Editorial Medullary Thyroid Carcinomaan Uncommon Cause of Thyroid Nodules but an Important Cause of Thyroid Neoplasms Several years ago, Hamburger and associatesI reported the following series of observations about thyroid nodules: (1) "Many patients have thyroid nodules"; (2) "some thyroid nodules are malignant, but not many"; and (3) "some patients" with malignant thyroid nodules "die from thyroid cancer, but not many." These sentiments were intended not to encourage indifference toward patients with thyroid nodules but rather to emphasize the need for careful selection Of surgical candidates. Nevertheless, they reflect the everyday experience of most clinicians. Knowledgeable physicians are aware, however, that everyday experience can be an inadequate guide for practicing medicine. If unusual disorders are not anticipated the diagnosis may be missed or the management compromised. Moreover, these unusual conditions often provide the most profound insights into human pathophysiology. Medullary thyroid carcinoma (MTC), a tumor that constitutes only 5 to 10% of all thyroid carcinomas, provides a good illustration of these principles. In retrospect, we can delineate several periods during which our understanding of this tumor developed and project some of the progress that might be expected in this field. Early Discoveries.-The period between 1959 and 1966 was one of seminal discoveries that related to calcitonin, the multiple endocrine neoplasia (MEN) syndromes, and MTC itself. Although amyloid-containing thyroid carcinomas had been described as early as 1801, not until 1959 was MTC classified as a separate histopathologic and clinical entity by Hazard and colleagues.' Paradoxically, they had to distinguish MTC not only from more malignant anaplastic carcinomas but also, because of artifacts in old formalin-fixed material, from papillary carcinoma. Subsequently (7 years later), Williams' deduced the cellular nature of MTC by showing the resemblance of this tumor to the parafollicular cell tumors of dogs and rats. This work is noteworthy because, unlike MTC in humans, production of amyloid is not a feature of MTC in these animals. In the years between the studies by Hazard and co-workers/ and by Williams," calcitonin was discovered by Copp, Hirsch, and their colAddress reprint requests to Dr. C. H. Emerson, Division of Endocrinology and Metabolism, University of Massachusetts Medical Center, 55 Lake Avenue North, S6-840, Worcester, MA 01655. Mayo Clin Proc 67:1006-1008,1992
leagues.'" In addition, Foster and associates? provided evidence that the parafollicular cells in the thyroid gland of dogs were the source of plasma calcitonin, and Sipple" and others drew attention to the association of thyroid carcinoma with pheochromocytoma. Finally, Williams? demonstrated that the type of thyroid carcinoma associated with pheochromocytoma was MTC. He also discussed the familial nature of this association and postulated that this entity was "...quite distinct from the syndrome characterized by pituitary, pancreatic, parathyroid,· and adrenal cortical hyperplasia and adenoma formation," now known as MEN type I. Development of Diagnostic Studies.-The next period, beginning in the late 1960s, was ushered in by the development of radioimmunoassays for calcitonin. During that time, methods for the early detection and treatment of familial variants of MTC were established. Although basal concentrations of serum calcitonin were low in many patients with MTC, Melvin and co-workers'? found that, after infusion of calcium, the level of serum calcitonin increased to a much greater extent in patients with MTC than in normal subjects. Shortly thereafter, Hennessy and colleagues" demonstrated that pentagastrin administered together with calcium was a more potent stimulus to secretion of calcitonin than was administration of calcium alone. Subsequently, protocols were developed in which calcium or pentagastrin (or both) was infused to detect C-cell hyperplasia, the premalignant phase of familial MTC, and