Medullary thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare type of neuroendocrine cancer that starts in the parafollicular cells (C cells) of the thyroid gland. The thyroid gland sits at the front of the neck, just below the larynx.

C cells produce calcitonin, a hormone that helps regulate calcium levels in the blood. When blood calcium levels are high, C cells release calcitonin, which helps lower calcium levels by reducing the amount of calcium released from bones and increasing the amount excreted by the kidneys. When blood calcium levels are low, less calcitonin is released. In MTC, where C cells grow abnormally and form a tumour, they often continue to produce excess calcitonin. This makes calcitonin one of the most important markers for diagnosing and monitoring MTC.

At NeuroEndocrine Cancer Australia (NECA), we support people diagnosed with medullary thyroid carcinoma and their families through education, resources, advocacy, and access to the NET Nurse, counselling, and dietitian support services.

Understanding medullary thyroid carcinoma

The thyroid is a butterfly-shaped gland in the neck that produces hormones regulating metabolism, energy levels, and many body systems. Most thyroid cancers arise from follicular cells, which are responsible for making thyroid hormones and absorbing iodine.

MTC is different. It starts in the parafollicular cells (C cells), which are specialised neuroendocrine cells found throughout the thyroid gland. C cells are part of the neuroendocrine system, meaning they receive signals from the body and release hormones into the bloodstream in response.

Because MTC arises from neuroendocrine cells, it is classified as a neuroendocrine cancer. This means its biology, behaviour, and treatment are fundamentally different from papillary, follicular, or other thyroid cancers.

When C cells grow abnormally, the resulting tumour often produces calcitonin in excess. Measuring blood calcitonin is one of the most sensitive and specific tests for MTC. Some tumours also produce carcinoembryonic antigen (CEA), another blood marker that is mainly used to monitor MTC and assess how the disease is progressing.

Prevalence of MTC

MTC accounts for approximately 1 to 4 per cent of all thyroid cancers but has a disproportionate impact, accounting for a significant proportion of thyroid cancer-related deaths due to its tendency to spread early to lymph nodes and distant organs.

MTC behaves very differently from the more common types of thyroid cancer. Because it arises from C cells rather than the hormone-producing follicular cells of the thyroid, it does not respond to radioiodine therapy; one of the most widely used treatments for other thyroid cancers. This distinction is important for people newly diagnosed with MTC who may be surprised that their treatment differs from what others with thyroid cancer receive.

Approximately 25 to 30 per cent of MTC cases are hereditary and linked to inherited change in the RET gene (called the RET proto-oncogene). Because of this genetic connection, testing and family screening are an essential part of managing MTC.

Sporadic and hereditary MTC

MTC is usually described as either sporadic or hereditary.

Sporadic MTC

Sporadic MTC accounts for approximately 70 to 75 per cent of all cases. It occurs without an inherited genetic cause, although non-inherited changes in the RET gene are found in many sporadic tumours.

Sporadic MTC typically develops in adults, most often between the ages of 40 and 60. It usually presents as a single tumour in one lobe of the thyroid gland.

Hereditary MTC

Hereditary MTC accounts for approximately 25 to 30 per cent of all cases. It is caused by an inherited germline mutation in the RET proto-oncogene and follows an autosomal dominant pattern of inheritance, meaning a person with this gene mutation has a 50 per cent chance of passing it to each of their children.

Hereditary MTC tends to develop at a younger age, often affects both lobes of the thyroid, and can occur as part of a broader inherited syndrome.

Types of hereditary MTC

Multiple Endocrine Neoplasia type 2A (MEN2A)

MEN2A is the most common hereditary form of MTC. People with MEN2A may develop:

• Medullary thyroid carcinoma (present in nearly all affected individuals)
• Phaeochromocytoma (a tumour of the adrenal gland that produces excess stress hormones)
• Primary hyperparathyroidism (overactivity of the parathyroid glands, which affects calcium levels)

MTC is usually the first tumour to develop in MEN2A. Ongoing monitoring for phaeochromocytoma and hyperparathyroidism is an important part of long-term management.

Multiple Endocrine Neoplasia type 2B (MEN2B)

MEN2B is less common but is associated with a more aggressive and earlier-onset form of MTC. Without preventative surgery, MTC can develop in infancy or early childhood in people with MEN2B.

