Management of Medullary Thyroid Cancer

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Management of Medullary Thyroid Cancer David Viola, MD, Rossella Elisei, MD* Endocrinol Metab Clin N Am - (2018)

Medullary thyroid cancer (MTC) is the third most common thyroid malignancy. • It originates from the parafollicular or calcitonin-producing C cells and maintains the features of these cells. • The exact incidence of MTC is unknown but its prevalence is approximately 3% to 5% of all thyroid malignancies and is estimated to be present in 0.4% to 1.4% of subjects with thyroid nodules. • The incidence peak of MTC is between the fourth and fifth decades but with a wide range of age at presentation. • No difference of prevalence between female and male subjects has been reported.

MTC can be sporadic or familial, in 75% and 25% of cases, respectively, and when familial it can be associated with other endocrine diseases, such as pheocromocytomaand parathyroid adenoma/hyperplasia causing hyperparathyroidism. • No environmental risk factors or ethnical predominance have been identified, although its pathogenesis has been recognized in the activation of the Rearranged during Transfection (RET) oncogene. • Germline mutations of RET are present in approximately 98% of hereditary cases whereas somatic RET mutation are reported in approximately 50% of sporadic cases.

The RET genetic screening can distinguish the familial from the sporadic form. • The prognosis of MTC is unfavorable, with a 10-year survival rate of MTC patients of approximately 50%. • Both the cure and survival rates of these patients are positively affected by an early diagnosis and precocious surgical treatment.

CLINICAL PRESENTATION • Most commonly, MTC is diagnosed in a subject with a thyroid nodule, either single or in the context of a multinodular goiter, without any other specific symptom. • In a few cases, however, untreatable diarrhea and/or flushing (Fig. 1) is present and associated with advanced metastatic disease. • Familial history must be carefully investigated because it can be positive for the presence of other cases of MTC, thus suggesting a familial/hereditary case. • The same hypothesis should be done if a patient has also a PHEO or a HPTH.

The hereditary syndromes present with MTC (100%) but involve multiple endocrine and non-endocrine organs and can be distinguished in • (1) multiple endocrine neoplasia type 2A (MEN 2A), in which PHEO (50%) and HPTH (25%) can be present; • (2) multiple endocrine neoplasia type 2B (MEN 2B), in which MTC is associated with PHEO (50%); and • (3) familial MTC (FMTC), which is the most frequent and characterized by the presence of isolated MTC. • A distinctive feature of MEN 2A is cutaneous lichen amyloidosis (CLA) (15%–20%) (Fig. 2) whereas cutaneous/mucosal neuromas (100%), megacolon (100%), and marfanoid habitus (100%) are peculiar to MEN 2B (100%), (Fig. 3).

The clinical course of MTC varies considerably in the three syndromes, being very aggressive and almost invariably unfavorable in MEN 2B, indolent in a majority of patients with FMTC, and with an intermediatedegree of aggressiveness in MEN 2A patients.

DIAGNOSIS • The most common presentation of sporadic cases is thyroid nodular disease. • In this case, physical examination, neck ultrasound (US), and US guided fine-needle aspiration cytology are among the most important diagnostic tools for MTC. • A cytologic smear of an MTC is characterized by isolated,oval to round, large polygonal or spindled cells. • Although the cytologic pattern is generally typical, there are several series that show a high percentage of failure in making a presurgical diagnosis.

Elevated basal levels of serum calcitonin, especially when greater than 100 pg/mL, are diagnostic of MTC. • Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic MTC. • Calcitonin screening allows the precocious diagnosis of MTC, usually when the tumor is still at its early stages, thus favoring successful surgical treatment and patient cure. • Patients diagnosed by serum calcitonin screening were demonstrated to have significantly better prognosis than those diagnosed by cytology or at histology.

There are several other conditions, however, in which basal levels of serum calcitonin may be elevated. • Differential diagnosis can be performed by calcium stimulation test. • Although in patients with MTC and elevated basal levels of calcitonin, calcium stimulation determines a 5-fold to 10-fold increase of serum levels of calcitonin, in other diseases, the calcitonin increase is limited or absent. • An additional tool for the diagnosis of MTC, especially when serum calcitonin is elevated but less than 100 pg/mL , is the measurement of calcitonin in the washout fluid of the needleused for the puncture of asuspected thyroid nodule.

