Medullary Thyroid Cancer: Symptoms, Types, Causes and Treatment

Medullary thyroid cancer (MTC) is a rare yet distinct form of thyroid cancer, notable for its unique origins, genetic underpinnings, and disease course. While it accounts for only a small percentage of all thyroid cancers, MTC is known for its potentially aggressive behavior and complex management. This article explores MTC in depth, focusing on its symptoms, types, causes, and the latest advances in treatment.

Symptoms of Medullary Thyroid Cancer

Medullary thyroid cancer often presents subtly, and its symptoms may overlap with other thyroid disorders. Early recognition is crucial, as the prognosis greatly depends on the stage at diagnosis. Understanding the range of symptoms can aid in timely medical attention and intervention.

Symptom	Description	Frequency/Significance	Source(s)
Neck Lump	Painless nodule in the thyroid region	Most common first sign	5 6
Hoarseness	Voice changes due to nerve involvement	Less common, indicates invasion	3 5
Dysphagia	Difficulty swallowing	May indicate local spread	5 6
Diarrhea	Paraneoplastic effect of calcitonin	Occurs in advanced disease	3 5 6
Flushing	Episodic skin flushing	Paraneoplastic, less frequent	3 5
Systemic Signs	Fatigue, weight loss	May occur in advanced/metastatic	5 9

Table 1: Key Symptoms

Common Local Symptoms

The most prevalent symptom is a painless lump or nodule in the front of the neck, often found incidentally. As the tumor grows, it may compress or invade nearby structures, leading to:

• Hoarseness, if the recurrent laryngeal nerve is involved
• Difficulty swallowing (dysphagia)
• Occasional pain or discomfort in the neck area

These features are similar to other thyroid malignancies, making clinical suspicion and diagnostic work-up essential 5 6.

Paraneoplastic and Systemic Manifestations

A hallmark of MTC is its origin from C-cells, which secrete calcitonin—a hormone that, when produced in excess, can lead to distinctive symptoms:

• Diarrhea: Occurs due to the hormone's effect on the gut, seen in advanced cases.
• Flushing: Paroxysmal skin redness and warmth, less common but specific 3 5.

Advanced disease can also cause generalized symptoms such as fatigue, unintentional weight loss, and, rarely, symptoms from distant metastases (e.g., bone pain or respiratory issues) 5 9.

Symptoms from Associated Endocrine Syndromes

In hereditary forms (MEN2 syndromes), symptoms may arise from other tumors (e.g., pheochromocytoma causing hypertension, hyperparathyroidism causing hypercalcemia) 3 7. This highlights the importance of a thorough systemic evaluation in patients with suspected familial MTC.

Types of Medullary Thyroid Cancer

Medullary thyroid cancer is not a single entity; it manifests in distinct forms with varying genetic and clinical profiles. Recognizing these types is vital for diagnosis, family screening, and management.

Type	Description	Inheritance/Features	Source(s)
Sporadic MTC	Isolated, not inherited, most common (~75%)	No family history	3 6 7
Hereditary MTC	Associated with RET mutations, ~25% of cases	Familial, often MEN2 syndromes	3 6 7 8
MEN2A	MTC with pheochromocytoma, hyperparathyroidism	Autosomal dominant, RET mutation	7 8
MEN2B	MTC with pheochromocytoma, mucosal neuromas, Marfanoid habitus	More aggressive, earlier onset	7 8
FMTC	Familial MTC without other endocrine tumors	RET mutation, less aggressive	7 8

Table 2: Types of MTC

Sporadic Medullary Thyroid Cancer

The majority of MTC cases (about 75%) are sporadic, meaning they arise without a family history or inherited genetic mutation. These typically present in adulthood and often as a single thyroid nodule. Sporadic cases can involve somatic (tumor-acquired) RET or RAS mutations 3 6 7.

Hereditary Medullary Thyroid Cancer

Hereditary MTC accounts for roughly 25% of cases and results from germline mutations in the RET proto-oncogene. It is inherited in an autosomal dominant pattern and subdivided into:

• Multiple Endocrine Neoplasia type 2A (MEN2A): Characterized by MTC, pheochromocytoma (adrenal tumor), and hyperparathyroidism. MEN2A patients are at risk for multiple tumors and require lifelong endocrine surveillance 7 8.
• Multiple Endocrine Neoplasia type 2B (MEN2B): Features MTC, pheochromocytoma, mucosal neuromas, and distinctive physical traits such as a Marfanoid body habitus. This subtype is more aggressive, with earlier onset 7 8.
• Familial Medullary Thyroid Cancer (FMTC): Only MTC is present in affected family members, without other endocrine tumors; generally, the disease is less aggressive than MEN2B 7 8.

Molecular profiling now reveals additional heterogeneity, with three molecular subtypes based on proteomic features: Metabolic, Basal, and Mesenchymal, each with unique genetic drivers and clinical behaviors 4.

Causes of Medullary Thyroid Cancer

Understanding what causes MTC is crucial for prevention, risk assessment, and development of targeted therapies. While many cancer types have environmental risk factors, MTC is notable for its genetic roots.

