Version May 2024
INTRODUCTION — Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland. MTC accounts for approximately 1 to 2 percent of thyroid cancers in the United States [1]. The production of calcitonin is a characteristic feature of this tumor.
Most medullary thyroid carcinomas are sporadic. However, approximately 25 percent are familial as part of the multiple endocrine neoplasia type 2 (MEN2) syndrome. The clinical manifestations, diagnosis, evaluation, and clinical staging of MTC will be covered in this topic review. Treatment of this disorder is discussed separately. MEN2 is reviewed in detail elsewhere.
●(See "Medullary thyroid cancer: Surgical treatment and prognosis".)
●(See "Classification and genetics of multiple endocrine neoplasia type 2".)
●(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)
●(See "Approach to therapy in multiple endocrine neoplasia type 2".)
CLINICAL PRESENTATION
Sporadic MTC — Sporadic medullary thyroid cancer (MTC) accounts for approximately 75 percent of all cases of the disease (table 1). The typical age of presentation is in the fourth and sixth decades of life [1].
●Symptoms and signs – The most common presentation of sporadic MTC is that of a solitary thyroid nodule, which occurs in 75 to 95 percent of patients [2-5]. The C cells are predominantly located in the upper portion of each thyroid lobe; thus, most tumors are located in this region. In most patients with MTC, the disease has already metastasized at the time of diagnosis. Approximately 70 percent of patients have clinically detectable cervical lymph node involvement, up to 15 percent have symptoms of upper aerodigestive tract compression or invasion such as dysphagia or hoarseness, and approximately 5 to 10 percent have distant metastatic disease [1,6]. Distant metastases may occur in the liver, lung, bones, and, less often, brain and skin. Nodal metastases are more common in patients with multifocal disease [7]. However, as calcitonin screening results in the identification of more "micro" medullary cancers, the number of patients with metastases at presentation appears to be decreasing [8-10]. Calcitonin screening for MTC in patients with thyroid nodules is controversial. (See 'Diagnosis' below and "Diagnostic approach to and treatment of thyroid nodules", section on 'Serum calcitonin concentration'.)
Systemic symptoms may occur due to hormonal secretion by the tumor. Tumor secretion of calcitonin, calcitonin gene-related peptide, or other substances can cause diarrhea or facial flushing in patients with advanced disease. In addition, occasional tumors secrete corticotropin (ACTH), causing ectopic Cushing syndrome.
●Biochemical tests – Basal serum calcitonin concentrations usually correlate with tumor mass but also reflect tumor differentiation, and they are almost always high in patients with a palpable tumor [6]. Most MTCs also secrete carcinoembryonic antigen (CEA), which, like calcitonin, can be used as a tumor marker [11,12]. In addition, the expression of CEA on MTC cells has led to the use of anti-CEA antibodies for immunotherapy. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Immunotherapy'.)
Thyroid function tests are normal in patients with MTC.
●Imaging – There are several ultrasound features of thyroid nodules (eg, hypoechoic, microcalcifications) that are associated with thyroid cancer risk. However, there are no ultrasound features that are pathognomonic for thyroid cancer. Furthermore, the majority of studies evaluating suspicious ultrasound characteristics of nodules focused on papillary thyroid cancer (see "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Criteria for identifying cancer'). In a small retrospective study examining the ultrasound characteristic of nodules that were histologically proven to be MTC and papillary thyroid cancer, 50 percent of MTCs were solid and hypoechoic and 16 percent showed microcalcifications, compared with 69.2 and 69.2 percent, respectively, for papillary thyroid cancers [13]. The presence of at least one suspicious ultrasound feature was almost equal in patients with MTC (58.3 percent) and controls with benign nodules (55.5 percent), whereas it was significantly more frequent in patients with papillary thyroid cancer (100 percent). In other series, hypoechogenicity was present in 50 to 89 percent and microcalcifications in 30 to 70 percent [14-16], and there was no difference in echogenicity or the presence or type of calcifications between MTC and papillary thyroid cancer [15,16]. Large areas of calcification (macrocalcification) were noted in 16 to 30 percent [13,15,16].
Rarely, the diagnosis of MTC is suggested by the presence of dense calcifications seen on radiographs or imaging of the anterior neck.
Inherited MTC — Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes (MEN2A and MEN2B) (table 2), each of which is transmitted in an autosomal dominant fashion and is associated with MTC. These syndromes result from different mutations in the RET proto-oncogene. In the past, familial MTC (FMTC, an inherited syndrome characterized by the presence of only MTC without hyperparathyroidism or pheochromocytoma) was considered a separate entity but is now considered a variant of MEN2A [1]. Hereditary MTC is typically bilateral and multicentric (see "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2"):
●Classical MEN2A is associated with MTC, pheochromocytoma, and primary parathyroid hyperplasia. While the penetrance of MTC is nearly 100 percent, there is inter- and intrafamily variability in the specific pattern of the other disease manifestations.