This approach is of particular diagnostic importance to ascertain the nature of suspicious neck lymph nodes detected at neck US to plan the most appropriate surgical treatment. • Although calcitonin is the most reliable tumor marker due to its high sensitivity and specificity, there are other peptides that may be released by the malignant transformed C cell. • Serum carcinoembryonic antigen (CEA) is usually elevated in advanced cases when distant metastases are present. • Recently, high levels of serum carbohydrate antigen 19.9 have been demonstrated to identify a subset of MTC patients with a worse prognosis and a higher risk of mortality in the short term.

As in many other neuroendocrine tumors, serum chromogranin, somatostatin, gastrin-releasing peptide, vasoactive intestinal peptide, neuron-specific enolase, and other neuroendocrine substances may be abnormally produced but none of them is useful for diagnosis. • Moreover, some MTC-secreted peptides may result in significant clinical manifestations: vasoactive intestinal peptide, serotonin, and prostaglandins may all contribute to flushing and diarrhea whereas ACTH may cause ectopic Cushing syndrome in approximately 1% of MTC cases.

RET genetic analysis should always be performed when the diagnosis of MTC has been established because it allows defining the sporadic or hereditary nature of MTC. • The presence of the mutation in an apparently sporadic case or in a family member of hereditary forms is of fundamental importance to guide future diagnostic and therapeutic strategies.

Hereditary Form • The hereditary nature of the MTC may be suspected on the basis of a positive family history or for the presence of other endocrine (ie, PHEO and/or HPTH) or non-endocrine disorders (ie, mucosal or cutaneous neuromas, marfanoid habitus, megacolon for MEN 2B , and CLA for MEN 2A). • However, 7% to 15% of apparently sporadic MTC are found to be hereditary cases. • Usually PHEO diagnosis follows the development and diagnosis of MTC, and the mean age at presentation is 30 to 40 years.

An elevated 24-hour urinary excretion of metanephrines is the most sensitive and specific test to diagnose PHEO that is often asymptomatic. • Once PHEO is suspected, an abdomen US for the localization of the adrenal mass should be performed but in some cases a computerized tomography (CT) scan and/or an MRI may be necessary. • The screening for PHEO should begin according to the type of RET mutation because the disease was diagnosed as early as 8 years, 12 years, and 19 years of age in subjects with more or less aggressive RET mutations.

Parathyroid glands may also be involved but only in MEN 2A. • Both adenomas and hyperplasia may be associated with an increase of the parathyroid hormone secretion, resulting in hypercalcemia and hypercalciuria. • In contrast with MEN 1 patients, HPTH is mild and often asymptomatic. • The mean age of HPTH diagnosis in MEN 2A is approximately 30 years and almost all experts agree that the screening for HPTH should begin not earlier than 11 years and 16 years in patients with more aggressive or less aggressive RET mutations, respectively. • In some families with MEN 2A Hirschsprung disease can be associated with MTC and the other endocrine neoplasias.

This association is peculiar because the pathogenesis of Hirschsprung disease is due to a loss-of-function mutation of RET gene whereas the mutations related to the MEN 2 syndromes are caused by gain-of-functionmutations. • There are only 4 RET codons (Fig. 4) that give origin to mutations with gain-of-function and loss-of-function and for this reason they are called Janus mutations.

Once the index case has been identified has a hereditary case, all first-degree relatives should be analyzed for the possibility of carrying the same RET germline mutation. • The genetic screening allows distinguishing the gene carriers, who are at risk to develop the syndrome ,from those who do not carry the mutation and do not need to performany specific follow-up and can be reassured. • Gene carriers should be immediately submitted to a clinical and biochemical evaluation to establish if one disease of the syndrome is already present.

