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MD Consult: Books: Goldman: Cecil Medicine: CALCITONIN

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

CALCITONIN

Biochemistry

The 32-amino acid structure of calcitonin, determined for several species, reveals a common 1,7-amino-terminal disulfide bridge and carboxy-terminal proline. Seven of the nine amino-terminal residues are identical in all calcitonin molecules. The interspecies structural differences in the rest of the molecule cause the submammalian (ultimobranchial) calcitonin molecules to be more potent in mammals than the mammalian calcitonin molecules. Thus, the potent salmon form of the hormone is the one used for treatment of osteoporosis, hypercalcemia, and Paget’s disease of bone. The greater chemical basicity of these submammalian calcitonin species probably accounts for their increased potency. In contrast to the other major bone-active peptides, parathyroid hormone and parathyroid hormone–related protein that have bioactive moieties processed from their precursors, a biologically active fragment of calcitonin has not been identified, and the entire molecule seems to be necessary for biologic activity.

Secretion and Production

The most important secretory regulation of calcitonin is mediated by ambient calcium. An acute elevation in blood calcium concentration increases the secretion of calcitonin, and an acute decrease in blood calcium level reduces the secretion of calcitonin. This action is mediated through the calcium-sensing receptor expressed by the thyroidal C cells. The effects of chronic changes in blood calcium concentration on secretion have not been as well defined. Chronic hypercalcemia may stimulate calcitonin production, but this compensatory response may be limited. Chronic hypocalcemia seems to increase calcitonin storage in C cells. Although various other factors have been reported to stimulate calcitonin secretion, only pentagastrin and its related peptides are consistent additional secretagogues. The high concentration of pentagastrin necessary to stimulate secretion does not support the presence of a normal entero–C cell secretory pathway, although mildly elevated calcitonin levels have been observed in chronic hypergastrinemia (e.g., ulcer drugs). Pentagastrin and calcium are clinically important agents for evaluating calcitonin secretion by both normal and malignant C cells. Although both are used for provocative testing of calcitonin secretion, the former is not widely available.

The effect of gonadal steroids and age on calcitonin production remains controversial. It is well established that blood concentrations of calcitonin are higher in males than in females and in children than in adults. Some studies report a decline in calcitonin secretion during adulthood and a stimulation of calcitonin production by estrogens and testosterone. These observations have led to the hypothesis that age- and menopause-related declines in calcitonin production contribute to the corresponding declines in bone mass seen in elderly persons, especially postmenopausal women. These observations provide a rationale for use of calcitonin in treating osteoporosis, but more complex hormonal abnormalities underlie this skeletal disorder.

   MEDULLARY THYROID CARCINOMA

Definition

MTC, a rare tumor of the calcitonin-producing C cells of the thyroid gland, accounts for approximately 5 to 10% of thyroid cancers. These cells migrate from the neural crest to the thyroid gland and to other sites of the diffuse neuroendocrine system during embryogenesis in mammals. In submammals, these cells form their own distinct organ, the ultimobranchial gland. The neural crest origin of C cells accounts for their production of a variety of biologically active substances. This embryologic origin may also explain the common association of MTC with other neuroendocrine tumors. Thus, MTC can occur as part of MEN type 2 or sporadically, the latter being more common. Whereas early reports emphasized sporadic tumors, the growing appreciation of the inherited nature of the tumor has resulted in an increased diagnosis of familial cases. Even in apparently sporadic cases in patients with no family history of the tumor, approximately 6% are found to have a genetic basis.

