Medullary thyroid cancer: Surgical treatment and prognosis

INTRODUCTION — Patients with medullary thyroid cancer (MTC) can be cured only by complete resection of the thyroid tumor and any local and regional metastases. For patients with residual or recurrent disease after primary surgery or for those with distant metastases, the most appropriate treatment (surgery, chemotherapy, or radiotherapy) is less clear.

This topic review will discuss the role of surgery as primary therapy and the approaches to treating patients with persistent or recurrent MTC after surgery. The approach outlined below is largely in agreement with American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines [1,2]. Recommendations for the timing of thyroidectomy in children with RET mutations and the role of chemotherapy in the treatment of MTC are reviewed elsewhere. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Preventive surgery' and "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

PREOPERATIVE EVALUATION — Newly diagnosed patients with medullary thyroid cancer (MTC) should be staged both biochemically and radiologically (algorithm 1). This evaluation is reviewed briefly below and in more detail elsewhere. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Evaluation'.)

The following tests should be performed:

●Calcitonin and CEA – Measurement of serum calcitonin and carcinoembryonic antigen (CEA) to determine whether they are produced by the tumor, and if so, as a baseline for comparison with results obtained after surgery. Among patients with either sporadic or familial tumors, those with higher preoperative serum calcitonin concentrations have larger tumors and are less likely to have normal serum concentrations after surgery than those with lower preoperative values [3].

●Ultrasonography – Ultrasonography of the neck to assess for local and regional disease. Additional imaging is necessary for patients with local lymph node metastases or with preoperative serum basal calcitonin >500 pg/mL (indicating high risk of local or distant metastatic disease).

●Analysis for pathogenic RET variants – Germline RET mutation analysis to determine which patients with apparently sporadic MTC have unsuspected germline RET mutations (the underlying defect in multiple endocrine neoplasia type 2 [MEN2]) and therefore heritable disease. Germline mutational analysis may be performed pre- or postoperatively. Even when performed preoperatively, the results are rarely known prior to surgery. The presence or absence of a germline mutation has little impact on the initial surgical approach.

●Screening for hyperparathyroidism and pheochromocytoma – Measurement of serum calcium and either plasma fractionated metanephrines or 24-hour urinary excretion of metanephrine and catecholamines to assess for hyperparathyroidism and pheochromocytoma, respectively. This testing should be performed in all patients who have either unknown RET mutation status or a germline RET mutation. In patients with negative RET mutation analysis and no family history of MEN2-related diseases, such testing typically is not required.

SURGICAL APPROACH

MTC confined to the neck — Total thyroidectomy rather than unilateral lobectomy is the preferred surgical approach. Up to 10 percent of patients with sporadic medullary thyroid cancer (MTC) and all patients with inherited MTC have bilateral or multifocal disease [1]; in addition, the latter all have premalignant diffuse C cell hyperplasia. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

The extent of cervical lymph node dissection depends on the findings on preoperative ultrasound as well as intraoperative identification of lymph node metastases.

The types of surgical procedures are described in detail elsewhere. (See "Thyroidectomy" and "Differentiated thyroid cancer: Surgical treatment", section on 'Approach to lymph node dissection'.)

No ultrasound evidence of cervical lymph node involvement — For most patients with MTC confined to the neck and no evidence of involved cervical lymph nodes on preoperative ultrasound, we routinely perform prophylactic bilateral dissection of the central lymph node compartment without prophylactic lateral neck dissection. Prophylactic central neck dissection is not required in patients with small intrathyroidal MTCs with a preoperative calcitonin <20 pg/mL, as metastatic lymph nodes are exceedingly rare in this circumstance [4].

For patients with intraoperative evidence of central cervical lymph node involvement, dissection of the involved lateral neck compartment is also performed.

●Central lymph node dissection – Prophylactic bilateral dissection of the central lymph node compartment (from the hyoid bone to the innominate veins and medial to the jugular veins) is the preferred initial treatment for most patients [1]. MTC usually spreads to the central neck nodes. In one study of 101 consecutive patients with MTC (and no previous surgery), lymph node metastases to the central compartment were seen in approximately 50 percent of both sporadic (n = 54) and hereditary (n = 47) cases [5]. Metastatic spread to central neck lymph nodes is exceedingly rare, however, if the preoperative basal calcitonin is <20 pg/mL [4].

