Last updated September 2, 2022

Management of Medullary Thyroid Carcinoma

Diagnosis

The current ATA risk categories for hereditary MTC should be changed. ( C )
  • The current level D category should be changed to a new category, “highest risk” (HST), that includes patients with MEN2B and the RETcodon M918T mutation.
  • The current level C category should be changed to a new category, “high risk” (H), that includes patients with MEN 2A and RETcodon C634 mutations.
  • The current level A and B categories should be combined into a new category “moderate risk” (MOD) that includes patients with hereditary MTC and RETcodon mutations other than M918T and C634.
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There should be two MEN2 syndromes: MEN2A and MEN2B. Within MEN2A, which accounts for 95% of MEN2 cases, there should be four variants: ( C )
  • Classical MEN2A (represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma (PHEO), or hyperparathyroidism HPTH, or both)
  • MEN2A with cutaneous lichen amyloidosis (CLA).
  • MEN2A with Hirschsprung's Disease (HD).
  • FMTC (families or individuals with RETgermline mutations who have MTC but neither PHEOs or HPTH).
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The recommended method of initial genetic testing for MEN2A is either a single or multi-tiered analysis to detect RET mutations in exon 10 (codons 609, 611, 618, and 620), exon 11 (codons 630 and 634), and exons 8, 13, 14, 15, and 16. ( B )
The most common RET mutations associated with MEN2A and MEN2B are shown in Table 2.
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Sequencing of the entire coding region should be reserved for situations where no RET mutation is identified, or there is a discrepancy between the MEN2 phenotype and the expected genotype. ( B )
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Patients with the MEN2B phenotype should be tested for the RET codon M918T mutation (exon 16), and if negative, the RET codon A883F mutation (exon 15). If there are no mutations identified in these two exons the entire RET coding region should be sequenced. ( B )
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Patients with presumed sporadic MTC should have genetic counseling and genetic testing to detect a RET germline mutation. ( B )
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Genetic counseling and genetic testing forRETgermline mutations should be offered to:
  1. first degree relatives of patients with proven hereditary MTC
  2. parents whose infants or young children have the classic phenotype of MEN2B
  3. patients with CLA
  4. infants or young children with HD and exon 10 RETgermline mutations
  5. adults with MEN2A and exon 10 mutations who have symptoms suggestive of HD.
( B )
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Other than for academic reasons or physician preference, it is not standard practice to analyze tumors of patients with sporadic MTC for somatic HRAS, KRAS or NRAS mutations or RETM918T mutations. ( C )
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In very rare families who meet the clinical criteria for MEN2A or 2B, despite negative sequencing of the entire RET coding region, the relatives at-risk should be periodically screened by conventional methods for MTC, PHEO, and HPTH. After the initial evaluation, screening should continue at 1-3 year intervals. ( C )
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Regarding hereditary MTC, the duty to warn a competent and capacitated patient or surrogate decision maker of the risk that an inherited RET mutation may pose to family members is standard of care. ( A )
  • This warning is ideally fulfilled in the setting of genetic counseling and should include a request for the patient to participate in identifying “at-risk” relatives. The “duty to warn” discussion should be a part of the informed consent process, where there is full disclosure of the seriousness of the disease and available forms of prevention and treatment. When a patient refuses to notify relatives or legal dependents of their risks, the physician should consider whether he has an ethical duty or obligation to warn family members at risk. He should consult a certified clinical ethicist either at his medical center, or another medical facility, or contact the American Thyroid Association Ethics Committee for guidance.
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In pediatric patients who have not reached the age of consent it may be necessary for physicians to seek state intervention to prevent harm when there is parental refusal to inform their children of the risk for developing a malignant tumor. Practitioners with pediatric populations should consult published documents for guidance. ( A )
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The duty to warn of genetic risk extends to both preconception and prenatal contexts. ( A )
  • Genetic counseling about the options of pre-implantation or prenatal diagnostic testing should be considered for all RET mutation carriers of childbearing age, particularly those with MEN2B. Parents who wish not to have prenatal RET mutation testing should be offered genetic counseling and informed of the availability of genetic testing of their child to detect a mutated RET allele. This is particularly important for mutations associated with the onset of MTC before 5 years of age.
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Clinicians should be aware that falsely high or low serum calcitonin (Ctn) levels might occur with a variety of clinical diseases other than MTC and consider this possibility when serum Ctn levels are disproportionate to the expected clinical findings. ( C )
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In interpreting serum Ctn data clinicians should be aware that Ctn levels are markedly elevated in children <3 years of age, especially <6 months of age. Also, Ctn levels are higher in males compared to females. ( B )
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Basal levels of serum Ctn and carcinoembryonic antigen (CEA) should be measured concurrently. In patients with advanced MTC a marked elevation in the serum CEA level out of proportion to a lower serum Ctn level, or normal or low levels of both serum Ctn and CEA, indicate poorly differentiated MTC. ( B )
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The assessment of a thyroid tumor with any feature suggestive of MTC should include immunohistochemical (IHC) analysis to determine the presence markers such as Ctn, chromogranin, and CEA, and the absence of thyroglobulin. ( B )
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Complete notation of the features of every MTC should follow the synoptic reporting guidelines of the College of American Pathologists Protocol for the Examination of Specimens from Patients with Carcinomas of the Thyroid Gland (www.cap.org). ( B )
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In patients with MTC morphological examination of the entire gland is recommended to determine the presence of C-Cell hyperplasia (CCH) or multifocal neoplasia. ( C )
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Thyroid nodules that are ≥1 cm in size should be evaluated by fine needle aspiration biopsy (FNA). FNA findings that are inconclusive or suggestive of MTC should have calcitonin measured in the FNA washout fluid and IHC staining of the FNA sample to detect the presence of markers such as Ctn, chromogranin, and CEA, and the absence of thyroglobulin. ( B )
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Realizing that opinions of experts vary regarding the usefulness of measuring serum Ctn levels in patients with nodular goiters, the Task Force recommends that physicians decide whether the technique is useful in the management of patients in their clinic. ( I )
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Patients presenting with a thyroid nodule on physical examination should have determination of serum levels of Ctn and CEA, and genetic testing for a RET germline mutation. The presence of a PHEO and HPTH should be excluded in patients with hereditary MTC.

