Frequency (%)
Features of MTC
Associated diseases
Sporadic MTC
70
Unifocal
MEN-2A
20
Autosomal dominant
Multifocal, bilateral
Pheochromocytoma
Primary parathyroid hyperplasia
Cutaneous lichen planus amyloidosis (rare)
Hirschsprung disease (rare)
MEN-2B
5
Autosomal dominant
Multifocal, bilateral
Pheochromocytoma
Multiple mucosal ganglioneuromatosis
Marfanoid body habitus
FMTC
5
Autosomal dominant
Multifocal, bilateral
None
RET gene is a proto-oncogene with 21 exons located on chromosome 10 (10q11.2) [7, 8, 15–17]. The RET gene encodes a transmembrane protein tyrosine kinase receptor for the glial cell line-derived neurotropic factor (GDNF) family members and their ligands such as artemin, neuturin, and persephin. The RET protein is composed of three functional domains involved in a variety of signaling pathways to regulate differentiation, proliferation, survival, and migration of the enteric neural progenitor cells and renal cells [7, 8]. Although the RET gene itself was initially discovered in 1985, its mutations were linked to inherited MTC in the early 1990s. Genetics of hereditary MTC syndromes is based on a series of missense germline mutations in different parts of the RET gene with autosomal dominant pattern and high penetrance. Frequently, a point mutation is the cause of malignant transformation. Several germline mutations have been found across 7 exons. Most of the mutations occur in exons 8, 10, 11, and 13–16. These mutations have different penetration rates to produce a variety of disease phenotypes. The most common mutation in MEN-2 patients is in exon 11 codon 634 (85 %) followed by mutations in codons 609, 611, 618, and 620 (10–15 %). Each of them has different importance for risk of developing MTC. C634 and M918T mutations in MEN-2A and MEN-2B, respectively, are associated with aggressive tumors and metastasis in early childhood within months from birth. Germline RET mutations are detected rarely in sporadic cases in 6–7 % of all patients [15].
Inherited forms of MTC occur in younger ages. Therefore, genetic counseling plays an important role in the detection of MTC risk. Genetic testing must be done in all patients with MTC. If germline mutation is detected in one case, all family members should be screened with proper genetic counseling and treatment, as necessary. Early or prophylactic thyroidectomy potentially cures this life-threatening disease in the affected kindreds [18].
On the other hand, about half of sporadic cases have acquired somatic RET mutation which were detected in the tumor cells [16, 17]. These mutations cannot be detected using regular genetic testing of leukocyte DNA, because these do not have any inheritance pattern and do not affect clinical management of an individual patient, routine genetic testing of all tumor samples is not recommended outside of an academic incentive.
22.3 Clinical Presentation
Patients with sporadic MTC are usually diagnosed in the fifth or sixth decades of life [9–13]. However, hereditary forms present in younger ages. There is a trend to be more frequent in female sex. MTC is an indolent disease and overall survival of 15–20 years is possible even in disseminated disease. Most patients present with metastatic disease at initial diagnosis. Common sites of distant metastatic spread include the bones, lungs, liver, and brain [9–13].
Asymptomatic thyroid mass or enlarged lymph nodes are typically the most common initial symptoms seen in 75–95 % of the patients. Because parafollicular C cells originating from neural crest are usually located in the upper thyroid lobes, masses are usually detected there [9–13]. These tumors are unilateral in sporadic MTC. However, hereditary forms usually present with bilateral and multifocal disease. Cervical lymph node involvement is detected in about half of the cases. Multifocality is an important risk factor for the lymph node metastasis [19]. Approximately 10 % of the patients experience local invasion or compression of aerodigestive tract causing hoarseness or dysphagia. Rarely, symptoms may occur due to distant metastases such as shortness of breath, bone pain, or fractures. Several hormones such as calcitonin, serotonin, and vasoactive intestinal peptide (VIP) are released from the tumor tissue. Flushing, sweating, weight loss, and diarrhea may occur due to these hormones.