In a retrospective series, patients treated with total thyroidectomy with central neck lymph node dissection required fewer reoperations than those receiving lesser procedures [6-8].

●Lateral lymph node dissection – Whether or not to perform lateral neck dissections in the absence of ultrasonographically identifiable lymph node metastases as part of the primary surgery remains controversial. The lateral jugular and mediastinal nodes should be carefully evaluated intraoperatively, followed by modified neck and/or mediastinal dissections only if positive nodes are identified. Although we do not routinely advise lateral neck dissections in the absence of identifiable lymph node metastases (regardless of the serum calcitonin level), dissection of the ipsilateral lateral lymph node compartment is performed for patients with intraoperative evidence of central lymph node involvement.

In one study, ipsilateral lateral lymph node metastases were found in 10 percent of patients with no central node involvement, 77 percent of patients with one to three central nodes, and 98 percent of patients with more than four central nodes; contralateral lateral lymph node metastases were found in 4.9 percent of patients with no central nodes, 38 percent of patients with one to nine central nodes, and 77 percent with more than nine central nodes [9].

The American Thyroid Association (ATA) guidelines committee could not achieve a consensus agreement on this topic but did recommend that prophylactic lateral neck dissections "may be considered based on serum calcitonin levels" [1]. Some members recommended against routine prophylactic lateral neck dissections if there was no evidence of disease on preoperative neck ultrasound. Other members utilized preoperative calcitonin values to guide the extent of prophylactic neck dissections by recommending prophylactic ipsilateral central and ipsilateral lateral neck dissection for patients with basal serum calcitonin values >20 pg/mL and prophylactic dissection of uninvolved contralateral lateral neck compartments for serum calcitonin >200 pg/mL [1].

The primary argument in favor of routine use of prophylactic lateral neck dissection in patients with a preoperative basal calcitonin level of ≤1000 pg/mL is that at least one-half of them will achieve biochemical cure (calcitonin <10 pg/mL) [4]. Since a biochemical cure is associated with 98 percent 10-year survival and approximately 3 to 4 percent recurrence rate, proponents of prophylactic lateral lymph node dissection argue that the benefits outweigh the additional risks and complications associated with routine use of prophylactic lateral neck dissections when done by experienced surgeons [10-12].

The counter argument is that long-term survival rates are also excellent in patients with a biochemical incomplete response to initial therapy (abnormal postoperative calcitonin in the absence of structural disease progression), ranging from 90 to 100 percent at 10 years of follow-up, with the highest survival rates seen in patients with intrathyroidal MTC without evidence for local or distant metastases [10,13,14]. Thus, the excellent outcomes attributed to more aggressive upfront resection of the lateral compartment subclinical lymph nodes may be more related to the underlying biology of the disease rather than to our therapeutic interventions. Furthermore, routine use of prophylactic lateral neck dissections will expose patients to additional morbidity, particularly knowing that most of these surgeries are not done by high-volume, very experienced surgeons.

Thus, it remains unclear if there is truly a survival benefit from more aggressive upfront lymph node dissection done in an effort to achieve an initial excellent response to therapy as opposed to a more measured surgical intervention, recognizing that some patients will have a biochemical incomplete response that may or may not require additional therapy in the future based on follow-up imaging and the trend in calcitonin/carcinoembryonic antigen (CEA) values.

Ultrasound evidence of cervical lymph node involvement — For patients with MTC involving the thyroid and known cervical lymph nodal involvement preoperatively, total thyroidectomy with bilateral central compartment dissection and dissection of the involved lateral neck compartment(s) is the preferred initial treatment. In addition to compartment-oriented dissection of the clinically involved ipsilateral neck, prophylactic neck dissection of uninvolved contralateral neck compartments should also be considered in patients with a basal calcitonin level greater than 200 pg/mL if there is no evidence of distant metastases [1].

