3.5.7 Medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare calcitonin-secreting tumour of the parafollicular or C cells of the thyroid. As the C cells originate from the embryonic neural crest, MTC often have the clinical and histological features of neuroendocrine tumours. They account for 8–12% of all thyroid carcinomas and occur in both sporadic and hereditary forms (1). The majority of patients have sporadic MTC (70%), while 30% have hereditary MTC. The sex ratio in sporadic MTC is 1:1.3 (male to female), while both sexes are nearly equally affected in the familial variety (2). The highest incidence of sporadic disease occurs in the fifth decade of life, while hereditary disease can be diagnosed earlier, depending on the possibility of genetic and biochemical screening.

The familial variety of MTC is inherited as an autosomal dominant trait with a high degree of penetrance and is associated with multiple endocrine neoplasia type 2 (MEN 2) syndrome (3). It is caused by germline-activating mutations of the RET proto-oncogene. Three distinct hereditary varieties of MTC are known, and each variant of MEN 2 results from a different RET gene mutation, with a good genotype–phenotype correlation:

These four varieties of MTC, three hereditary and one nonhereditary, are clinically distinct with respect to incidence, genetics, age of onset, association with other diseases, histopathology of the tumour, and prognosis (Table 3.5.7.1). Many patients with MEN 2B have an earlier onset in the first year of life and more aggressive MTC with a higher morbidity and mortality than in patients with MEN 2A. They often do not have a family history of the disease. Their tumours and characteristic appearance are therefore due to de novo mutations that present as sporadic cases of potentially hereditary disease. In contrast, the clinical course of MTC in FMTC is more benign than in MEN 2A and MEN 2B with a late onset or no clinically manifest disease, and the prognosis is relatively good. Therefore a family history is often inadequate in establishing familial disease and more thorough evaluation by genetic and biochemical screening often reveals a family history of MTC in a patient originally thought to have the sporadic form of the disease.

Detection of MTC in patients has changed in recent years with the introduction of specific strategies: calcitonin screening in patients with thyroid nodules and screening with molecular methods for RET proto-oncogene mutations in patients with apparently sporadic MTC and in family members at risk for MTC. By earlier identification of patients with MTC, the presentation has changed from clinical tumours to preclinical disease, resulting in a high cure rate of affected patients with much better prognosis.

The histological appearance of MTC is enormously variable with regard to cytoarchitecture (solid, trabecular, or insular) and cell shape (spindle, polyhedral, angular, or round). The presence of stromal amyloid is characteristic in about 50–80% of MTC patients. This feature had been an auxiliary diagnostic criterion for MTC before the use of calcitonin immunocytochemistry.

Hereditary MTC characteristically presents as a multifocal process with C-cell hyperplasia in areas distinct from the primary tumour. Bilateral C-cell hyperplasia is a precursor lesion to hereditary MTC with a penetrance approaching nearly 100% in gene carriers (5). The time frame of the progression from C-cell hyperplasia to microscopic carcinoma remains unclear but may take years (6). The earliest reported finding of C-cell hyperplasia in MEN 2A is at 20 months of age, and children with MEN 2B may have this lesion at birth. Metastasis may be found first in central and lateral cervical and mediastinal lymph nodes of the neck in 10% of patients with a micro MTC operated on after discovery at familial screening, and in up to 90% of patients operated on for clinical MTC. Metastases outside the neck and mediastinum may occur during the course of the disease in the lung, liver, and bone.

