MEDULLARY THYROID CANCER Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

Medullary Thyroid Cancer Medullary thyroid cancer (MTC) is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin. Medullary tumors are the third most common of all thyroid cancers. Medullary Thyroid Cancer 75% Sporadic MTC Inherited MTC MEN (N/A) 25 % Non-MEN familial MTC Outcome depends on extent of disease, nature of tumor biology, and overall efficacy of surgical treatment. Advances in genetic testing in have revolutionized the management of this disease

Characteristics of Medullary Thyroid Cancer Occurs in 4 clinical settings and can be associated with other endocrine tumors More common in females than males (except for inherited cancers) Regional metastases (spread to neck lymph nodes) occurs early in the disease Spread to distant organs occurs late and can be to the: Liver Bone Brain Adrenal medulla Usually originates in the upper central lobe of the thyroid

Medullary Thyroid Cancer Clinical symptoms Lump at the base of neck – difficulty swallowing Locally advanced disease may present with hoarseness, dysphagia, and respiratory difficulty Paraneoplastic syndromes, including Cushing or carcinoid syndrome Diarrhea may occur from secondary to high plasma calcitonin levels Distant metastases (e.g., lung, liver, bone) may result in weight loss, lethargy, and bone pain

Medullary Thyroid Cancer Clinical symptoms Cushing syndrome: May present with paraneoplastic syndromes, including Cushing or carcinoid syndrome Severe diarrhea: The tumor produces high levels of a calcitonin, that may cause severe diarrhea. Facial flushing: A red face, neck, or chest paired with warm or burning sensations may occur Bone pain: People with MTC may have bone pain if the cancer has spread to form bone lesions. Weight loss: Unusual weight loss in advanced MTC that has spread beyond the thyroid into other organs.

Physical Physical examination may demonstrate a dominant thyroid nodule at the base of the neck. Palpable cervical lymphadenopathy signifies disease that has progressed locally. Abdominal pain, jaundice, and rarely, bone tenderness may occur in patients with systemic metastases. Causes Medullary carcinoma of the thyroid (MTC) has a genetic association with multiple endocrine neoplasia (MEN) 2A and 2B. Mutations in RET can lead to MTC development in cells derived from neural crest tissue. Sporadic MTC occurs in 75% of patients. Familial MTC constitutes the other 25%.

Differential diagnosis Anaplastic Thyroid Carcinoma De Quervain Thyroiditis Follicular Thyroid Carcinoma Goiter Graves Disease Hyperthyroidism Intestinal Carcinoid Tumor Medullary Thyroid Carcinoma Papillary Thyroid Carcinoma Thyroid Lymphoma Thyroid Nodule Toxic Nodular Goiter Type 2 Multiple Endocrine Neoplasia

Laboratory Studies Preoperative laboratory testing in patients with possible medullary thyroid carcinoma (MTC) has three purposes: To predict the extent of metastatic disease; this will determine the extent of preoperative imaging and may alter the surgical approach In patients with MEN 2, to identify primary hyperparathyroidism and/or pheochromocytoma —comorbid conditions that alter the surgical approach and surgical priorities To identify RET mutation carriers so that testing of appropriate family members can allow for early diagnosis and treatment of affected individuals

Calcitonin Calcitonin is the principal biochemical marker in MTC; it is used for detection, staging, postoperative management, and prognosis. The higher that the calcitonin levels are above normal, the greater the likelihood of MTC; basal levels of >100 pg/mL have been found to have 100% positive predictive value for MTC. Screening studies in patients with MEN 24-hour urinalysis for catecholamine metabolites (e.g., VMA, metanephrine) to rule out concomitant pheochromocytoma in patients with MEN type 2A or 2B. Pheochromocytoma must be treated before MTC. Screening for the development of familial MTC in family members of patients with a history of MTC or MEN 2A or 2B

Imaging Studies Medullary Thyroid Cancer Preoperative ultrasonography to detect lymph node metastases. Preoperative CT scanning of the chest and neck and abdomen 3-phase,Contrast-enhanced MRI imaging (MRI) to detect metastatic disease Fine-needle aspiration that yields cytological information, allowing diagnosis of MTC.

Medullary thyroid carcinoma on ultrasound with typical small calcifications (arrows)

Fine needle aspirate with immunostaining for calcitonin in medullary cancer of the thyroid. The nuclei of the tumor cells are placed eccentrically and are larger and more pleomorphic than those of normal follicular cells. Immunocytologic staining for calcitonin is positive (brown staining which is best seen at the arrow). The background contains many red cells that nonspecifically take up the stain.

Surgical specimen showing typical histologic appearance of medullary cancer.

Treatment Surgery and radiation therapy have been the major treatments for medullary thyroid carcinoma. A total thyroidectomy with bilateral neck dissection is the gold standard for treating medullary thyroid cancer, and is the most definitive means of achieving a cure in patients without distant metastases or extensive nodal involvement.

Treatment Radiation External beam radiotherapy is recommended when there is a high risk of regional recurrence, even after optimum surgical treatment Unlike other differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease Protein kinase inhibitors Block the abnormal kinase proteins involved in the development and growth of medullary cancer cells, response in 10-30% Vandetanib the first drug approved by FDA for late-stage (metastatic) MTC in patients ineligible for surgery. Side effects of this drug include hypertension, nausea, diarrhea, cardiac electrical abnormalities, thrombotic or bleeding episodes.

Characteristics of Medullary Thyroid Cancer Poor prognostic factors include mean: Older than 50 years old Distant spread (metastases) In patients with other endocrine tumors due to MEN II-B syndrome. Residual disease (following surgery) or recurrence can be detected by measuring calcitonin hormone: Should be measured every 4 months for the first few years and then every 6 months for the rest of life

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