micronodular MTC. Protocols based on hormonal endpoints are still central to the screening and management of MTC, and evolution and dialogue in this area continue. Although screening with pentagastrin alone is used by several MTC study groups, some'? consider combined stimulation with calcium and pentagastrin to be associated with a lower false-negative rate than use of pentagastrin alone. MTCs produce peptides other than calcitonin, two of which are also encoded by the calcitonin gene. Thus, testing based on their measurement has been proposed but has had limited application. For patients with palpable nodules, fine-needle aspiration biopsy reveals findings suggestive of cancer in almost 90% of patients. These specimens often contain features such as amyloid that are specific for MTC.! Variants of MTC.-During the past decade, the various types of MTC have become more precisely defined. Currently, at least three familial types of MTC are known to exist, all of which are transmitted in an autosomal dominant pattern with 100% penetrance and variable expressivity." MEN IIa and lib are both associated with pheochromocytoma. In approximately 10 to 20% of patients with
1006
Mayo Clin Proc, October 1992, Vol 67
MEN IIa, hyperparathyroidism also develops." Recently, a variant of MEN IIa was described in which some family members were affected by cutaneous lichen amyloidosis, 13 which was thought to be a distinct entity. The cutaneous lesions are probably unrelated to production of calcitonin or other products by the tumor. Investigators have long known that amyloid is confined to the primary or metastatic lesions of MTC. In the case of this syndrome, the intensely pruritic cutaneous lesions do not contain amyloid and sometimes predate the onset of MTC. Family members with MEN lIb are unaffected by hyperparathyroidism but have mucosal neuromas, diffuse ganglioneuromas of the gastrointestinal tract, skeletal abnormalities, and a marfanoid habitus. Several large kindreds with MTC but without pheochromocytoma or hyperparathyroidism have been described. 14 These variants are referred to as non-MEN MTC, MTC without pheochromocytoma, or familial MTC only. Patients are considered to have sporadic MTC if results of family screening studies are negative and if they do not have a pheochromocytoma or the MEN lIb phenotype. Mayo Study.-Elsewhere in this issue of the Mayo Clinic Proceedings (pages 934 to 940), Gharib and colleagues discuss the frequency and behavior of the various types of MTC. This report describes 65 patients who had their primary surgical treatment before the development of screening procedures for MTC. In certain patients, the diagnosis must have been based on old pathologic material because some operations were performed as early as 1946. Of the 65 patients in the series, only 7 were thought to have familial MTC. This percentage is considerably lower than the 25% reported from the M. D. Anderson Hospital" and also from the Swedish Cancer Registry." Screening Studies.-Although some patients in the article by Gharib and associates may have been incorrectly classified because of incomplete data on family members, recent series most likely overestimate the relative proportion of cases of MTC that are familial. This possibility is likely because most screening programs are not directed to the entire population but rather to relatives of patients with MTC. For example, the annual number of cases of MTC in the Swedish Cancer Registry increased almost threefold after the advent of screening. 16 For an unbiased survey of all stages of MTC, subjects selected at random should undergo screening. Such a study would be formidable because the sample size must be large. This approach is needed, however, to assess the number of cases of subclinical sporadic MTC, which, in comparison with familial MTC, is less likely to be detected. This information is important not only for comparing the relative incidence of sporadic and familial cases of MTC but also for comparing their associated outcomes.
