Medullary carcinoma of the thyroid

Medullary thyroid cancer comprises 3-5% of all thyroid cancers.

MTC is responsible for 8% of thyroid cancer related deaths.

Its recurrence and disease specific mortality rates significantly exceed those of well differentiated thyroid cancer.

Most commonly presents as a solitary thyroid nodule in patients in the 4th-6 decade of life.

MTC is a neuroendocrine tumor that arises from the C cells of the thyroid, which do not accumulate radioiodine but do secrete calcitonin.

Sporadic, or isolated, MTC accounts for 75% of cases; the remaining 25% are part of multiple endocrine neoplasia type 2 (MEN2), an autosomal-dominant syndrome caused by germline-activating mutations in the RET proto-oncogene.

Despite advances in genetic screening for the RET proto-oncogene, preliminary population studies have yet to show a definitive impact on disease prognosis. 

Approximately 15 to 20% of patients with MTC cases are familial and associated with germline mutations in the rearranged during transfection (RET) protooncogene multiple endocrine neoplasia type two (MEN2).

Medullary thyroid cancer (MTC) is usually diagnosed on physical examination as a solitary neck nodule. 

Early spread to regional lymph nodes is common.

Distant metastases occur in the liver, lung, bone, and brain.

Because of its propensity for vascular invasion, lymph node involvement and distant metastasis, MTC is difficult to cure.

It is often associated with an indolent clinical course, and may take years or decades to progress, with an overall survival of approximately 70 to 80% at 10 years.

Occasionally lymph nodes in the neck are the first manifestation because metastases occur in cervical lymph nodes frequently.

70% of patients with a palpable medullary thyroid cancer have evidence of cervical lymph node metastases at the time of surgery.

Patients presenting with a thyroid nodule, flushing and diarrhea suggest the presence of widespread metastatic disease.

25% of medullary thyroid cancer occur in patients with an inherited multiple endocrine neoplasia syndrome.

Sporadic MTC usually is unilateral,and occurs in 75% of cases.

MTC in association with multiple endocrine neoplasia (MEN) syndromes is always bilateral and multicentric, with presentation earlier in life.

MTC is typically the first abnormality observed in both MEN 2A and 2B syndromes.

Estimated 1300-2200 cases in 2010 in the United States.

Clinical course is generally indolent and frequently involves early lymphatic dissemination.

More aggressive than differentiated thyroid cancers, but overall an indolent malignancy with 10 year survival rates of 69-89%.

Can be aggressive with high mortality.

Prognosis depends on patient age, histologic grade, and status of surgical resection.

All cases should be checked for germline RET mutations to determine if it is hereditary.

Patients with a worse prognosis tend to be older, have higher-grade lesions, and have undergone incomplete surgical resection of the lesion. 

The 5-year relative survival for stages I to III is about 93% compared to 28% for stage IV. 

Disease-free survival (DFS) in younger patients (< 21 y) with hereditary MTC was best predicted by TNM staging and preoperative basal calcitonin level of less than 30 pg/mL. 

Basal calcitonin >30 ng/L, genotypic mutations at codon 918 of the RET gene, and young age of symptom onset were key factors in deciding surgical timing, with consideration for thyroidectomy versus screening by age 5 due to high risk. 

In a meta-analysis of 27 studies involving 984 MTC patients who underwent reoperation, it was found that normalization of calcitonin after reoperation occurred in 16.2% of patients overall. Patients who underwent targeted selective lymph node removal procedures showed normalization of calcitonin in only 10.5% of cases, while normalization was seen in 18.6% of those who underwent compartment-oriented procedures.

In patients who present with metastatic disease have a median survival of 3 years.

Isolated medullary carcinoma of the thyroid (MTC) typically demonstrates a relatively indolent biologic progression.

While regional lymph node metastases are possible, the lesion may not spread outside of the cervical region until several months later.

MTC associated with multiple endocrine neoplasia (MEN) syndromes may have a more aggressive course, which also depends on associated comorbidity (eg, pheochromocytoma indicative of the more aggressive MEN2B).

Malignant neoplasm of neuroendocrine parafollicular C cells that represents about 5-10% of thyroid tumors.

Permanent hypoparathyroidism and recurrent laryngeal nerve palsy reportedly occur in less than 2% of virgin neck dissections. 

Reoperation is associated with a considerably higher risk of these injuries.

Arises from the neural crest, specifically the parafollicular C cells of the thyroid gland.

