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.

Approximately 25% the cancer develops in families. When MTC occurs by itself it is termed familial 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.^[1]

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Markers

While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in blood. ^[2]

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. RET is involved in the regulation of cell growth and development and its mutation is responsible for nearly all cases of hereditary or familial medullary thyroid carcinoma. Its 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% 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 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.^[3]

Unlike differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease.^[4]

External beam radiotherapy should be considered for patients at high risk of regional recurrence, even after optimum surgical treatment. Brierley et al., conducted a retrospective study and found that external beam radiation was beneficial in some patients.^[5]

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 are now being studied.^[6] Preliminary results show clear evidence of response of a small percentage of patients, providing hope for future advances.

Prognosis

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 in patiants with abnormal calcitonin levels postsurgery, has been recently published (2005) in a retrospective study of 65 MTC patients; see Barbet, et al.^[7] 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