MEDULLARY THYROID CARCINOMA

MEDULLARY THYROID CARCINOMA

Medullary thyroid carcinoma (MTC) is an uncommon cancer that arises from the neural crest—derived C cells of the thyroid gland.

MTC accounts for 5% of thyroid cancers, and there will be approximately 3000 new cases in the United States in 2015. MTC occurs either sporadically (75% of cases) or as part of the multiple endocrine neoplasia (MEN) syndromes, MEN 2A (Online Mendelian Inheritance in Man [OMIM] #171400) or MEN 2B (OMIM #162300), or the related syndrome familial medullary thyroid carcinoma (FMTC) (OMIM #155240). The incidence of MEN 2A and FMTC combined is approximately 1 in 100,000 live births, whereas the incidence of MEN 2B is approximately 1 in 2,000,000 live births.

As the lateral thyroid complex closes during embryogenesis, the C cells are incorporated within the middle and upper portions of the thyroid lobes. Because of its anatomic location, MTC is classified as a thyroid tumor; however, considering its origin from the neural crest rather than the thyroid follicular cells, it is a neuroendocrine tumor. Sporadic MTC occurs as a solitary tumor in one thyroid lobe, whereas hereditary MTC develops in both thyroid lobes and is multicentric. In patients with hereditary MTC, the first manifestation of a C-cell disorder is C-cell hyperplasia (CCH) that progresses over time to microinvasive MTC and then to invasive MTC.

The C-cell mass is much greater in the thyroid glands of men than in women, which accounts for the higher serum calcitonin levels seen in men compared with women.

The C cells have diverse biosynthetic activity and secrete calcitonin (CTN) and carcinoembryonic antigen (CEA), which are excellent serum markers for the presence of a C-cell disorder. CTN was once thought to be important in calcium homeostasis; however, its physiologic importance has been called into question. The RET protooncogene encodes a single-pass transmembrane receptor of the tyrosine kinase family of proteins. At several stages of development, it is expressed in cells derived from the branchial arches (parathyroids), the neural crest (brain, parasympathetic and sympathetic ganglia, thyroid C cells, adrenal medulla, and enteric ganglia), and the urogenital system. Activating, germline point mutations in RET are present in virtually all hereditary MTCs, and somatic RET mutations are present in approximately half of sporadic MTCs. Recently, it was discovered that somatic mutations in HRAS, KRAS , and rarely NRAS are present in sporadic MTCs and are almost always mutually exclusive with the presence of somatic RET mutations.

Approximately 75 RET mutations have been reported in association with MEN 2A, MEN 2B, and FMTC. The mutations for MEN 2A and FMTC are located in exons 5, 8, 10, 11, 13, 14, 15, and 16. The mutations for MEN 2A are mostly located in the extracellular, cysteine-rich region of exon 10 (including codons 609, 611, 618, and 620) and exon 11 (including codons 630 and 634). Approximately 85% of the mutations associated with MEN 2A involve RET codon 634, about half of which are C634R RET mutations. The RET mutations in MEN 2B cause constitutive activation, which alters substrate specificity, presumably owing to a conformational change in the binding pocket of the kinase. Approximately 95% of mutations causing MEN 2B are in codon M918T, and 5% are in codon A883F. Rare cases of MEN 2B are caused by double somatic RET mutations involving codon V804M and either codon Y806C, S904C, or E805K.

In 50% of patients with MEN 2B and 10% of patients with MEN 2A and FMTC, the disease arises de novo. In such founder cases, the de novo mutation almost always derives from the paternal allele.

The peak incidence of sporadic MTC is in the fifth decade of life, and most patients present with a solitary thyroid nodule and lymph node metastases. Clinically, the tumors are more aggressive than papillary thyroid carcinoma and follicular thyroid carcinoma but less aggressive than anaplastic thyroid carcinoma. The 10-year survival rate is 75%. In the expectation of detecting MTC at any early stage, clinicians in Europe evaluate serum CTN levels in patients with thyroid nodules who have no history of hereditary MTC. The detection rate of MTC is less than 0.5%, however, and clinicians in the United States have not adopted this practice.

CLINICAL MANIFESTATIONS OF MULTIPLE ENDOCRINE NEOPLASIA 2a, 2B, and FAMILIAL MEDULLARY THYROID CARCINOMA

MULTIPLE ENDOCRINE NEOPLASIA (MEN) 2A
·         Medullary thyroid carcinoma (~100%)

·         Pheochromocytoma (incidence of 50% in families with a RET codon 634 germline mutation but less in families with other RET codon mutations)

·         Hyperparathyroidism (incidence of 30% in families with a RET codon 634 germline mutation but less in families with other RET codon mutations.)

VARIANTS OF MEN 2A
·         MEN 2A with cutaneous lichen amyloidosis (almost always associated with a RET codon 634 germline mutation.)