For gene carriers who have not yet developed any diseases belonging to the MEN 2 syndrome, a strict follow-up is suggested. • Many germline RET mutations have been recognized and are clearly associated with specific phenotypes. • According to the different RET mutations and their associated phenotypes, the American Thyroid Association (ATA) has distinguished the RET mutations into 3 levels of risk to develop MTC: highest (ATA-HST), high (ATA-H), and moderate (ATA MOD) (see Fig. 4). • This classification, together with the serum levels of serum calcitonin, is relevant to better plan screening and treatment strategies.

highest risk” (HST) that includes patients with MEN2B and the RET codon M918T mutation . • “high risk” (H) that includes patients with the RET codon C634 mutations and the RET codon A883F mutation. • “moderate risk” (MOD) that include patients with hereditary MTC and RET codon mutations other than M918T, C634, and A883F.

THERAPY AND FOLLOW-UP • Initial Treatment • An early diagnosis and complete surgical treatment are the bases for the definitive cure of MTC patients. • Total/near total thyroidectomy is considered standard treatment in both sporadic and hereditary MTC. • The need for total thyroidectomy is supported by the presence of multicentric and bilateral disease in a majority of hereditary and in approximately 6% of sporadic MTCs.

An additional reason in favor of total thyroidectomy is that 7% to 15% of apparently sporadic cases are hereditary forms with multicentric/bilateral disease associated with C-cell hyperplasia. • Due to the high prevalence of central compartment lymph node metastases (50%– 75%), many clinicians suggest performing central compartment lymph node dissection (CCLND) with total thyroidectomy as initial treatment. • Considering that this prevalence is the same whether the primary tumor is less than 1 cm or greater than 4 cm, prophylactic CCLND should be performed independently of the primary tumor size and the presurgical evidence of lymph node involvement.

More recent evidences suggest using preoperative calcitonin values to determine the extent of lymph node dissection. • It seems that there is virtually no risk of lymph node metastases when preoperative calcitonin level is less than 20 pg/mL (normal reference range <10 pg/mL). • In these cases, the prophylactic CCLND, that is affected by a high risk of surgical complications, particularly of permanent hypoparathyroidism, might be avoided.

Calcitonin values higher than 20 pg/mL, 50 pg/mL, 200 pg/Ml , and 500 pg/mL seem associated with the presence of lymph node metastases in the ipsilateral central and ipsilateral lateral neck, in the contralateral central neck, in the contralateral lateral neck, and in the upper mediastinum, respectively. • It is demonstrated, however, that the highest values of serum calcitonin are the expression of metastatic disease, and the prophylactic CCLND would probably not change the course of the disease. • In these cases, the surgery extension could be limited to the lymph nodes compartments that have been demonstrated involved by the disease at neck US.

The age at thyroidectomy is a well-known risk factor for morbidity and mortality, particularly in infants. • In this regard, a greater concern is represented by young RET gene carriers who, if rendered hypoparathyroid, would be exposed to the need of calcium and vitamin D supplementation for the rest of their lives. • According to the ATA guidelines, total thyroidectomy should be performed in the first year/first months of life in MEN 2B (ATA-HST), before 5 years of age in MEN 2A (ATA-H), and when calcitonin levels become elevated or in childhood if the parents do not wish to embark on a lengthy period of evaluation in MEN 2A (ATA-MOD).

Considering the great heterogeneity, however, in the age of onset among different families and within the same family and recent evidences that patient cure could be achieved by tailoring the surgical treatment in different subjects according to basal and stimulated calcitonin levels, an individualized approach is proposed. • This is mainly because also experienced surgeons have great difficulty localizing the parathyroid glands in young children and infants. • Moreover, some pediatricians have some concerns regarding the potential detrimental effects of insufficient thyroid hormone replacement that can impair brain development and normal growth.

Thus, prophylactic thyroidectomy associated with CCLND within the first year of life should be reserved for MEN 2B children. • Moreover, because the CCLND in children, as well as in adults, is the major cause of hypoparathyroidism, the ATA guidelines suggest that children with MEN 2 who have been decided to be submitted to total thyroidectomy can avoid prophylactic CCLND when calcitonin values are less than 40 pg/mL and there is no US evidence of lymph node metastases. • Regardless of age and presenting symptoms, all hereditary MTC patients and apparently sporadic cases not yet definitively ascertained as true sporadic must be investigated for the presence of PHEO and HPTH.