The primary secretory product of MTC is calcitonin, which serves as a highly sensitive tumour marker. Measurement of monomeric calcitonin with two-site assays remains the definitive test for prospective diagnosis of MTC (7). The test is widely available, accurate, reproducible, and cost-effective. Normal calcitonin levels are below 3.6 pmol/l. Basal calcitonin concentrations usually correlate with tumour mass and are almost always high in patients with palpable tumours (8). Similarly, elevated plasma calcitonin levels following surgery to remove the tumour are indicative of persistent or recurrent disease. In patients with postoperative normal or slightly elevated basal calcitonin, provocative stimulation of calcitonin release using pentagastrin or calcium is done to confirm the absence or presence of residual tumour. The test is administered by giving pentagastrin 0.5 μg/kg body weight as an intravenous bolus over 5–10 s or calcium gluconate 2.5 mg/kg body weight as an intravenous infusion over 30 s; calcitonin measurements are made 2 and 5 min after initiation of the infusion. For patients with recurrence or persistence of MTC the peak observed after pentagastrin stimulation is usually 5–10 times higher than basal levels, while patients with normal basal and stimulated postoperative calcitonin levels are probably disease free.

Measurement of plasma calcitonin has been part of the routine evaluation of patients with thyroid nodules; up to 3% of patients with thyroid nodules have pathological calcitonin concentrations and about 0.6% have an MTC (9). The prevalence of MTC was nearly 100% when basal calcitonin levels were more than 36 pmol/l and pentagastrin-stimulated levels more than 360 pmol/l measured with specific and sensitive two-site assays. It is well known that basal calcitonin can also be elevated up to 36 pmol/l during normal childhood and pregnancy, as well as in different malignant tumours, Hashimoto’s thyroiditis, and chronic renal failure. Many increases of calcitonin are unrelated to MTC and are commonly caused by C-cell hyperplasia not related to MTC. Patients with these conditions, however, usually have blunted or absent stimulatory responses to calcitonin secretagogues and should not be operated on. After careful evaluation, calcitonin measurement in nodular thyroid disease allows early diagnosis and early surgery of MTC, reducing the significant mortality associated with this malignant tumour. There are a number of other substances, including carcinoembryonic antigen (CEA), PDN-21 (katacalcin), chromogranin A, neuron-specific enolase, somatostatin, and ACTH, that are produced by MTC and which may help to differentiate it from other tumours.

The responsible gene for MEN 2 (OMIM 171400, 162300, 155240) was localized to centromeric chromosome 10 by genetic linkage analysis in 1987. Activating germline point mutations of the RET proto-oncogene were identified in 1993 (10). Analysis of RET in families with MEN 2 revealed that only affected family members had germline missense mutations in eight closely located exons (Fig. 3.5.7.1).

The RET gene has 21 exons and encodes a receptor tyrosine kinase that appears to transduce growth and differentiation signals in several developing tissues including those derived from the neural crest. It is expressed in cells such as C cells, the precursors of MTC, and in phaeochromocytomas. The RET gene codes for a receptor that has a large extracellular cysteine-rich domain which is thought to be involved in ligand binding, a short transmembrane domain, and a cytoplasmic tyrosine kinase domain which is activated upon ligand-induced dimerization. Hereditary MTC is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Mutation of the extracellular cysteine at exon 11 codon 634 causes ligand-independent dimerization of receptor molecules, enhanced phosphorylation of intracellular substrates, and cell transformation. Mutation of the intracellular tyrosine kinase (codon 918) has no effect on receptor dimerization but causes constitutive activation of intracellular signalling pathways and also results in cellular transformation (11). There is a significant age-related progression from C-cell hyperplasia to MTC, which correlates with the transforming capacity of the respective RET mutations.

At present, mutation analysis has identified over 50 different missense mutations associated with the development of MEN 2. Although some overlap exists between RET mutations and the resulting clinical subtype of MEN 2, 85% of patients with MEN 2A have a mutation of codon 634 (exon 11); mutations of codons 609, 611, 618, and 620 account for an additional 10–15% of cases. Phaeochromocytomas are associated with codon 634 and 918 mutations in approximately 50% of patients, and are ssociated with mutations in exon 10 (codon 609, 611, 618, 620) in adout 20% of patients and rarely in exon 15 (codon 791, 804) (12). Hyperparathyroidism in MEN 2A is most commonly associated with codon 634 mutations, and in particular with the C634R mutation. In FMTC, germline mutations are distributed throughout the RET gene with an accumulation in exon 13 (codons 768, 790, and 791), exon 14 (codons 804 and 844), and rarely exon 10 (codons 618 and 620); some of these mutations have also been identified in families with MEN 2A. More than 95% of MEN 2B patients have mutations in codon 918 (exon 16), but mutations are rarely identified at codon 883 exon 15.

