Sporadic Medullary Thyroid Carcinoma

Introduction to Chapter 26, Sporadic Medullary Thyroid Carcinoma.

Introduction

Medullary thyroid carcinoma (MTC) comprises 1% to 2% of all new cases of thyroid cancer in the United States, a number that is significantly smaller than historically documented, due to the increasing incidence of papillary thyroid cancer. MTC occurs as two distinct clinical entities, hereditary (25%) and sporadic (75%). Although these entities share the same etiology, arising from the neuroendocrine parafollicular or C-cells of the thyroid, sporadic MTCs tend to be more aggressive than hereditary MTC, with more frequent metastasis to cervical lymph nodes. Surgical removal of the thyroid and regional lymph nodes remains the mainstay of therapy for MTC. New advances in targeted therapy with tyrosine kinase inhibitors (TKIs) have recently improved progression-free survival for advanced MTC.

Several organizations have published guidelines on the management of MTC in the last decade. The 2015 guidelines from the American Thyroid Association (ATA) provide the most recent in-depth recommendations on the full spectrum of MTC diagnosis and treatment. This chapter will review pathophysiology; genetics; differences between sporadic and hereditary MTC; clinical presentation; clinical course; diagnostic considerations, including workup and staging; primary surgical treatment decision-making; follow-up and surveillance; surgical management of recurrent disease; radiation therapy; and management of distant metastatic disease, including systemic and targeted therapies.

Pathophysiology

An understanding of histology and the importance of C-cells, calcitonin, and carcinoembryonic antigen (CEA) form the underpinnings of the appropriate diagnosis and management of MTC. The genetic underpinnings of MTC help distinguish sporadic and hereditary forms of the disease and are important for understanding prognostic and diagnostic considerations when a patient is found to have sporadic MTC.

Histology and C-Cells

During embryogenesis, the ultimobranchial bodies arising from the neural crest migrate to the upper and middle poles of each thyroid lobe. These give rise to C-cells, which make up 1% of thyroid cells. C-cells are neuroectodermal in origin and have neuroendocrine function through the secretion of calcitonin. MTC is only classified as a thyroid cancer because of its location; in truth, it is a neuroendocrine tumor, compared with the more common follicular (thyroid) cell-derived cancers. In noncancer specimens, C-cells normally exist in clusters of six to eight cells at the periphery of thyroid follicles.

MTC was first described in the 1900s as an amyloid tumor and was considered a variant of anaplastic thyroid carcinoma. In 1959, Hazard, Hawk, and Crile first described its unique appearance. Grossly, the tumor is well demarcated, firm, gray-white, and gritty. Microscopically, the cells are uniform round, polygonal, or spindle-shaped cells with finely granular eosinophilic cytoplasm and central nuclei. The cells tend to form sheets or nests with peripheral palisading in a vascular stroma. The presence of amyloid is considered to be a distinctive feature of MTC, although it may not be found in all cases. The amyloid arises from calcitonin or procalcitonin, a different precursor than other amyloid-rich tumors. C-cell hyperplasia is associated with MTC, particularly in the familial form, and is thought to be a precursor in the malignant transformation to MTC.

The histologic diagnosis of MTC may be difficult, as it can be confused with papillary or follicular thyroid cancers, as well as paragangliomas, sarcomas, and lymphoma. The diagnosis may be aided by staining for cytokeratins CK7 and CK18, as well as TTF1, and chromogranin A. The most important diagnostic markers, however, are calcitonin chromogranin, CEA, and a lack of thyroglobulin staining. Histologically, MTC can be classified according to dominant patterns. Histologic groups include the classic, amyloid-rich, insular, trabecular, and epithelial variants. Classic variants are most common (48.9%) followed by the amyloid-rich variants (38.3%).

Calcitonin and Carcinoembryonic Antigen

C-cells secrete calcitonin and other substances, including CEA, histaminase, neuron-specific enolase, calcitonin gene-related peptide, somatostatin, thyroglobulin, thyrotropin-stimulating hormone, adrenocortical stimulating hormone, gastrin-related peptide, serotonin, chromogranin, and substance P. Calcitonin has been shown to be integral in calcium homeostasis in other vertebrate species, but its role in humans remains unclear.

Calcitonin and CEA are useful tumor markers that can be measured in blood in the basal state. CEA has a longer half-life than calcitonin and is not unique to MTC, making it a less specific marker. Calcitonin levels are almost always elevated in patients with sporadic MTC, and levels are usually correlated with the amount of MTC tumor mass in the body. Measurement of calcitonin is helpful in screening patients at risk for MTC and in the follow-up of patients after treatment. After primary surgery for MTC, persistent or recurrent elevation of calcitonin indicates the presence of local, regional, or distant disease. Imaging may not localize a tumor mass, and some patients in this situation have an indolent course. Historically, calcitonin was often measured after stimulation by administration of the secretagogue pentagastrin. However, this was uncomfortable for patients, causing nausea, diaphoresis, agitation, and urinary urgency. Today, improvements in the accuracy of measuring basal levels of calcitonin have made stimulated testing unnecessary.

