Medullary Thyroid Cancer Management: 5 Things to Know

Danica M. Vodopivec Kuri, MD; Herbert Chen, MD


January 12, 2023

Medullary thyroid cancer (MTC) is a rare a neuroendocrine tumor that arises from the parafollicular C cells of the thyroid, which are neural crest derivatives and produce calcitonin and carcinoembryonic antigen (CEA) — both used as tumor markers. Although MTC accounts for less than 5% of thyroid cancer cases, it is more aggressive than most other thyroid cancer subtypes. Stage and age at diagnosis are strong prognostic predictors, and the 5-year relative survival for stages I-III is 93% compared with 29% for stage IV.

Here, we discuss five key aspects of the diagnosis and treatment of MTC.

1. MTC is sporadic or hereditary, and the RET proto-oncogene is its most common driver mutation.

MTC can be sporadic in 75% of cases and hereditary in the remaining 25%, with the latter comprising the polyglandular cancer syndrome known as multiple endocrine neoplasia 2 (MEN2) types A and B. MEN2A is characterized by MTC, pheochromocytoma up to 50% of the time, primary hyperparathyroidism (PHPT) up to 30% of the time, and with less frequency, cutaneous lichen amyloid and Hirschsprung disease. MEN2B represents the most aggressive type of MEN2. Patients with MEN2B develop MTC; pheochromocytoma; and characteristic body features, including marfanoid habitus with mucosal neuromas. The management of MTC is the same for both sporadic and hereditary forms.

The RET proto-oncogene, the most common genetic alteration in MTC, is present in MEN2 syndromes and in sporadic MTC. Mutually exclusive with RET mutations, point mutations of RAS have been reported in sporadic MTC, but with variable frequency (18%-80%), and the remainder cases of sporadic MTC do not have identifiable mutations.

2. The initial diagnosis of MTC requires a clinical, radiologic, cytologic, and biochemical evaluation followed by genetic testing.

In most patients, MTC is diagnosed incidentally in the absence of symptoms, whereas other patients may experience compressive neck symptoms, diarrhea, and/or flushing; the latter two are a result of serotonin, histaminase, vasoactive intestinal peptide, prostaglandins, and kinins secreted by tumor C cells. Rarely, patients can present with paraneoplastic Cushing syndrome from the ectopic release of adrenocorticotropic hormone by the C cells.

MTC is initially diagnosed by ultrasound-guided fine-needle aspiration (FNA) biopsy of a thyroid nodule. There are no distinctive features between MTC and a follicular-derived thyroid cancer. Therefore, cytologic findings suggestive of MTC should be further evaluated with immunohistochemistry. MTC stains positive for calcitonin, chromogranin, and CEA and negative for thyroglobulin. The advent of molecular genetic testing for thyroid nodules has significantly improved the identification of MTC among indeterminate FNA samples. The routine use of calcitonin as a screening tool in all patients with a thyroid nodule is not warranted.

After a cytologic diagnosis of MTC, serum calcitonin and CEA levels should be measured (preoperative levels), followed by testing for a RET germline mutation. All patients with MTC should undergo genetic testing because up to 7% of apparent sporadic MTC cases are indeed de novo hereditary mutations. In addition, roughly 75% of patients with MEN2B have a de novo germline RET mutations. It could take up to 3 weeks for genetic testing results to come in. Thus, during this waiting period after the initial cytologic diagnosis of MTC, clinicians should ask about personal and family history of PHPT and pheochromocytoma; order serum calcium, albumin, intact parathyroid hormone, and plasma metanephrine measurements; and examine patients for the characteristic body features of MEN2B. The presence of pheochromocytoma and PHPT should always be excluded before neck surgery. Surgical resection of pheochromocytoma takes priority over thyroid surgery. Knowing that a patient has PHPT before thyroidectomy alerts the surgeon to do a four-gland exploration while undergoing total thyroidectomy.

Preoperative neck ultrasound is mandatory to evaluate the extent of disease and help guide operative planning. A preoperative calcitonin level > 500 pg/mL, extensive neck disease, and/or symptoms of distant metastases warrant further preoperative imaging. These additional imaging tools include CT of the neck with contrast to assess retropharyngeal lymph nodes and tumor invasion, CT of the chest with contrast to evaluate mediastinal lymph node and lung metastases, CT of the abdomen with liver protocol or MRI of the abdomen with contrast to detect liver metastases, and bone scintigraphy and/or axial MRI to unmask bone metastases.

3. Total thyroidectomy with cervical lymph node dissection is standard treatment for patients with MTC and offers the best chance of cure.

Total thyroidectomy with cervical lymph node dissection is the only curative treatment for MTC. Unfortunately, there is an approximately 10% cure rate when the cancer has spread to the cervical lymph nodes at the time of initial surgery.

When it comes to the extent of surgery, there are two schools of thought. The first proposes a total thyroidectomy with prophylactic central neck dissection (CND, level VI) when ultrasound indicates normal lymph nodes. It also reserves lateral neck dissection (LND, levels II-V) for sonographic evidence of disease. The second school of thought considers serum calcitonin levels, recommending prophylactic CND and ipsilateral LND when the serum calcitonin level is > 20 pg/mL and prophylactic dissection of the contralateral neck compartment when serum calcitonin level is > 200 pg/mL. When the initial diagnosis includes distant metastatic disease, surgical resection of neck disease is reasonable, even when not curative, to prevent future invasion of important neck structures (recurrent laryngeal nerve, trachea, esophagus, main vessels).