The association between disease phenotype and RET mutation genotype has important implications for the clinical management of MEN 2 patients and their families. There is a correlation between the specific germline RET mutation and the age of onset and aggressiveness of MTC development and the presence of nodal metastases. This information is used to stratify RET mutations into four risk levels: patients with ATA(American Thyroid Association)-A mutations (codons 609, 768, 790, 791, 804, and 891) have a high risk for MTC development and growth, patients with ATA-B mutations (codons 609, 611, 618, 620, and ATA-C (codon 634) are at a higher risk, and patients with ATA-D mutations (codons 883 and 918) are at the highest risk for early development and growth of MTC (13, 13a).

Approximately 23–60% of sporadic MTC have a codon 918 somatic (present in tumour only) mutation identical to the germline mutation found in MEN 2B. Some reports suggest that patients with sporadic MTC with codon 918 somatic mutations have more aggressive tumour growth and a poorer prognosis (14).

The most common clinical presentation of sporadic MTC is a single nodule or thyroid mass found incidentally during routine examination (1). The presentation does not differ from that observed in papillary or follicular thyroid carcinoma. A thyroid nodule identified by physical examination is generally evaluated by ultrasonography and radioisotopic scanning (Fig. 3.5.7.2). MTC shows hypoechogenic regions, sometimes with calcifications, and a thyroid scan almost always shows no trapping of radioactive iodine or technetium. Cytological examination of the cold hypoechogenic nodule will lead to a strong suspicion, or a correct diagnosis in most cases, of sporadic MTC. A plain radiograph of the neck sometimes reveals a characteristic dense coarse calcification pattern.

A plasma calcitonin measurement can clarify the diagnosis, since preoperative calcitonin levels correlate significantly with tumour size (8) and, in the presence of a palpable MTC, the plasma calcitonin concentration will usually be greater than 36 pmol/l. The CEA level will be elevated in most cases with clinically evident tumours. Therefore measurement of plasma calcitonin in patients with thyroid nodules has been advocated as a routine procedure by some European consensus groups (15).

Genetic testing for RET mutations in patients with elevated calcitonin levels may also be helpful in apparently sporadic cases of MTC, since, if a mutation is found, it will imply that the disease is hereditary and that the family should be screened. The frequency of germline mutations, either inherited or de novo, in a larger series of apparently sporadic MTC patients varied between 1% and 7% (16).

Metastases to cervical and mediastinal lymph nodes are found in two-third of patients at the time of initial presentation. Distant metastases to lung, liver, and bone occur late in the course of the disease. Diarrhoea is the most prominent of the hormone-mediated clinical features of MTC and is often seen in patients with advanced disease. In addition, occasional tumours secrete ACTH causing Cushing’s syndrome. Given the possibility that any patient with MTC may have MEN 2, preoperative testing must also include a 24-h urinary excretion of catecholamines (to rule out phaeochromocytoma) and measurement of calcium (to rule out hyperparathyroidism).

The clinical presentation and manifestation of familial MTC in index cases does not appear to differ from that in patients with sporadic MTC. MTC is often the initial manifestation of MEN 2 syndrome, as the other manifestations, phaeochromocytoma and hyperparathyroidism, develop later in the course of the disease (3). Less common presentations of MTC include recognition during search initiated after an associated disease such as bilateral phaeochromocytoma or multiglandular hyperparathyroidism becomes apparent. The diagnosis of familial MTC in index cases is often made postoperatively when pathohistological examination may show multifocal bilateral MTC accompanied by diffuse C-cell hyperplasia. Rare variants of MEN 2A exist, including MEN 2A with cutaneous lichen amyloidosis and FMTC (or MEN 2A) with Hirschsprung’s disease.