People with MEN2B may develop:

• Medullary thyroid carcinoma
• Phaeochromocytoma
• Mucosal neuromas (small benign growths around the lips, tongue, and digestive tract)
• A marfanoid body type (tall, slender build with long limbs)

Because MTC in MEN2B can develop very early and aggressively, early genetic identification and preventative thyroid surgery are critical.

Familial MTC (FMTC)

In some families, MTC occurs without the other endocrine tumours seen in MEN2A or MEN2B. This is called familial MTC. It tends to follow a less aggressive course and often presents in adulthood.

Symptoms of medullary thyroid carcinoma

In the early stages, MTC often causes no symptoms. Many cases are found during imaging or examination performed for another reason.

As the tumour grows, symptoms may include:

• A painless lump or swelling in the neck
• Hoarseness or changes to the voice
• Difficulty swallowing (dysphagia)
• A feeling of pressure or fullness in the neck
• Shortness of breath in some cases

In rare cases, people may develop symptoms caused by excess calcitonin circulating in the bloodstream:

• Persistent or watery diarrhoea
• Flushing of the face or neck

These hormone-related symptoms are more common when MTC has spread to other parts of the body, particularly when there is a high burden of metastatic disease, such as involvement of the liver.

Rarely, some tumours produce other hormones that can cause additional symptoms. This is uncommon but may be investigated if symptoms are unusual.

Diagnosis of medullary thyroid carcinoma

Diagnosing MTC usually involves imaging, biopsy, blood tests, and genetic assessment.

1. Thyroid ultrasound

Ultrasound is usually the first investigation when a thyroid nodule or neck lump is identified. It helps assess the size, location, and characteristics of the nodule and any nearby lymph nodes.

2. Fine needle aspiration biopsy

A fine needle aspiration (FNA) biopsy involves passing a thin needle into the nodule to collect a small sample of cells for examination under the microscope. Immunohistochemical staining for calcitonin on the biopsy sample helps confirm an MTC diagnosis.

3. Blood tests

Blood tests for calcitonin are essential in diagnosing and monitoring MTC. CEA can be useful marker for monitoring

• Calcitonin is highly sensitive and specific for MTC. An elevated calcitonin level in a person with a thyroid nodule strongly suggests MTC.
• CEA is another tumour marker produced by many MTC tumours. It is used alongside calcitonin to help assess the extent of disease and monitor for recurrence.

4. Genetic testing

Current medical guidelines recommend that all people diagnosed with MTC undergo RET gene testing. This helps determine whether the MTC is hereditary or sporadic, guides treatment planning, and identifies whether family members are at risk.

Testing is usually performed using a blood sample. A clinical geneticist or genetic counsellor is often involved in discussing the implications of the results.

5. Imaging and staging

Once MTC is confirmed, imaging is used to assess whether the cancer has spread beyond the thyroid gland.

Tests may include:

• CT scan of the neck, chest, abdomen, and pelvis
• MRI in selected cases
• Bone scan
• Neck ultrasound to assess lymph nodes
• Ga-68 DOTATATE PET/CT in selected cases

The most appropriate investigations depend on blood marker levels, clinical findings, and specialist advice.

Phaeochromocytoma screening before surgery

Before any surgery for MTC, particularly when hereditary MTC (such as MEN2) is suspected or confirmed,it is critical to screen for phaeochromocytoma: a tumour of the adrenal gland that produces excess stress hormones (catecholamines).

If an undetected phaeochromocytoma is present when surgery is performed, the stress of anaesthesia can trigger a life-threatening surge in blood pressure known as a hypertensive crisis.

Screening is performed through blood or urine tests for metanephrines. If a phaeochromocytoma is found, it must be treated before thyroid surgery proceeds.

Staging of medullary thyroid carcinoma

Staging describes how far the cancer has spread. MTC is staged using the TNM classification system, which considers:

• The size and extent of the primary tumour in the thyroid
• Whether nearby lymph nodes are involved
• Whether the cancer has spread to distant organs such as the lungs, liver, or bones

Staging helps guide treatment decisions and provides information about prognosis.

Treatment options for medullary thyroid carcinoma

Treatment depends on the tumour stage, whether the MTC is sporadic or hereditary, the RET mutation involved, and overall health.

A multidisciplinary team may include an endocrine surgeon, endocrinologist, medical oncologist, nuclear medicine specialist, genetic counsellor, radiologist, pathologist, and NET nurse.