·         MEN 2A with Hirschsprung disease (most common in families with RET germline mutation most commonly involving codon 620)

FAMILIAL MEDULLARY THYROID CARCINOMA (FMTC)
·         Since the original description of this syndrome, there has been confusion about the designation FMTC. Most clinicians now consider it a variant of MEN 2A.
MEN 2B
·         Medullary thyroid carcinoma (~100%)

·         Pheochromocytoma (50%)

·         Mucosal neuroma, ganglioneuromatosis, marfanoid habitus, colonic abnormalities, characteristic physical appearance (~100%)

MEN 2A (80% of cases), MEN 2B (5% of cases), and FMTC (15% of cases) are inherited as autosomal dominant traits with near-complete penetrance and, in the cases of MEN 2A and MEN 2B, variable expressivity. Approximately 50% of patients with MEN 2A (and a codon 634 mutation) develop pheochromocytomas, the frequency being much lower in association with mutations in codons 609, 611, 618, and 620. Before the availability of biochemical and genetic screening in families with MEN 2A, the most frequent cause of death was pheochromocytoma, not MTC. The deaths occurred most often in patients during childbirth or interventional procedures. Thus, pheochromocytoma must be excluded in patients with a confirmed or presumptive diagnosis of hereditary MTC. With rare exceptions, the pheochromocytoma should be excised first in patients who also have MTC.

Parathyroid hyperplasia occurs in up to 30% of patients with MEN 2A and is usually associated with a RET codon 634 mutation. The disease is frequently asymptomatic, with the only abnormality being an elevated serum calcium concentration.

Patients with MEN 2A may also develop cutaneous lichen amyloidosis (CLA) or Hirschsprung disease (HD). CLA occurs in about 25% of patients and involves the interscapular region of the back, corresponding to dermatomes T2 through T6. Pruritus, the dominant symptom, leads to repetitive scratching and secondary skin changes characterized by the deposition of amyloid. The lesion may be evident in infancy, thus serving as a precursor marker of MEN 2A. Cutaneous lichen amyloidosis is almost always associated with a RET codon 634 mutation.

HD, manifested by the absence of intrinsic ganglion cells in the distal gastrointestinal tract, has been reported in 30 or more families with MEN 2A or FMTC and is associated with mutations in RET exon 10 involving codons 609 (15%), 611 (4%), 618 (30%), and 620 (50%). In functional studies, the cell surface expression of RET with these codon mutations is lower than that found with a codon 634 mutation. This suggests a novel mechanism whereby the specified RET mutations have low transforming activity, which is sufficient to trigger the development of MTC and pheochromocytoma, yet is insufficient to stimulate differentiation of intestinal ganglion cells. It is also of interest that 50% of patients with familial HD and 30% of patients with sporadic HD have germline RET mutations.

Patients with MEN 2B develop mucosal neuromas, ganglioneuromatosis throughout the aerodigestive tract, hypotonia, skeletal malformations, and medullated corneal nerves. They also develop colonic dysfunction manifested by abdominal pain and occasionally intestinal obstruction. Patients have a characteristic physical appearance, which may not be evident early in life. The failure to diagnose MEN 2B at a young age can be catastrophic because MTC is often evident soon after birth, and regional or distant metastases occur soon thereafter. The MTC associated with MEN 2B is much more aggressive than that occurring with MEN 2A or FMTC. The primary basis for the difference is that MEN 2B mutations are associated with significantly higher basal kinase activity compared with mutations in MEN 2A and FMTC. Patients with FMTC develop only MTC, which, relative to the tumors in patients with MEN 2A and MEN 2B, is slow growing. Many clinicians consider FMTC a variant of MEN 2A.

The measurement of serum levels of CTN, either in the basal state or following the intravenous administration of the secretagogues calcium, pentagastrin, or both, was initially the primary method of establishing the diagnosis of a C-cell disorder. With the discovery that MEN 2A, MEN 2B, and FMTC are caused by mutations in the RET protooncogene, direct DNA analysis became the method of choice for identifying affected family members who had inherited a mutated RET allele. At present, the determination of CTN is primarily used to detect persistent or recurrent MTC following thyroidectomy or to evaluate response to therapy in patients with regional or metastatic disease. As we have learned more about the variable clinical expression of MEN 2A in families with the identical RET mutation, however, the measurement of basal and stimulated serum CTN levels has assumed importance in timing early thyroidectomy in young family members with RET mutations. The two-site, two-step, chemiluminescent, immunometric assay that is highly specific for monomeric CTN is the preferred method for quantitating serum CTN levels.

At present, direct DNA analysis of RET has become the preferred method of detecting RET mutations in families with hereditary MTC. The Gene Tests directory currently lists 63 laboratories that perform DNA analysis for RET mutations. Almost all laboratories use direct sequence analysis to evaluate mutations in exons 10, 11, 13, 14, 15, and 16, and some laboratories include exon 8. If no mutations are found in these exons, the entire coding region of RET can be sequenced. It is important to perform direct DNA analysis for RET mutations in all patients with presumed sporadic MTC because approximately 7% of them will have hereditary MTC. A diagnosis of hereditary MTC in this setting mandates a different treatment strategy for the patient, as well as his family members, who should be offered the opportunity for clinical evaluation and genetic testing.