Symptoms of the other diseases such as hyperparathyroidism and pheochromocytoma may be the initial presentation of hereditary MTC.
22.4 Diagnosis
Fine-needle aspiration cytology (FNAC) is the gold standard technique for the diagnosis of MTC [20]. The pooled estimate of FNAC detection rate in MTC patients is 56 % in a recent meta-analysis. Sometimes, pathological features cannot be easily discriminated from other malignancies. In those cases, immunohistochemical staining for calcitonin, carcinoembryonic antigen (CEA), and chromogranin A might be useful. Another recent approach is to measure aspiration needle washout fluid calcitonin levels [21].
Basal serum calcitonin and CEA levels are usually elevated [22–24]. Some authors suggest that serum calcitonin has a higher sensitivity compared to FNAC in the diagnosis of MTC [22, 23]. Calcitonin levels are correlated with tumor burden and multifocality. Calcitonin levels greater than 3,000 pg/mL generally indicate metastatic disease [23]. Besides confirming diagnosis, serial measurement of calcitonin is useful for confirming treatment efficacy and monitoring disease progression or recurrence. Similarly, high CEA level above 100 ng/mL is associated with lymph node and distant metastasis [24]. Calcitonin and CEA levels are useful for postoperative surveillance. Preoperative high level of CEA is a prognostic factor. Serum calcitonin stimulation test is useful in familial MTC patients without RET mutation and pathological borderline cases.
After diagnosis, neck ultrasonography is used to evaluate lymph nodes. Chest and abdomen contrast-enhanced computerized tomography must be done for staging, especially in patients with lymph nodes in the neck or basal calcitonin levels >400 pg/mL. 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET/CT) is not routinely recommended for initial staging [25–27]. Its sensitivity is modest and may be recommended for a small subset of more biologically aggressive MTCs or detecting metastasis with elevated calcitonin levels >1,000 pg/mL [25, 26]. Tumor–node–metastasis (TNM) staging system suggested by the Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC) is recommended for staging (Table 22.2) [28].
Table 22.2
Staging of medullary thyroid cancers
Stage | TNM classification | Definition |
|---|---|---|
Stage I | T1,N0,M0 | Tumor ≤2 cm in greatest dimension and is limited to the thyroid gland (T1) |
Stage II | T2–T3,N0 | Tumor >2 cm, limited to the thyroid, or any tumor with minimal extrathyroidal extension (T2–T3) |
Stage III | T1–T3,N1a,M0 | Any tumor limited to the thyroid, or any tumor with minimal extrathyroidal extension (T1–T3) and presence of nodal metastasis in level VI (N1a) |
Stage IV | T4,N0–N1a,M0 T1–T4,N1b,M0 Any T, any N, M1 | Tumor with gross extrathyroidal soft tissue extension (T4), or lymph node involvement outside of level VI (N1b), or distant metastases (M1) |
22.5 Treatment
Surgical resection remains the mainstay of primary treatment for MTC [29, 30]. There is limited evidence for external beam radiotherapy (EBRT) as a local therapeutic modality [31]. Treatment options for patients with advanced MTC are limited. Cytotoxic chemotherapy has negligible efficacy with poor response rates and short duration of response [29, 30]. Partial response (PR) rates of single-agent regimens such as doxorubicin, dacarbazine, capecitabine, and 5-fluorouracil have been <30 %. There is an obvious “unmet medical need” for novel therapeutic approaches in advanced MTC. Recent years have witnessed remarkable advances in the understanding of the molecular biology of MTC leading to introduction of novel agents directed to these targets.
22.5.1 Surgery
There is general consensus that the only curative treatment of MTC is meticulous total thyroidectomy with removal of any visible tumoral tissue from the cervical region coupled with ipsilateral modified radical neck dissection provided that there is no advanced disease [32, 33]. Inherited MTC is almost always multicentric and bilateral, and about 5–6 % of patients with sporadic MTC turn out to be familial and multicentric. Furthermore, intraglandular lymphatic spread is possible in sporadic cases. Therefore, partial thyroidectomy is not recommended.