Locally advanced or metastatic MTC — In patients with locally advanced or metastatic disease, total thyroidectomy with resection of involved lymph node compartments is recommended in most patients. Since the goals of surgery are largely palliative in this setting, a less aggressive surgical approach to the thyroid primary and to lymph node dissection in the central and lateral neck compartments may be warranted in order not to impair speech, swallowing, parathyroid function, and shoulder mobility [1]. In the presence of grossly invasive disease, more extended procedures with resection of involved neck structures may be appropriate in properly selected patients, but function-preserving (speech, swallowing) approaches are preferred. Disfiguring radical neck dissections do not improve prognosis and are not indicated. The surgical approach should be individualized based upon the patient's wishes, life expectancy, and other medical comorbidities [1].

The role of RET-targeted kinase inhibitors prior to thyroidectomy as neoadjuvant therapy for locally advanced or metastatic RET-mutated MTC is under investigation [15-18]. The goal of neoadjuvant therapy is to decrease the size of a locally advanced tumor in order to make the surgery more effective with less morbidity. Preliminary data suggest that selpercatinib prior to surgical intervention can be associated with a decrease in tumor size and a likely improvement in preservation of major structures. However, pathology reports demonstrate fibroadipose tissue deposits, extranodal extension, and fibrosis, which makes the surgery technically challenging [16]. A clinical trial evaluating the efficacy and safety of selpercatinib prior to surgical intervention for the treatment of RET-altered thyroid cancer is ongoing [19]. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

MTC diagnosed after lobectomy — If medullary thyroid cancer (MTC) is diagnosed postoperatively after a unilateral lobectomy, management options include completion thyroidectomy (eg, removal of the remaining thyroid tissue) or observation with monitoring of serum calcitonin levels. Because patients with hereditary MTC uniformly have bilateral disease, all patients with hereditary MTC should have a completion thyroidectomy.

The approach in patients with sporadic MTC is less certain, and there are few data to guide management decisions. The incidence of bilateral disease in patients with sporadic MTC is low, ranging from 0 to 9 percent [1,4,20]. Therefore, completion thyroidectomy is not routinely indicated in patients without a germline RET mutation. However, we do perform completion thyroidectomy in sporadic MTC if the postoperative serum calcitonin is elevated above the upper normal value of the reference range or if there is imaging evidence of persistent disease in the thyroid or regional lymph nodes [1].

POSTOPERATIVE MANAGEMENT

Monitor for postoperative complications — Immediately after surgery, the patient should be monitored closely for the development of hypoparathyroidism or injury to either the recurrent or superior laryngeal nerves. These complications are reviewed in detail elsewhere. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Complications' and "Thyroidectomy", section on 'Calcium supplementation'.)

Thyroxine therapy — Thyroxine (levothyroxine, T4) therapy should be started immediately after surgery; an appropriate initial dose is 1.6 mcg/kg of body weight (ie, approximately 0.075 to 0.15 mg daily). The adequacy of therapy should be evaluated clinically and by measurement of serum thyroid-stimulating hormone (TSH) in six weeks. The goal of T4 therapy should be to restore and maintain a euthyroid state; suppression of serum TSH concentrations is not indicated in patients with medullary thyroid cancer (MTC), because C cells are not TSH responsive. Similarly, adjuvant therapy with radioiodine is contraindicated because the tumor cells do not concentrate iodine [21].

Assessment of tumor samples for somatic mutations — Somatic mutations in RET, HRAS, KRAS, or, rarely, NRAS can be identified in tumors of patients with sporadic MTC. In some [22-24], but not other [25], studies, tumors with an identifiable RET mutation had a more aggressive course than those without a mutation. Nonetheless, we agree that somatic mutational analysis of tumor samples is not required as part of routine clinical care [1]. However, molecular characterization of the primary tumor (or metastatic foci) is recommended in patients with progressive metastatic disease that warrants systemic therapy in order to identify tumors that harbor a somatic RET mutation (which would suggest treatment with a specific RET inhibitor). (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

SUBSEQUENT MANAGEMENT — After thyroidectomy, it is important to evaluate patients to determine if surgery was curative [10]. We measure serum calcitonin and carcinoembryonic antigen (CEA) to assess for cure. Subsequent management depends upon these values.

Serum calcitonin and CEA measurement — Serum calcitonin and carcinoembryonic antigen (CEA) should be measured two to three months after surgery to detect the presence of residual disease. Patients who have normal serum CEA and undetectable serum calcitonin values are considered biochemically cured and have the best prognosis [10,13,26,27]. Among those in one large series who were biochemically cured, the five-year recurrence rate was only 5 percent [11].