The primary treatment for patients with MTC, whether sporadic or hereditary, is total thyroidectomy. Resection of lymph nodes in the central compartment is included in all adults and in children with MEN 2B but is excluded in outwardly normal youngsters with MEN 2A and FMTC who are undergoing early thyroidectomy based on directed DNA analysis. If enlarged cervical lymph nodes are evident on preoperative ultrasound examination or at the time of thyroidectomy, the involved anatomic nodal compartment should also be resected. During the thyroidectomy, great care must be taken to preserve the parathyroid glands, the recurrent laryngeal nerves, and the external branch of the superior laryngeal nerve. Postoperatively, serum calcitonin is normal in only 10% of patients with node-positive disease compared with 60% of patients with node-negative disease. Many patients with regional lymph node metastases have a good prognosis, however, with 5- and 10-year survival rates of 80 and 70%, respectively.

Repeat neck operation following initial thyroidectomy is indicated in patients with complications from recurrent tumor compressing or invading vital structures, such as the spinal cord, airway, or esophagus. Also, patients who have intractable diarrhea due to markedly elevated tumor hormone secretions, presumably CTN, may obtain symptom relief by tumor debulking. Patients who develop persistent or recurrent MTC following thyroidectomy, as indicated by elevated serum levels of CTN or CEA, are also candidates for reoperation; however, the benefit of such surgical procedures is open to question because there are no long-term data on quality of life and survival. Rarely, patients with MTC develop Cushing syndrome due to the inappropriate secretion of adrenocorticotrophic hormone (ACTH) or corticotropin-releasing hormone. Such patients have advanced disease, and bilateral adrenalectomy may be required if steroidogenesis inhibitors are ineffective. Inappropriate secretion of ACTH is a poor prognostic sign, associated with an average survival of 2 years.

The treatment of pheochromocytoma is adrenalectomy. Hyperparathyroidism is managed by either subtotal parathyroidectomy or total parathyroidectomy with heterotopic autotransplantation.

For patients with locally advanced or metastatic MTC, single-agent or combined chemotherapeutic regimens have been minimally effective, being characterized by low response rates of short duration. External beam radiotherapy is indicated primarily for the treatment of localized metastases, primarily of the central nervous system or bone.

With the demonstration that the tyrosine kinase inhibitor imatinib induced remissions in patients with chronic myelogenous leukemia and gastrointestinal stromal tumors, there was hope that similar molecular targeted therapeutics (MTTs) would be developed for other solid tumors, including MTC. In a recent prospective, randomized, placebo-controlled, double-blind, phase III trial, patients treated with the MTT vandetanib had a significantly prolonged progression-free survival compared with placebo. On the basis of this study, the U.S. Food and Drug Administration (FDA) approved vandetanib for the treatment of patients with advanced MTC. The FDA also recently approved a second MTT, cabozantinib, based on similar results of a phase III trial. Thus, effective systemic therapies are available for patients with advanced MTC, and additional studies of other MTTs have recently been initiated.

In patients with a hereditary cancer syndrome, the removal of an organ destined to become malignant should be considered in the light of five factors. There should be (1) near-complete penetrance of the mutated gene, (2) a reliable method of detecting family members who have inherited a mutated allele, (3) minimal morbidity associated with removal of the organ at risk, (4) excellent replacement therapy for the function of the removed organ, and (5) a reliable method for determining whether the operative procedure has been curative. Few hereditary malignancies meet all of these criteria; fortunately, MEN 2A, MEN 2B, and FMTC meet each of them. Young members of kindred with hereditary MTC who are found to have a mutatedRET allele on genetic screening have the greatest likelihood of being cured by early thyroidectomy. Surgeons in several countries have reported success with this operative procedure, and the question is no longer should it be done but at what age.

The Consensus Committee of the 7th International Workshop on MEN, the National Comprehensive Cancer Network, and the American Thyroid Association have all proposed guidelines for the timing of prophylactic thyroidectomy in patients with MEN 2A, MEN 2B, and FMTC. The recommendations of the three groups are similar, in that children with MEN 2B (or with mutations in codons 918 or 882) should have thyroidectomy at the time of diagnosis, even during the first months of life. Children with MEN 2A and mutations in codons 611, 618, 620, or 634 should have the thyroid removed at or before 5 years of age. In children with mutations in other RET codons, the recommended timing of thyroidectomy is less clear but is generally between 5 and 10 years of age.

Several factors portend an adverse outcome in patients with MTC. Poor prognosis is associated with older age, advanced disease at the time of diagnosis of a large primary tumor, lymph node metastases, markedly elevated serum levels of CTN and CEA preoperatively, extrathyroidal invasion of the trachea or soft tissues, and distant metastases. Patients with MEN 2B and patients with MEN 2A who have RET mutations in codon 634 have a poorer prognosis than those with RET mutations in other codons. Also, in patients with sporadic MTC, the presence of a RET M918T mutation, compared with other codon mutations, is associated with a more aggressive tumor and a poor prognosis. Patients apparently cured by thyroidectomy are followed at 6-month intervals with measurement of serum levels of CTN and CEA. The doubling times of serum CTN are especially useful in predicting the course of the disease. CTN doubling times of less than 6 months (compared with those greater than 24 months) are associated with a very poor prognosis.

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