OVERVIEW: What every practitioner needs to know

Are you sure your patient has medullary thyroid cancer? What are the typical findings for this disease?

Thyroid nodules are not uncommon in children and approximately 26% of these nodules represent malignancies. The vast majority of these malignancies are differentiated thyroid cancers (DTC), meaning that they are derived from and maintain features of normal thyroid cells. Medullary thyroid cancer (MTC) is a malignant tumor that arise from the parafollicular cells (or C-cells) of the thyroid gland and represents less than 5% of pediatric thyroid cancers. In the pediatric-age group, MTC is rarely sporadic, it more commonly occurs as a part of one of two tumor syndromes, either multiple endocrine neoplasia 2A (MEN2A) or MEN2B.

Patients with MEN2A have normal clinical appearance and are predisposed to developing primary hyperparathyroidism and pheochromocytoma. Patients with MEN2B have specific physical exam features, which can include mucosal neuromas of the eyelid, lips, tongue, buccal mucosa, and intestines. The intestinal neuromas may present with chronic constipation from pseudo-obstruction. In addition, patients have a marafanoid body habitus with a long, narrow facies, pectus excavatum, pes cavus, scoliosis, and high arched palate. MEN2B is associated with early onset and more aggressive MTC, an increased risk of developing pheochromocytoma, but not with an increased risk of hyperparathyroidism.

In general, patients that are evaluated for a thyroid nodule or a family history of MEN2A are asymptomatic. Patients with MEN2B may have symptoms related to the mucosal neuromas and/or a history of chronic constipation (pseudo-obstruction) from the presence of intestinal ganglioneuromas.

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What other disease/condition shares some of these symptoms?

There are several other tumor syndromes associated with an increased risk of developing thyroid nodules and thyroid cancer (see Differentiated Thyroid Cancer chapter), however, there are no other syndromes associated with an increased risk of developing MTC.

The most common etiology of a thyroid nodule is a benign thyroid adenoma or cyst. The most common diagnosis of a thyroid malignancy is differentiated thyroid cancer, with 90-95% being papillary thyroid cancer and 5-10% being follicular thyroid cancer.

Other causes of thyroid enlargement that may be mistaken for a nodule include; assymetric thyroid enlargement (goiter) from autoimmune thyroiditis or a thyroglossal duct cyst. Rarely, the thyroid can be the site of metastasis from a non-thyroid malignancy such as lymphoma.

In children and adolescents, cervical adenopathy is very common, usually due to an upper respiratory infection, minor head and neck trauma, or irritation. If the cervical adenopathy persists and/or increases over a 1-2 month time frame, evaluation for a more serious etiology should be pursued. The differential of cervical adenopathy includes; infection (cat scratch disease, mycoplasma and others), rheumatological disease, or malignancy (lymphoma, thyroid cancer and others).

What caused this disease to develop at this time?

  • MTC is associated with activating mutations in the RET proto-oncogene.

    Most children with MEN2A have a germline RET mutation. That is, the mutation was inherited from one parent in an autosomal dominant pattern (= 50% chance of having the mutation and the disease).

    Most children with MEN2B have a de novo mutation meaning the mutation is new, there is no family history.

  • Similar mutations are often found in other endocrine organs, to include the parathyroid and adrenal glands. The risk of developing these additional tumors relates to both the specific RET proto-oncogene mutation and the family history. Mutation specific risks and screening guidelines can be found in the American Thyroid Association (ATA) MTC guidelines (
    http://thyroidguidelines.net/medullary/taskforce)

  • The presence of the RET proto-oncogene mutation is associated with an almost 100% chance of developing MTC.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Thyroid function studies can be helpful in determining etiology of a thyroid nodule but they are not helpful in diagnosing MTC.

Calcitonin, a hormone produced from the parafollicular cells of the thyroid gland, can be used to help confirm the diagnosis of MTC. There are age specific normative values so make sure to refer to age reference norms provided by the laboratory. In general, calcitonin levels should be less than 10-15 pg/ml before 10 years of age and less than 5-10 p.m/ml during adolescence. In children over the age of 3-years with a thyroid US revealing nodules < 0.5 cm, a level of < 30-40 pg/ml is associated with a very low risk of having metastatic MTC. Calcitonin can also be measured by immunohistochemical staining of thyroid or lymph node tissue as well as in wash-out fluid from fine needle aspiration biopsy.