Pathobiology

A palpable tumor is the most common physical finding in the patient with MTC. The tumor is usually firm and is located in the middle or upper lobes of the gland. Bilateral and multicentric tumors are common in patients with MEN, whereas a unilateral and single site is more common in sporadic cases. In hereditary MTC, multifocal C-cell hyperplasia is a precursor to frank malignancy. Calcification can be present in the tumor, and this may result in a radiographic pattern that is characteristic enough to help in its clinical diagnosis. Similarly, the presence of amyloid in the tumor can assist in histologic diagnosis. However, cytologic diagnosis is made difficult by the finding that the cells of MTC can be arranged in a variety of patterns. Therefore, the diagnosis of MTC is conclusively made by demonstrating calcitonin in the tumor by immunohistologic testing with a calcitonin antibody. The presence of abnormal calcitonin-producing cells may be revealed by diagnostic fine-needle aspiration of the thyroid. Hyperplasia of the C cells can antedate the frank malignancy of MTC, especially in the familial forms of the tumor. C-cell hyperplasia is often too subtle to be appreciated by light microscopy, and immunohistology for calcitonin is necessary to make this diagnosis. The advent of genetic testing for MEN 2 has provided additional strategies for distinguishing MTC from other thyroid tumors.

Clinical Manifestations and Natural History

The natural history of the tumor is variable. The clinical behavior of MTC is usually intermediate between that of aggressive anaplastic thyroid cancer and that of indolent papillary and follicular thyroid cancer. Local lymph node spread is common, and metastases to lung, liver, and bone occur with some frequency. MTC in which all or most of the cells produce calcitonin generally has a better prognosis than more heterogeneous tumors in which calcitonin production is not uniform. Even in the most aggressive tumors, calcitonin production is usually sufficient to serve as a specific marker for this thyroid cancer. However, there may be rare instances in which calcitonin production has ceased. The 5-year survival rate of patients with metastatic MTC approximates 50%. Survival can vary from several months to 3 decades after diagnosis.

In hereditary MTC, a germline mutation of the RET proto-oncogene leads to development of microscopic carcinoma as early as 2 to 3 years of age. Palpable hereditary MTC is most commonly identified in the 15- to 30-year range. Approximately 25% of sporadic MTCs appear to be initiated by a somatic RET mutation; although such a mutation could occur at any age, sporadic MTC most commonly presents in the third or fourth decade, with a range from less than 2 years to more than 80 years.

One of the interesting features of MTC is its variable aggressiveness. In general, hereditary MTC associated with MEN 2a is less aggressive than either sporadic MTC or that associated with MEN 2b (discussed later). Sporadic MTCs with somatic codon 918 RET proto-oncogene mutations or MTCs associated with MEN 2b (codon 918 germline mutation of the RET proto-oncogene) are the most aggressive and are associated with a shorter survival time. Serum calcitonin or carcinoembryonic antigen doubling times can be useful for prognosticating survival. A calcitonin or carcinoembryonic antigen doubling time of less than 1 year, measured over a period of several years because of the variability of calcitonin measurements, is generally an indication of an aggressive tumor.

   Multiple Endocrine Neoplasia

Definition

In addition to sporadic tumors, MTC can occur in association with other endocrine tumors as part of a MEN syndrome, designated MEN 2, to distinguish it from MEN 1, which consists of parathyroid, pancreatic, and pituitary tumors ( Chapter 250 ). MEN 2 (Sipple’s syndrome) is an autosomal dominant syndrome that can be clinically classified into two subtypes, 2a and 2b ( Table 267-2 ).


TABLE 267-2   — 
MULTIPLE ENDOCRINE NEOPLASIA 2

   MEN 2a (Sipple’s syndrome)

   Medullary thyroid carcinoma
   Pheochromocytoma
   Parathyroid neoplasia
   Variants of MEN 2a

   MEN 2a with cutaneous lichen amyloidosis
   MEN 2a with Hirschsprung’s disease
   Familial medullary thyroid carcinoma
   MEN 2b

   Medullary thyroid carcinoma
   Pheochromocytoma
   Parathyroid disease (rare)
   Marfanoid habitus
   Intestinal ganglioneuromatosis and mucosal neuromas

MEN = multiple endocrine neoplasia.

