Medullary thyroid cancer

Medullary thyroid cancer
Classification and external resources
Micrograph of medullary thyroid carcinoma. H&E stain.
ICD-10	C73
ICD-9	193
OMIM	155240
eMedicine	med/2272
MeSH	D013964

Medullary thyroid cancer (MTC) is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.^[1]

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.^[2]

Markers

While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in blood.^[3]

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.

Clinical features

The major clinical symptom of metastatic medullary thyroid carcinoma is diarrhea; 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.

Treatment

Surgery can be effective when the condition is detected early, but a risk for recurrence remains.^[1][4]

Unlike differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease.^[5]

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.^[6]

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.^[7] 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 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^[8].

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. ^[9] A new drug application is pending for the first half of 2012. ^[10]

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%^[11], 83%^[12] or 86%^[13], and the 10-year survival rate is 75%^[11].

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.^[14]

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..^[15] 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.

References

1. ^ ^{a b} Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. "Thyroid and Parathyroid Cancers" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
2. ^ Dionigi G, Bianchi V, Rovera F, et al. (2007). "Medullary thyroid carcinoma: surgical treatment advances". Expert Rev Anticancer Ther 7 (6): 877–85. doi:10.1586/14737140.7.6.877. PMID 17555398. 
3. ^ Fragu P (2007). "Calcitonin's fantastic voyage: from hormone to marker of a genetic disorder". Gesnerus 64 (1–2): 69–92. PMID 17982960. 
4. ^ Schlumberger M, Carlomagno F, Baudin E, Bidart JM, Santoro M (2008). "New therapeutic approaches to treat medullary thyroid carcinoma". Nat Clin Pract Endocrinol Metab 4 (1): 22–32. doi:10.1038/ncpendmet0717. PMID 18084343. 
5. ^ Quayle FJ, Moley JF (2005). "Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes". J Surg Oncol 89 (3): 122–9. doi:10.1002/jso.20184. PMID 15719378. 
6. ^ Brierley J, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T (1996). "Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control". Thyroid 6 (4): 305–10. doi:10.1089/thy.1996.6.305. PMID 8875751. 
7. ^ "American Thyroid Association - Thyroid Clinical Trials". http://www.thyroidtrials.org. Retrieved 2007-12-21. 
8. ^ "FDA approves new treatment for rare form of thyroid cancer". http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm250168.htm. Retrieved 7 April 2011. 
9. ^ "Success for the EXAM trial". http://www.exelixis.com/node/215. Retrieved 24 October 2011. 
10. ^ "Thyroid cancer drug cabozantinib prolongs PFS". http://www.curetoday.com/index.cfm/fuseaction/news.showNewsArticle/id/13/news_id/3299. Retrieved 24 October 2011. 
11. ^ ^{a b} Numbers from National Cancer Database in the US, from Page 10 in: F. Grünwald; Biersack, H. J.; Grںunwald, F. (2005). Thyroid cancer. Berlin: Springer. ISBN 3-540-22309-6. 
12. ^ Barbet, J.; Campion, L.; Kraeber-Bodere, F.; Chatal, J. -F.; Group, T. G. T. E. S. (2005). "Prognostic Impact of Serum Calcitonin and Carcinoembryonic Antigen Doubling-Times in Patients with Medullary Thyroid Carcinoma". Journal of Clinical Endocrinology & Metabolism 90: 6077. doi:10.1210/jc.2005-0044. PMID 16091497.  edit
13. ^ National Cancer Institute > Medullary Thyroid Cancer Last Modified: 12/22/2010
14. ^ cancer.org > Thyroid Cancer By the American Cancer Society. In turn citing: AJCC Cancer Staging Manual (7th ed).
15. ^ Barbet J, Campion L, Kraeber-Bodéré F, Chatal JF (2005). "Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma". J. Clin. Endocrinol. Metab. 90 (11): 6077–84. doi:10.1210/jc.2005-0044. PMID 16091497. http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=16091497.