The timing of measurement of serum calcitonin after surgery is important because the serum calcitonin concentration falls slowly in some patients, with the nadir not being reached for several months [28]. However, in patients who are surgically cured, calcitonin levels begin to rapidly decline within the first postoperative hour [29], often achieving undetectable levels within the first few postoperative days in patients destined to achieve a biochemical cure [30-34]. Therefore, serum calcitonin measurements as early as a few days to weeks after surgery can provide early evidence of biochemical remission in many patients, but elevated levels in the immediate postoperative period do not necessarily indicate persistent disease.

Undetectable calcitonin and normal CEA — For patients with undetectable calcitonin levels and carcinoembryonic antigen (CEA) values within the normal reference range after surgery (ie, biochemically cured), subsequent follow-up should include (algorithm 2):

●Physical examination twice yearly for two years and then yearly thereafter.

●Measurement of serum calcitonin and CEA levels twice yearly for two years and then yearly thereafter.

●Neck ultrasound 3 to 12 months postoperatively (depending on the extent of lymph node involvement prior to surgery) to establish a baseline.

Additional imaging is not required unless the calcitonin or CEA values rise during follow-up.

Persistent hypercalcitoninemia — A high basal serum calcitonin value three or more months after surgery is presumptive evidence of residual disease. Thirty to 55 percent of patients with palpable medullary thyroid cancer (MTC) or nonpalpable but macroscopic MTC who undergo attempted curative resection have persistently high serum calcitonin concentrations [5,6,11,35,36].

The prognosis for patients with postoperative hypercalcitoninemia depends primarily upon the patient's age and the extent of disease at the time of initial surgery [6,11,13,37-39]. In a series of 899 patients with MTC (57 percent sporadic), the 10-year survival in the patients with postoperative hypercalcitoninemia (57 percent of the total group) was 70 percent compared with 98 percent in patients who were biochemically cured [11]. Younger age at surgery and absence of lymph node involvement were predictive of biochemical cure.

Further evaluation and management depend upon the magnitude of the elevation in the serum calcitonin concentration (algorithm 2). In addition, for patients with persistent elevation, assessment of calcitonin and CEA doubling times provides sensitive markers for progression and aggressiveness of metastatic MTC [40,41]. (See 'Prognosis' below.)

●Calcitonin <150 pg/mL – Calcitonin values that are detectable but less than 150 pg/mL two to six months after surgery usually indicate persistent locoregional disease in the neck. Therefore, neck ultrasound with or without additional cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging [MRI] of the neck) should be performed to evaluate for the presence of persistent macroscopic metastatic disease. Serum calcitonin and CEA are measured every 6 to 12 months.

If imaging is positive, meticulous dissection of all cytologically confirmed local and regional nodal tissue can be considered if there is no evidence of disease outside of the neck or mediastinum. As in the primary surgical setting, compartment-oriented neck dissections are recommended when surgery is performed for cytologically confirmed locoregional disease. More focused neck dissections may be appropriate in previously dissected neck compartments. However, outside of centers experienced in managing these patients, only those with overt disease in the neck and no distant metastases should undergo neck dissection in this setting. (See 'Management of persistent/recurrent disease' below.)

If imaging is negative and the serum calcitonin values measured every three to six months remain stable, neck ultrasound is usually performed every 6 to 12 months for two to three years, then less often during long-term follow-up. Additional imaging should be considered in patients with rising calcitonin and CEA values, with the type and frequency of testing based on both the magnitude and rate of rise of these biochemical markers. (See 'Small volume, asymptomatic' below.)

●Calcitonin ≥150 pg/mL – Calcitonin values that remain ≥150 pg/mL two to six months after surgery increase the likelihood that the patient may have distant metastases [1,2]. Therefore, patients with postoperative calcitonin levels that are ≥150 pg/mL should undergo neck ultrasound and additional imaging (CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases) to identify possible distant metastases. The liver is the most common site of metastases in patients with MTC, occurring in approximately 45 percent of patients with advanced disease [1]. Liver metastases are best identified with three-phase contrast-enhanced liver CT or contrast-enhanced liver MRI. Other sites include bone, brain, and lung.