EDITORIAL 1007
Prognosis.-Although patients with sporadic MTC are said to have a poorer prognosis than those with familial MTC, Samaan and colleagues'> found this generalization untrue if patients were matched for extent of tumor burden. The effect of tumor burden on prognosis is echoed in the results reported by Gharib and co-workers, who found that, even within a group composed primarily of patients with sporadic MTC, the extent of disease was one of the most important indicators of prognosis. Despite all these factors, investigators uniformly agree that the behavior of MTC in kindreds with MEN lIb is particularly aggressive.F'!' Therefore, screening and prophylactic thyroidectomy for C-cell hyperplasia in this group of patients should be initiated at an early age. In contrast, data from the non-MEN familial MTC kindreds suggest that their prognosis may be relatively good. 14 Genetic Studies.- Whereas the cellular and hormonal features of MTC were established in previous decades, information about the genetic basis of familial MTC has been obtained in recent years. Concurrent reports in 1987 described use of restriction fragment length polymorphisms for probing oflymphocytic DNA to map a germline abnormality in MEN IIa to the centromeric region of chromosome 10.17 We now know that all three major types of familial MTC and also the cutaneous lichen amyloidosis variant can be mapped to the same chromosomal region." Whether the abnormality in these syndromes is present in the same gene or in a group of closely situated genes remains to be determined." The next goal is to determine the precise molecular defects in the abnormal gene or genes of chromosome 10. Such defects probably differ among the familial MTC syndromes. Furthermore, molecular variants are possible among different kindreds with the same type of familial MTC. This information is likely to be relevant not only to neuroectodermal differentiation and tumorigenesis but also in unforeseen areas. Just as few individuals or expert panels could have predicted that the studies performed by Copp and associates" of the rate of change in plasma calcium concentration in thyroparathyroidectomized dogs would lead to a test for cancer, all the advances that might emanate from molecular biologic studies of MTC are difficult to anticipate. In clinical medicine, this information will clearly allow more precise genetic counseling, simplify screening programs, and facilitate identification of affected persons at birth or even in utero so that prophylactic thyroidectomy can be performed at an early age. A need exists for this capability in the MEN Ilb kindreds. Conclusion.-Physicians can await further developments with the realization that the best current approach is to remember that MTC may be present in patients with thyroid nodules or nodular goiter. In addition to laboratory tests, the most useful procedures are a thorough physical examination
1008 EDITORIAL
Mayo Clin Proc, October 1992, Vol 67
and elicitation of the family history. When MTC is detected, pheochromocytoma should be ruled out before thyroidectomy is performed. If the surgical specimen shows C-ce11 hyperplasia or multiple tumors, family screening studies should be performed. This analysis can be accomplished in the most up-to-date manner by contacting one of the active research groups in this field. Regardless of whether the patient has familial or sporadic MTC, the conclusion reported by Gharib and colleagues-that early diagnosis and complete initial resection of the tumor are important-seems valid. Charles H. Emerson, M.D. lrini E. Veronikis, M.D. Division of Endocrinology and Metabolism University of Massachusetts School of Medicine Worcester, Massachusetts
6. 7. 8. 9. 10. 11.
12. 13.
14.
REFERENCES 1.
2. 3. 4.
5.
Hamburger n, Miller JM, Kini SR: Clinical-Pathological Evaluation of Thyroid Nodules: Handbook and Atlas. Southfield, Michigan, Joel I. Hamburger, 1979, pp 3-19 Hazard JB, Hawk WA, Crile G Jr: Medullary (solid) carcinoma of the thyroid-a clinicopathologic entity. J Clin Endocrinol Metab 19:152-161,1959 Williams ED: Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 19:114-118,1966 Copp DH, Cameron EC, Cheney BA, Davidson AGF, Henze KG: Evidence for calcitonin-a new hormone from the parathyroid that lowers blood calcium. Endocrinology 70:638-649, 1962 Hirsch PF, Gauthier GF, Munson PL: Thyroid hypocalcemic principle and recurrent laryngeal nerve injury as factors affecting the response to parathyroidectomy in rats. Endocrinology 73:244-252, 1963
15.
16.
17.