Surgery

Surgery is the primary treatment for MTC and the only potentially curative option.

The standard approach involves:

• Total thyroidectomy: removal of the entire thyroid gland
• Central compartment neck dissection: removal of lymph nodes in the central neck region

Because MTC tends to spread to lymph nodes early, lymph node removal is an important part of surgery even when lymph node involvement is not obvious before the operation.

For people with certain inherited RET gene changes, risk-reducing thyroidectomy may be recommended before MTC develops. The timing of this preventative surgery depends on the specific RET variant and the level of cancer risk, and is determined in consultation with a specialist multidisciplinary team.

Why MTC does not respond to radioiodine

Unlike papillary and follicular thyroid cancers, MTC does not respond to radioiodine (I-131) treatment. This is because C cells do not absorb iodine: only follicular cells do.

Similarly, TSH suppression therapy (used routinely in other thyroid cancers) is not part of MTC management.

This information can help people with MTC understand why their care plan may include different treatments and specialist input compared with more common forms of thyroid cancer.

Thyroid hormone replacement

After total thyroidectomy, the thyroid gland is no longer present to produce thyroid hormones. Lifelong daily thyroid hormone replacement medication (thyroxine) is required to prevent hypothyroidism and maintain normal body function.

Targeted systemic therapies

For advanced, metastatic, or progressive MTC that cannot be managed with surgery alone, systemic therapies may be considered.

Older multi-targeted kinase inhibitors, including vandetanib and cabozantinib, have been used for advanced MTC and may still be considered in selected cases.

More recently, highly selective RET inhibitors have been developed and represent an important advance for people whose tumours carry a RET mutation. Selpercatinib specifically targets the abnormal RET signalling that drives tumour growth and may be considered for people with advanced RET mutated MTC requiring systemic therapy.

The choice of treatment depends on tumour stage, RET mutation status, previous treatments, overall health, and specialist recommendation.

External beam radiotherapy

Radiotherapy is not a standard first-line treatment for MTC but may be considered in selected cases, such as when local disease cannot be fully removed surgically or to treat symptomatic spread to specific sites.

Genetic counselling and family screening

For people with a confirmed germline RET mutation, genetic counselling is strongly recommended. This helps individuals and families understand:

• What the mutation means for their own health
• The risk to first-degree relatives (children, siblings, and parents each have a 50 per cent chance of inheriting the same mutation.
• Options available to family members, including genetic testing, preventative surgery, and ongoing surveillance
• Monitoring requirements for related conditions such as phaeochromocytoma and hyperparathyroidism

First-degree relatives of a person with a confirmed RET mutation should be offered genetic testing. This process is known as cascade testing.

Family members who test positive for a high-risk RET mutation may have risk reducing thyroidectomy recommended to them, sometimes during childhood or early adulthood, depending on the specific mutation identified and the associated risk level.

The timing of preventative surgery is guided by specialist assessment and current clinical guidelines.

Living with medullary thyroid carcinoma

Living with MTC can involve lifelong monitoring, thyroid hormone replacement, management of related endocrine conditions, and the emotional impact of a diagnosis that may have implications for family members.

For many people, the hereditary nature of MTC adds a significant dimension; not only for their own health, but for the health of their children, siblings, and parents. Genetic counselling can help families navigate these concerns with appropriate support.

Thyroid hormone replacement after surgery is generally well-tolerated, and many people live well for many years following treatment. For those with advanced or metastatic disease, ongoing treatment and monitoring become part of long-term life management.

Good supportive care can make a significant difference. This may include nutritional support, psychological care, symptom management, and connection with others who understand the neuroendocrine cancer experience.

Calcitonin and CEA monitoring

After surgery, calcitonin and CEA levels are monitored regularly through blood tests. In people with residual or recurrent disease, clinicians may calculate the calcitonin doubling time.

Calcitonin doubling time measures how quickly calcitonin levels are rising over time:

• A short doubling time (less than six months) suggests more rapidly progressive disease and may prompt closer surveillance or escalation of treatment.
• A long doubling time (greater than two years) is associated with more slowly progressing disease and a more favourable outlook.

Understanding doubling time helps clinicians tailor follow-up intensity and treatment decisions to each individual.

