Medullary thyroid cancer

Medullary thyroid cancer

Medullary thyroid cancer
Classification and external resources

Micrograph of medullary thyroid carcinoma with amyloid deposition (left of image). Near normal thyroid follicles are also seen (right of image).
H&E stain.
[1]

ICD-10

C73

ICD-9

193

OMIM

155240

MedlinePlus

000374

eMedicine

med/2272

MeSH

D013964

[2]
[3]
[4]
[5]

[6]

Medullary thyroid cancer (MTC) is a form of thyroid carcinoma which originates from the parafollicular cells (C
cells), which produce the hormone calcitonin.[7] Medullary tumors are the third most common of all thyroid cancers.
They make up about 3% of all thyroid cancer cases.
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.

Medullary thyroid cancer

Signs and symptoms

The major clinical symptom of metastatic medullary thyroid carcinoma
is diarrhea; occasionally a patient will have flushing episodes. Both
occur particularly with liver metastasis, and either symptom may be the
first manifestation of the disease. The flushing that occurs in medullary
thyroid carcinoma is indistinguishable from that associated with
carcinoid syndrome. In MTC, the flushing, diarrhea, and itching
(pruritis) are all caused by elevated levels of calcitonin gene products
(calcitonin or calcitonin gene-related peptide). Alternatively, the
flushing and diarrhea observed in carcinoid syndrome is caused by
elevated levels of circulating serotonin.
Medullary thyroid carcinoma may also produce a thyroid nodule and
enlarged cervical lymph nodes.

Medullary thyroid carcinoma on ultrasound with

typical small calcifications (arrows)

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.

Markers
While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in
blood.
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.

Genetics
Mutations (DNA changes) in the RET proto-oncogene, 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.

Medullary thyroid cancer

Prognosis
Depending on source, the overall 5-year survival rate for medullary thyroid cancer is 80%,83% or 86%,[8] and the
10-year survival rate is 75%.[]
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.[9] The prognosis of MTC is poorer than that of follicular and papillary thyroid cancer when
it has metastasized (spread) beyond the thyroid gland.
The prognostic value of measuring calcitonin and carcinoembryonic antigen (CEA) concentrations in the blood was
studied in 65 MTC patients who had abnormal calcitonin levels after surgery (total thyroidectomy and lymph node
dissection). The prognosis correlated with the rate at which the postoperative calcitonin concentration doubles,
termed the calcitonin doubling time (CDT), rather than the pre- or postoperative absolute calcitonin level:
CDT less than 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 more than 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 calcitonin doubling time was a better predictor of MTC survival than CEA but following both tests is
recommended.[10][11]

Treatment
Surgery and radiation therapy have been the major treatments for medullary thyroid carcinoma.

Surgery
Extensive surgery can be effective when the condition is detected early, but a risk for recurrence remains. About half
of patients have metastasis to regional lymph nodes at the time of diagnosis.
The European Society of Endocrine Surgeons have published recommendations for the management of this
condition.[12] The timing of surgery depends on the type of mutation present. For those in the highest risk group,
surgery is recommended in the first year of life. In lower risk cases surgery may be delayed up to the age of ten
years, the precise timing depending on the mutation and other factors.

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

Clinical trials of protein kinase inhibitors, which block the abnormal kinase proteins involved in the development
and growth of medullary cancer cells, showed clear evidence of response in 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.
Vandetanib, trade name Caprelsa, was the first drug (April 2011) to be approved by US Food and Drug
Administration (FDA) for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are
ineligible for surgery.

Medullary thyroid cancer

Cabozantinib, trade name Cometriq, was granted marketing approval (November 2012) by the U.S. FDA for this
indication.

References
[1]
[2]
[3]
[4]
[5]
[6]
[7]

http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ C73
http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=193
http:/ / omim. org/ entry/ 155240
http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000374. htm
http:/ / www. emedicine. com/ med/ topic2272. htm
http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2014/ MB_cgi?field=uid& term=D013964
Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. "Thyroid and Parathyroid Cancers" (http:/ / www. cancernetwork. com/
cancer-management-11/ chapter05/ article/ 10165/ 1402668) in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer
Management: A Multidisciplinary Approach (http:/ / www. cancernetwork. com/ cancer-management-11/ ). 11 ed. 2008.
[8] National Cancer Institute > Medullary Thyroid Cancer (http:/ / www. cancer. gov/ cancertopics/ pdq/ treatment/ thyroid/ HealthProfessional/
page7) Last Modified: 12/22/2010
[9] cancer.org > Thyroid Cancer (http:/ / www. cancer. org/ cancer/ thyroidcancer/ detailedguide/ thyroid-cancer-survival-rates) By the American
Cancer Society. In turn citing: AJCC Cancer Staging Manual (7th ed).
[10] Thyroid Carcinoma. NCCN guidelines. http:/ / www. nccn. org/ professionals/ physician_gls/ pdf/ thyroid. pdf
[11] ASCO SEP 3rd edition
[12] Niederle B, Sebag F, Brauckhoff M (2013) Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease-a consensus
statement of the European Society of Endocrine Surgeons (ESES).Langenbecks Arch Surg

Article Sources and Contributors

Article Sources and Contributors

Medullary thyroid cancer Source: http://en.wikipedia.org/w/index.php?oldid=584490156 Contributors: Andrux, Angelito7, Arcadian, Arnoldberk, Bathosrex, Cortamears, Eleassar,
FeatherPluma, Ground Zero, Headbomb, Immunize, J04n, Jmh649, Jwc012, Mikael Hggstrm, Nephron, Ossip Groth, PKT, R'n'B, Rfgagel, Rhcastilhos, Rich Farmbrough, Rod57, Rosenwig,
Rytyho usa, Sanya3, Smartse, Squids and Chips, Urgos, Wouterstomp, 18 anonymous edits

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