●MEN2B shares the inherited predisposition to MTC and pheochromocytoma present in classical MEN2A, but does not include hyperparathyroidism. MTC occurs in almost all patients. The tumor develops at an earlier age and may be more aggressive than in MEN2A. Patients typically have a marfanoid habitus (but do not have Marfan syndrome), mucosal neuromas, and intestinal ganglioneuromatosis.
In the index case, the clinical presentation and manifestations of MEN2-associated MTC are similar to those of sporadic MTC. The most common presentation is that of a solitary thyroid nodule or cervical lymphadenopathy. Early diagnosis (prior to any clinical manifestations) by screening of "at-risk" family members in MEN2 kindreds is important because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy. (See "Classification and genetics of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Screening of family members in MEN2 kindreds' and "Approach to therapy in multiple endocrine neoplasia type 2".)
DIAGNOSIS — The diagnosis of medullary thyroid cancer (MTC) is usually made after fine-needle aspiration (FNA) biopsy in a patient who has a solitary thyroid nodule (or a dominant nodule within a multinodular goiter) (picture 1). The sensitivity of FNA is 50 to 80 percent, although higher sensitivity can be obtained by the addition of immunocytochemical staining for calcitonin [17,18]. Occasionally, the diagnosis of MTC is made through molecular testing of cytologically indeterminate nodules, as many of the molecular assays include markers for MTC [19]. If the clinical suspicion for MTC is high (eg, patient with diarrhea, flushing, and a thyroid nodule), calcitonin can be measured in the washout of the FNA biopsy needle [20], although this may not be readily available in many commercial laboratories.
In some cases, the diagnosis of MTC is made after thyroid lobectomy for a suspicious or indeterminate FNA biopsy. Surgical specimens from patients with MTC show spindle-shaped and frequently pleomorphic cells without follicle development because these cells originate from the calcitonin-producing parafollicular C cells of the thyroid (picture 2).
The use of serum calcitonin screening to complement ultrasound and FNA in the routine diagnosis of thyroid nodules is controversial in the United States [21]. Measurement of serum calcitonin has not been a part of the routine evaluation of patients with thyroid nodules in the United States. The high frequency of falsely high serum calcitonin values, the inability to confirm the high calcitonin by pentagastrin stimulation in the United States, and the accuracy of FNA biopsy would argue against a change in this recommendation. Further, occasional patients with locoregional metastases or locally invasive MTC will have normal unstimulated serum calcitonin concentrations [2]. In some countries (eg, European countries) where pentagastrin is available, however, serum basal and stimulated calcitonin levels are routinely used in the evaluation of thyroid nodules to facilitate the preoperative diagnosis of MTC. This topic is discussed in detail separately. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Serum calcitonin concentration'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis in a patient presenting with a neck mass is extensive and varies with the age of the patient at presentation. The majority of these masses represent benign thyroid nodules and cysts (see "Diagnostic approach to and treatment of thyroid nodules"). Neck masses that are not of thyroidal origin may be from congenital (ie, vascular anomaly), inflammatory (lymph node enlargement), or other neoplastic (primary or metastatic disease) disorders. The differential diagnosis of a neck mass is reviewed separately. (See "Differential diagnosis of a neck mass".)
In addition to medullary thyroid cancer (MTC), elevated calcitonin results may also be seen in patients with hypercalcemia, hypergastrinemia, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, goiter, and chronic autoimmune thyroiditis [22,23]. Furthermore, prolonged treatment with omeprazole (greater than two to four months), beta blockers, and glucocorticoids has been associated with hypercalcitoninemia [24]. In addition, the presence of heterophilic antibodies to calcitonin can falsely elevate serum calcitonin levels [25].
Elevated carcinoembryonic antigen (CEA) levels can also occur in patients with heterophilic antibodies, gastrointestinal tract inflammatory disease, benign lung disease, and nonthyroid malignancies [1]. Cigarette smoking may also elevate CEA.
EVALUATION — For patients diagnosed with medullary thyroid cancer (MTC) on the basis of cytologic evaluation of a thyroid nodule, evaluation should include measurement of serum calcitonin, carcinoembryonic antigen (CEA), ultrasonography of the neck (if not already performed), genetic testing for germline RET mutations, and biochemical evaluation for coexisting tumors, especially pheochromocytoma. Our approach outlined below is largely consistent with National Comprehensive Cancer Network (NCCN) and American Thyroid Association (ATA) Guidelines for Management of Medullary Thyroid Cancer (algorithm 1) [1,26].
