CHAPTER 254 MEDULLARY THYROID CARCINOMA AND CALCITONIN
TABLE 254-1 MULTIPLE ENDOCRINE NEOPLASIA (MEN) TYPE 2 AND RELATED SYNDROMES MEN 2A Medullary thyroid carcinoma (≈100%) Pheochromocytoma (50%) Hyperparathyroidism (20–30%) 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 (≈100%) Pheochromocytoma (50%) Mucosal neuroma, ganglioneuromatosis, marfanoid habitus, colonic abnormalities, characteristic phenotype (100%)
254 MEDULLARY THYROID CARCINOMA AND CALCITONIN SAMUEL A. WELLS JR.
MEDULLARY THYROID CARCINOMA DEFINITION
Medullary thyroid carcinoma (MTC) is a relatively uncommon form of thyroid cancer that occurs either sporadically or as part of multiple endocrine neoplasia (MEN) type 2.
MTC accounts for 5 to 10% of thyroid cancers, and there are 1500 to 3000 new cases in the United States each year. In 25% of cases, MTC occurs as a uniform component of MEN 2 or related syndromes: MEN 2A, (80%), MEN 2B (5%), and familial MTC (15%) (Table 254-1). The incidence of the hereditary forms of MTC is 1 in 30,000 persons.
MTC originates from the neural crest–derived C cells, which localize within the upper poles of the thyroid lobes during embryogenesis as the lateral thyroid complex closes. Even though MTC occurs within the thyroid parenchyma, it is actually a neuroendocrine tumor, as it does not arise from the thyroid follicular cells. Sporadic MTC occurs as a solitary tumor, whereas in the hereditary forms of MTC, the tumor involves both thyroid lobes and is multifocal. In patients with hereditary MTC, the first manifestation of this
C-cell disorder is C-cell hyperplasia, which progresses over time to microinvasive MTC and then invasive MTC. The C cells have diverse biosynthetic activity and secrete calcitonin, carcinoembryonic antigen (CEA), chromogranin-A, histaminase, somatostatin, gastrin-releasing peptide, and adrenocorticotropin. Of these markers, calcitonin and CEA are the most useful clinically, and both are excellent serum markers for MTC. The hormone calcitonin was once thought to be important in calcium homeostasis; however, its physiologic importance has recently been called into question. Histologically, the MTC cells are spindle shaped, and special staining demonstrates calcitonin and CEA. With age, the central portion of the tumor calcifies, which can be seen on radiographic imaging studies. Dominant-negative, activating, germline, missense, and point mutations in the RET proto-oncogene are present in virtually all cases of hereditary MTC. Somatic RET mutations are demonstrated in at least half of sporadic MTCs. RET is located in the pericentromeric region of chromosome 10q11.2 and spans 21 exons, including more than 60 kb of genomic DNA. RET is highly conserved, and homologues have been found in lower vertebrates and the fruit fly. RET plays a central role in various intracellular signaling cascades that regulate cellular differentiation, proliferation, migration, and survival. The RET protein is expressed in developing neuroendocrine cells (including thyroid C cells; adrenal medullary cells; parathyroid cells; neural cells, including parasympathetic and sympathetic ganglion cells; and cells of the testis and urogenital tract). MEN 2A, MEN 2B, and familial MTC (FMTC) are inherited as autosomal dominant traits with near-complete penetrance and, in the case of MEN 2A and MEN 2B, variable expressivity. Approximately 75 RET mutations have been reported in association with MEN 2A, MEN 2B, and FMTC, and 95% of families with one of the forms of hereditary MTC have demonstrated RET mutations. The mutations for MEN 2A are located mostly in the extracellular, cysteine-rich region of exon 10 (including codons 609, 611, 618, and 620) and exon 11 (including codons 630 and 634). Approximately 85% of the mutations associated with MEN 2A involve RET codon 634, approximately half of which are C634R RET mutations. The mutations characteristic of FMTC also occur in exons 10 and 11; however, noncysteine point mutations have also been found in exon 8 (codons 532 and 533), exon 13 (codons 768, 790, and 791), exon 14 (codons 804 and 844), exon 15 (codon 891), and exon 16 (codon 912). Unlike the mechanism in MEN 2A and FMTC, MEN 2B mutations occur in the kinase domain and cause constitutive RET activation in a monomeric form of RET, thereby altering substrate specificity, presumably due to a conformational change in the binding pocket of the kinase. Approximately 95% of mutations causing MEN 2B are in codon 918 (exon 16), and 5% are located in codon 883 (exon 15). It is estimated that the disease arises de novo in 50% of patients with MEN 2B and in 10% of patients with MEN 2A and FMTC. In all founder cases studied thus far, the de novo mutation arose from the paternal allele.
