Medullary thyroid cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Medullary thyroid cancer was first discovered by John Beach Hazard, an American pathologist, in 1959.^[1] Medullary thyroid cancer may be classified according to mode of occurrence into 2 groups: sporadic medullary thyroid cancer and inherited medullary thyroid cancer. The development of medullary thyroid cancer is the result of genetic mutation of RET proto-oncogene. On gross pathology, well circumscribed, gray, white, or yellow in color mass is a characteristic finding of medullary thyroid cancer. On microscopic histopathological analysis, polygonal to the spindle to small cells, interstitial edema, and vascular hyalinized stroma are characteristic findings of medullary thyroid cancer. Medullary thyroid cancer is caused by a mutation in the RET proto-oncogene. If left untreated, patients with medullary thyroid cancer may progress to develop metastasis. Common complications of medullary thyroid cancer include vocal cord compression, dysphagia, and dyspnea. The presence of metastasis is associated with a particularly poor prognosis among patients with medullary thyroid cancer. The 5-year event free survival rate is 80%. The hallmark of medullary thyroid cancer is lump in the neck. A positive family history of medullary thyroid cancer or multiple endocrine neoplasia is suggestive of medullary thyroid cancer. The most common symptoms of medullary thyroid cancer include diarrhea, flushing, and dysphagia. Laboratory findings consistent with the diagnosis of medullary thyroid cancer include decreased thyroid stimulating hormone, elevated calcitonin, and decreased calcium. Surgery is the mainstay of treatment for medullary thyroid carcinoma.

Medullary thyroid cancer was first discovered by John Beach Hazard, an American pathologist, in 1959.^[1]

Medullary thyroid cancer may be classified according to the mode of occurrence into 2 groups: sporadic medullary thyroid cancer and inherited medullary thyroid cancer.

The development of medullary thyroid cancer is the result of genetic mutation of RET proto-oncogene. On gross pathology, well circumscribed, gray, white, or yellow color mass is a characteristic finding of medullary thyroid cancer. On microscopic histopathological analysis, polygonal to the spindle to small cells, interstitial edema, and vascular hyalinized stroma are characteristic findings of medullary thyroid cancer.

Medullary thyroid cancer is caused by a mutation in the RET proto-oncogene.

Medullary thyroid cancer must be differentiated from anaplastic thyroid carcinoma, papillary thyroid carcinoma, and Hurthle cell carcinoma.

The incidence of medullary thyroid cancer is approximately 1000 per 100,000 individuals in the United States per year. The incidence of medullary thyroid cancer increases with age; the median age at diagnosis peaks in the 3rd to 4th decades.

Common risk factors in the development of medullary thyroid cancer are a family history of medullary thyroid cancer and a family history of multiple endocrine neoplasia.

According to the American Society of Clinical Oncology, screening for medullary thyroid cancer by RET gene testing is recommended for children with an increased risk of medullary thyroid cancer.

If left untreated, patients with medullary thyroid cancer may progress to develop metastasis. Common complications of medullary thyroid cancer include vocal cord compression, dysphagia, and dyspnea. The presence of metastasis is associated with a particularly poor prognosis among patients with medullary thyroid cancer. The 5-year event-free survival rate is 80%.

According to the American Joint Committee on Cancer (AJCC)^[2] there are 4 stages of medullary thyroid cancer based on the clinical features and findings on imaging. Each stage is assigned a letter and a number that designates the tumor size, number of involved lymph node regions, and metastasis.

The hallmark of medullary thyroid cancer is lump in the neck. A positive family history of medullary thyroid cancer or multiple endocrine neoplasia is suggestive of medullary thyroid cancer. The most common symptoms of medullary thyroid cancer include diarrhea, flushing, and dysphagia.

Patients with medullary thyroid cancer usually appear thin and cachexic. Physical examination of patients with medullary thyroid cancer is usually remarkable for thyromegaly, lymphadenopathy and anxiety.

Laboratory findings consistent with the diagnosis of medullary thyroid cancer include decreased thyroid stimulating hormone, elevated calcitonin, and decreased calcium.

CT scan may be helpful in the diagnosis of medullary thyroid cancer.

Neck ultrasound may be performed to detect medullary thyroid cancer.

Other diagnostic studies for medullary thyroid cancer include nuclear imaging, which demonstrates increased uptake of radioactive iodine in the areas of metastases.

The predominant therapy for medullary thyroid cancer is surgical resection. Adjunctive chemoradiation may be required. The optimal therapy for medullary thyroid cancer depends on the stage at diagnosis.

Surgery is the mainstay of treatment for medullary thyroid carcinoma.

There are no established measures for the primary prevention of medullary thyroid cancer.