PHEO, if present, must be treated before MTC and patients need to be adequately prepared to avoid hypertensive crisis that could be life threatening. • The diagnosis of HPTH is not less important because the delay in diagnosis could lead to further surgical treatment in the same region exposing the patient to a higher rate of surgical complications. • Hormone replacement therapy with L-thyroxine (LT4) should be started immediately after thyroidectomy. • At variance with differentiated thyroid cancer parafollicular C cells and MTC are not dependent on thyrotropin; thus, there is no need to treat patients with ”LT4 suppressive” therapy.

Substitutive LT4 treatment aiming to keep thyrotropin values within the normal range is adequate. • In cases of aggressive local disease, the initial surgical treatment can be incomplete. • In these cases, external beam radiotherapy (EBRT) can be considered but its real therapeutic role is still controversial. • From a recent Surveillance, Epidemiology, and End Results program analysis, it seems clear that there is no survival benefit in patients with MTC and positive lymph nodes.

For this reason, the benefit of an EBRT treatment should be compared with the risks of exposing patients to the acute and chronic toxicity of this treatment. • Moreover, the surgeons and clinicians should accurately consider the possibility that the patients could be candidates for reoperation in the neck because the procedure is more difficult and associated with significant complications if EBRT has been previously performed.

Follow-up and Diagnosis of Persistent/Recurrent Disease • Three months after the initial treatment, a control, including physical examination, neck US, and measurement of serum thyrotropin, basal calcitonin, and CEA , should be performed. • Due to the prolonged half-lives, if performed too early, measurement of serum calcitonin and CEA may be misleading, especially if high serum values were present before surgery. • If basal calcitonin is undetectable, the patient can be considered in clinicalremission with a low risk of recurrence (10%). • If a calcium stimulation test for calcitonin is also negative, the risk of recurrence drops to 3%.

Measurement of CEA is not necessary in cases of undetectable levels of serum calcitonin. • Subjects who are still having low but detectable calcitonin values (<150 pg/mL) after initial surgery can present distant metastatic disease but in a majority of cases persistent/recurrent disease is confined to neck lymph nodes. • These patients can be followed every 6 months to 12 months with physicalexamination, neck US, and measurement of serum basal calcitonin and CEA.

Detectable serum calcitonin levels are compatible with long-term survival during which calcitonin may remain stable over time or slowly increase. • In this case, frequent and repeated imaging studies (eg, CT, PET, and bone scan) are unnecessary and harmful. • In cases of postoperative basal calcitonin values higher than 150 pg/mL or in those in which calcitonin increase substantially over time, patients should be evaluated with imaging studies. • In particular, patients with calcitonin higher than 5000 pg/mL present distant metastatic disease in more than 50%, and sites of metastases can be detected in almost all cases in which calcitonin is higher than 20,000 pg/mL.

The most sensitive imaging studies to detect MTC in different sites are USfor the neck, CT for the chest, MRI for the liver, and MRI and bone scintigraphy for the skeleton. • In some cases, other imaging techniques, such as PET with different tracers (fluorodeoxyglucose F 18 [18FDG], dihydroxyphenylalanine F 18 [18F-DOPA], dotatate gallium Ga 68 [68Ga-DOTATATE], and so forth) may be useful. • To avoid repeated and unnecessary imaging studies in patients who are usually long survivors, after initial staging, except in rare cases, CT scans should be performed no more than annually and according to the serum calcitonin trend of increase.

Both serum calcitonin and CEA levels doubling times (DTs) are good predictors of survival, in particular the former, and can also predict disease progression, as demonstrated by the evidence that when calcitonin and CEA DTs were concordant and less than 25 months, progressive disease (PD) was observed in almost all cases (94%), whereas when calcitonin and CEA DTs were discordant and less than 25 months, PD was still present but in a lower number of cases (56%). • The DTs of calcitonin and CEA can be easily calculated on the ATA Web site and is useful in choosing the most appropriate time to submit a patient to a new CT scan.

Other Treatments for Persistent/Recurrent Disease • A second surgical treatment with a curative intent is generally not recommended, in fact, only one-third of MTC patients has been demonstrated to have postoperative basal and stimulated serum calcitonin in the normal range and more rarely calcitonin is undetectable. • In the clinical management of patients with MTC, the identification of those who might benefit from this treatment is of great importance; however.