C cells constitute approximately 1% of thyroid cells.

C cells are located throughout the thyroid gland but mainly at the junction of the upper third and lower two-thirds, where the majority of medullary thyroid cancers are found.

C cells secrete a variety of peptides and hormones and medullary carcinoma of the thyroid is characterized by calcitonin secretion.

Calcitonin is a diagnositic and prognostic maker.

Serum calcitonin of greater than 100 pg/mL is considered suspicious for MTC.

Calcitonin and CEA are both tumor markers for MTC: with a good prognosis they exhibit slowly increasing levels.

When doubling time of these 2 markers is more than two years they have a 10 year survival.

When the doubling times of these two tests are less than two years overall survival is poor.

CEA is elevated greater than 50% of patients.

CEA of greater than 30 ng/mL is suggestive of a poor prognosis and is unlikely surgical intervention will be curative.

CEA greater than 100 ng/mL suggests extensive lymph node involvement and distant metastases.

An increasing CEA in the presence of the stable calcitonin level suggests dedifferentiation of the tumor and a worse prognosis.

A rapid drop CEA levels following since surgery suggest high likelihood of cure.

MTC cells can produce several other hormones, including corticotropin, serotonin, melanin, and prostaglandins.

Paraneoplastic syndromes (eg, carcinoid syndrome, Cushing syndrome) can occur in these patients.

Chromogranin A is a useful marker for prognosis and diagnosis in MTC.

Cervical lymph node involvement in 31-33% of T1 cases, 53% of T2 cases and 100% of T3-4 cases.

The sporadic form of disease more often presents as a palpable nodule versus familial medullary thyroid carcinoma.

Contralateral and upper mediastinal nodes are at risk for local regional spread of the disease.

Distant metastases are observed in only 2-33% of the cases during the primary staging.

The incidence of distant metastases is 45% as the disease progresses.

Survival rate at 10 years 95% for patients with tumor limited to the thyroid.

10 year survival is less than 50% in patients with distant metastatic disease.

Clinical course of MTC is usually more aggressive than that of differentiated thyroid cancer with higher rates of recurrence and mortality, particularly in young individuals.

Sproadic MCT typically present in the 5th or 6th decades.

Sporadic disease has a slight female preponderance.

MEN2A and familial medullary carcinoma of the thyroid typical present in the 3rd decade of life.

MEN2A is the most common of MEN2 disorder and includes MTC, pheochromocytoma, and primary hyperparathyroidism.

MTC is the predominant disorder, greater than 95%, in MEN2A and accounts for 75% of the hereditary MTC.

MEN2A Is characterized by multifocal and bilateral disease presenting in early adulthood.

MEN2A mortality associated with MTC and early recognition and intervention are necessary so the process can be cured or prevented by early thyroidectomy screening at risk family members.

MEN2A associated with pheochromocytomas and up to 50% of cases..

MEN2A associated with hyperparathyroidism in up to 20-35% of patients.

MEN2B associated MCT presents in individuals younger than 20 years.

MEN2B patients develop medullary carcinoma of the thyroid and a very early age with a very aggressive course.

100% of patients with MEN2B develop medullary carcinoma of the thyroid at a young age, so the diagnosis is delayed and these patients are seldom cured.

Prophylactic curative thyroidectomy is required in the neonatal period in the patients identified by genetic screening.

Most common presentation of sporadic MTC is a neck mass-either an enlarged thyroid nodule or a metastatic lymph node.

Sporadic MTC lesions usually unifocal and start in the posterior thyroid, and may invade surrounding tissues with hoarseness dysphagia and dyspnea.

Elevated levels of calcitonin may need to diarrhea, weight loss or flushing.

10-15% of patients with sporadic disease present metastatic disease most commonly mediastinum, liver, lungs, and bone.

Patients with MTC in the MEN2 syndrome, we have multifocal and bilateral disease.

Patients with MTC in the MEN2 syndrome may have been associated pheochromocytoma, hyperparathyroidism and have flushing, diarrhea, and weight loss due to elevated calcitonin levels.

Patients with MTC in the MEN2 syndrome rarely can have Cushing’s syndrome secondary to ectopic corticotropin production by the tumor.

Most patients with familial MTC or MEN2 are now identified by genetic testing of at risk family members.

Patients with a family history of germline mutation of the RET gene have a 50% chance of inheriting the same mutation.

