Medullary thyroid cancer
Encyclopedia
Medullary thyroid cancer (MTC) is a form of thyroid carcinoma
which originates from the parafollicular cell
s (C cells), which produce the hormone calcitonin
.
Approximately 25% of medullary thyroid cancer is genetic in nature, caused by a mutation in the RET proto-oncogene
. This form is classified as familial MTC. When MTC occurs by itself it is termed sporadic MTC. When it coexists with tumors of the parathyroid gland and medullary component of the adrenal glands (pheochromocytoma
) it is called multiple endocrine neoplasia type 2 (MEN2
).
It was first characterized in 1959.
.
A second marker, carcinoembryonic antigen
(CEA), also produced by medullary thyroid carcinoma, is released into the blood and it is useful as a serum
or blood
tumor marker
. In general measurement of serum CEA is less sensitive than serum calcitonin for detecting the presence of a tumor, but has less minute to minute variability and is therefore useful as an indicator of tumor mass.
, located on chromosome 10, lead to the expression
of a mutated receptor tyrosine kinase
protein, termed RET (REarranged during Transfection). RET 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. Its germline mutation may also be responsible for the development of hyperparathyroidism
and pheochromocytoma
. Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50/50 probability of inheriting the mutant RET proto-oncogene
from the affected parent. DNA analysis makes it possible to identify children who carry the mutant gene; surgical removal of the thyroid in children who carry the mutant gene is curative if the entire thyroid gland is removed at an early age, before there is spread of the tumor. The parathyroid tumors and pheochromocytomas are removed when they cause clinical symptomatology. Hereditary medullary thyroid carcinoma or multiple endocrine neoplasia (MEN2) accounts for approximately 25% of all medullary thyroid carcinomas.
Seventy-five percent of medullary thyroid carcinoma occurs in individuals without an identifiable family history and is assigned the term "sporadic". Individuals who develop sporadic medullary thyroid carcinoma tend to be older and have more extensive disease at the time of initial presentation than those with a family history (screening is likely to be initiated at an early age in the hereditary form). Approximately 25-60% of sporadic medullary thyroid carcinomas have a somatic mutation (one that occurs within a single "parafollicular" cell) of the RET proto-oncogene
. This mutation is presumed to be the initiating event, although there could be other as yet unidentified causes.
; occasionally a patient will have flushing
episodes. Both occur particularly with liver
metastasis
. Occasionally, diarrhea or flushing will be the initial presenting complaint. The flushing that occurs in medullary thyroid carcinoma is indistinguishable from that associated with carcinoid
syndrome. The presumed cause of flushing and diarrhea is the excessive production of calcitonin
gene products (calcitonin
or calcitonin gene-related peptide
) and differs from the causation of flushing and diarrhea in carcinoid
syndrome. Sites of spread of medullary thyroid carcinoma include local lymph nodes in the neck
, lymph nodes in the central portion of the chest
(mediastinum
), liver
, lung
, and bone
. Spread to other sites such as skin or brain occurs but is uncommon.
Unlike other differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease.
External beam radiotherapy
should be considered for patients at high risk of regional recurrence, even after optimum surgical treatment. A retrospective study in 1996 found that external beam radiation was beneficial in some patients.
In April 2011 Vandetanib
became the first drug to be approved by US FDA for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.
In October 2011, Cabozantinib
met its primary endpoint in a phase 3 trial (EXAM) conducted by Exelixis
investigating its effect on progression-free survival for patients with medullary thyroid cancer. A new drug application
is pending for the first half of 2012.
By overall cancer staging
into stages I to IV, the 5-year survival rate is 100% at stage
I, 98% at stage II, 81% at stage III and 28% at stage IV.
The prognostic value of measuring calcitonin
and carcinoembryonic antigen
(CEA) concentrations in the blood in patients with abnormal calcitonin levels postsurgery has been recently published (2005) in a retrospective study of 65 MTC patients; see Barbet, et al.. The post-surgical times ranged from 2.9 years to 29.5 years; all 65 patients continued to have abnormal calcitonin levels after total thyroidectomy and bilateral lymph node dissection. The prognosis of surviving MTC appears to be correlated with the rate at which a patient's postoperative calcitonin concentration doubles, rather than the pre- or postoperative absolute calcitonin level.
The result of the 65 patient study can be summarized with respect to the calcitonin doubling time (CDT):
CDT < 6 months: 3 patients out of 12 (25%) survived 5 years. 1 patient out of 12 (8%) survived 10 years. All died within 6 months to 13.3 years.
CDT between 6 months and 2 years: 11 patients out of 12 (92%) survived 5 years. 3 patients out of 8 (37%) survived 10 years. 4 patients out of 12 (25%) survived to the end of the study.
