams (5), this tumor arises from the parafollicular or C-cells of the thyroid gland. Several investi gators (6-8) have demonstrated that MCT synthesizes and secretes the hormone thyrocalcitonin (TCT). In addition to the secretion of TCT, MCT has on occasion been shown to secrete a variety of other substances including ACTH (9), histami nase (10), prostaglandins (II), and serotonin (12). Approximately 30% of patients with MCT have an associated diarrhea. Seroto nin prostaglandins, and TCT have all been proposed as agents that provoke this ,
ISupported in part by a Grant (RR-30) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health, Bethesda, Maryland. 263
264
WELLS & ONTJES
symptom; however, its etiology remains uncertain. TCT has been shown to increase the intestinal secretion of water and electrolytes when administered to normal subjects. The dosages of TCT required for this effect produce plasma TCT levels equivalent to those seen in many patients with MCT (13).
Annu. Rev. Med. 1976.27:263-268. Downloaded from www.annualreviews.org Access provided by Auburn University on 02/02/15. For personal use only.
CLINICAL PRESENTAnON Usually in MEN-II, the MCT is diagnosed first. Patients seek medical advice because of a lump in the neck or, less frequently, because of hoarseness or symptoms related to metastatic disease. Occasionally patients are symptomatic from functional pheochromocytomas, and a diagnosis of MCT is made subsequently. It is unusual for signs or symptoms of hyperparathyroidism to initiate the diagnosis. A genetic variant of MEN-II has been described in which patients with MCT and pheochromocytomas have associated multiple mucosal neuromas or neurofibromas, intestinal ganglioneuromatosis, characteristic facies, and a Marfanoid habitus (14). Patients with this variant can often be diagnosed in childhood because the character istic facies and mucosal neuromatosis are apparent at a very early age.
DIAGNOSIS In 1968 several investigators (6-8) almost simultaneously demonstrated that MCT synthesizes and secretes TCT. This provided a rather unique clinical situation in which TCT was thought to serve as a marker for medullary thyroid carcinoma. Subsequently it has been shown that virtually all patients with MCT have elevated levels of TCT detectable in the peripheral blood. Other investigators have reported TCT to be elevated in various patients with disease states, including thyroiditis (15), the Zollinger-Ellison syndrome (16), oat cell carcinoma ( 17), and other non thyroid tumors (18). This does not, however, detract from the usefulness of TCT measure ment in patients suspected of having MCT, especially in kindreds with MEN-II where family members of an affected parent or sibling are at risk. It has been demonstrated in patients with MEN-II that an elevated level of TCT can often be detected before clinical disease is apparent. Several patients have been reported (19, 20) in whom an elevatedTCT was the only clue to diagnosis, there being no thyroid disease palpable clinically or demonstrable on radioactive thyroid scanning. Melvin & Tashjian ( 19) demonstrated that the infusion of calcium ion into MCT patients caused a marked elevation in TCT secretion, thus increasing the sensitivity of that hormonal measurement as a diagnostic test. Subsequently, Wolfe and asso ciates (21) described two sisters who had small but progressive increases of serum TCT in response to calcium infusion. The thyroid glands were removed and subse quent pathologic examination revealed C -cell hyperplasia, a supposedly premalig nant state. C ooper et al (22) had demonstrated in pigs that the infusion of pentagastrin markedly stimulated the release of TCT. Subsequently, Hennessy and associates (23) demonstrated that pentagastrin was a more potent stimulator of TCT release in MCT patients than was calcium infusion. Furthermore, the peak ofTCT response
Annu. Rev. Med. 1976.27:263-268. Downloaded from www.annualreviews.org Access provided by Auburn University on 02/02/15. For personal use only.
MULTIPL E ENDOCRINE NEOPL ASIA TYPE II
265
occurred 1-5 min following pentagastrin injection, as compared to 30 min following calcium infusion (Figure 1). In a subsequent study of a family with MEN-II, Hennessy et al (24) and Wells et al (25) demonstrated the superiority of pentagas trin stimulation in the early diagnosis of MCT. They described a total of five patients who had no elevated levels of TCT in response to calcium infusion [15 mg kg-I 4 hrl]. Four of the patients were children and all had elevated levels ofTCT in the peripheral blood following stimulation with pentagastrin (0.5 mg kg-I) (Figure 2). At surgery all of these children had very small tumors confined to the thyroid gland. The fifth patient was an adult who had no detectable elevation of TCT in the peripheral blood following calcium or pentagastrin stimulation. An elevated level of TCT, however, was detected in plasma sampled from a selectively catheterized inferior thyroid vein during pentagastrin stimulation. At subsequent surgery this patient was found to have C-cell hyperplasia. Selective venous catheterization with or without pentagastrin stimulation has also been described as a sensitive method of detecting foci of metastatic disease (25, 26). 1500
; z
�
PENTAGASTRIN INJECTION
5 1000
500
z
;;:;;::;:
� "=;:::::;'-�---� 100,..J.oo"l!"f--r-r-r 30 5 10 15 60 120 180 240 MINUTES
NO