Adjuvant external beam radiation therapy (EBRT) to the neck remains controversial for patients with advanced, not completely resected locoregional disease. Two recent studies, including a large database study, showed no improvement in overall survival. In addition, EBRT is not free of morbidity to the patient and increases the risk for fistula formation if multikinase inhibitors (MKIs) with antiangiogenic properties are later introduced.

Children who test positive for a RET germline mutation should undergo prophylactic thyroidectomy, and its timing varies on the basis of the RET mutation American Thyroid Association (ATA) risk category. Prophylactic thyroidectomy is done with the intent to remove the at-risk thyroid before metastasis develops while minimizing surgical complications and remaining free of disease. Children in the ATA "highest risk" category, those with MEN2B with RET codon M918T mutation, should undergo total thyroidectomy during the first year of life. Those who test positive for MEN2A with codon 634 mutations and MEN2B with A883F are in the ATA "high risk" category and should undergo thyroidectomy at age 5 years or before if elevated calcitonin levels are detected.

4. After initial thyroid surgery, surveillance consists of monitoring calcitonin and CEA levels and obtaining imaging modalities on the basis of tumor marker levels.

After surgery, levothyroxine should be administered to maintain euthyroidism, and radioactive iodine treatment is not indicated. Calcitonin and CEA levels should be obtained 3 months after surgery, which is considered as nadir or new baseline. Both of these tumor markers need to be collected at the same time and in a fasting state every 6 months to get reliable doubling times. Signs of poor prognosis are a calcitonin doubling time of less than 6 months, a large tumor burden with disproportionately low tumor markers, or rising CEA levels compared with stable or declining calcitonin levels. The latter two scenarios indicate a poorly differentiated MTC.

Elevated postoperative calcitonin levels to < 150 pg/mL are concerning for persistent or recurrent neck disease. In this instance, neck ultrasound is the indicated surveillance imaging modality. On the other hand, if calcitonin levels are > 150 pg/mL, distant metastatic disease is suspected, and monitoring should consist of neck ultrasound alternating with neck CT with contrast, chest CT with contrast, abdomen CT with liver protocol or abdomen MRI with contrast, and musculoskeletal pelvis and axial MRI with or without bone scintigraphy. Fluorodeoxyglucose PET-CT is not recommended in MTC because it is less sensitive in detecting disease than the above-mentioned imaging modalities. On the other hand, 68Ga DOTATATE PET-CT is useful when tumor markers are rising and conventional imaging fails to correlate with new or progressing lesions. It also adds great value in detecting bone metastases. Overall, there is superiority in detecting bone metastases with 18F-NaF PET-CT.

5. Systemic treatment for MTC is reserved for progressive, unresectable, locally advanced, or metastatic disease for which there are no other effective treatments.

In most cases, metastatic MTC presents as a slow-growing indolent disease with a gradual increase in tumor markers over time. This type of disease presentation requires active surveillance without the need for systemic therapy for years. Repeat neck surgery can be considered in persistent or recurrent cervical disease that progresses over time. Localized treatments such as EBRT, surgical resection (metastasectomy), chemoembolization, or cryoablation may be used to treat a single focus or area of metastasis. Localized treatments are used to control oligometastatic disease when stable in all but one area, alleviate pain, reduce morbidity, or treat refractory diarrhea. For instance, delivering EBRT to a bone metastasis alleviates pain and reduces morbidity by preventing a pathologic fracture.

The decision to start a patient on tyrosine kinase inhibitors (TKIs) should never be taken lightly. These agents are not curative, confer toxicities with unknown long-term effects, require long-term use for disease control, require shorter interval of follow-up visits, and lose efficacy over time owing to acquired resistance of cancer cells. In general, TKIs are reserved for advanced metastatic disease with at least one of the following characteristics: progressive (based on RECIST) within 12-14 months; symptomatic and is not amenable to any localized or symptom-specific therapies; invasion of nearby structures not amenable to localized therapies; calcitonin and/or CEA doubling time less than 6 months, with small individual lesions that add up to a large tumor burden; or severe, intractable MTC-related diarrhea or paraneoplastic Cushing syndrome with lack of an alternative effective treatment.

Several TKIs have been approved by the US Food and Drug Administration (FDA) for the treatment of MTC. Vandetanib and cabozantinib are nonselective MKIs that were approved by the FDA in 2011 and 2012, respectively. Selpercatinib and pralsetinib are selective RET TKIs approved in 2020 by the FDA and may be used as first or subsequent lines of therapy for RET-mutated MTC. As the name suggests, selective RET inhibitors are potent receptors to specific agents, a quality that makes them better tolerated with fewer adverse events. In a recent case study, after the neoadjuvant use of selpercatinib in a patient with initially unresectable, locally advanced MTC, the patient underwent complete resection successfully. When it comes to sporadic MTC with RAS or another nontargetable mutation, nonselective MKIs are the recommended treatment.

Looking toward new therapies for MTC, tumor vaccines, peptide receptor radionuclide therapy, and glial-derived neurotrophic factor family receptor alpha 4–directed CAR-T immunotherapy are being studied in clinical trials.

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