If imaging is negative, monitoring with physical examination, measurement of serum calcitonin and CEA, and evaluation of the neck with ultrasonography should continue. The frequency of repeating imaging studies will be dependent on the magnitude and rate of rise of the calcitonin and CEA values. As an example, patients with stable postoperative serum calcitonin values in the 150 to 300 pg/mL range are usually followed with yearly neck ultrasound for several years, reserving repeat cross-sectional imaging (neck, chest, abdomen) to look for distant metastases in those patients with rising calcitonin or CEA values.

18-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) scans are considered only when the serum calcitonin is higher than 500 to 1000 pg/mL. In one report of 28 patients with MTC, PET had a sensitivity of 78 percent when calcitonin was >1000 pg/mL but failed to detect disease if calcitonin was <500 pg/mL [42]. Alternative PET tracers such as fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) [43-46] and gallium-68 (68Ga) radiolabeled somatostatin analogue peptides (DOTATATE, DOTATOC, and DOTANOC) [46-52] have been studied and appear to be more sensitive for disease detection than FDG PET scanning. The precise role for these alternative tracers is being defined.

Radionuclide bone imaging can be helpful in selected cases when cross-sectional imaging fails to identify the source of the persistent hypercalcitoninemia [53-55]. Attempted localization of disease by catheterization of the hepatic veins, both internal jugular veins, and the innominate veins, with measurements of serum calcitonin before and after calcium stimulation or laparoscopic examination of the liver, is rarely considered and only if these findings would impact clinical management [56].

If imaging is positive, treatment depends upon the site of disease and may include surgical resection and/or external beam radiation therapy (EBRT). (See 'Management of persistent/recurrent disease' below.)

Management of persistent/recurrent disease — Treatment options for patients with recurrent/residual disease include observation/active surveillance, surgical resection, EBRT, and other directed therapies (such as radiofrequency ablation, cryoablation, embolization) or systemic therapies. In the past, patients with identifiable residual or recurrent MTC were operated on routinely. However, despite routine lymphadenectomy or excision of palpable tumor, their serum calcitonin concentrations often did not normalize after surgery [57]. This has led to a more critical evaluation of the need for and timing of therapeutic interventions and reevaluation of the role of cautious observation in properly selected patients. The following approach to management of residual disease is based upon observational studies and clinical experience.

The recommended treatment approach for persistent/recurrent disease depends upon a variety of clinical factors, including:

●Whether or not the disease can be localized

●The volume of disease

●The precise location(s) of the metastatic disease

●Whether or not the disease is causing symptoms

●The rate (or likelihood) of clinically significant structural disease progression

●RET mutational status

Small volume, asymptomatic

●Biochemical evidence of disease without structural correlate – Patients with detectable calcitonin and/or abnormal CEA values without structurally identifiable disease are best followed with observation. The extent and frequency of cross-sectional imaging is dependent on the magnitude and doubling time of calcitonin and CEA (see 'Persistent hypercalcitoninemia' above). In the absence of structurally identifiable disease, we do not suggest additional surgery or systemic therapies.

In the absence of gross residual disease, we also do not recommend routine use of postoperative EBRT as adjuvant therapy, even if the postoperative calcitonin and CEA values are abnormal. We reserve adjuvant EBRT for very select patients with extensive preoperative gross extrathyroidal extension or large-volume, multicompartment macroscopic lymph node involvement [1].

The lack of randomized trials makes it difficult to provide definitive recommendations with regard to the use of EBRT as adjuvant therapy. We feel that EBRT in this setting may improve locoregional control but are not convinced that there is an overall survival benefit [58]. Furthermore, the potential benefits of improved locoregional control must be weighed against the wide range of acute and chronic toxicities associated with EBRT.

In a retrospective study of 51 patients with persistently elevated calcitonin (ranging from 540 to 400,000 pg/mL) and no evidence of residual disease, the local relapse rate was significantly lower in those who were treated with radiation therapy because of advanced local disease at presentation (29 versus 59 percent) [59]. There was no difference in 10-year survival between the two groups (72 versus 60 percent).