Repeatneck surgery should be suggested for rapidly growing lymph node metastases at risk of infiltration of vital neck structures, symptomatic lesions, or ulceration that is unlikely in MTC. • Capsular invasion and more than 10 lymph node metastases in the primary surgical specimens are significant predictors of poor response to reoperation. • Neck lymph node metastases after adequate initial diagnosis and treatment are present mostly in metastatic patients and can be followed by neck US in a majority of cases.

Similarly to lymph node recurrence, surgical treatment of distant metastatic lesions is not indicated except for those that could compromise vital structures and/or be life threatening. • Liver metastases may be amenable to surgical treatment in some cases. • This procedure may be useful in large, single, increasing in size liver metastases, particularly if associated with symptoms, such as diarrhea or pain. • As an alternative, local treatments, such as radiofrequency ablation, thermablation chemoembolization, and transarterial radioembolization, can be appropriate and less invasive.

These local approaches could be always considered also for lung or bone metastases, because, if feasible, they can be useful to delay systemic therapy. • External beam radiotherapy (EBRT) can be used only occasionally for the treatment of lung metastases and be reserved for rare symptomatic cases (cough, dyspnea, difficulty in swallowing , and so forth). • The main reason is that EBRT of lungs carries a high risk of radiation fibrosis and respiratory failure that can become the real risk of death for these patients. • Incases of painful bone metastases present, EBRTmay be useful to provide relief.

A monthly intravenous infusion of zoledronic acid or a monthly subcutaneous administration of denosumab possibly reduces the skeletal-related adverse events (AEs) and should be performed especially when bone lesions are multiple. • Alternative approaches to prevent/delay fractures may be radiofrequencyablation, vertebroplasty , or kyphoplasty. • Brain metastases may also be treated with EBRT or stereotaxic radiosurgery to obtain local control, prolong survival, and improve quality of life. • Surgical resection for asymptomatic brain metastases is almost always not indicated because it exposes patients with rapidly progressive systemic disease to useless risks.

When metastatic lesions are multiple and localized in different organs, systemic therapy should be considered if disease progression is documented. • Classical cytotoxic chemotherapy for advanced metastatic MTC has shown limited response rates (15%–20%) and short duration. • Treatment with several radiolabeled molecules has been widely explored. • A promising approach documenting complete remission or partial remission seems to come from the treatment of MTC patients with radiolabeled (yttrium 90 or lutetium 177) peptides targeting somatostatin receptors.

Since 2005, a new interest for targeted therapy in MTC has been growing. • The rationale for this interest was represented by the presence of RET mutation in virtually all familial cases and in a majority of advanced sporadic cases. • In addition to RET, other important targets (ie, vascular endothelial growth factor receptor [VEGFR], epidermal growth factor receptor [EGFR], hepatocyte growth factor receptor [MET], and so forth) were demonstrated to be overexpressed in this tumor and represented the molecular basis of treating this disease with tyrosine kinase inhibitors (TKIs)..

The most important drugs and targets investigated in MTC are summarized in Table 1. • One of the first drugs investigated on MTC was motesanib. • In a phase II trial, the lack of a placebo arm and strict inclusion criteria led to the enrollment of many patients with stable disease and poor results in terms of efficacy. • For these reasons the drug never reached the market. In the following years, other phase II clinical trials with axitinib, pazopanib, and lenvatinib have been performed.

All of them showed interesting results but these drugs were never evaluated in a phase III study. • The efficacy of vandetanib has been investigated in MTC with a prospective, randomized, double-blind phase III trial that showed good results in terms of efficacy and tolerability compared with placebo (ZETA trial). • The improvement of symptoms and a significant prolongation of the progression-free survival (PFS) in patients treated with vandetanib compared with those treated with placebo have been considered relevant. • For this reason, in 2011 and 2013, vandetanib was approved for the treatment of symptomatic and progressive MTC by the Food and Drug Administration and the European Medicines Agency, respectively

Management of Medullary Thyroid Cancer