Austin LA, Heath H III: Calcitonin: physiology and pathophysiology. N Engl J Med 304:269-278, 1981 Foster GV, MacIntyre I, Pearse AGE: Calcitonin production and the mitochondrion-rich cells of the dog thyroid. Nature 203:1029-1030,1964 Sipple JH: The association ofpheochromocytoma with carcinoma of the thyroid gland. Am J Med 31:163-166, 1961 Williams ED: A review of 17 cases of carcinoma of the thyroid and phaeochromocytoma. J Clin Pathol 18:288-292, 1965 Melvin KEW, Miller HH, Tashjian AH Jr: Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Engl J Med 285: 1115-1120, 1971 Hennessy JF, Gray TK, Cooper CW, Ontjes DA: Stimulation of thyrocalcitonin secretion by pentagastrin and calcium in two patients with medullary carcinoma of the thyroid. J CUn Endocrinol Metab 36:200-203, 1973 Lairmore TC, Wells SA Jr: Medullary carcinoma of the thyroid: current diagnosis and management. Semin Surg Oncol 7:92-99, 1991 Grauer A, Raue F, Gagel RF: Changing concepts in the management of hereditary and sporadic medullary thyroid carcinoma. Endocrinol Metab Clin North Am 19:613-635, September 1990 Lairmore TC, Howe JR, Korte JA, Dilley WG, Aine L, Aine E, Wells SA Jr, Donis-Keller H: Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 9:181-192, 1991 Samaan NA, Schultz PN, Hickey RC: Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 67:801805, 1988 Bergholm D, Adami H-O, Bergstrom R, Johansson H, Lundell G, Telenius-Berg M, Akerstrom G, Swedish MTC Study Group: Clinical characteristics in sporadic and familial medullary thyroid carcinoma: a nationwide study of 249 patients in Sweden from 1959 through 1981. Cancer 63:1196-1204,1989 Nelkin BD, de Bustros AC, Mabry M, Baylin SB: The molecular biology of medullary thyroid carcinoma: a model for cancer development and progression. JAMA 261:31303135, 1989
leagues.'" In addition, Foster and associates? provided evidence that the parafollicular cells in the thyroid gland of dogs were the source of plasma calcitonin, and Sipple" and others drew attention to the association of thyroid carcinoma with pheochromocytoma. Finally, Williams? demonstrated that the type of thyroid carcinoma associated with pheochromocytoma was MTC. He also discussed the familial nature of this association and postulated that this entity was "...quite distinct from the syndrome characterized by pituitary, pancreatic, parathyroid,· and adrenal cortical hyperplasia and adenoma formation," now known as MEN type I. Development of Diagnostic Studies.-The next period, beginning in the late 1960s, was ushered in by the development of radioimmunoassays for calcitonin. During that time, methods for the early detection and treatment of familial variants of MTC were established. Although basal concentrations of serum calcitonin were low in many patients with MTC, Melvin and co-workers'? found that, after infusion of calcium, the level of serum calcitonin increased to a much greater extent in patients with MTC than in normal subjects. Shortly thereafter, Hennessy and colleagues" demonstrated that pentagastrin administered together with calcium was a more potent stimulus to secretion of calcitonin than was administration of calcium alone. Subsequently, protocols were developed in which calcium or pentagastrin (or both) was infused to detect C-cell hyperplasia, the premalignant phase of familial MTC, and micronodular MTC. Protocols based on hormonal endpoints are still central to the screening and management of MTC, and evolution and dialogue in this area continue. Although screening with pentagastrin alone is used by several MTC study groups, some'? consider combined stimulation with calcium and pentagastrin to be associated with a lower false-negative rate than use of pentagastrin alone. MTCs produce peptides other than calcitonin, two of which are also encoded by the calcitonin gene. Thus, testing based on their measurement has been proposed but has had limited application. For patients with palpable nodules, fine-needle aspiration biopsy reveals findings suggestive of cancer in almost 90% of patients. These specimens often contain features such as amyloid that are specific for MTC.! Variants of MTC.-During the past decade, the various types of MTC have become more precisely defined. Currently, at least three familial types of MTC are known to exist, all of which are transmitted in an autosomal dominant pattern with 100% penetrance and variable expressivity." MEN IIa and lib are both associated with pheochromocytoma. In approximately 10 to 20% of patients with
1006
Mayo Clin Proc, October 1992, Vol 67
MEN IIa, hyperparathyroidism also develops." Recently, a variant of MEN IIa was described in which some family members were affected by cutaneous lichen amyloidosis, 13 which was thought to be a distinct entity. The cutaneous lesions are probably unrelated to production of calcitonin or other products by the tumor. Investigators have long known that amyloid is confined to the primary or metastatic lesions of MTC. In the case of this syndrome, the intensely pruritic cutaneous lesions do not contain amyloid and sometimes predate the onset of MTC. Family members with MEN lIb are unaffected by hyperparathyroidism but have mucosal neuromas, diffuse ganglioneuromas of the gastrointestinal tract, skeletal abnormalities, and a marfanoid habitus. Several large kindreds with MTC but without pheochromocytoma or hyperparathyroidism have been described. 14 These variants are referred to as non-MEN MTC, MTC without pheochromocytoma, or familial MTC only. Patients are considered to have sporadic MTC if results of family screening studies are negative and if they do not have a pheochromocytoma or the MEN lIb phenotype. Mayo Study.