RET gene genetic carriers have a 100% lifetime risk of developing malignancy.

10 year disease specific survival rate is approximately 75% (Kloos RT et al).

55% 10-year survival for patients stage III and IV.

All patients with preoperative diagnosis of MTC should be screened for pheochromocytoma and hyperparathyroidism.

Sporadic form 70-80% of cases, whereas the remaining 20-30% of cases are represented by three familial forms.

Sporadic disease usually presents in the fifth and sixth decades of life, while familial forms present at earlier ages.

3 hereditary forms-familial medullary thyroid carcinoma, multiple endocrine neoplasia types 2A and 2 B.

MTC tumors are vascular and have increased expression of vascular endothelial growth factor (VEGF) is associated with increased tumor growth and invasiveness.

C cells of predominantly located in the upper portion of the thyroid lobes, and therefore patients with sporadic disease present with upper pole nodules.

Cervical adenopathy and metastatic disease is seen at initial presentation in about 50% of patients.

Metastases are present in more than 70% of patients with palpable disease.

About 15% of patients upper aerodigestive symptoms related to tumor invasion or compression, in patients with sporadic disease.

5-10% of patients will have lung or bone metastases.

Diagnosis most commonly made by fine needle aspiration of the thyroid nodule, with an accuracy of 50-80%.

Surgery is the only successful treatment to cure this disease.

Surgery remains the standard of care for localized disease and for oligometastatic disease. 

Recommended to have a total thyroidectomy and unilateral modified neck dissection in sporadic disease and bilateral cervicolateral dissection in the hereditary form of the disease.

Management relies on aggressive upfront surgical, resection, including total thyroidectomy, and bilateral central neck dissection.

There is a movement to less aggressive surgery with hemithyroidectomy with comparable results.

Local regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of staged approach to clinically node negative lateral neck.

When recurrent disease is technically resectable reoperative surgery can be undertaken with minimal morbidity.

The above adds to the growing body of evidence that prophylactic lateral dissection is not indicated in clinically node negative patients.

MTC does not respond to radioactive iodine or conventional chemotherapy.

In patients with palpable disease total thyroidectomy is the appropriate treatment accompanied by a central neck node dissection.

Calcitonin levels are elevated in all patients with palpable medullary thyroid cancer.

In patients with probable disease removal of all of nodal tissue in the central neck improves recurrent and survival rates when compared to procedures that remove only grossly involved lymph nodes.

Lateral compartment lymph node involvement is related to the extent of nodal disease in the central nodal compartment, and resection of lateral nodes should be based on the findings of central notable disease.

Hereditary forms associated with multicentric carcinomas in 56%-85% of patients.

The process is multifocal and the bilateral in approximately 90% of patients with hereditary forms of the disease, and only in 20% of patients with the sporadic form.

Mutations of the RET proto-oncogene leading to increased tyrosine kinase activity and cell growth, identified as the underlying cause.

Germline mutations in the RET proto-oncogene cause hereditary MTC, and somatic RET mutations are present in up to 50% of patients with sporadic disease.

Majority of patients with hereditary form have a mutation in the RET kinase gene and 25% of patients with the sporadic form have this mutation.

10-20% of MCTs the germline mutation in RET causes the hereditary syndrome of multiple endocrine neoplasia type 2A or 2B, which is associated with pheochrmocytoma and parathyroid hyperplasia.

MEN2 syndromes have strong correlations between mutant RET genotype and clinical phenotype.

Mutations in RET codon 634 commonly leads to MTC and pheochromocytoma.

Mutations in RET codon 883 leads to MTC but rarely pheochromocytoma.

In 80-90% of cases the disease arises sporadically in C cells.

The majority of sporadic MCTs are related to M918T mutation.

All patients with or who are at risk for MTC should undergo genetic screening for germline RET mutations.

The diagnosis of pheochromocytoma must be excluded in all cases of MTC prior to surgery, and if present should be removed before thyroidectomy.

After completion of primary treatment persistent or recurrent hypercalcitoninemia is reported to occur in 29-85% of the cases.

Calcitonin, a hormone secreted by thyroid C cells is used as a clinical biomarker for the detection of medullary thyroid cancer.

Calcitonin levels are almost always elevated in patients with medullary thyroid of cancer.

Calcitonin is a biomarker for detection of medullary thyroid cancer, and serum levels below 10 pg/mL are considered to be evidence of the absence of medullary thyroid cancer, whereas levels above 100 pg/mL are highly predictive of medullary thyroid cancer.