There are no established measures for the secondary prevention of medullary thyroid cancer.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Medullary thyroid cancer was first discovered by Dr. John Beach Hazard, an American pathologist, in 1959.

• In 1959, Dr. Hazard described medullary (solid) thyroid carcinoma.^[1][2]
• In 1961, Dr. Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma.
• In 1966, Dr. Williams proposed the C-cells as the origin of medullary thyroid cancer.^[3]
• In 1966, Dr. Pearse proposed the name C-cell indicating their function in calcitonin secrestion.^[4]
• In 1978, Dr. Cameron suggested that medullary thyroid cancer produces thyrocalcitonin from parafollicular cells.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Medullary thyroid cancer may be classified according to the mode of occurrence into 2 groups: sporadic medullary thyroid cancer and inherited medullary thyroid cancer.

• Medullary thyroid cancer may be classified according to the mode of occurrence into 2 groups: sporadic medullary thyroid cancer and inherited medullary thyroid cancer.
• Sporadic medullary thyroid cancer^[1][2]

• Sporadic medullary thyroid cancer (75% of the cases)
• Inherited medullary thyroid cancer (25% of the cases)
  • MEN2A (23%)
  • MEN2B (2%)
  • Familial medullary thyroid cancer (FMTC)(rare)

• Medullary thyroid cancer may be classified according to histologic variants into:^[3]
  • Papillary or pseudopapillary due to the presence of papillary structures or artifactual structures resembling papillae.
  • Glandular
  • Giant cells
  • Spindle cell
  • Small cell and Neuroblastoma-like
  • Paraganglioma-like
  • Onchocytic cell
  • Clear cell
  • Angiosarcoma-like
  • Squamous cell
  • Melanin-producing
  • Amphicrine

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Development of medullary thyroid cancer is the result of genetic mutation of RET proto-oncogene. On gross pathology, well-circumscribed, gray, white, or yellow-colored masses are characteristic findings of medullary thyroid cancer. On microscopic histopathological analysis, polygonal to the spindle to small cells, interstitial edema, and vascular hyalinized stroma are characteristic findings of medullary thyroid cancer.

• Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.^[1]
• Mutations in the RET proto-oncogene (REarranged during Transfection), located on chromosome 10, lead to the expression of a mutated receptor tyrosine kinase protein.
• RET proto-oncogene is involved in the regulation of cell growth and development and its germline mutation is responsible for nearly all cases of hereditary or familial medullary thyroid carcinoma.
• Germline mutation of RET may also be responsible for the development of hyperparathyroidism and pheochromocytoma.
• Medullary thyroid cancer may be sporadic or hereditary as part of MEN type 2 A and B.^[2][3]
• Sporadic form accounts for 80% of the cases. This form usually occurs unilaterally.
• Medullary thyroid carcinoma is a subtype of thyroid cancer which accounts for 5-10% of all thyroid malignancies.
• It is characterized by consistent production of a hormonal marker called calcitonin.
• Metastatic involvement may be seen in up to 50% at the time of presentation.
• Approximately 25% of reported cases of medullary thyroid carcinoma are familial.
• Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait.
• In the familial form, the tumor is almost always bilateral.
• In addition, the familial form may be associated with benign or malignant tumors of other endocrine organs, commonly referred to as the multiple endocrine neoplasia syndromes.
• Familial medullary thyroid carcinoma syndromes include:^[4]
• Multiple endocrine neoplasia type 2A
• Multiple endocrine neoplasia type 2B
• familial non-multiple endocrine neoplasia syndromes
• Medullary carcinoma usually presents as a hard mass and is often accompanied by blood vessel invasion.
• Metastases to regional lymph nodes are found in about 50% of cases.

• Medullary thyroid cancer is associated with RET proto-oncogene mutations.^[5]

• Medullary thyroid cancer may be associated with:^[6][7][8]
  • MEN2A
  • MEN2B
  • Pheochromocytoma
  • Parathyroid adenoma
  • Cutaneous lichen amyloidosis
  • Mucosal neuroma
  • Von Hippel-Lindau Disease
  • Neurofibromatosis type 1

• Medullary thyroid cancer is usually a well circumscribed, gray, white, or yellow colored mass which is gritty to firm in consistency.^[9]

• On microscopic histopathological analysis, presence of amyloid is a characteristic finding of medullary thyroid cancer.^[10][11]
• Other microscopic features associated with the diagnosis of medullary thyroid cancer include:
  • The majority of tumor cells are epithelioid, but spindle cells may be found as well.
  • The nuclei demonstrate the characteristic granular appearance known as salt-and-pepper.
  • The cytoplasm of tumor cells contains perinuclear calcitonin-containing azurophilic granules that are best seen in samples stained with the May–Grünwald–Giemsa stain.