●Small-volume residual disease outside of cervical lymph nodes (thyroid bed or soft tissue metastases) – Small-volume disease outside of cervical lymph nodes is usually the result of gross extrathyroidal extension into major structures in the neck, and it often reflects microscopic disease remaining after all macroscopic disease has been surgically resected (R1 resection). Usually, this is microscopic disease involving muscle, airway, esophagus, soft tissues in the neck, or thyroid bed. As these patients are at high risk of locoregional recurrence, we suggest EBRT as adjuvant therapy in this setting.

Structurally identifiable small-volume disease can also be a manifestation of an early soft tissue recurrence of MTC, in which case the initial treatment option would be surgical resection, usually followed by EBRT (or occasionally EBRT alone if surgery is unlikely to be successful or likely to result in unacceptable morbidity).

Retrospective analyses have suggested that radiotherapy may prolong the interval until disease progression or recurrence in some patients. In one retrospective series, as an example, the 10-year rate of control of local and regional disease was 86 percent in patients with residual microscopic neck disease who received postoperative radiotherapy versus 52 percent in those who were not treated [58].

●Small-volume lymph node metastases – For most MTC patients with persistent, asymptomatic small-volume locoregional disease (subcentimeter lymph node metastases), we suggest active surveillance as the best management option. Reoperation is frequently not curative and can be associated with morbidity (ie, hypoparathyroidism, injury to recurrent laryngeal nerve or accessory nerve). In addition, observation of asymptomatic, stable lymph node metastases is nearly always recommended if the basal serum calcitonin is >1000 pg/mL or if more than five metastatic lymph nodes were removed with a previous surgery as reoperation is almost never curative in these settings [1]. Patients are followed with serial cross-sectional imaging at 6- to 12-month intervals, and surgical intervention is reserved for patients that have documented structural disease progression.

●Small-volume distant metastases – Similar to asymptomatic small-volume lymph node metastases, small-volume distant metastases (subcentimeter metastatic foci) are usually followed with observation. It is not uncommon for small pulmonary and liver metastases to remain asymptomatic and progress very slowly (or not all) over many years.

Large volume or symptomatic

●Macroscopic gross residual disease in the thyroid bed or cervical soft tissue metastases – If the gross residual disease is confirmed to be unresectable or if the patient/treatment team agree that a complete surgical resection would produce unacceptable morbidity, we suggest EBRT to improve locoregional control. While systemic therapy (such as multitargeted kinase inhibitors or selective RET inhibitors in RET-mutated tumors) can be considered in this setting, our preference is to use EBRT to achieve local regional control as the initial treatment unless there are other pressing indications to begin systemic therapy [60].

●Symptomatic or large-volume locoregional lymph node disease – Resection of large-volume locoregional lymph node disease may be necessary to prevent invasion into surrounding major structures. Occasionally, lymph node metastases can present as painful lesions that can be readily palliated with surgical resection. However, since additional surgery rarely achieves a biochemical cure if the basal serum calcitonin is >1000 pg/mL or if more than five metastatic lymph nodes were removed with a previous surgery, cautious observation or systemic therapies (tyrosine kinase inhibitors) can be considered for asymptomatic large-volume lymph node metastases detected in this setting.

●Symptomatic or large-volume distant metastasis – Rather than immediately initiating systemic therapy, we prefer to treat individual (or a few) isolated symptomatic or large-volume distant metastases with locally directed therapies such as surgical resection, EBRT, embolization, or radiofrequency ablation. For patients with symptomatic or progressive metastatic disease that cannot be effectively treated by locally directed therapies, systemic treatment with biologic response modifiers (ie, multitargeted kinase inhibitors or selective RET inhibitors in RET-mutated tumors) may improve progression-free survival. Molecular characterization of the primary tumor or metastatic foci is recommended prior to initiating systemic therapy in order to identify patients with sporadic MTC that may harbor a somatic RET mutation, which would likely respond to specific RET inhibitors. Kinase inhibitors are reviewed in more detail separately. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

Locally directed therapies are recommended in the following clinical settings:

•Large-volume solitary metastatic lesions in the lung, liver, or brain should be considered for surgical resection. Radiofrequency ablation may be an option for smaller peripheral lung metastases.