Ultrasound (US) examination of the neck should be performed in all patients with MTC. Contrast enhanced CT of the neck and chest, three-phase contrast-enhanced multi-detector liver CT, or contrast-enhanced MRI of the liver, and axial MRI and bone scintigraphy are recommended in patients with extensive neck disease and signs or symptoms of regional or distant metastases. These studies should also be conducted in all patients with a serum Ctn level greater than 500 pg/mL. ( C )
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Neither FDG-PET/CT nor F-DOPA-PET/CT is recommended to detect the presence of distant metastases. ( E )
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Treatment

Patients with MTC and no evidence of neck lymph node metastases by US examination and no evidence of distant metastases should have a total thyroidectomy and dissection of the lymph nodes in the central compartment (level VI). ( B )
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In patients with MTC and no evidence of neck metastases on US, and no distant metastases, dissection of lymph nodes in the lateral compartments (levels II-V) may be considered based on serum Ctn levels. (I)
Note: The Task Force did not achieve consensus on this recommendation
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Patients with MTC confined to the neck and cervical lymph nodes should have a total thyroidectomy, dissection of the central lymph node compartment (level VI), and resection of the involved lateral neck compartments (level II-V). When preoperative imaging is positive in the ipsilateral lateral neck compartment but negative in the contralateral neck compartment, contralateral neck dissection should be considered if the basal calcitonin level is greater than 200 pg/mL. ( C )
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In the presence of extensive regional or metastatic disease, less aggressive surgery in the central and lateral neck may be appropriate to preserve speech, swallowing, parathyroid function, and shoulder mobility. External beam radiotherapy (EBRT), systemic medical therapy, and other nonsurgical therapies should be considered to achieve local tumor control. ( C )
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Following unilateral thyroidectomy for presumed sporadic MTC completion thyroidectomy is recommended in patients with a RET germline mutation, an elevated postoperative serum Ctn level, or imaging studies indicating residual MTC. ( B )
Note: The presence of an enlarged lymph node in association with a normal serum Ctn level is not an indication for repeat surgery.
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In patients having an inadequate lymph node dissection at the initial thyroidectomy a repeat operation, including compartment oriented lymph node dissection, should be considered if the preoperative basal serum Ctn level is <1,000 pg/mL and ≤5 metastatic lymph nodes were removed at the initial surgery. ( C )
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During a total thyroidectomy for MTC, normal parathyroid glands should be preserved in situ on a vascular pedicle. ()
Note: If all normal parathyroid glands are resected, or if none appears viable at the termination of the procedure, slivers of a parathyroid gland should be transplanted into the sternocleidomastoid muscle in patients with sporadic MTC, MEN2B, or MEN2A and a RET mutation rarely associated with HPTH. In patients with MEN2A and a RET mutation associated with a high incidence of HPTH the parathyroid tissue should be transplanted in a heterotopic muscle bed.
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Serum thyroid stimulating hormone (TSH) should be measured within 4-6 weeks postoperatively. Replacement therapy with levothyroxine should be administered with the goal of maintaining serum TSH levels in the euthyroid range. ( B )
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Serum calcium levels should be monitored postoperatively. Oral calcium and vitamin D should be administered to patients who develop symptomatic hypocalcemia. Chronic replacement therapy is indicated in patients who cannot be weaned from the initial medication. ( B )
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Experienced physicians and surgeons in tertiary care centers should be responsible for the management of children with MEN2A or MEN2B. ( B )
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Children in the ATA-HST category with a RET codon M918T mutation should have a thyroidectomy in the first year of life, perhaps even in the first months of life. In the absence of suspicious lymph nodes the performance of a central neck dissection should be based on whether the parathyroid glands can be identified and left in situ or autotransplanted. The surgeon and pediatrician caring for the patient, in consultation with the child’s parents, should decide the timing of thyroidectomy. ( C )
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Children in the ATA-H category should have a thyroidectomy performed at age 5 years or earlier, based on the detection of elevated serum Ctn levels. A central neck dissection should be performed in children with serum Ctn levels >40 pg/mL, or with evidence on imaging or direct observation of lymph node metastases. The surgeon and pediatrician caring for the patient, in consultation with the child’s parents, should decide the timing of thyroidectomy. ( B )
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Children in the ATA-MOD category should have a physical examination, US of the neck, and measurement of serum Ctn levels beginning around 5 years of age. The timing of thyroidectomy should be based on the detection of an elevated serum Ctn level. However, 6-month or annual evaluations may extend to several years or decades. ( B )
Note: Parents who are concerned about a long-term evaluation program, may opt to have their child’s thyroid gland removed around 5 years of age. The surgeon and pediatrician caring for the patient, in consultation with the child’s parents, should decide the timing of thyroidectomy.
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Screening for PHEO should begin by age 11 years for children in the ATA-H and ATA-HST categories and by age 16 years in children in the ATA-MOD category. Screening consists of measuring free plasma metanephrines and normetanephrines, or 24-hour urinary metanephrines and normetanephrines. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. ( C )
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Patients with MEN2A or MEN2B and a histological diagnosis of MTC regardless of age and presenting symptoms must have a PHEO excluded prior to any interventional procedure. The presence of a PHEO must be excluded in women with MEN2A or MEN2B who are planning a pregnancy or are pregnant. If a PHEO is detected it should be removed preferably during pregnancy. ( C )
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If they coexist, a PHEO should be removed prior to surgery for either MTC or HPTH. ( B )
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After appropriate preoperative preparation a PHEO should be resected by laparoscopic or retroperitoneoscopic adrenalectomy. ( B )