The peak incidence of sporadic MTC is in the fifth decade of life, and most patients present with a solitary thyroid nodule and lymph node metastases, although the latter may not be evident on physical examination. Clinically,
CHAPTER 254 MEDULLARY THYROID CARCINOMA AND CALCITONIN
the tumors are more aggressive than papillary thyroid carcinoma and follicular thyroid carcinoma, and overall, the 10-year survival rate is 75%. MTC occurs in virtually all patients with MEN 2A, MEN 2B, and FMTC and is the most common cause of death in affected patients. Approximately 50% of patients with MEN 2A and MEN 2B develop pheochromocytomas (Chapters 235 and 239). An undiagnosed pheochromocytoma, which makes itself known during induction of anesthesia for thyroidectomy or childbirth, can be catastrophic and often lethal. Thus, pheochromocytoma must be excluded in all patients with a confirmed or presumptive diagnosis of hereditary MTC (Chapter 235). Parathyroid hyperplasia occurs in 30% of patients with MEN 2A and usually involves all four glands. The disease is frequently asymptomatic, with the only abnormality being an elevated serum calcium concentration. There is a strong relationship between genotype and phenotype in patients with MEN 2A. For example, pheochromocytomas are most common in patients with mutations in exon 11 (particularly codon 634). Also, the presence of hyperparathyroidism is associated with codon 634 mutations, especially the C634R mutation. The clinical aggressiveness of MTC (age of onset, tumor size, frequency of regional and distant metastases) is related to the form of hereditary MTC. For example, MTC associated with MEN 2B is much more aggressive than that occurring with MEN 2A or FMTC. The primary basis for the difference is that MEN 2B mutations are associated with greater basal kinase activity and thus are more highly activating compared with mutations occurring in MEN 2A and FMTC. Patients with MEN 2A may also develop one of two associated disorders: cutaneous lichen amyloidosis or Hirschsprung’s disease. Cutaneous lichen amyloidosis occurs in about 25% of patients with MEN 2A and involves the interscapular region of the back, corresponding to dermatomes T2 through T6. Pruritus, the dominant symptom, leads to repetitive scratching and secondary skin changes characterized by the deposition of amyloid. The lesion may be evident in infancy, thus serving as a precursor marker of MEN 2A. Cutaneous lichen amyloidosis is associated with a RET codon 634 mutation. Hirschsprung’s disease, manifested by the absence of intrinsic ganglion cells in the distal gastrointestinal tract, has been reported in 30 or more families with MEN 2A or FMTC and is associated with mutations in exon 10 of RET involving codons 609 (15%), 611 (4%), 618 (30 to 35%), and 620 (50%). In functional studies, the cell surface expression of RET with these codon mutations is lower than that found with codon 634 mutation, suggesting a novel mechanism whereby the mutations have a dual effect: causing the transformation of C cells, leading to MTC, and interfering with transportation of the protein to the plasma membrane, resulting in the absence of ganglion cells and the development of Hirschsprung’s disease. Patients with MEN 2B develop mucosal neuromas, ganglioneuromatosis throughout the aerodigestive tract, hypotonia, and medullated corneal nerves. They also develop colonic dysfunction manifested by abdominal pain and occasionally intestinal obstruction requiring surgery. Patients have a characteristic physical appearance, which may not be evident very early in life. The failure to diagnose MEN 2B at a young age can be catastrophic because MTC develops early; it is often evident soon after birth, and regional or distant metastases occur soon thereafter. Patients with FMTC develop only MTC, which, relative to the tumors in patients with MEN 2A and MEN 2B, is slow growing. There has been some question whether FMTC is a distinct disease entity or a form of MEN 2A.