Cause/Mechanism	Description	Role/Prevalence	Source(s)
RET Mutations	Germline or somatic mutations in RET gene	Main driver in hereditary MTC	3 4 7 8
RAS Mutations	Somatic mutations (mainly in sporadic MTC)	Found in some sporadic cases	4 8
Other Genes	BRAF, NF1, CDKN1B mutations	Emerging/less common drivers	4 7
miRNA Alterations	Differences in miR-127 and others	May influence aggressiveness	7
Family History	Autosomal dominant inheritance in 25% cases	Key risk for hereditary MTC	3 7

Table 3: Causes of MTC

Genetic Mutations: RET and Beyond

• RET Proto-oncogene: The RET gene encodes a receptor tyrosine kinase essential for cell growth and development. Germline mutations in RET are the primary cause of hereditary MTC (MEN2A, MEN2B, FMTC), while somatic RET mutations occur in many sporadic tumors 3 4 7 8.
  • Specific codon mutations (e.g., Cys634Arg in MEN2A) are linked to disease subtype and severity 7.
  • RET testing allows for early identification and prophylactic treatment in at-risk individuals 7 8.
• RAS Mutations: Somatic RAS mutations have been identified in a proportion of sporadic MTCs, providing alternative oncogenic drivers where RET is not mutated 4 8.
• Other Genetic Alterations: Recent studies have identified mutations in BRAF, NF1, and CDKN1B, and emerging evidence suggests miRNA expression differences (like miR-127) may affect tumor behavior 4 7.

Inheritance Patterns and Family Risk

Hereditary cases follow an autosomal dominant inheritance, so first-degree relatives of affected individuals are at significant risk. Genetic counseling and testing are crucial for families with known RET mutations 3 7.

Non-Genetic Factors

Unlike other thyroid cancers, environmental factors (e.g., radiation) are not established causes of MTC. The disease is primarily driven by intrinsic genetic changes 2 3 7.

Treatment of Medullary Thyroid Cancer

Treatment for MTC has advanced considerably, especially with the advent of targeted therapies. However, early diagnosis and complete surgical removal remain the cornerstones of cure.

Therapy Type	Main Approach	Indication/Outcome	Source(s)
Surgery	Total thyroidectomy + lymph node dissection	Standard, curative in localized disease	3 6 7 10
Targeted TKIs	Vandetanib, Cabozantinib	Progressive/metastatic disease	1 5 8 9 11 13
RET-specific TKIs	Next-generation RET inhibitors	Advanced disease with RET mutations	8 9 11
Radiotherapy	External beam for palliation	Local control, not curative	10 13
PRRT	Peptide receptor radionuclide therapy	Advanced/metastatic, clinical trials	12 13
Chemotherapy	Cytotoxic agents	Limited benefit, rarely used	11 13

Table 4: Treatment Modalities

Surgery: The Primary Treatment

• Total Thyroidectomy: Complete removal of the thyroid gland is the definitive treatment for localized MTC. It is often combined with central and lateral neck lymph node dissection to address potential spread 3 6 7 10.
• Prophylactic Surgery: In hereditary MTC, thyroidectomy may be performed preemptively in gene carriers, sometimes in childhood, depending on mutation risk 7 8.

Surgery offers the only chance for cure, especially when performed before metastasis 3 6 7 10.

Systemic Therapies for Advanced Disease

• Targeted Tyrosine Kinase Inhibitors (TKIs): For inoperable, recurrent, or metastatic MTC, multikinase inhibitors (vandetanib and cabozantinib) have shown to improve progression-free survival but do not cure the disease 1 5 8 9 11 13.
  • Next-generation RET-selective TKIs are promising for patients with RET-driven tumors, offering higher potency and fewer side effects 8 9 11.
• Peptide Receptor Radionuclide Therapy (PRRT): Uses radiolabeled somatostatin analogues or CCK2R-targeted agents to deliver targeted radiation. Shows disease stabilization or partial response in many patients with limited toxicity 12 13.
• Chemotherapy: Traditional cytotoxic agents have limited efficacy and are now rarely used, reserved for cases unresponsive to other systemic treatments 11 13.

Radiotherapy and Local Control

• External Beam Radiotherapy: Used for palliation or local control in residual or recurrent disease, especially when surgery is not feasible. It does not improve overall survival 10 13.

Monitoring and Follow-up

• Biochemical Markers: Serum calcitonin and carcinoembryonic antigen (CEA) levels are key for postoperative monitoring and early detection of recurrence 3 11.
• Genetic Testing: Ongoing surveillance for gene carriers in families with hereditary MTC is vital 3 7 8.

Future Directions

• Combination therapies, immunotherapy, and novel targeted agents are under investigation to overcome resistance and improve outcomes in advanced MTC 4 8 9 11 13.

Conclusion

Medullary thyroid cancer is a rare but significant form of thyroid cancer, marked by its neuroendocrine origin, genetic complexity, and variable clinical course. Early diagnosis and complete surgical resection remain vital, but advances in genetic testing and targeted therapies are transforming the management landscape.

Key points covered:

• MTC often presents as a neck lump, with possible local, paraneoplastic, or systemic symptoms.
• It occurs in sporadic and hereditary forms, the latter associated with MEN2 syndromes and RET mutations.
• RET proto-oncogene mutations are the main cause; other genetic and molecular changes also contribute.
• Surgery is the mainstay of treatment; targeted therapies and radionuclide therapy offer hope for advanced disease.
• Ongoing research aims to enhance early detection, expand treatment options, and improve survival for patients with advanced MTC.

By understanding the nuances of MTC, patients and clinicians can work together to optimize outcomes through timely diagnosis, personalized therapy, and vigilant long-term care.