Medullary thyroid cancer	Image	Image
Medullary thyroid carcinoma
Medullary thyroid cancer amyloid
Thyroid MedullaryCarcinoma Comedonecrosis
Medullary thyroid carcinoma spindle cell
Medullary thyroid carcinoma spindle cell

• For more images of medullary thyroid cancer please click here

• Markers associated with medullary throid cancers include:^[12][13][10]
  • Calcitonin
  • Chromogranin
  • CEA
  • Calcitonin gene-related peptide (CGRP)
  • Somatostatin
  • Serotonin

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Medullary thyroid cancer is caused by a mutation in the RET proto-oncogene.

• Development of sporadic medullary thyroid cancer is the result of somatic mutation of RET proto-oncogene.^[1][2][3]
• Hereditary form of medullary thyroid cancer is the result of germline mutation of RET proto-oncogene that are associated with MEN 2 syndromes.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Ammu Susheela, M.D. [3]

Medullary thyroid cancer must be differentiated from anaplastic thyroid carcinoma, papillary thyroid carcinoma, paraganglioma, carcinoid tumor, and Hurthle cell carcinoma.

• Medullary thyroid cancer must be differentiated from the following:

• Anaplastic thyroid carcinoma
• Papillary thyroid carcinoma
• Hurthle cell carcinoma
• Paraganglioma
• Carcinoid
• Metastatic Melanoma

Disease Name	Age of Onset	Gender Preponderance	Signs/Symptoms	Imaging Feature(s)	Macroscopic Feature(s)	Microscopic Feature(s)	Laboratory Findings(s)	Other Feature(s)	Microscopic Appearance
Medullary Thyroid Cancer[1][2][3][4]	Incidence increases with age More common in the 3rd to 4th decades of life	Both genders are affected equally	Solitary thyroid nodule Mostly affects upper lobe of thyroid gland Possible systemic symptoms due to hormonal secretion by the tumor Cervical lymphadenopathy	On ultrasound: Solitary hypoechoic nodule with or without calcification Imaging features are not characteristic of this cancer	Single non-encapsulated mass Gray-tan color	Sheets of cells in an amyloid stroma	Secretes calcitonin Normal thyroid function tests Carcinoembryonic antigen (CEA) may be used as a tumor marker Rarely negative for calcitonin	Can be part of MEN 2A and 2B syndrome Can be associated with RET mutation
Papillary Thyroid Cancer[5][6][4]	More common in the middle aged (30 – 50 years of age)	More commonly affects women	Asymptomatic thyroid mass or nodule Compressive symptoms, such as: Difficulty swallowing/breathing Persistent cough Stridor Vocal chord paralysis Rapid enlarging mass	On ultrasound Solitary mass with an irregular outline Located in the sub-capsular region High vascularity Imaging features are not characteristic of this cancer	Solitary hypoechogenic nodule with lobulated margin which may extend into adjacent tissues Calcification may be present or not	Empty-appearing nuclei with central clearing (Orphan Annie eye) Psammoma bodies	Thyroid function tests can be normal Serum thyroglobulin can be used as a tumor marker	History of radiation to the head and neck BRAF and/or RET mutation may be present The most common type of thyroid cancer
Follicular Thyroid Cancer[6][4][7]	Peak incidence at 40 – 60 years of age	More commonly affects women	Asymptomatic thyroid mass or nodule Compressive symptoms, such as: Difficulty swallowing/breathing Persistent cough Stridor Vocal chord paralysis Rapid enlarging mass	On ultrasound: Solid hypoechoic nodule with a peripheral halo indicating fibrous capsule Irregular margin Imaging features are not characteristic of this cancer	Single encapsulated nodule Thick and irregular capsule Can be cystic or hemorrhagic in appearance	Invades thyroid capsule and vasculature Uniform follicles	Thyroid function tests can be normal Serum thyroglobulin can be used as a tumor marker	RAS mutation may be present PAX8–PPARγ translocations
Anaplastic Thyroid Cancer[8][9][10]	More common among older individuals Mean age at diagnosis is 65 years	More commonly affects women	Rapidly enlarging thyroid mass May manifest with compressive symptoms Can present with signs/symptoms of metastasis Constitutional symptoms may be present Hard nodular goiter without tenderness	On ultrasound: Solid hypoechoic nodule with a peripheral halo indicating fibrous capsule Irregular margin Imaging features are not characteristic of this cancer	Solid tumor with areas of necrosis and hemorrhage Infiltrative pattern	Undifferentiated, devastatingly aggressive variant of papillary/follicular thyroid cancer	Normal thyroid function tests	Poor prognosis May be associated with TP53 mutation
Follicular Adenoma[11]	More commonly affects individuals older than 50 years of age	More commonly affects women	Asymptomatic or symptoms of hyperthyroidism	Solitary nodule which may show echogenicity or not	Solitary, spherical, and encapsulated lesion Well demarcated from the surrounding parenchyma	Uniform follicles Absence of capsular or vascular invasion	Functional adenoma: Elevated T3, T4 Decreased TSH	May be considered functional or hot May be considered non-functional or cold
Multinodular Goiter[12]	Commonly affects individuals older than 60 years of age	More commonly affects women	Thyroid enlargement Signs/symptoms of hypo/hyperthyroidism	Multiple nodules with different echogenicity Calcification may be present	Multiple thyroid nodules	Variable sized follicles Some may show papillary projections without nuclear characteristics of papillary thyroid cancer	Classified as toxic and non-toxic Toxic: Hyperthyroidism Non-toxic: Normal thyroid function tests	Benign condition
Thyroid Lymphoma[13] [14][15][16]	Affects adults or elderly	More common among women	Rapidly enlarging mass/nodule of thyroid Compressive symptoms may be present Constitiutional symptoms can be present in 10% P/E:Firm, hard thyroid Fixed to the nearby structures Immobile even during swallowing Cervical or supraclavicular lymphadenopathy may be present	On ultrasound: Hypoechogenic appearance Difficult to distinguish from chronic thyroiditis	Thyroid nodule/mass Fixed to adjacent tissue Firm texture	It is of B cell lineage in the majority of cases Dffuse, large B-cell lymphomas is the most common subtype Marginal zone lymphoma is the second most common type	No specific test Some patients may have hypothyroidism Patients can also have antibodies against thyroid peroxidase or thyroglobulin	Preexisting chronic autoimmune (Hashimoto’s) thyroiditis is a known risk factor for this condition