Clinical Manifestations

Pheochromocytoma

Pheochromocytoma is a component of MEN 2a and 2b, in which the tumor can be bilateral or unilateral ( Chapter 246 ). Bilateral and multifocal pheochromocytomas are very common in this clinical setting, with an incidence of more than 50%. This figure contrasts with a usual bilateral incidence of less than 10% for sporadic pheochromocytomas and only 20 to 50% for other familial pheochromocytomas. Other hereditary forms of bilateral pheochromocytoma include von Hippel–Lindau disease, hereditary paraganglioma syndromes, and, rarely, MEN 1 and neurofibromatosis type 1. Adrenal medullary hyperplasia is a predecessor of the pheochromocytomas seen with MTC. The increase in adrenal medullary mass results from diffuse or multifocal proliferation of adrenal medullary cells, primarily those found within the head and body of the glands. The biochemical and clinical manifestations of this tumor may be elusive, so diagnostic tests for pheochromocytoma should be pursued vigorously in patients with MEN 2, with appropriate testing and retroperitoneal imaging. Decades of routine screening for pheochromocytomas in patients with MEN 2 have led to a change in the clinical presentation. Large pheochromocytomas that put patients at high risk for sudden death are seen only in rare patients with previously undiscovered MEN 2 or in patients with known MEN 2 who decline screening. More commonly, patients are identified by subtle clinical features or modest abnormalities of catecholamine or metanephrine production. Measurement of plasma metanephrine is the most convenient diagnostic procedure for identifying these tumors, and the measurement of serum chromogranin A may have diagnostic value. Early diagnosis and appropriate treatment combined with the routine use of adrenergic blockade have rendered death or serious morbidity from pheochromocytoma uncommon in this disorder. For a more detailed description and evaluation of pheochromocytoma, see Chapter 246 .

Hyperparathyroidism

Hyperparathyroidism occurs in 10 to 20% of patients with MEN 2; it is more common in MEN 2a and rarely occurs in MEN 2b. It also occurs in patients with MEN 1. The presence of hyperparathyroidism thus should always make one consider the possibility of MEN. The differential diagnosis of hereditary hypercalcemia includes familial hypercalcemic hypocalciuria, familial parathyroid adenoma–jaw tumor syndromes, familial parathyroid hyperplasia, MEN 1, and MEN 2a. Parathyroid hyperplasia is more common than adenoma, an important consideration for surgical exploration of all parathyroid glands. The RET proto-oncogene is expressed in parathyroid tissue and is likely to account for the neoplastic changes.

Multiple Mucosal Neuromas

The presence of neuromas with a centrofacial distribution is the most consistent nonendocrine component of MEN 2b ( Chapter 246 ). The most common location of neuromas is the oral cavity. The oral lesions are almost invariably present by the first decade and in some cases even at birth. Mucosal neuromas can also be present in the eyelid, conjunctiva, cornea, and other mucosal surfaces. The most prominent microscopic feature of neuromas is an increase in the size and number of nerves. These hypertrophied nerve fibers are readily seen with a slit lamp and occasionally by direct ophthalmologic examination. Hypertrophied corneal nerves have also been identified in MEN 2a, although no mucosal neuromas have been reported in this syndrome.

Gastrointestinal tract abnormalities are part of the multiple mucosal neuroma syndrome. The most common of these is gastrointestinal ganglioneuromatosis, which usually occurs in the small and large intestines but has also been noted in the esophagus and stomach. Neurologic dysfunction is frequently associated with swallowing abnormalities, megacolon, diarrhea, and constipation, and it is the most common presenting manifestation in childhood. The diarrhea may also result from excess production of bioactive substances by the MTC. In any case, diarrhea is the most common symptom of MTC. The association of MTC with Hirschsprung’s disease is also recognized.