•Oligometastatic lesions in the bone can be treated with surgical resection, EBRT, embolization, and/or antiresorptive agents (eg, bisphosphonates, denosumab). EBRT is often utilized to palliate painful bone metastases or decrease the risk of fracture from progressive growth of a bone metastasis. (See "Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors", section on 'General approach to the patient'.)

•Multiple liver metastases may be amenable to localized therapies such as transarterial chemoembolization or, less commonly, percutaneous ethanol ablation or radiofrequency ablation.

•Skin metastases are usually treated with surgical resection or, less commonly, with EBRT.

Palliation of the symptoms associated with hormonal excess — Diarrhea and ectopic Cushing syndrome, the most common hormonal excess syndromes, are usually seen in the setting of large-volume persistent/recurrent disease.

●Diarrhea – Usually associated with large-volume liver metastases, the diarrhea associated with MTC can have a major impact on quality of life. Dietary measures such as avoiding alcohol intake and maintaining a diet that limits high-fiber foods can be augmented with antimotility agents (loperamide, diphenoxylate/atropine, or codeine) as first-line therapy. Somatostatin analogs may provide modest symptomatic improvement in some patients. In selected patients, debulking of large tumor deposits with surgery or chemoembolization may improve diarrhea.

●Ectopic Cushing syndrome – We prefer vandetanib (prior to medical or surgical adrenalectomy) as first-line therapy for ectopic Cushing syndrome, based on reports of a very rapid decline in serum cortisol levels in several patients [61,62]. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Vandetanib'.)

Because Cushing syndrome is associated with severe and debilitating side effects, treatment should be strongly considered even in the setting of large-volume persistent/recurrent disease. In our experience, medical therapy (ketoconazole, metyrapone, mitotane, mifepristone) is generally suboptimally effective and poorly tolerated. Tumor debulking is unlikely to be effective as these patients usually have multiple sites of large-volume disease. Conversely, we find that bilateral adrenalectomy is well tolerated and effective but challenging, given the comorbidities associated with large-volume MTC and hypercortisolism. (See "Overview of the treatment of Cushing syndrome", section on 'Nonresectable tumors'.)

PROGNOSIS — Age and stage of disease at the time of diagnosis have been shown to be important factors that influences prognosis [1,6]; the 5- and 10-year disease-free survival rates are higher among patients 40 years old or less as compared with patients over age 40 years (95 versus 65 percent and 75 versus 50 percent, respectively) [6,63]. However, another study found no effect of age if survival was compared with the expected mortality rates in the general population [64]. The 10-year survival rates for patients with stages I, II, III, and IV medullary thyroid cancer (MTC) are 100, 93, 71, and 21 percent, respectively [1,11].

A nomogram that integrates age, sex, postoperative calcitonin, vascular invasion, and TNM (tumor, node, metastasis) status has been developed that can be used to easily predict cause-specific mortality [65]. Furthermore, using an approach previously validated in non-MTC [66], a response to the therapy stratification system was shown to have a higher proportion of variance explained for predicting clinical outcomes than the TNM/American Joint Committee on Cancer (AJCC) system [10,13].

Calcitonin and carcinoembryonic antigen (CEA) doubling times provide sensitive markers for progression and aggressiveness of metastatic MTC. Calcitonin doubling times less than 6 to 12 months are associated with poor survival, while doubling times >24 months are associated with a very favorable prognosis [40,41]. Furthermore, a tumor volume doubling time of ≤1 year in pulmonary metastases is associated with poorer overall survival [67].

Controlling for the effect of age, the prognosis of patients with inherited disease is probably similar to those with sporadic disease [68,69]. Specific germline mutations in RET predict the aggressiveness of the tumor [1]. As an example, patients with multiple endocrine neoplasia type 2B (MEN2B; germline RET mutation codon 918) are more likely to have invasive disease and therefore a worse prognosis than those with either classical multiple endocrine neoplasia type 2A (MEN2A) or familial MTC [68]. In some [22-24], but not other [25], studies, tumors with an identifiable RET mutation (ie, a somatic mutation) had a more aggressive course than those without a mutation.