Because presence of lymphatic spread is of prognostic significance, optimal lymph node dissection is mandatory with “compartmental hierarchy” concept [34, 35]. Prognosis depends on age at diagnosis, stage of disease, and extent of initial thyroid or neck surgery [36]. Interestingly, some reports failed to show that the extent of lymphadenectomy improves the outcome in patients with MTC [37]. Lymph nodes in the central compartment between the hyoid bone and the innominate vessels, laterally to both internal jugular veins and carotid arteries, and posteriorly to the tracheal esophageal groove should be dissected. If central nodes are involved with metastasis, an ipsilateral modified neck dissection should be performed with removal of the contralateral central nodes. If central nodes are negative for metastasis, biopsy of the lateral lymph nodes is not required, but some authors recommend routine initial contralateral neck dissection. Mediastinal dissection with sternotomy may be considered in cases with gross detectable disease contained within the mediastinum. The role of salvage neck surgery remains controversial in MTC [34, 35]. Palliative re-operation may be performed for compressive symptoms or risk for imminent compression or invasion of the trachea or major vessels. Lymphadenectomy should be very restrictive in the presence of locally advanced and/or metastatic disease. Anticipated complications of surgery include vocal cord paralysis, airway obstruction, and hemoptysis.
22.5.2 Radiotherapy
EBRT may be suggested as adjuvant treatment in patients with less than optimal lymph node dissection or with extrathyroidal disease [31]. Clinical studies warrant the use of postoperative adjuvant EBRT in patients at high risk for locoregional recurrence such as locally invasive tumor, grossly positive surgical margins, extranodal tumor extension, and detectable calcitonin after surgery. In this setting, adjuvant RT may reduce the 10-year local recurrence rate by half [38]. Some MTC patients treated with EBRT might enjoy prolonged survival duration [39]. However, some authors argued against treating MTC with EBRT because they consider MTC to be relatively radioresistant [40, 41]. EBRT is best suited for palliative purposes such as symptomatic central nervous system and bone metastases or irresectable local neck recurrences [42].
22.5.3 Chemotherapy
Treatment with either single-agent or combination cytotoxic chemotherapy has been generally inadequate. Experience in this field is largely limited to small case series or phase II studies with no phase III studies available to date. Single agents with some antitumor activity in MTC include dacarbazine, doxorubicin, DTIC, cisplatin, cyclophosphamide, streptozotocin, fluorouracil, and vincristine [43–45]. Various combinations of these chemotherapeutic drugs resulted in PR of 15–20 % with no documented complete responses. In spite of inducing short-lived PRs in <30 % of the advanced MTC patients, doxorubicin treatment is approved by the US Food and Drug Administration (FDA) for the treatment of metastatic thyroid cancer including MTC. Among other cytotoxics, DTIC is the only agent recommended by the National Comprehensive Cancer Network (NCCN) for symptomatic or progressive MTC patients despite to its modest activity in non-controlled trials [46].
Because chemotherapy in advanced MTC has an insufficient efficacy, it should be reserved for patients with progressive disease refractory to targeted agents.
22.5.4 Somatostatin Analogues
Somatostatin analogues have been used with some success in (NETs), especially in symptomatic patients for symptom palliation. Octreotide, synthetic analogue of somatostatin, has been tried in MTC patients [47]. There is no randomized controlled study, but only case series or non-controlled studies which were not able to demonstrate any consistent antitumor effect. All studies showed subjective and biological PR in about 25 % of the MTC patients with no improvement in tumor load. It seems that somatostatin analogues are only helpful in alleviating symptoms.