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

The incidence of medullary thyroid cancer is approximately 14.3 per 100,000 individuals worldwide. The incidence of medullary thyroid cancer increases with age; Sporadic form of medullary thyroid cancer commonly presents in the fifth and sixth decade of life. The familial form tends to appear earlier in life.

• The overall incidence of thyroid cancer is approximately 14.3 per 100,000 individuals worldwide.^[1][2]

• The incidence of medullary thyroid cancer increases with age.^[3]
• Sporadic form of medullary thyroid cancer commonly presents in the fifth and sixth decade of life.^[4]
• The familial form tends to appear earlier in life.

• Medullary thyroid cancer affects women more frequently than men. However, this gender disparity tends to decrease by advancing the age of individuals.^[3]

• Medullaty thyroid cancer is more common among white and hispanic ethnicities than Asian/Pacific Islanders and blacks.^[3][5]

• The overall mortality rate of thyroid cancer is 0.5 per 100,000 worldwide.^[2]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Common risk factors in the development of medullary thyroid cancer are family history of medullary thyroid cancer and family history of multiple endocrine neoplasia.

• Common risk factors associated with medullary thyroid cancer include:^[1][2]
  • Family history of medullary thyroid cancer
  • Family history of multiple endocrine neoplasia
  • A prior history of pheochromocytoma, mucosal neuroma, or hyperparathyroidism

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

According to the US preventive service task force, screening for medullary thyroid cancer is not recommended.

• According to the US preventive service task force, screening for medullary thyroid cancer is not recommended.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

If left untreated, patients with medullary thyroid cancer may progress to develop metastasis. Common complications of medullary thyroid cancer include vocal cord compression, dysphagia, and dyspnea. The presence of metastasis is associated with a particularly poor prognosis among patients with medullary thyroid cancer. The 5-year event-free survival rate is 80%.

• The symptoms of sporadic medullary thyroid cancer usually develop in the fifth and sixth decade of life and start with a nodule in the upper lobe of the thyroid.^[1]
• In 50% of the patients, the initial presentation may be metastatic cervical adenopathy.
• Symptoms of adjacent structures compression or invasion may manifest in 15% of the patients.
• Without treatment, the patient will develop symptoms of metastasis such as to lungs and/or bones, which may eventually lead to death.

• Possible complications of medullary thyroid cancer include:
  • Metastases to lung, bones, liver, and brain^[1]
  • Hypocalcemia after surgery due to parathyroid removal
  • Dysphagia
  • Hoarseness
  • Diarrhea
  • Cushing’s syndrome

• Medullary thyroid cancer prognosis depends on the stage of the disease at the time of diagnosis.^[2][3]
• The 5-year relative survival rate is 93% for stage I to III.
• The 5-year survival rate for stage IV is 28%.
• Medullary thyroid cancer is associated with a 5-year survival rate of 86% and 10-year survival rate of 65%.

Template:WikiDoc Sources