Marfanoid Habitus

Some patients with MEN 2b have a tall, slender body with long arms and legs, an abnormal ratio of upper to lower body segments, and poor muscle development. Other features associated with the marfanoid habitus may include dorsal kyphosis, pectus excavatum or pectus carinatum, pes cavus, and a high-arched palate. In contrast to patients with true Marfan’s syndrome, these patients do not have aortic arch abnormalities, ectopia lentis, homocyst(e)inuria, or mucopolysaccharide abnormalities.

Pathobiology and Pathogenesis

Hereditary Medullary Thyroid Carcinoma (Familial Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia 2)

Genetic linkage studies mapped the gene for MEN 2 to a centromeric chromosome 10 locus, and RET proto-oncogene mutations were subsequently identified for the associated clinical syndromes (see Tables 267-1 and 267-2 [1] [2]). The gene encodes a receptor tyrosine kinase. Two broad classes of mutations have been identified ( Fig. 267-1 ). Six specific codons (609, 611, 618, 620, 630, and 634) in the extracellular domain of the tyrosine kinase receptor encoded by RET change a conserved cysteine to another amino acid. Codon 634 mutations, and by inference other extracellular domain mutations, cause receptor dimerization and activation and initiate the transformation of C cells. A second class of less common mutations involves the intracellular domain, with the most common located at codon 918 (see Fig. 267-1 ). This coding change results in receptor activation in the absence of dimerization. Other intracellular domain mutations occur at codons 768, 790, 791, 804, 883, and 891. Identification of the mutation in a family member can be a guide to the appropriate genetic diagnosis. The clinical syndromes associated with each of these mutations are described in Figure 267-1 . Mutations of other components of the RET signaling system (glial cell–derived neurotrophic factor and the glial cell–derived neurotrophic factor-α1 receptor) have not been identified in MTC (see Fig. 267-1 ).

FIGURE 267-1  The RET proto-oncogene/glial cell–derived neurotrophic factor receptor (GDNFR)-α1 complex. Mutations of the RET proto-oncogene receptor are causative for multiple endocrine neoplasia type 2a (MEN 2a), familial medullary thyroid carcinoma (FMTC), MEN 2a/cutaneous lichen amyloidosis (MEN 2a/CLA), MEN 2 associated with Hirschsprung’s disease, or MEN 2b. Mutations of the extracellular cysteine-rich region of the receptor (Cys) and intracellular tyrosine kinase domain (TK) have been identified as germline mutations in the indicated syndromes. Somatic mutations of the RET proto-oncogene have also been identified in sporadic MTC. GDNF is a small peptide ligand for the RET/GDNF receptor complex.

In familial MTC, the earliest identified histologic abnormality associated with the RET proto-oncogene mutations is C-cell hyperplasia. It appears that a second genetic event at the RET locus may hasten or facilitate transformation. These events include loss of the normal RET allele or amplification of the mutant RET allele. The specific somatic mechanisms for amplification include trisomy 10 (two mutant chromosome 10 copies) or tandem duplication of the mutant RET gene. Evidence for loss of normal copies of genes on chromosomes 1p, 3q, 13q, and 22q suggests that other as yet unidentified genes are likely involved in the progression observed in hereditary MTC.

Because most familial cases have an identifiable RET mutation, as can occur in even apparently sporadic cases, screening should be vigorously pursued by routine testing of RET exons 10, 11, 13, 14, 15, and 16, with sequencing of the remaining 15 exons if indicated. The clinician should be aware that technical errors can occur in testing and should be prepared to use more than one laboratory for confirmation studies.

Germline RET Mutations in Apparently Sporadic Medullary Thyroid Carcinoma

The discovery of RET proto-oncogene mutations in MTC has uncovered unidentified kindreds with hereditary MTC in which the proband masqueraded as sporadic MTC. Approximately 6% of patients with apparently sporadic MTC have germline RET mutations indicative of familial MTC. Although most are members of previously unidentified kindreds, some are examples of de novo mutations, most commonly of codon 634. This finding has led to the identification of additional family members at risk for development of MTC. A consensus has evolved that all patients with apparently sporadic MTC should have a germline RET analysis.