Once it was discovered that C cells secrete calcitonin, the measurement of serum levels of this hormone, either in the basal state or following the intravenous administration of the secretagogues calcium or pentagastrin, became the primary method of establishing the diagnosis of a C-cell disorder. With the discovery that MEN 2A, MEN 2B, and FMTC are caused by mutations in the RET proto-oncogene, direct DNA analysis to detect a mutated RET allele replaced serum calcitonin measurement as the method of choice for identifying affected family members. At present, the measurement of serum calcitonin is used to evaluate disease progression, either after thyroidectomy for MTC or during the course of medical treatment for advanced disease. In European countries it is common practice to measure basal serum calcitonin in patients with nodular thyroid disease; this technique has proved more effective than fine-needle aspiration cytology in detecting patients with MTC. The Gene Tests directory currently lists 38 laboratories that perform DNA analysis for RET in MEN 2A, MEN 2B, FMTC, and sporadic MTC (http:// www.genetests.org). Almost all the laboratories use direct sequence analysis to evaluate mutations in exons 10, 11, 13, 14, 15, and 16, and some laboratories include exon 8. If no mutations are found in these exons, the entire coding
region of RET can be sequenced. RET mutations in exons 10 or 11 are identified in more than 95% of families demonstrating a germline transmission of MEN 2A or FMTC. Approximately 7% of patients with presumed sporadic MTC actually have MEN 2A or FMTC; therefore, it is important to perform direct DNA analysis on all patients with “sporadic” disease. The diagnosis of hereditary MTC widens the disease spectrum to be considered by the responsible physician, and it also creates the obligation to screen family members, some of whom will have early-stage MTC.
TREATMENT The primary treatment for patients with MTC is total thyroidectomy and resection of lymph nodes in the central compartment of the neck, an area bounded by the hyoid bone superiorly, the thoracic inlet inferiorly, and the carotid sheaths laterally (levels I through VI). Total thyroidectomy is indicated because the incidence of intrathyroid lymphatic spread is 10 to 20%, and even though the disease appears to be sporadic, the patient’s hereditary status is usually unknown at the time of thyroidectomy. If lymph nodes are palpable in the ipsilateral or contralateral neck or are evident on preoperative ultrasound examination, the respective lymph node compartments (levels II through V) are cleared. During the procedure, great care must be taken to preserve the parathyroid glands, the recurrent laryngeal nerve, and the external branch of the superior laryngeal nerve. The preoperative serum levels of calcitonin and CEA are important predictors of nodal metastases. Half of patients with serum calcitonin levels greater than 3000 pg/mL and 30% of patients with CEA levels greater than 10 ng/nL have lymph node metastases. Spread to regional nodes is associated with treatment failure, indicated by normalization of the serum calcitonin in only 10% of patients with node-positive disease, compared with 60% of patients with node-negative disease. Even though surgical resection seldom cures patients with regional lymph node metastases, many have a good prognosis, with 5- and 10-year survival rates of 80 and 70%, respectively. Repeat neck operation following initial thyroidectomy is indicated in patients with serious complications from recurrent tumor compressing or invading vital structures, such as the spinal cord, airway, or esophagus. Relief often follows tumor excision or debulking. Also, patients who have intractable diarrhea due to markedly elevated tumor hormone secretions, presumably calcitonin, may obtain symptom relief by tumor ablation. Rarely, patients with MTC develop Cushing’s syndrome due to the inappropriate secretion of adrenocorticotropin or corticotropin-releasing hormone. Such patients usually have advanced disease, and bilateral adrenalectomy may be required if steroidogenesis inhibitors are ineffective. This is a poor prognostic sign and is associated with an average survival of 2 years. Patients who develop persistent or recurrent MTC following thyroidectomy, as indicated by elevated serum levels of calcitonin or CEA, are also candidates for reoperation; however, the benefit of such surgical procedures is open to question, with a lack of long-term data on quality of life and survival. The treatment of pheochromocytoma is adrenalectomy, as described in Chapter 235. Hyperparathyroidism is managed by either three-and-a- half-gland parathyroidectomy or total parathyroidectomy and heterotopic autotransplantation. For patients with locally advanced or metastatic MTC, single-agent or combined chemotherapeutic regimens have been minimally effective, and chemotherapy does not play a major role in those with advanced disease. Similarly, external beam radiotherapy has little effect on primary tumors or soft tissue metastases and is indicated only for the treatment of central nervous system or bone metastases. With the demonstration that the tyrosine kinase inhibitor imatinib induced remissions in patients with chronic myelogenous leukemia and gastrointestinal stromal tumors, there was hope that similar small-molecule therapeutics would be developed for patients with MTC. The tyrosine kinase inhibitor vandetanib inhibits vascular endothelial growth factor signaling, angiogenesis, tumor growth, KDR tyrosine kinase activity, and oncogenic RET kinases. A phase II clinical trial of vandetanib in locally advanced or metastatic hereditary MTC resulted in partial remissions in 20% of patients and a disease control rate of 80%. Similar results have been observed with other tyrosine kinase inhibitors. Thus, there is hope that effective systemic therapies will be available for patients with advanced disease and perhaps for patients with minimal disease after primary thyroidectomy for MTC.