Would imaging studies be helpful? If so, which ones?

Ultrasound (US) is the best imaging study to evalute for potential thyroid lesions. Over 70% of MTC will have calcifications on US exam of the thyroid. US must include examination of the lateral neck for evidence of abnormal lymph nodes.

If baseline calcitonin is >400 pg/ml, whole body radiological screening should be completed, including a chest/neck computed tomography (CT), 3 phase contrast-enhanced liver CT or magnetic resonance imaging (MRI) with contrast.

Confirming the diagnosis

The most current consensus for the evaluation and treatment of MTC were published in 2009 by the American Thyroid Association. The guidelines can be found at ATA MTC Guidelines ( PUBMED:19469690) or they can be directly downloaded from http://thyroidguidelines.net/medullary/taskforce

If you are able to confirm that the patient has medullary thyroid cancer, what treatment should be initiated?

  • For patients with MEN, identified by family history (MEN 2A) or by physical exam and early onset of MTC (MEN 2B), care should be provided in a multi-disciplinary center. The team should consist of providers with expertise in evaluating and treating pediatric patients with thyroid nodules and thyroid cancer from the following specialties; endocrinology, surgery, pathology, radiology, genetics, and social work services. Referral and collaboration with a center that has a Hereditary Cancer Predisposition center is essential.

  • Treatment – for patients with;

    Positive RET proto-oncogene testing (MEN2) and no clinically apparent MTC (normal physical exam and negative US).

    Prophylactic total thyroidectomy, the timing dictated by the specific mutation and the family history.

    Patients with
    MEN2A – total thyroidectomy beginning at age 5, dictated by the specific mutation and family history of expression. Please refer to ATA guidelines for specific recommended ages.

    Patients with
    MEN2B – based on physical exam and/or RET proto-oncogene testing (codon 918 or 883) – total thyroidectomy as soon as diagnosis and as young as 1 year of age.

  • Apparent MTC

    Total thyroidectomy and central neck (level VI) neck dissection.

    Lateral neck dissection if staging US and/or MRI shows metastasis to lateral neck lymph nodes.

    If the diagnosis of a RET proto-oncogene or MTC is confirmed, screening for hyperparathyroidism (MEN2A only) and pheochromocytoma (MEN 2A and 2B) should be completed prior to surgery.

  • Note: Unlike differentiated thyroid cancers, there is no role for radioactive iodine treatment. The goal is to surgically remove the thyroid gland before MTC develops and spreads. Once MTC metastasizes surgery is rarely curative and there are no approved pharmaceutical therapies for MTC that have been shown to be associated with long-term remission.

What are the adverse effects associated with each treatment option?

Surgical resection is the only effective treatment for MTC, however, it is associated with several risks. The risk of surgical complications increase with younger age of the patient and less experience of the surgeon. Thyroid surgery should be performed by a ‘high-volume’ surgeon (performing more than 30 thyroid surgeries per year) in a pediatric setting.

Hypocalcemia is seen in approximately 30-40% of patients in the immediate post-operative period and is due to parathyroid bruising or stunning related to the procedure. Treatment may include parenteral doses of calcium and calcitriol. About 1% of patients will have permanent hypoparathyroidism.

Recurrent laryngeal nerve injury is seen in less than 3% of patients.

Permanent hypothyroidism is part of the intended result of the surgery, therefore patients must remain on lifelong thyroid hormone replacement therapy. Thyroid hormone suppression is not necessary.

What are the possible outcomes of medullary thyroid cancer?

The goal of prophylactic thyroidectomy is to elimante the risk of developing MTC. However, a lifelong risk of developing hyperparathyroidism (MEN2A only) and pheochromocytoma (MEN 2A and 2V) exists. For specifics of time of surveillance, please refer to ATA guidelines.

For patients diagnosed with metastatic MTC the likelihood of cure is extremely low. Further surgery should be limited to large lesions that are symptomatic or pose risk to the patient.

Other clinical manifestations that might help with diagnosis and management

For patients that have prophylactic thyroidectomy after age 10 years of age, or sooner if any concern based on screening labs or symptoms, it is important to screen the patient for the associated disease prior to surgery.

– Hyperparathyroidism: Serum calcium with intact PTH.