Somatic Mutations in Sporadic Medullary Thyroid Carcinoma

Somatic mutations (non-germline mutations acquired during cell growth) of RET codon 918 are found in approximately 25% of sporadic tumors (see Fig. 267-1 ), and evidence suggests that sporadic MTCs with this mutation are more aggressive and are associated with shorter survival. In the aggressive tumors with a codon 918 mutation, it is not clear whether the mutation is the initiating abnormality or one that is acquired in the progression from a less to a more malignant phenotype.

Diagnosis

Genetic Testing

Genetic testing is used to identify individuals, especially children, at risk for development of familial MTC and MEN 2. These tests are available from a variety of commercial sources (http://www.genetests.org). Testing is best performed on peripheral blood leukocytes. The presence of a specific mutation and the propensity to develop the clinical syndrome of MEN 2 or familial MTC essentially indicate full concordance. Genetic testing can be complicated by numerous laboratory or sampling errors. Because genetic testing has become the “gold standard” for diagnosis of hereditary MTC and decisions regarding thyroidectomy are based on these results, it is prudent to repeat the genetic test on a separate peripheral blood sample, preferably in more than one laboratory. It is reasonable to exclude an individual with two or more negative genetic test results in the context of a family with hereditary MTC from further screening efforts. Although genetic testing has a great impact on the diagnosis and treatment of MTC, it has little impact on the management of adrenal medullary and parathyroid disease, in which manifestations generally develop later.

Calcitonin

Expression of the calcitonin gene is the molecular hallmark of MTC. This expression results in the production of calcitonin by the tumor and secretion of the hormone into blood. Most patients with MTC have an increased circulating concentration of calcitonin that can be detected by immunoassay and that reflects the increase in tumor mass. Usually, the basal blood concentration of calcitonin is sufficiently elevated to be diagnostic of the presence of the tumor. In the early stages of the disease, however, the basal concentrations of calcitonin may not be readily distinguished from normal values. In these circumstances, provocative testing of calcitonin secretion can reveal the presence of the abnormal C cells. Such testing is also clinically indicated for the relative of a patient with familial MTC when early diagnosis is sought, although, as discussed, genetic testing has largely replaced calcitonin testing in MEN 2 kindreds with an identifiable RET mutation. Family screening is no longer recommended for patients with apparently sporadic tumors and a negative RET proto-oncogene analysis. The predicted probability that a patient with sporadic MTC with a negative RET test will have hereditary MTC is very low, probably in the 0.1% range, thus making calcitonin testing largely unnecessary in this situation. The two most commonly used provocative agents for calcitonin secretion are calcium and the synthetic gastrin analogue pentagastrin (not generally available for clinical use in United States at present), alone or in combination. Most tumors respond to either agent with a diagnostic increase in calcitonin secretion. Calcitonin blood measurements can also be used to evaluate therapy and monitor tumor recurrence. Interpretation must be made according to the specific performance of the assay procedure used.

Treatment

Surgical Therapy

Surgery is the treatment of choice for the three types of neoplasia in MEN 2. Because all these conditions are potentially lethal, especially MTC and pheochromocytoma, but can be cured in their early stages, aggressive therapy is warranted. Early surgery is effective treatment and can be curative. Management of the individual components of MEN 2 generally follows the accepted procedures for each neoplasm. The sequence of treatment, however, is guided by several important principles. In adults with the fully formed MEN 2a syndrome, pheochromocytomas, commonly bilateral, should be treated first because they can be life-threatening. Management of thyroid and parathyroid disorders follows. Accepted surgical procedures include unilateral or bilateral adrenalectomy for diseased glands by anterior, posterior, or laparoscopic approaches or unilateral cortical sparing adrenalectomy in an attempt to preserve adrenal cortical function. Bilateral adrenalectomy at an early age is recommended in the rare kindred with a history of malignant pheochromocytoma. In adults with palpable MTC (>1 cm), metastasis to local lymph nodes is common, and total thyroidectomy and compartment-oriented lymph node dissection should be performed to enhance the likelihood of complete removal of all tumor. Hyperparathyroidism may be managed by either subtotal parathyroidectomy or total parathyroidectomy with transplantation of parathyroid tissue to the nondominant forearm.