Serum calcitonin and CEA — The serum calcitonin and carcinoembryonic antigen (CEA) concentrations should be measured in patients diagnosed with MTC on the basis of cytologic evaluation of a thyroid nodule. These tests can establish that the tumor is capable of hypersecreting the hormones and, if so, the values can be compared with postoperative values. Postoperatively, results may provide a prognostic factor or indicate biochemical cure [27].
In a study of 226 patients with MTC (50 percent sporadic MTC, 33 percent multiple endocrine neoplasia [MEN] type 2A [MEN2A], 1 percent MEN type 2B [MEN2B], and 16 percent familial MTC [FMTC]), preoperative serum calcitonin concentrations were significantly correlated with tumor size in both the sporadic and familial cases [28]. In addition, among 45 patients who had a preoperative serum calcitonin concentration of 50 pg/mL or less, 44 had normal concentrations after surgery. In contrast, only 50 of 120 patients with preoperative serum calcitonin concentrations higher than 50 pg/mL had normal concentrations after surgery. In a second study of 224 patients with MTC, 28 of 45 patients (62 percent) without nodal metastases had normal calcitonin postoperatively, while only 18 of 177 (10 percent) of node positive patients had normal postoperative calcitonin levels [29].
Assessment of calcitonin and CEA doubling times postoperatively provides sensitive markers for progression and aggressiveness of metastatic MTC [30,31]. As an example, postoperative calcitonin doubling time was a prognostic factor for survival in a study of 65 patients followed for 3 to 30 years [30]. Ten-year survival was 8, 37, and 100 percent for doubling times under six months, between six months and two years, and greater than two years, respectively.
Radiologic evaluation — MTC can spread by local invasion or metastasis within the neck or distantly [4,6]. When MTC is diagnosed by fine-needle aspiration (FNA) biopsy, ultrasonography of the neck is indicated to look for cervical lymph node involvement.
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 [32]. In this setting, we suggest cross-sectional imaging including chest computed tomography (CT), neck CT, three-phase contrast-enhanced liver CT or contrast-enhanced liver magnetic resonance imaging (MRI), axial MRI, and bone scintigraphy.
In patients suspected of having skeletal metastases, MRI may be superior to other imaging modalities [33].
We do not recommend 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) imaging or somatostatin receptor imaging for routine initial screening for metastatic disease. The sensitivity of FDG-PET scanning for detecting metastatic disease is variable [34,35] but improves with higher calcitonin levels (sensitivity 78 versus 20 percent for basal calcitonin value greater than or less than 1000 pg/mL, respectively) [36]. However, positron emission tomography (PET) scanning with alternative tracers (eg, 18F-dihydroxyphenylalanine [18F-DOPA]) is showing promising results for the detection of recurrent/persistent disease in patients with elevated calcitonin levels and for the selection of patients who may benefit from peptide receptor radionuclide therapy targeting somatostatin receptors, utilizing 68Ga-DOTA peptides (eg, [68Ga]Ga-DOTANOC, [68Ga]Ga-DOTATOC, [68Ga]Ga-DOTATATE) [37-40]. The use of radionuclide imaging with 111-In-octreotide or 99m-Tc-DMSA [41,42] is not recommended for routine initial screening for metastatic disease [43].
Genetic screening in sporadic MTC — We suggest germline RET testing in all patients with newly diagnosed C cell hyperplasia or apparently sporadic MTC. Initial germline testing in patients with C cell hyperplasia or apparently sporadic MTC should include sequencing of exons 10, 11, and 13 through 16 of the RET gene. Sequencing of the remaining exons in the RET gene should be considered in patients with clinical features or family history highly suggestive of hereditary medullary syndromes who demonstrate no mutations in exons 10, 11, or 13 through 16 [44]. While it is possible for clinicians to directly order genetic testing from reference laboratories, we strongly encourage consultation with genetic counselors who are familiar with both the ethical issues and legal informed consent requirements (which can vary significantly in different regions) that are involved in germline testing [1].
When the index patient is positive for a germline mutation, family members should be offered genetic counseling and genetic screening. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Screening of family members in MEN2 kindreds'.)