Management of related endocrine conditions

People with MEN2A require ongoing monitoring for associated conditions:

• Phaeochromocytoma: regular biochemical screening with blood or urine metanephrine tests. If found, phaeochromocytoma must be treated before any other surgery.
• Primary hyperparathyroidism: monitoring of calcium and parathyroid hormone levels. Treatment may be needed if calcium levels become elevated.

People with MEN2B should also be screened for phaeochromocytoma on a regular basis.

Follow-up and surveillance

Follow-up after MTC treatment depends on the tumour stage, whether surgery achieved complete removal, and whether the MTC is sporadic or hereditary.

Surveillance typically includes:

• Regular calcitonin and CEA blood tests
• Monitoring of calcitonin doubling times
• Neck ultrasound
• CT, MRI, or functional imaging when indicated by rising markers or clinical symptoms
• Biochemical screening for phaeochromocytoma in hereditary MTC
• Monitoring of calcium and parathyroid hormone levels in MEN2A

For people with undetectable calcitonin and CEA after surgery, less frequent follow-up may be appropriate. For those with elevated or rising markers, the frequency and intensity of surveillance will be guided by the rate of change.

Research and future directions

Research into MTC continues to improve diagnosis, treatment, and genetic understanding.

Important areas of development include:

• More precise and selective RET-targeted therapies
• Understanding resistance mechanisms to current targeted treatments
• Better risk stratification based on specific RET mutation codon profiling
• Improved understanding of sporadic MTC biology, including the role of non-RET mutations
• Refined surveillance strategies for RET mutation carriers
• Novel imaging approaches for staging and monitoring
• Better management of advanced and metastatic disease

Clinical trials may be available for some people with advanced or treatment-resistant MTC.

Support available through NeuroEndocrine Cancer Australia

A diagnosis of medullary thyroid carcinoma can feel isolating and overwhelming, especially when it raises concerns about inherited risk and the health of family members.

NeuroEndocrine Cancer Australia provides support for people affected by MTC and their families, including:

• Access to the NET Nurse service
• Specialist NET dietitian
• Specialist NET counsellor
• Patient and carer information and resources
• Support for navigating rare cancer care
• Education about neuroendocrine cancer
• Guidance on questions to ask your care team
• Connection to specialist information and support pathways

For support, information, and guidance after an MTC diagnosis, contact NeuroEndocrine Cancer Australia.

References

1. WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine Tumours. 5th ed. Lyon: International Agency for Research on Cancer; 2022. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Endocrine-And-Neuroendocrine-Tumours-2022
2. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 https://pubmed.ncbi.nlm.nih.gov/25741868/
3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial (ZETA). J Clin Oncol. 2012;. https://pubmed.ncbi.nlm.nih.gov/22025146/
4. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer (EXAM). J Clin Oncol. 2013 https://pubmed.ncbi.nlm.nih.gov/24002501/
5. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020. https://pubmed.ncbi.nlm.nih.gov/32846061/
6. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021. https://pubmed.ncbi.nlm.nih.gov/34133939/
7. Romei C, Elisei R. A narrative review of genetic alterations in primary thyroid epithelial cancer. Int J Mol Sci. 2021: https://pubmed.ncbi.nlm.nih.gov/33578986/
8. Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009; https://pubmed.ncbi.nlm.nih.gov/19469690/
9. Moura MM, Cavaco BM, Pinto AE, Leite V. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 2011 https://pubmed.ncbi.nlm.nih.gov/21325462/
10. Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab. 2010 https://pubmed.ncbi.nlm.nih.gov/20371667/
11. Raue F, Frank-Raue K. Update on multiple endocrine neoplasia type 2: focus on medullary thyroid carcinoma. J Endocr Soc. 2018. https://pubmed.ncbi.nlm.nih.gov/30038064/
12. Schlumberger M, Bastholt L, Dralle H, et al. European thyroid association guidelines for metastatic medullary thyroid cancer. Eur Thyroid J. 2012 https://pubmed.ncbi.nlm.nih.gov/24782992/
13. Pacini F, Castagna MG, Brilli L, Pentheroudakis G. Thyroid cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 https://pubmed.ncbi.nlm.nih.gov/22997443/
14. Brierley JD, Gospodarowicz MK, Wittekind C, eds. TNM Classification of Malignant Tumours. 8th ed. Oxford: Wiley-Blackwell; 2017. https://www.uicc.org/resources/tnm