Medical Therapy

Various agents have been tried for the treatment of MTC, but the results have been generally disappointing. Chemotherapy, radiopharmaceuticals, immunotherapy, and chemoembolization can be palliative or stabilizing, but the disease usually progresses. Phase I and II studies of small organic molecules that inhibit phosphorylation of the RET receptor showed preliminary evidence of efficacy for those tumors with germline or somatic mutations of RET. Multiple pharmaceutical corporations have produced competing molecules. Clinical trials over the next several years should provide clarity on the efficacy of these compounds.

Gene Therapy

Hereditary MTC is currently unique among genetic malignant diseases in that identification of a genetic abnormality leads to a specific therapeutic intervention. In other genetic malignant diseases such as colon or breast carcinoma, the identification of a germline mutation leads to increased surveillance, but this information is only rarely used to direct a specific therapy.

The identification of a mutation of the RET proto-oncogene indicates that the affected individual has a greater than 90% probability of developing MTC at some point during life. A 25-year history of prospective screening for MEN 2 has provided reasonable evidence that more than 85% of children who have had total thyroidectomy in the teenage years currently have no evidence of disease. This experience has been sufficiently positive that the consensus in the endocrine community is that total thyroidectomy and central node dissection should be performed in most children with MEN 2a and a germline RET mutation (codons 611, 618, 620, 634, or 891) by the age of 6 years. Other rarer mutations (609, 768, 790, 791, and 804) that cause MEN 2a or familial MTC appear to be associated with less aggressive MTC, and in some kindreds with these mutations, death or serious morbidity from MTC is rare. Deferral of thyroidectomy until the teenage years or until calcitonin abnormalities appear in these unique kindreds may be appropriate.

Death from MTC in MEN 2a or hereditary MTC before prospective screening with calcitonin testing occurred in the fourth or fifth decade, with rare deaths caused by MTC in the third or fourth decade. Thus, the results of prospective studies that were initiated 25 years ago are only now providing meaningful evidence that early intervention is beneficial. Even though a still longer period of observation will be required before definitive conclusions can be drawn, there is growing confidence that early thyroidectomy combined with appropriate care of pheochromocytomas can restore lifespan close to normal for most patients with hereditary MTC and can render death from metastatic MTC a rare event.

Management of Complications: Persistent Postoperative Calcitonin Measurements in Patients with Medullary Thyroid Carcinoma

A vexing problem for clinicians is the persistence of calcitonin elevations following primary surgical management. The major question is whether reoperation to remove all identifiable lymph nodes in the neck (compartment-oriented dissection) has value. Some experience supports reoperative strategy in patients with persistent disease who have not previously had a lymph node dissection. In the selection of these patients, it is important to perform a careful search for distant metastatic disease and to exclude hepatic, bone, and pulmonary metastasis by appropriate imaging studies. Imaging procedure, both general (e.g., computed tomography, magnetic resonance imaging, positron emission tomography) and specific (e.g., labeled calcitonin and carcinoembryonic antigen antibodies and octreotide scanning), can be useful in identifying local spread and distant metastases. Some physicians perform laparoscopy with direct hepatic visualization to identify hepatic metastasis. In patients with no evidence of distant metastatic disease, reoperative compartment-oriented lymphadenectomy may be appropriate. Approximately one of five carefully selected patients will have normalized serum calcitonin levels following microsurgical dissection (calcitonin values nondetectable following pentagastrin). No long-term follow-up studies in this group of patients have been performed to determine whether this type of surgical intervention affects morbidity or mortality related to MTC, yet the lack of other effective therapy for this disease makes it a reasonable consideration.

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