Note: Subtotal adrenalectomy to preserve adrenal cortical function should be considered as an alternative procedure.
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Patients with no adrenal glands require glucocorticoid and mineralocorticoid replacement therapy and should be carefully monitored to assure that their steroid levels are adequate. Patients should be educated regarding the risk of adrenal crisis and wear a bracelet or a necklace indicating that they have no adrenal glands and are on corticosteroid replacement therapy. Glucocorticoid supplementation will be required if they become severely ill or are injured ( B )
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Patients in the ATA-H and ATA-MOD categories should be screened for HPTH at the time of screening for PHEO (by age 11 years in patients in the ATA-H category and by age 16 years in patients in the ATA-MOD category). ( C )
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In patients with HPTH, only the visibly enlarged parathyroid glands should be resected. ( C )
Note: If all four glands are enlarged, surgical options include subtotal parathyroidectomy with a piece of one gland left in situ on a vascular pedicle, or total parathyroidectomy with a heterotopic autograft.
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Patients who develop HPTH subsequent to thyroidectomy for MTC should have localization studies performed prior to repeat neck surgery. At reoperation all enlarged parathyroid glands should be removed, and parathyroids of normal size should be left in situ. If only one enlarged parathyroid gland is identified, and there is histological documentation that three parathyroid glands have been removed previously, a portion of the enlarged gland should either be left in situ with an adequate blood supply, or grafted to a heterotopic site. ( C )
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Clinicians should consider the American Joint Committee on Cancer TNM classification (Table 3A&B), the number of lymph node metastases, and postoperative serum Ctn levels in predicting outcome and planning long-term follow-up of patients treated by thyroidectomy for MTC. ( C )
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Serum levels of Ctn and CEA should be measured 3 months postoperatively, and if undetectable or within the normal range they should be measured every six months for 1 year and then yearly thereafter. ( C )
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Patients with elevated postoperative serum Ctn levels <150 pg/mL should have a physical examination and US of the neck. If these studies are negative the patients should be followed with physical examinations, measurement of serum levels of Ctn and CEA, and US every 6 months. ( C )
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If the postoperative serum Ctn level exceeds 150 pg/mL, patients should be evaluated by imaging procedures including neck US, chest CT, contrast-enhanced MRI or three-phase contrast-enhanced CT of the liver, bone scintigraphy, and MRI of the pelvis and axial skeleton. ( C )
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In patients with detectable serum levels of Ctn and CEA following thyroidectomy, the levels of the markers should be measured at least every six months to determine their doubling times ( B )
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Surgical resection of persistent or recurrent loco-regional MTC in patients without distant metastases should include compartmental dissection of image-positive or biopsy-positive disease in the central (level VI) or lateral (levels II-V) neck compartments. Limited operative procedures, such as resection of only grossly metastatic lymph nodes, should be avoided unless there has been prior extensive surgery in a compartment. ( C )
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Postoperative radioactive iodine (RAI) is not indicated following thyroidectomy for MTC. However, it should be considered in patients whose primary tumor and lymph node metastases contain MTC mixed with either PTC or follicular thyroid carcinoma. ( E )
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Postoperative adjuvant EBRT to the neck and mediastinum should be considered in patients at high risk for local recurrence (microscopic or macroscopic residual MTC, extrathyroidal extension, or extensive lymph node metastases), and those at risk of airway obstruction. The potential benefits must be weighed against the acute and chronic toxicity associated with the therapy. ( C )
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Systemic therapy should not be administered to patients who demonstrate increasing serum Ctn and CEA levels but have no documented metastatic disease. Nor should systemic therapy be administer to patients with stable low volume metastatic disease, as determined by imaging studies, serum Ctn, and CEA doubling times>2 years. ( C )