An important question is what proportion of patients with apparently sporadic MTC have unsuspected germline mutations in the RET proto-oncogene (the underlying defect in MEN2) and, therefore, have heritable disease. Studies of unselected patients with MTC have found, on average, that approximately 6 to 7 percent (range 1.5 to 24 percent) have germline RET mutations [45-49]. In one report, 35 of 482 patients (7.3 percent) with apparently sporadic MTC had mutations, and in 18 of these 35, gene carriers were identified in relatives [49]. Seventy-five percent of the familial medullary cases had no prior family history.
A much higher percentage (approximately 60 percent) of patients with sporadic MTC have somatic (acquired) mutations in the RET gene within the tumor cells (table 1) [50-53]. These mutations are present only in the tumor cells and are not detected by standard genetic testing, ie, using leukocyte DNA. The presence of somatic RET mutations correlate with lymph node metastases, persistent disease, and lower survival [54]. However, in one study, only mutations in exons 15 and 16 of the RET gene were associated with the worse prognosis, while those in other exons had a more indolent course [52]. Since it is unclear how knowledge of a specific somatic (acquired) RET mutation should impact initial clinical management and follow-up, we do not routinely evaluate primary tumor samples for RET mutational status. However, in patients with symptomatic or structurally progressive disease being considered for a systemic therapy (multitargeted kinase inhibitors or selective RET inhibitors in RET-mutated tumors), we routinely perform somatic mutational profiling of tumor tissue.
Testing for coexisting tumors — Most patients require biochemical evaluation for coexisting tumors (particularly pheochromocytoma and hyperparathyroidism) prior to thyroidectomy. Even when genetic screening is performed preoperatively, the results are rarely known prior to surgery.
For patients with unknown RET mutational status and for patients who have a germline RET mutation, we measure:
●Serum calcium (to rule out hyperparathyroidism requiring concomitant surgical intervention).
●Plasma fractionated metanephrines (as the initial screen for pheochromocytoma).
Normal plasma fractionated metanephrines values exclude a symptomatic catecholamine-secreting neoplasm, but mildly elevated values of normetanephrine could be falsely positive, in which case additional evaluations including 24-hour urinary fractionated metanephrines, catecholamines, and adrenal imaging may be required to effectively rule in or rule out pheochromocytoma prior to surgery. Adrenal imaging should not be performed unless there is biochemical evidence suggesting a possible pheochromocytoma. (See "Clinical presentation and diagnosis of pheochromocytoma".)
In a patient with negative RET proto-oncogene testing and no family history of MEN2 syndrome, biochemical testing for coexisting tumors is typically not required.
STAGING
TNM staging — The pathological tumor, node, metastasis (pTNM) criteria for clinicopathologic tumor staging (eighth edition) adopted by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) are based upon tumor size and the presence or absence of extrathyroidal invasion, local and regional nodal metastases, and distant metastases (table 3) [55]:
●Stage I – Medullary thyroid cancers (MTCs) that are less than 2 cm in diameter without evidence of disease outside of the thyroid gland
●Stage II – Tumors >2 cm confined to the thyroid or tumors of any size without lymph node metastasis that demonstrate gross extrathyroidal extension invading only the strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles)
●Stage III – Tumors of any size demonstrating metastatic lymph node involvement in the central neck (levels VI or VII; pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal lymph nodes) with or without gross invasion into the strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles)
●Stage IV – Any distant metastases, or lymph node involvement outside of the central neck (level VI/VII), or gross invasion into other structures of the neck (beyond just strap muscle involvement)
One study evaluated the prognostic significance of a previous TNM staging scheme in patients with MTC, most of whom were treated by total thyroidectomy and then followed for a median of four years [3]. Although the follow-up was short, mortality due to MTC was 0 percent in patients with stage I disease, 13 percent in stage II, 56 percent in stage III, and 100 percent in stage IV [3]. A subsequent analysis of MTC patients using the National Cancer Database and the SEER (Surveillance, Epidemiology, and End Results) data set demonstrated that the seventh and eighth editions of the AJCC staging system were associated with five-year overall survival rates of 95 percent in stage I, 91 percent in stage II, 89 percent in stage III, and 68 percent in stage IV. Furthermore, disease-specific survival rates were 100 percent in stage I, 99 percent in stage II, 97 percent in stage III, and 82 percent in stage IV [56].