MEN 2B has a typical phenotype with visible physical stigmata such as raised bumps on the lips and tongue (due to cutaneous neuromas), ganglioneuromas throughout the gastrointestinal tract, and a marfanoid habitus (long thin extremities, an altered upper–lower body ratio, slipped femoral epiphysis, pectus excavatum) with skeletal deformations and joint laxity. These patients have disease onset in the first year of life with the most aggressive form of MTC.

The diagnosis of FMTC can only be considered when four or more family members across a wide range of ages have isolated MTC. In general, the clinical course of MTC in familial MTC is more benign and typically has a late onset or is not a clinically manifest disease.

DNA testing becomes the optimal test for early detection of MEN 2 especially in ‘at risk’ families. At present, genetic testing is performed before the age of 5 years in all first-degree relatives of an index case (in MEN 2B patients directly after birth). Mutations in the RET proto-oncogene can be used to confirm the clinical diagnosis and identify asymptomatic family members with the syndrome (Fig. 3.5.7.3). Those who have a negative test can be reassured and require no further biochemical screening.

The age of onset of MTC and tumour aggressiveness in MEN 2 depends on the codon mutated. This genotype–phenotype correlation is the basis for stratifying mutations into four risk levels concerning the risk for MTC development and growth. Decision making in the clinical management of MEN 2 patients depends on the risk level classification, especially the timing of prophylactic thyroidectomy and the extent of surgical resection in presymptomatic RET mutation carriers (13, 13a).

Phaeochromocytomas occur in approximately 20–50% of MEN 2A patients depending on the mutation. Phaeochromocytomas are associated with codon 634 and 918 mutations in approximately 50% of patients, and are associated with mutations in exon 10 (codons 609, 611, 618, and 620) in about 20% of patients and rarely in exon 15 (codons 791 and 804) (13, 14). As with MTC, the phaeochromocytomas of MEN 2 are also multicentric with diffuse adrenomedullary hyperplasia developing bilateral phaeochromocytomas in one-half of the cases, but often after an interval of several years (12). Almost all phaeochromocytomas are located in an adrenal gland, and malignant phaeochromocytomas are rare. In index cases, the clinical manifestation of phaeochromocytoma associated with MEN 2 is similar to that in sporadic cases with signs and symptoms such as headache, palpitations, nervousness, tachycardia, and hypertension. However, phaeochromocytomas are usually identified early as a result of regular biochemical screening in gene carriers, and clinical manifestations are thus subtle or absent. It is unusual for phaeochromocytoma to precede the development of MTC and be the initial manifestation of MEN 2. Annual biochemical screening by measuring plasma and/or 24-h urinary excretion of catecholamines and metanephrines should be performed. Once the biochemical diagnosis is made, imaging studies such as MRI or m-iodobenzylguanidine (MIBG) scanning are appropriate. The presence of phaeochromocytoma must be ruled out before any surgical procedure. Patients with MTC should be evaluated for possible phaeochromocytoma. A coexisting phaeochromocytoma should be removed before thyroidectomy.

Primary hyperparathyroidism, with hypercalcaemia and an elevated serum parathyroid hormone level occurs in 10–25% of MEN 2 gene carriers (especially codon 634). Hyperparathyroidism develops slowly, is usually mild, and clinical features do not differ from those seen in mild sporadic hyperparathyroidism. The diagnosis is established by finding high parathyroid hormone concentrations in the presence of hypercalcaemia. Pathological findings show chief cell hyperplasia involving multiple glands. Annual measurement of serum calcium concentration in gene carriers is probably adequate for screening purposes.