-Elsewhere in this issue of the Mayo Clinic Proceedings (pages 934 to 940), Gharib and colleagues discuss the frequency and behavior of the various types of MTC. This report describes 65 patients who had their primary surgical treatment before the development of screening procedures for MTC. In certain patients, the diagnosis must have been based on old pathologic material because some operations were performed as early as 1946. Of the 65 patients in the series, only 7 were thought to have familial MTC. This percentage is considerably lower than the 25% reported from the M. D. Anderson Hospital" and also from the Swedish Cancer Registry." Screening Studies.-Although some patients in the article by Gharib and associates may have been incorrectly classified because of incomplete data on family members, recent series most likely overestimate the relative proportion of cases of MTC that are familial. This possibility is likely because most screening programs are not directed to the entire population but rather to relatives of patients with MTC. For example, the annual number of cases of MTC in the Swedish Cancer Registry increased almost threefold after the advent of screening. 16 For an unbiased survey of all stages of MTC, subjects selected at random should undergo screening. Such a study would be formidable because the sample size must be large. This approach is needed, however, to assess the number of cases of subclinical sporadic MTC, which, in comparison with familial MTC, is less likely to be detected. This information is important not only for comparing the relative incidence of sporadic and familial cases of MTC but also for comparing their associated outcomes.
EDITORIAL 1007
Prognosis.-Although patients with sporadic MTC are said to have a poorer prognosis than those with familial MTC, Samaan and colleagues'> found this generalization untrue if patients were matched for extent of tumor burden. The effect of tumor burden on prognosis is echoed in the results reported by Gharib and co-workers, who found that, even within a group composed primarily of patients with sporadic MTC, the extent of disease was one of the most important indicators of prognosis. Despite all these factors, investigators uniformly agree that the behavior of MTC in kindreds with MEN lIb is particularly aggressive.F'!' Therefore, screening and prophylactic thyroidectomy for C-cell hyperplasia in this group of patients should be initiated at an early age. In contrast, data from the non-MEN familial MTC kindreds suggest that their prognosis may be relatively good. 14 Genetic Studies.- Whereas the cellular and hormonal features of MTC were established in previous decades, information about the genetic basis of familial MTC has been obtained in recent years. Concurrent reports in 1987 described use of restriction fragment length polymorphisms for probing oflymphocytic DNA to map a germline abnormality in MEN IIa to the centromeric region of chromosome 10.17 We now know that all three major types of familial MTC and also the cutaneous lichen amyloidosis variant can be mapped to the same chromosomal region." Whether the abnormality in these syndromes is present in the same gene or in a group of closely situated genes remains to be determined." The next goal is to determine the precise molecular defects in the abnormal gene or genes of chromosome 10. Such defects probably differ among the familial MTC syndromes. Furthermore, molecular variants are possible among different kindreds with the same type of familial MTC. This information is likely to be relevant not only to neuroectodermal differentiation and tumorigenesis but also in unforeseen areas. Just as few individuals or expert panels could have predicted that the studies performed by Copp and associates" of the rate of change in plasma calcium concentration in thyroparathyroidectomized dogs would lead to a test for cancer, all the advances that might emanate from molecular biologic studies of MTC are difficult to anticipate. In clinical medicine, this information will clearly allow more precise genetic counseling, simplify screening programs, and facilitate identification of affected persons at birth or even in utero so that prophylactic thyroidectomy can be performed at an early age. A need exists for this capability in the MEN Ilb kindreds. Conclusion.-Physicians can await further developments with the realization that the best current approach is to remember that MTC may be present in patients with thyroid nodules or nodular goiter. In addition to laboratory tests, the most useful procedures are a thorough physical examination
1008 EDITORIAL
Mayo Clin Proc, October 1992, Vol 67
and elicitation of the family history. When MTC is detected, pheochromocytoma should be ruled out before thyroidectomy is performed. If the surgical specimen shows C-ce11 hyperplasia or multiple tumors, family screening studies should be performed. This analysis can be accomplished in the most up-to-date manner by contacting one of the active research groups in this field. Regardless of whether the patient has familial or sporadic MTC, the conclusion reported by Gharib and colleagues-that early diagnosis and complete initial resection of the tumor are important-seems valid. Charles H. Emerson, M.D. lrini E. Veronikis, M.D. Division of Endocrinology and Metabolism University of Massachusetts School of Medicine Worcester, Massachusetts
6. 7. 8. 9. 10. 11.