– Pheochromocytoma: Serum or urine metanephrine/normetanephrine panel.

What complications might you expect from the disease or treatment of the disease?

The diagnosis of MEN2 has medical, social, and psychosocial implications for the patient and their family. All families should undergo evaluation by a genetic counselor and be evaluated by social work services and behavioral health specialists. There may be an increased rate of depression, anxiety and stress associated with the diagnosis of MEN and MTC and, therefore, it is important to offer patients access to appropriate support. This is best accomplished in the context of a multi-disciplinary center with experience in treating thyroid cancers and inheritable tumor syndromes. Evaluation and counseling should be conducted on a regular basis.

Are additional laboratory studies available; even some that are not widely available?

Metastatic MTC can produce other endocrine hormones that can lead to autonomous production of ACTH resulting in cyclic flushing and Cushing’s syndrome and other neuroendocrine manifestations. MTC can also produce carcino-embryonic antigen (CEA). CEA levels may correlate with disease burden and may be used to help follow patients with metastatic MTC.

How can medullary thyroid cancer be prevented?

Early identification of patients at risk for having a RET proto-oncogene and early prophylactic thyroidectomy in these persons is essential. The prevention of MTC through screening for the RET proto-oncogene is one of the most powerful examples of the benefit that the molecular era of medicine has brought to patient care.

What is the evidence?

Kloos, RT, Eng, C, Evans, DB, Francis, GL, Gagel, RF, Gharib, H. “Medullary thyroid cancer: management guidelines of the American Thyroid Association”. Thyroid. vol. 19. 2009 Jun. pp. 565-612. (A consensus on the evaluation and management by some of the leading experts in thyroid disease.)

Waguespack, SG, Rich, TA, Perrier, ND, Jimenez, C, Cote, GJ. “Management of medullary thyroid carcinoma and MEN2 syndromes in childhood”. Nat Rev Endocrinol. vol. 7. 2011 Aug 23. pp. 596-607. (A consensus on the evaluation and management of MEN focused on the pediatric age group.)

Wells, SA, Robinson, BG, Gagel, RF, Dralle, H, Fagin, JA, Santoro, M. “Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial”. J Clin Oncol. 2011 Oct 24. (The double blind trial that subsequently led to FDA approval of Vandetanib for treatment of MTC under the Vandetanib Risk Evaluation Mitigation Strategy (REMS) Program.)

Daniels, GH. “Screening for Medullary Thyroid Carcinoma with Serum Calcitonin Measurements in Patients with Thyroid Nodules in the United States and Canada”. Thyroid. 2011 Sep 21. (A manuscript suggesting that routine screening of baseline calcitonin in patients with thyroid nodules is not indicated and may lead to increased, unnecessary surgery from false positive results.)

Noullet, S, Trésallet, C, Godiris-Petit, G, Hoang, C, Leenhardt, L, Menegaux, F. “Surgical management of sporadic medullary thyroid cancer”. J Visc Surg.. vol. 148. 2011 Sep. pp. e244-9. (A review of the surgical approach to treating MTC.)

Ball, DW. “Management of medullary thyroid cancer”. Minerva Endocrinol. vol. 36. 2011 Mar. pp. 87-98. (An update to the management of MTC after publication of the 2009 ATA guidelines.)

Rosenthal, MS, Diekema, DS. “Pediatric ethics guidelines for hereditary medullary thyroid cancer”. Int J Pediatr Endocrinol. vol. 2011. 2011. (A discussion of ethical considerations in genetic screening in multiple endocrine neoplasia syndrome.)

Ongoing controversies regarding etiology, diagnosis, treatment

Ongoing clinical trials regarding the efficacy of pharmaceutical therapy to include tyrosine kinase inhibitors are currently underway.

In patients with a family history that reflects later onset of disease expression (ie. later onset of developing MTC), it may be acceptable to delay prophylactic thyroidectomy if cautious and deliberate surveillance is used, to include annual thyroid US and calcitonin level testing. The opposite may also occur, with earlier than predicted expression of disease (i.e. earlier occurrence of MTC) and in these families earlier prophylactic thyroidectomy should be pursued. MTC has been reported in patients less 1 year of age. Further studies are needed to more clearly define the relation between a specific RET proto-oncogene mutation and the variation of expression within each family.

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