Genetics: Sporadic Versus Hereditary

By definition, patients with hereditary MTC have a germline mutation in the RET proto-oncogene (see Chapter 27 , Syndromic Medullary Thyroid Carcinoma: MEN 2A and MEN 2B). As the name implies, the majority of patients with sporadic MTC do not have germline mutations, although 1% to 7% of patients with no family history of MTC will have germline mutations. It is important to refer patients without a family history of MTC for genetic counseling and testing for a germline mutation for several reason. First, if a patient with apparently sporadic MTC is found to have a germline RET mutation, other blood relatives harboring the same mutation may be identified by genetic testing, starting with first-degree relatives, and appropriate therapy or preventative surgery can be initiated. Second, if a patient is found to have a germline RET mutation, he or she may then be screened for hyperparathyroidism and pheochromocytoma. More studies regarding these issues are needed and future guidelines terminology may change, but it is likely that the specific RET mutation will continue to influence the approach to surgical management, risk of recurrence, and need to test for association with other endocrine neoplasms.

Somatic mutations are identified in tumor cells only compared with germline mutations that can be detected in all cells of the body. In the past there has been no routine clinical indication for testing the tumors of patients with apparently sporadic MTC for somatic mutations. However, there is growing evidence that this type of sporadic RET mutation may predict responsiveness to systemic therapy with TKIs, suggesting a future clinical role for testing tumors for somatic mutations. Somatic mutations or rearrangements involving RET have been identified in 40% to 50% of sporadic MTCs. In a tumor with a somatic RET mutation, not all cells may harbor the mutation. Most of the mutations identified in sporadic MTCs are point mutations involving the same codons associated with the MEN 2 syndromes, including 918, 634, and 883. Of sporadic MTCs with alterations of RET , 60% to 80% are found to have the M918T mutation. Patients with sporadic MTCs bearing a RET mutation (particularly M918T) have a more advanced stage at diagnosis, increased rates of recurrent or persistent disease after resection, and poorer long-term survival (10 to 20 years) than those without this RET mutation.

Clinical Presentation and Usual Clinical Course

MTCs occur in two clinical settings, sporadic and hereditary. Hereditary MTC is discussed elsewhere in this book (see Chapter 27 , Syndromic Medullary Thyroid Carcinoma: MEN 2A and MEN 2B). Much of the MTC literature combines data on hereditary and sporadic tumors together, making it difficult to compare these entities. Overall, sporadic MTCs behave in a similar fashion to hereditary MTCs with a similar prognosis when adjusted for stage, although hereditary MTCs are more likely to be bilateral or multifocal (> 90% compared with 32% in sporadic MTC) and to present at a less advanced stage.

Sporadic MTCs usually present in the fourth to sixth decades of life as a mass in the neck from the thyroid tumor or cervical nodal metastases. In addition to a neck mass, symptoms of dysphagia, shortness of breath, or hoarseness may be present in approximately 15% of cases. Less commonly, they may be discovered after detection of elevated calcitonin or CEA levels in patients with a nodular thyroid. Some patients present with distant metastases or with diarrhea secondary to secretory products from the MTC tumor cells. Rarely, MTC is discovered to be the cause of an elevated CEA level—for example, in a patient being followed after treatment of colon cancer.

MTC frequently metastasizes to regional lymph nodes. Central compartment metastases are present in patients with T1 and T4 tumors 14% and 86% of the time, respectively, whereas lateral compartment metastases are present in patients with T1 an T4 tumors 11% and 93% of the time, respectively. Serum calcitonin levels correlate with nodal disease burden and location. In all, 70% of patients with MTC who present with a palpable thyroid mass also have cervical metastases, and 10% have distant metastases. Hematogenous spread may occur to the lungs, liver, bones, brain, and soft tissues.

Although the clinical course of MTC may be more aggressive than differentiated thyroid cancers such as papillary thyroid carcinoma (PTC), MTC is nonetheless a relatively indolent malignancy, with reported 10-year survival rates from 69% to 89%. Multivariate analysis has shown patient age and stage to be significant prognostic factors. Ten-year survival rates for patients with stage I, II, III, or IV are 100%, 93%, 71%, and 21%, respectively. The clinical course is somewhat unpredictable; patients with distant metastases may often live for years.

Patients with normal basal serum calcitonin levels after surgery have better long-term survival rates, with 97.7% survival at 10 years. Studies of survival rates have found close associations with calcitonin doubling times. In one study of patients undergoing total thyroidectomy and bilateral cervical lymph node dissection, all patients with calcitonin doubling times > 24 months were alive at the end of the study, whereas patients with doubling times < 6 months had 5- and 10-year survival rates of 25% and 8%, respectively. Patients with doubling times between 6 and 24 months had 5- and 10-year survival rates of 92% and 37%, respectively.

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