12. 13.
14.
REFERENCES 1.
2. 3. 4.
5.
Hamburger n, Miller JM, Kini SR: Clinical-Pathological Evaluation of Thyroid Nodules: Handbook and Atlas. Southfield, Michigan, Joel I. Hamburger, 1979, pp 3-19 Hazard JB, Hawk WA, Crile G Jr: Medullary (solid) carcinoma of the thyroid-a clinicopathologic entity. J Clin Endocrinol Metab 19:152-161,1959 Williams ED: Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 19:114-118,1966 Copp DH, Cameron EC, Cheney BA, Davidson AGF, Henze KG: Evidence for calcitonin-a new hormone from the parathyroid that lowers blood calcium. Endocrinology 70:638-649, 1962 Hirsch PF, Gauthier GF, Munson PL: Thyroid hypocalcemic principle and recurrent laryngeal nerve injury as factors affecting the response to parathyroidectomy in rats. Endocrinology 73:244-252, 1963
15.
16.
17.
Austin LA, Heath H III: Calcitonin: physiology and pathophysiology. N Engl J Med 304:269-278, 1981 Foster GV, MacIntyre I, Pearse AGE: Calcitonin production and the mitochondrion-rich cells of the dog thyroid. Nature 203:1029-1030,1964 Sipple JH: The association ofpheochromocytoma with carcinoma of the thyroid gland. Am J Med 31:163-166, 1961 Williams ED: A review of 17 cases of carcinoma of the thyroid and phaeochromocytoma. J Clin Pathol 18:288-292, 1965 Melvin KEW, Miller HH, Tashjian AH Jr: Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Engl J Med 285: 1115-1120, 1971 Hennessy JF, Gray TK, Cooper CW, Ontjes DA: Stimulation of thyrocalcitonin secretion by pentagastrin and calcium in two patients with medullary carcinoma of the thyroid. J CUn Endocrinol Metab 36:200-203, 1973 Lairmore TC, Wells SA Jr: Medullary carcinoma of the thyroid: current diagnosis and management. Semin Surg Oncol 7:92-99, 1991 Grauer A, Raue F, Gagel RF: Changing concepts in the management of hereditary and sporadic medullary thyroid carcinoma. Endocrinol Metab Clin North Am 19:613-635, September 1990 Lairmore TC, Howe JR, Korte JA, Dilley WG, Aine L, Aine E, Wells SA Jr, Donis-Keller H: Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 9:181-192, 1991 Samaan NA, Schultz PN, Hickey RC: Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 67:801805, 1988 Bergholm D, Adami H-O, Bergstrom R, Johansson H, Lundell G, Telenius-Berg M, Akerstrom G, Swedish MTC Study Group: Clinical characteristics in sporadic and familial medullary thyroid carcinoma: a nationwide study of 249 patients in Sweden from 1959 through 1981. Cancer 63:1196-1204,1989 Nelkin BD, de Bustros AC, Mabry M, Baylin SB: The molecular biology of medullary thyroid carcinoma: a model for cancer development and progression. JAMA 261:31303135, 1989