The definitive treatment for MTC is surgery no matter whether MTC is sporadic or familial, primary or recurrent, or restricted to the thyroid gland or extending beyond it. Several studies have shown that survival in patients with MTC is dependent upon the adequacy of the initial surgical procedure. The appropriate surgery for MTC is total thyroidectomy and careful lymph node dissection of the central and if necessary lateral compartment of the neck. The latter is necessary for tumour staging and prevention of later midline complications related to local metastatic disease. If there is no evidence of local lymph node metastases during the primary surgical procedure, a surgical cure is likely and further neck dissection is probably unnecessary. Total thyroidectomy is absolutely necessary in hereditary cases because of the bilateral and multifocal nature of MTC. If the initial surgical procedure was inadequate, then reoperation with an appropriate surgical procedure is indicated. In contrast, unilateral lobectomy is sufficient in a patient with sporadic MTC showing a single unilateral tumour focus and normal plasma calcitonin levels after provocative testing. All patients should receive adequate l-thyroxine replacement therapy after total thyroidectomy (17).

Perhaps the most difficult problem associated with the management of MTC is what to do with the patient who has persistently elevated plasma calcitonin levels after an adequate surgical procedure. In almost all cases, persistent elevation of plasma calcitonin implies the presence of tumour. A thorough evaluation should be undertaken to define the extent of local and distant metastatic disease. Localization of metastases or recurrence can be done by different imaging methods such as ultrasonography of neck and abdomen, CT of neck, mediastinum, lung, and liver, or an MRI technique. Selective venous catheterization with blood sampling for calcitonin determination is helpful in detecting liver metastases at a very early stage and identifying a particular region of the neck or mediastinum that the surgeon should focus upon. Octreotide or [¹⁸F]2-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) scanning may also be helpful, especially in identifying lung metastases at a very early stage of MTC. At the conclusion of these diagnostic procedures, a decision regarding reoperation must be made. If the primary operation was inadequate, if there is no evidence of distant metastases, and if local disease is found in the neck or/and mediastinum, reoperation is advocated. A successful cure, even long after the primary operation, is possible in a small number of patients by meticulous lymph node dissection of all compartments of the neck and mediastinum, with the complete removal of the lymphatic and fatty tissue between important anatomical structures. This surgical technique has produced a cure rate of 25% in such patients. If distant metastases are found, there is no indication for surgical intervention unless the patient develops diarrhoea or local complications, for which tumour debulking may be beneficial.

Recommendations for the timing of prophylactic thyroidectomy in MEN 2 patients are based upon a model that utilizes genotype–phenotype correlations to stratify mutations into four risk levels (13). In the cases of higher risk mutations, a thyroidectomy is recommended at the age of 5 years with ATA-C and B mutations (codons 609, 611, 618, 620, and 634), and as early as possible, preferably in the first year after birth, for patients with ATA-D mutations (codons 883 and 918) (6). For patients with ATA-A mutations (codons 768, 790, 791, 804, and 891) there are three alternatives concerning recommended age at prophylactic surgery: some authors suggest thyroidectomy at age 5, others at age 10, while others suggest that surgery may be postponed until an abnormal C-cell stimulation test result is observed (i.e. an abnormal calcitonin response to pentagastrin or calcium stimulation) (18). Further studies, particularly regarding rare mutations, are necessary before common recommendations can be made (19).

Surgery for phaeochromocytoma in MEN 2 should precede surgery for MTC. Before adrenalectomy all patients should receive appropriate pharmacotherapy (α- with/or without β-adrenergic antagonist). Approximately one-third of patients who undergo a unilateral adrenalectomy will eventually require a second operation for contralateral phaeochromocytoma, but this may not occur for many years, during which time the patient will not be steroid dependent. Adrenal cortical-sparing adrenalectomy is a promising technique for preventing adrenal insufficiency.