CDT > 2 years: 41 patients out of 41 (100%) were alive at the end of the study. These included 1 patient whose calcitonin was stable, and 11 patients who had decreasing calcitonin levels.
The 65 patients had a median age of 51 (range was 6 to 75), with 24 age 45 years or younger and 41 older than 45 years. The gender representation was 31 males and 34 females. All patients shared the following characteristics: 1) had total thyroidectomy and lymph node dissection; 2) had non-zero calcitonin levels after surgery; 3) had at least 4 serum calcitonin measurements after surgery; 4) had a status that could be confirmed at the conclusion of the study.
The same study noted that calcitonin doubling time is a statistically better predictor of MTC survival, compared with CEA.
Thyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...
which originates from the parafollicular cell
Parafollicular cell
Parafollicular cells are cells in the thyroid that produce and secrete calcitonin. They are located adjacent to the thyroid follicles and reside in the connective tissue. These cells are large and have a pale stain compared with the follicular cells or colloid...
s (C cells), which produce the hormone calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
.
Approximately 25% of medullary thyroid cancer is genetic in nature, caused by a mutation in the RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
. This form is classified as familial MTC. When MTC occurs by itself it is termed sporadic MTC. When it coexists with tumors of the parathyroid gland and medullary component of the adrenal glands (pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
) it is called multiple endocrine neoplasia type 2 (MEN2
Multiple endocrine neoplasia type 2
Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary...
).
It was first characterized in 1959.
Markers
While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in bloodBlood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
.
A second marker, carcinoembryonic antigen
Carcinoembryonic antigen
Carcinoembryonic antigen is a glycoprotein involved in cell adhesion. It is normally produced during fetal development, but the production of CEA stops before birth. Therefore, it is not usually present in the blood of healthy adults, although levels are raised in heavy smokers...
(CEA), also produced by medullary thyroid carcinoma, is released into the blood and it is useful as a serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
or blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
tumor marker
Tumor marker
A tumor marker is a substance found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types. There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer...
. In general measurement of serum CEA is less sensitive than serum calcitonin for detecting the presence of a tumor, but has less minute to minute variability and is therefore useful as an indicator of tumor mass.
Genetics
Mutations (DNA changes) in the RET proto-oncogeneRET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
, located on chromosome 10, lead to the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of a mutated receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
protein, termed RET (REarranged during Transfection). RET 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. Its germline mutation may also be responsible for the development of hyperparathyroidism
Hyperparathyroidism
Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone . The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels...
and pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
. Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50/50 probability of inheriting the mutant RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
from the affected parent. DNA analysis makes it possible to identify children who carry the mutant gene; surgical removal of the thyroid in children who carry the mutant gene is curative if the entire thyroid gland is removed at an early age, before there is spread of the tumor. The parathyroid tumors and pheochromocytomas are removed when they cause clinical symptomatology. Hereditary medullary thyroid carcinoma or multiple endocrine neoplasia (MEN2) accounts for approximately 25% of all medullary thyroid carcinomas.
Seventy-five percent of medullary thyroid carcinoma occurs in individuals without an identifiable family history and is assigned the term "sporadic". Individuals who develop sporadic medullary thyroid carcinoma tend to be older and have more extensive disease at the time of initial presentation than those with a family history (screening is likely to be initiated at an early age in the hereditary form). Approximately 25-60% of sporadic medullary thyroid carcinomas have a somatic mutation (one that occurs within a single "parafollicular" cell) of the RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
. This mutation is presumed to be the initiating event, although there could be other as yet unidentified causes.
Clinical features
The major clinical symptom of metastatic medullary thyroid carcinoma is diarrheaDiarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
; occasionally a patient will have flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
episodes. Both occur particularly with liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. Occasionally, diarrhea or flushing will be the initial presenting complaint. The flushing that occurs in medullary thyroid carcinoma is indistinguishable from that associated with carcinoid
Carcinoid
Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
syndrome. The presumed cause of flushing and diarrhea is the excessive production of calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
gene products (calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
or calcitonin gene-related peptide
Calcitonin gene-related peptide
Calcitonin gene related peptide is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11...
) and differs from the causation of flushing and diarrhea in carcinoid
Carcinoid
Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
syndrome. Sites of spread of medullary thyroid carcinoma include local lymph nodes in the neck
Neck
The neck is the part of the body, on many terrestrial or secondarily aquatic vertebrates, that distinguishes the head from the torso or trunk. The adjective signifying "of the neck" is cervical .-Boner anatomy: The cervical spine:The cervical portion of the human spine comprises seven boney...