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In patients with persistent or recurrent MTC following thyroidectomy one should consider laparoscopic or open evaluation and biopsy of the liver to exclude occult metastases before subjecting them to a long and arduous repeat neck operation. ( C )
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Brain imaging should be performed in patients with metastatic MTC and neurologic symptoms, including patients who are candidates for systemic therapy. Patients with isolated brain metastases are candidates for surgical resection or EBRT (including stereotactic radiosurgery). Whole brain EBRT is indicated for multiple brain metastasis. ( C )
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Patients with spinal cord compression require urgent treatment with glucocorticoid therapy and surgical decompression. If patients are not candidates for surgery, EBRT alone should be administered. ( C )
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Patients with MTC who have fractures or impending fractures require treatment. Therapeutic options include surgery, thermoablation (radiofrequency or cryotherapy), cement injection, and EBRT. ( C )
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Treatment with denosumab or bisphosphonates is recommended for patients with painful osseous metastases. ( C )
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Surgical resection should be considered in patients with large solitary lung metastases. Radiofrequency ablation should be considered when the metastases are peripheral and small. Systemic therapy should be considered in patients with multiple metastases that are progressively increasing in size. ( C )
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Surgical resection should be considered in patients with large isolated hepatic metastases. Chemoembolization should be considered in patients with disseminated tumors <30 mm in size involving less than a third of the liver. ( C )
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If possible cutaneous metastases should be excised surgically. Multiple cutaneous lesions are best treated by EBRT or ethanol injection. ( C )
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Palliative therapy, including surgery, EBRT, or systemic therapy, should be considered in patients with metastases causing pain, mechanical compression, or signs and symptoms of hormonal excess. ( C )
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The use of single agent or combinatorial cytotoxic chemotherapeutic regimens should not be administered as first-line therapy in patients with persistent or recurrent MTC, given the low response rates and the advent of promising new treatment options. ( D )
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Treatment with radiolabeled molecules or pre-targeted radio-immunotherapy may be considered in selected patients, ideally in the setting of a well-designed clinical trial. ( C )
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In patients with significant tumor burden and symptomatic or progressive metastatic disease according to Response Evaluation Criteria in Solid Tumors (RECIST), treatment with tyrosine kinase inhibitors (TKIs), targeting both RET and vascular endothelial growth factor receptor, should be considered as systemic therapy. ( A )
Note: The TKIs vandetanib or cabozantinib can be used as single agent first line systemic therapy in patients with advanced progressive MTC.
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Patients with advanced MTC and diarrhea should be treated initially with anti-motility agents. Alternative therapies include somatostatin analogues and local therapies such as surgery or chemoembolization. ( C )
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Patients with metastatic MTC and Cushing’s syndrome due to ectopic production of adrenocorticotropic hormone or corticotropin-releasing hormone are often markedly debilitated and should be treated despite their poor prognosis. ( C )
  • Note: Treatment options include medical therapy with ketoconazole, mifepristone, aminoglutethimide, metyrapone, or mitotane. In cases refractory to medical treatment bilateral adrenalectomy is an option.
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Recommendation Grading

Overview

Title

Management of Medullary Thyroid Carcinoma

Authoring Organization

Publication Month/Year

June 3, 2015

Supplemental Implementation Tools

Quick-Reference Guide, Quick-Reference Guide

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient, Radiology services

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Assessment and screening, Diagnosis, Management, Treatment

Keywords

anaplastic thyroid cancer, medullary thyroid carcinoma (MTC), sporadic medullary thyroid carcinoma, MTC, Medullary Thyroid Cancer