Dynamic risk stratification — Using the same concepts that were initially developed for differentiated thyroid cancer (see "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Dynamic risk stratification'), dynamic risk stratification for MTC allows clinicians to modify initial AJCC staging risk estimates over time based on the biological behavior the tumor and the response to therapy in individual patients [57,58]. For application in MTC, the definitions of the response to therapy categories needed to be modified to utilize calcitonin and carcinoembryonic antigen (CEA) as tumor markers (rather than thyroglobulin). At each follow-up visit, patients are classified as having one of the following clinical outcomes:
●Excellent response – An undetectable calcitonin and normal-range CEA in the absence of structurally identifiable disease
●Biochemical incomplete response – A detectable calcitonin or elevated CEA in the absence of structurally identifiable disease
●Structural incomplete response – The presence of recurrent or persistent structurally identifiable disease
In three retrospective studies examining MTC patients with a median of five to seven years of follow-up, an excellent response to therapy was associated with a structural disease recurrence rate of 1 to 4 percent and a biochemical recurrence rate of 11 to 15 percent, with a disease-specific mortality of <3 percent [59-61]. However, patients with a biochemical incomplete response demonstrated a disease-specific mortality of 11 percent with the vast majority demonstrating persistent biochemical evidence of disease (51 to 53 percent) or structural evidence of disease (32 to 37 percent). The poorest outcomes were seen in those patients with a structural incomplete response to initial therapy with disease-specific mortality rates of 38 to 56 percent.
As noted above, the calcitonin and CEA doubling times can also provide meaningful insights into prognosis and expected course of disease progression that can further refine these response to therapy assessments [30,31]. (See 'Serum calcitonin and CEA' above.)
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
●Clinical presentation – Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland; it accounts for approximately 1 to 2 percent of thyroid carcinomas. The production of calcitonin is a characteristic feature of this tumor. Most cases are sporadic (table 1). (See 'Clinical presentation' above.)
A solitary thyroid nodule is the most common presentation of sporadic MTC (in 75 to 95 percent of patients). In most patients, the disease has already metastasized at the time of diagnosis. Basal serum calcitonin concentrations usually correlate with tumor mass but also reflect tumor differentiation, and they are almost always high in patients with a palpable tumor. (See 'Clinical presentation' above.)
●Diagnosis – The diagnosis of sporadic MTC is usually made after fine-needle aspiration (FNA) biopsy in a patient who has a solitary thyroid nodule (or a dominant nodule within a multinodular goiter) (picture 1). The sensitivity of FNA is improved by the addition of immunohistochemical staining for calcitonin. The routine use of serum calcitonin screening to complement FNA in the routine diagnosis of thyroid nodules is controversial in the United States. (See 'Diagnosis' above and "Diagnostic approach to and treatment of thyroid nodules", section on 'Serum calcitonin concentration'.)
●Evaluation – For patients diagnosed with MTC on the basis of cytologic evaluation of a thyroid nodule, evaluation includes biochemical, radiologic, and genetic testing (algorithm 1). (See 'Evaluation' above.)
•Serum calcitonin and CEA – Initial biochemical testing should include measurement of serum calcitonin and carcinoembryonic antigen (CEA). These tests can establish that the tumor is capable of hypersecreting the hormones and, if so, the values can be compared with postoperative values. Postoperatively, results may provide a prognostic factor or indicate biochemical cure. (See 'Serum calcitonin and CEA' above.)
•Radiologic evaluation – When MTC is diagnosed by fine-needle aspiration (FNA) biopsy, ultrasonography of the neck is indicated (if not already performed) to look for cervical lymph node involvement. 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 'Radiologic evaluation' above.)
•Genetic testing for germline RET mutations – Some patients with apparently sporadic MTC have unsuspected germline RET mutations (the underlying defect in multiple endocrine neoplasia type 2 [MEN2]) and, therefore, heritable disease. We suggest germline RET testing to all patients with newly diagnosed C cell hyperplasia or apparently sporadic MTC. (See 'Genetic screening in sporadic MTC' above.)
•Testing for coexisting tumors – Given the possibility that any patient with MTC may have MEN2, if results of germline RET testing are unknown (or positive), preoperative testing must also include measurement of serum calcium (to rule out hyperparathyroidism requiring concomitant surgical intervention) and testing for pheochromocytoma. We suggest plasma fractionated metanephrines as the initial screen for pheochromocytoma. (See 'Testing for coexisting tumors' above.)
●Staging – Initial staging is based upon tumor size and the presence or absence of extrathyroidal invasion, local and regional nodal metastases, and distant metastases (table 3). Dynamic risk stratification for MTC allows clinicians to modify initial staging risk estimates over time based on the biological behavior the tumor and the response to therapy in individual patients. (See 'Staging' above.)
●Management – The management of MTC is discussed in detail separately. MEN2 is also reviewed separately. (See "Medullary thyroid cancer: Surgical treatment and prognosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Classification and genetics of multiple endocrine neoplasia type 2" and "Approach to therapy in multiple endocrine neoplasia type 2".)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