PREVENTION There are several hereditary cancer syndromes for which the causative abnormality has been identified. In many of these syndromes, removal of the organ at risk for malignancy is considered a preventive strategy. Patients with MEN 2A, MEN 2B, and FMTC are ideal candidates for prophylactic thyroidectomy because the genetic mode of inheritance is characterized by near-complete penetrance, and direct DNA analysis identifies carriers of a mutated RET allele who are destined to develop MTC. Furthermore, the thyroid is easily
removed, with minimal morbidity and virtually no mortality; there is a suitable replacement for the organ’s function; and there is a reliable serologic test to determine whether the patient has been rendered disease free. Apparently normal, young members of kindreds with hereditary MTC who are found to have a mutated RET allele on genetic screening have the greatest likelihood of being cured by prophylactic thyroidectomy. Surgeons in several countries have reported success with this operative procedure, and the question is no longer should it be done but at what age. The Consensus Committee of the 7th International Workshop on MEN, the EUROMEN group, and the International Guideline Committee of the American Thyroid Association have all proposed guidelines for the timing of prophylactic thyroidectomy in patients with MEN 2A, MEN 2B, and FMTC. The recommendations of the three groups are similar, in that children with MEN 2B (or with mutations in codons 918 or 882) should have thyroidectomy at the time of diagnosis, even during the first months of life. Children with mutations in codons 611, 618, 620, or 634 should have the thyroid removed at or before 5 years of age. In children with mutations in other RET codons, the recommended timing of thyroidectomy is less clear but is generally between 5 and 10 years of age. Some clinicians use basal or stimulated calcitonin levels to determine the timing of thyroidectomy.
A poor prognosis is associated with the following findings: a large primary tumor, metastases to regional lymph nodes, markedly elevated serum levels of calcitonin and CEA preoperatively, extrathyroidal invasion of the trachea or soft tissues intraoperatively, elevated and increasing serum levels of calcitonin and CEA postoperatively, and radiographic evidence of distant metastases. Generally, MTC is more aggressive in patients with sporadic disease than in those with hereditary disease. Also, patients with MEN 2B and patients with MEN 2A who have RET mutations in codon 634 have a poorer prognosis than those with RET mutations in other codons. Patients apparently cured by thyroidectomy are followed at 6-month intervals by the measurement of serum levels of calcitonin. The doubling time of serum calcitonin is very useful in predicting the course of the disease; calcitonin doubling times less than 6 months (vs. those >24 months) are associated with a poor prognosis. SUGGESTED READINGS Ahmed SR, Ball DW. Incidentally discovered medullary thyroid cancer: diagnostic strategies and treatment. J Clin Endocrinol Metab. 2011;96:1237-1245. Patients with persistently elevated serum calcitonin levels, positive RET test, or nodal disease are good candidates for thyroidectomy, whereas patients with undetectable calcitonin, negative RET testing, and no sonographic abnormalities often may be watched conservatively. Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612. Recommendations for managing patients with MEN 2 and related syndromes. Romei C, Cosci B, Renzini G, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011;74:241-247. RET genetic screening in apparently sporadic cases is a major tool for the preclinical diagnosis and early treatment of unsuspected affected family members.