Other factors that may predict a poor prognosis include cellular heterogeneity, paucity of tumor immunostaining for calcitonin [70], prominent tissue immunostaining for galectin-3 [71] or immunostaining for CEA associated with scant or absent tissue staining for calcitonin [72], high preoperative serum CEA [73], a less than 10-fold increase in preoperative calcitonin levels after stimulation with pentagastrin [74], an elevated procalcitonin-to-calcitonin ratio [75], and a rising CEA level associated with a stable or declining calcitonin level.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Medullary thyroid cancer".)

SUMMARY AND RECOMMENDATIONS

●Preoperative evaluation – For patients with newly diagnosed medullary thyroid cancer (MTC), preoperative evaluation should include measurement of serum calcitonin, carcinoembryonic antigen (CEA), ultrasonography of the neck (if not already performed), genetic testing for germline RET mutations (can be performed pre- or postoperatively), and, in all patients who have either unknown RET mutation status or a germline RET mutation, biochemical evaluation for coexisting tumors (especially pheochromocytoma) (algorithm 1).

For patients with local lymph node metastases on ultrasound or with preoperative serum basal calcitonin >500 pg/mL (indicating high risk of local or distant metastatic disease), additional imaging is required to assess for metastatic disease. (See 'Preoperative evaluation' above and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Evaluation'.)

●Surgical approach – For patients with sporadic MTC, we recommend total thyroidectomy rather than lobectomy for initial therapy (Grade 1B). Owing to the multicentric and bilateral nature of hereditary MTC (and its precursor C cell hyperplasia), total thyroidectomy is the only way to cure hereditary MTC. (See 'Surgical approach' above and "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Medullary thyroid cancer'.)

For patients with MTC confined to the neck and no evidence of involved cervical lymph nodes on preoperative ultrasound, we routinely perform bilateral dissection of the central lymph node compartment without prophylactic lateral neck dissection. For patients with evidence of central cervical lymph node involvement, dissection of the involved lateral neck compartment is also performed.

For patients with locally advanced or metastatic disease, total thyroidectomy with resection of involved lymph node compartments is performed in most patients. However, since the goals of surgery are largely palliative in this setting, a less aggressive approach to both the primary tumor and to locoregional metastases may be warranted.

●Postoperative levothyroxine replacement – Thyroxine (levothyroxine, T4) therapy should be started immediately after surgery. The goal of T4 therapy is to restore and maintain euthyroidism. Suppression of serum thyroid-stimulating hormone (TSH) concentrations is not indicated in patients with MTC, because C cells are not TSH responsive. Similarly, adjuvant therapy with radioiodine is not indicated, because the tumor cells do not concentrate iodine. (See 'Thyroxine therapy' above.)

●Postoperative assessment – Serum calcitonin and CEA should be measured two to three months after surgery to detect the presence of residual disease. (See 'Serum calcitonin and CEA measurement' above.)

•Calcitonin undetectable – For patients with undetectable postoperative calcitonin levels, we measure serum calcitonin and CEA levels twice yearly for two years and then yearly if values are stable. We typically obtain a neck ultrasound 6 to 12 months postoperatively to establish a baseline. Serial ultrasound evaluations are not required in patients with undetectable postoperative calcitonin levels. (See 'Undetectable calcitonin and normal CEA' above.)

•Calcitonin persistently elevated – For patients with persistent hypercalcitoninemia, further evaluation depends upon the magnitude of the elevation in the serum calcitonin concentration and the calcitonin and CEA doubling times (algorithm 2). (See 'Persistent hypercalcitoninemia' above.)

-Calcitonin <150 pg/mL – Patients with postoperative calcitonin levels that are detectable but less than 150 pg/mL (two to six months after surgery) should have neck imaging (ultrasound with or without computed tomography [CT] or magnetic resonance imaging [MRI]) to identify persistent locoregional disease.

-Calcitonin ≥150 pg/mL – Patients with postoperative calcitonin levels that are ≥150 pg/mL (two to six months after surgery) should undergo additional imaging (CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases) to identify possible distant metastases.

●Management of persistent or recurrent disease – Treatment options for patients with recurrent/residual disease include observation/active surveillance, surgical resection, external beam radiation therapy (EBRT), and other directed therapies (such as radiofrequency ablation, cryoablation, embolization) or systemic therapies. Choice of therapy depends upon clinical factors, RET mutational status, and the potential morbidities of therapy. (See 'Management of persistent/recurrent disease' above.)