, lymph nodes in the central portion of the chest
Chest
The chest is a part of the anatomy of humans and various other animals. It is sometimes referred to as the thorax or the bosom.-Chest anatomy - Humans and other hominids:...
(mediastinum
Mediastinum
The mediastinum is a non-delineated group of structures in the thorax, surrounded by loose connective tissue. It is the central compartment of the thoracic cavity...
), liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, and bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
. Spread to other sites such as skin or brain occurs but is uncommon.
Treatment
Extensive surgery can be effective when the condition is detected early, but a risk for recurrence remains.Unlike other differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease.
External beam radiotherapy
External beam radiotherapy
External beam radiotherapy or teletherapy is the most common form of radiotherapy. The patient sits or lies on a couch and an external source of radiation is pointed at a particular part of the body...
should be considered for patients at high risk of regional recurrence, even after optimum surgical treatment. A retrospective study in 1996 found that external beam radiation was beneficial in some patients.
Drugs
After a long period during which surgery and radiation therapy formed the major treatments for medullary thyroid carcinoma, clinical trials of several new tyrosine kinase inhibitors were running in 2007. Preliminary results show clear evidence of response 10-30% of patients. In the majority of responders there has been less than a 30% decrease in tumor mass yet the responses have been durable; responses have been stable for periods exceeding 3 years. The major side effects of this class of drug include hypertension, nausea, diarrhea, some cardiac electrical abnormalities, and thrombotic or bleeding episodes.In April 2011 Vandetanib
Vandetanib
Vandetanib , also known as ZD6474, is an antagonist of the vascular endothelial growth factor receptor and the epidermal growth factor receptor ....
became the first drug to be approved by US FDA for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.
In October 2011, Cabozantinib
Cabozantinib
Cabozantinib is a small molecule inhibitor of the tyrosine kinases Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis.It is being developed by Exelixis Inc....
met its primary endpoint in a phase 3 trial (EXAM) conducted by Exelixis
Exelixis
Exelixis is a genomics-based drug discovery company located in South San Francisco, Ca. It works on the development of anti-cancer therapies. Exelixis has several compounds in various stages of FDA approval including :...
investigating its effect on progression-free survival for patients with medullary thyroid cancer. A new drug application
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
is pending for the first half of 2012.
Prognosis
The prognosis of MTC is poorer than that of follicular and papillary thyroid cancer when it has metastasized (spread) beyond the thyroid gland. Depending on source, the overall 5-year survival rate for medullary thyroid cancer is 80%, 83% or 86%, and the 10-year survival rate is 75%.By overall cancer staging
Cancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
into stages I to IV, the 5-year survival rate is 100% at stage
Cancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
I, 98% at stage II, 81% at stage III and 28% at stage IV.
The prognostic value of measuring calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
and carcinoembryonic antigen
Carcinoembryonic antigen
Carcinoembryonic antigen is a glycoprotein involved in cell adhesion. It is normally produced during fetal development, but the production of CEA stops before birth. Therefore, it is not usually present in the blood of healthy adults, although levels are raised in heavy smokers...
(CEA) concentrations in the blood in patients with abnormal calcitonin levels postsurgery has been recently published (2005) in a retrospective study of 65 MTC patients; see Barbet, et al.. The post-surgical times ranged from 2.9 years to 29.5 years; all 65 patients continued to have abnormal calcitonin levels after total thyroidectomy and bilateral lymph node dissection. The prognosis of surviving MTC appears to be correlated with the rate at which a patient's postoperative calcitonin concentration doubles, rather than the pre- or postoperative absolute calcitonin level.
The result of the 65 patient study can be summarized with respect to the calcitonin doubling time (CDT):
CDT < 6 months: 3 patients out of 12 (25%) survived 5 years. 1 patient out of 12 (8%) survived 10 years. All died within 6 months to 13.3 years.
CDT between 6 months and 2 years: 11 patients out of 12 (92%) survived 5 years. 3 patients out of 8 (37%) survived 10 years. 4 patients out of 12 (25%) survived to the end of the study.
CDT > 2 years: 41 patients out of 41 (100%) were alive at the end of the study. These included 1 patient whose calcitonin was stable, and 11 patients who had decreasing calcitonin levels.
The 65 patients had a median age of 51 (range was 6 to 75), with 24 age 45 years or younger and 41 older than 45 years. The gender representation was 31 males and 34 females. All patients shared the following characteristics: 1) had total thyroidectomy and lymph node dissection; 2) had non-zero calcitonin levels after surgery; 3) had at least 4 serum calcitonin measurements after surgery; 4) had a status that could be confirmed at the conclusion of the study.
The same study noted that calcitonin doubling time is a statistically better predictor of MTC survival, compared with CEA.