22.5.5 Tyrosine Kinase Inhibitors
Targeted therapies with small molecule inhibitors of tyrosine kinases (TKI) have been used in cancers with demonstrated driving mutations involved in the pathogenesis. The better defined is the target, the better is the response to treatment with its inhibitors. These molecules target several tyrosine kinases involved in a variety of steps of the signal transduction pathways regulating proliferation, survival, gene expression, angiogenesis, and migration functions. Therefore, these “multikinase” inhibitors have successfully been used in thyroid cancers including MTC directed to RET, vascular endothelial growth factor receptor (VEGFR), and the epidermal growth factor receptor (EGFR). It has been proposed that inhibition of a single kinase receptor may result in upregulation of compensatory signaling pathways to sustain cell growth. Multikinase inhibitors have been developed to bypass this potential resistance mechanism.
22.5.5.1 Cabozantinib
Cabozantinib (XL184) is an oral TKI with activity against c-MET, VEGFR-2, and RET [48, 49]. Activation of these receptors has been implicated in both development and progression of MTC. Inhibition of c-MET, which is the receptor for hepatocyte growth factor (HGF), may confer additional activity against MTC.
A phase I open-label dose-escalation study of cabozantinib was performed in patients with advanced solid tumors including 37 patients with MTC [50]. An objective PR was achieved in 10 of 35 patients with measurable disease in the MTC cohort. Stable disease (SD) of 6 months or longer was observed in 15 patients. Overall 68 % of the patients experienced SD + PR at the sixth month of assessment. Documented responses were independent of the RET mutation status of the tumors, suggesting that antineoplastic effects of the drug were due to inhibition of targets other than RET pathway [50]. Following the remarkable results of phase I study, a double-blind, randomized phase III EXAM study of cabozantinib 140 mg daily was conducted in 330 patients with progressive MTC [51]. Randomization was 2:1 (cabozantinib to placebo) and the primary endpoint was progression-free survival (PFS). A statistically significant improvement in estimated median PFS was observed in the cabozantinib group (11.2 vs. 4.0 months) (HR 0.28, 95 % CI 0.19–0.40; p < 0.001). One-year PFS was 47.3 % for cabozantinib and 7.2 % for placebo. Response rate (all PR) for cabozantinib was 28 % (vs. none for placebo) regardless of RET mutation status. There was no statistically significant difference in overall survival (OS).
Side effects were considerable. Of all patients, 79 % required dose reductions and 16 % discontinued cabozantinib permanently. Common adverse events seen in ≥10 % of the patients included diarrhea, palmar–plantar erythrodysesthesia, fatigue, nausea, weight loss, loss of appetite, hypertension, hemorrhage, hypocalcemia, and elevated liver function tests. Grade 3 or 4 adverse events were reported in 69 % of cabozantinib-treated patients. Significant electrocardiographic abnormalities (QT prolongation) were not encountered in the trial, as was observed with vandetanib [52].
In a subgroup analysis, cabozantinib markedly improved PFS in the subset of patients whose tumors contained RETM918T mutations (61 vs. 17 weeks; HR 0.15, 95 % CI 0.08–0.28) or whose tumors contained RAS mutations (47 vs. 8 weeks; HR 0.15, 95 % CI 0.02–1.10) [53]. The results of the phase III EXAM trial caused FDA to approve cabozantinib for patients with progressive metastatic MTC in November 2012.
22.5.5.2 Vandetanib
Vandetanib (ZD6474) is an oral small molecule TKI that blocks RET, VEGFR-1, VEGFR-2, and EGFR. The efficacy of vandetanib in hereditary MTC has been assessed in two phase II open-label, single-arm studies. The first phase II clinical trial enrolled 30 patients with hereditary, unresectable, or metastatic MTC to receive vandetanib at 300 mg/day [54]. A PR was achieved in six (20 %) and SD in 16 (53 %) patients. Median PFS was 27.9 months. Common adverse events were diarrhea, rash, fatigue, and nausea. The second phase II study enrolled 19 patients who receive vandetanib at 100 mg/day with escalation after progression to 300 mg/day [55]. Antitumor activity of low-dose vandetanib was verified with similar results (16 % PR and 53 % SD) and similar adverse events despite to lower dose.
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