The tumor may secrete measurable levels of calcitonin and active peptides such as ACTH or calcitonin-Jean related peptide which can contribute to the presence of diarrhea, Cushing’s syndrome or facial flushing in patients with extensive disease.

High levels of calcitonin are associated with diarrhea.

Most patients with sporadic disease and some patients with hereditary MTC diseasepresent with a thyroid nodule.

Patients with a thyroid nodule have clinically enlarged nodes in up to 75% of patints.

MTC cells do not concetrate radioactive iodine, and patients present with a cold nodule on thyroid scans.

Hormone therapy for suppression of the disease is ineffective.

Neck ultrasound can categorize neck masses and additional thyroid lesions or suspicious lymph nodes and help to perform a fine needle aspiration to confirme the diagnosis.

Histologically there are uniform cells with stromal amyloid deposition,C-cell hyperplasia of greater than 6 cells per follicle.

In evaluation CT scan or MRI of the neck and chest may demonstrate involvement of lymph nodes deep in the neck or in the mediastinum not seen by ultrasound.

If preoperative calcitonin level is greater than 400 pg per mL, or there are local lymph node metastases patient should undergo CT scan or MRI of the liver.

PET scans have variable sensitivity, which is increased when calcitonin levels are greater than 1000 pg per mL.

CT scan may show thyroid nodules with calcifications and possible of extrathyroidal disease.

Fine needle aspiration of a palpable nodule or a cervical lymph node is a sensitive diagnostic tool.

The tumor may invade the adjacent larynx, trachea, esophagus, and recurrent laryngeal nerve involvement.

In familial disease the nodules are usually bilateral and multifocal.

Lymph node involvement is usually an early event, with Level VI and VII central nodes most often involved, followed by levels II through V on the ipsilateral side.

Contralateral neck lymph node involvement is also frequent, and metastases to the mediastinum may occur.

Metastases to the lung, liver and bones can occur and metastases may be miliary and difficult to diagnose.

In patients with palpable disease hoarseness, dysphagia, and respiratory problems are present in approximately 15% of patients, and 10-15% will have metastases.

Patients may develop pheochromocytoma and hyperparathyroidism.

Arises from the parafollicular C cells.

Radiotherapy and chemotherapy considered to be inefficient.

10-year survival influenced by age, stage, and postoperative basal calcitonin levels (Rendl G et al).

Advances in genetic testing have revolutionized the management of MTC by allowing risk stratification of patients with inherited mutations and identifying molecular targets for therapy. 

Prophylactic thyroidectomy is indicated for patients who carry mutations that put them at risk for aggressive MTC.  

Patients with advanced disease respond in phase I trials to XL184 and sorafenib combined with tipifarnib which inhibit the RET kinase enzyme along with other pathways.

Vandetanib (Zactima, Caprelsa) effective treatment.

A small molecule tyrosine kinase inhibitor of RET, EGFR, and vascular endothelial growth factor kinases.

Vandetanib is a once daily oral drug that targets RET dependent, VEGF receptor dependent, and epidermal growth factor receptor dependent signaling.

Vandetanib (Zactima, Caprelsa) is recommended at a dose of 300 mg orally once daily, and for patients with moderate renal impairment with severe impairment the starting dose should be 200 mg daily.

Vandetanib (Zactima, Caprelsa) was utilized in a randomized double-blind trial involving 331 patients with unresectable locally advanced and metastatic disease and was associated with a median progression free survival of 22.6 months compared with 16 point one month with placebo.

Vandetanib (Zactima) associated with diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue and rash.

Vandetanib can prolong the QT interval and Torsades de pointes and sudden death have occurred in patients.

Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome.

Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to vandetanib administration and electrolytes should be monitoried periodically.

A phase 3 study of Cabozantinib has met the requirements progression free survival in patients with progressive, unresectable, locally, or metastatic performance of medullary thyroid cancer.

EXAM trial of Cabozantinib of 330 patients with medullary thyroid cancer showed a medium PFS of 6.7 months versus 3.4 months with placebo.

Sorafenib approved for treatment.

The combination of sorafenib and everolimus has a 40% response rate and 40% progression free survival of 6.8 months (Sherman E et al).

RET inhibitor ((Selpertinib)) has demonstrated durable efficacy.

Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib  in patients with RET-mutant medullary thyroid cancer (LIBRETTO investigators).

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