The parathyroid glands in MEN 2 patients are frequently found to be enlarged at thyroidectomy for MTC and should therefore be carefully evaluated. The goal in MEN 2 patients with primary hyperparathyroidism is to excise the enlarged glands and to leave at least one normal parathyroid gland intact. If they are all enlarged, a subtotal parathyroidectomy or total parathyroidectomy with autotransplantation should be performed.

All patients with MTC should undergo calcitonin and CEA determination at regular intervals after total thyroidectomy. Normal basal and pentagastrin-stimulated calcitonin levels suggest a tumour-free state and thus patients require no further treatment. They can be followed-up at yearly intervals with physical examination and calcitonin determination (Fig. 3.5.7.4).

Patients with persistent elevation of plasma calcitonin after total thyroidectomy should be thoroughly evaluated to define the extent of local and distant disease (see above). If there is no evidence of distant metastases and if local disease is found in the neck, reoperation is advocated using meticulous dissection and microsurgical techniques.

In patients remaining calcitonin-positive with evidence of noncurable and nonoperable disease (diffuse distant metastases) or occult disease (no local recurrence is found and adequate operation has been done), close observation of changes in serum calcitonin and CEA concentration is required. Many patients may exhibit a remarkably stable course and no further treatment is recommended; a ‘wait and see’ approach is advocated, as experience with nonsurgical therapy in the management of slowly growing metastatic MTC has been disappointing (20, 21). In those patients whose disease shows rapid and steady progress, e.g. doubling of tumour marker in less than 1 year, intervention with chemotherapy, radiotherapy, or tyrosine kinase inhibitors can be considered as a palliative therapeutic modality.

The role of regional external radiotherapy in the treatment of MTC continues to be controversial. In patients with inoperable tumour, radiotherapy can offer prolonged palliation and achieve local tumour control. Radiotherapy may be helpful for patients with expanding final stage lesions or painful osseous metastases, but the response is poor.

As MTC is relatively insensitive to chemotherapy and the results are correspondingly poor, such treatment might be indicated when the tumour mass seems to have escaped local control and entered a more aggressive growth phase. Monotherapy with adriamycin (60 mg/m² every 3 weeks) or a combination of adriamycin and cisplatin has been used in some trials but with a response rate below 30%. Life quality, toxic side effects, and survival have to be taken into account when chemotherapy is recommended. Therefore chemotherapy in advanced MTC must be individualized based on clinical grounds.

The natural history of sporadic MTC is variable. The spectrum ranges from years of dormant residual disease after surgery to rapidly progressive disseminated disease and death related to either metastatic thyroid tumour or complications of phaeochromocytoma in MEN 2. The 10-year survival rates for all MTC patients ranges from approximately 61% to 76% (2, 22, 23). The overall prognosis is comparable to differentiated papillary and follicular carcinoma of the thyroid and much better than the more aggressive anaplastic thyroid cancer. There is general agreement that tumour stage and surgical management have a favourable influence on the clinical course of the disease. Early detection and surgical treatment of MTC is likely to be curative; more than 95% of patients detected at an early stage of disease remain disease-free (normal or undetectable calcitonin values). The main factors that influence survival are the stage of disease at the time of diagnosis, size of the tumour, and lymph node involvement. The excellent prognosis associated with identification of MTC at its earliest stage underscores the importance of prospective screening (calcitonin screening) and early diagnosis (RET mutation analysis) which must be followed by adequate therapy.

Advances in our understanding of the molecular pathways underlying the different MEN 2 phenotypes may aid in the development of individualized therapeutic modalities based on codon-specific inhibition of tumour growth. RET seems to be a promising target for molecular therapy of patients with MTC. Different strategies that might obstruct the kinase function of RET are on the way (20). Some competitive inhibitors of ATP binding have been tested and are now in clinical trials. Vandetanib (ZD6474, AstraZeneca), a multikinase inhibitor, inhibits the wild-type enzyme and most of the activated forms of RET.