17.1 Introduction

Medullary thyroid carcinoma (MTC) is an uncommon malignancy with unique clinical and pathological features that influence patient evaluation and surgical approach. MTC accounts for 5 to 10% of all thyroid cancers. MTCs arise from the parafollicular or thyroid C cells and do not take up iodine, whereas differentiated thyroid cancers (papillary and follicular) arise from the thyroid follicular parenchyma and do concentrate iodine. MTC is hereditary in 25% of cases (multiple endocrine neoplasia type 2 syndromes). ¹ Early surgical intervention is the cornerstone of treatment with complete excision of the primary tumor and nodal metastases. Residual and/or recurrent disease in the neck is also generally managed by surgical resection because adjuvant therapies have yet to demonstrate a durable benefit. New systemic treatments with targeted molecular therapies have shown promise in clinical trials.

17.2 Pathology

C cells constitute approximately 1% of thyroid cells, contributing 0.1% of the normal thyroid mass, and are derived embryologically from the ultimobranchial body and the fourth branchial pouch. They are found throughout the thyroid but are concentrated in the posterior upper third of the gland, generally arranged in groups of six to eight cells at the edge of thyroid follicles. C cells are responsible for the production of several peptides and hormones, the most notable of which is calcitonin, a polypeptide hormone whose physiological effect is to decrease serum calcium. Calcitonin has minimal, if any, effect on normal calcium homeostasis in humans, and no appreciable functional deficit has been identified with loss of C cells following total thyroidectomy. However, as a product of C cells, and therefore of MTC cells, calcitonin has been shown to be a highly sensitive and specific tumor marker. It can be measured in the blood, both in the basal state and after stimulation, by administration of a secretagogue, such as calcium or pentagastrin (not available in the United States). Calcitonin is useful in prethyroidectomy screening of patients with hereditary MTC and in posttreatment surveillance of all MTC patients.

Tumors of MTC are usually slow-growing and indolent, grossly noted to be gray and firm with well-demarcated margins, and they are commonly found in the upper portion of the thyroid lobes. On histology, cells are uniform and generally polygonal or spindle shaped, with central nuclei and finely granular eosinophilic cytoplasm (Fig. 17.1). Most MTC cells also stain positive for carcinoembryonic antigen (CEA) and negative for thyroglobulin. ² A feature of MTC tumors found in one-third of cases is the presence of stromal amyloid, which is composed of calcitonin or procalcitonin molecules. Sporadic tumors vary considerably in size, but most are solitary, whereas the majority of tumors in familial forms are multifocal and bilateral. ³ C-cell hyperplasia, believed to be a precursor to malignant transformation in MTC, is most commonly present in familial forms and can often be found distant to the primary carcinoma within the gland. ^{4 , 5 , 6 , 7}

17.3 Clinical Course

Patients with sporadic MTC or index cases of familial MTC often present with a palpable mass within the thyroid or neck. Sporadic MTC may arise clinically at any age, but the incidence typically peaks between the fourth and sixth decade of life, considerably later than in patients with known familial syndromes. Sporadic MTC also demonstrates a slight female predominance. ^{8 , 9} Approximately 15% of patients who present with clinically apparent disease may be symptomatic with dysphagia, dyspnea, or hoarseness; nodal metastases are present in regional lymph nodes in more than 50% of patients who present with palpable primary tumors. ¹⁰ The most frequently involved lymph nodes reside in the central compartment (level VI), followed by levels II through V in the ipsilateral jugular chain of nodes, then the contralateral lateral nodes. ¹¹ Metastatic spread to the upper and anterior mediastinum may be observed, and hematogenous dissemination to distant sites, including the liver, lungs, bone, brain, and soft tissues, may occur throughout the course of MTC. ^{1 , 11} Diagnosis of distant metastases may be made more difficult due to the fine miliary pattern of metastatic disease, which is poorly visualized by standard imaging; however, diagnostic laparoscopy with direct visualization of the liver may help to identify small metastatic deposits in 25% of patients with elevated calcitonin levels following therapeutic surgery. ¹²

Per the American Joint Committee on Cancer (AJCC) TNM classification system, the 10-year survival rates for patients with stages I through IV disease are 100%, 93%, 71%, and 21%. ¹³ Adjusted 10-year survival rates range from 70% to > 85%; however, higher long-term survival rates up to 98% have been reported for patients whose serum calcitonin levels return to normal after surgery. ^{11 , 13 , 14 , 15 , 16 , 17} In a series of 1,252 patients diagnosed with MTC between 1973 and 2002 who were monitored by the Surveillance, Epidemiology, and End Results (SEER) registry, 48% were diagnosed with localized disease, 35% with extension beyond the thyroid and regional disease, and 13% with distant metastases. A similar trend was revealed in 10-year survival rates at 95.6%, 75.5%, and 40%, respectively. The average size of primary tumor at the time of diagnosis was 2.8 cm. Multivariate analysis indicated that older age, higher tumor stage at diagnosis, lesser extent of thyroidectomy, and external beam radiation therapy (EBRT) were significant negative predictors of overall survival. ¹⁸ In several other studies, age at diagnosis and tumor stage were the most sensitive prognostic factors; other predictors included postoperative basal calcitonin levels, extent of surgical intervention, and presence of distant metastases. ^{16 , 19}

17.4 Familial MTC Classification

Though the majority of MTC is sporadic in origin, a familial syndrome must be considered in any patient presenting with a new diagnosis of MTC. Multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) are the hereditary syndromes that include MTC as a hallmark, though these vary in aggressiveness of malignancy and associated conditions. Familial non-MEN MTC (FMTC) is characterized by the presence of MTC only and has been designated a variant of MEN 2A by the new American Thyroid Association (ATA) guidelines (Wells, et al). ⁸² All are autosomal-dominant conditions and have a high penetrance for MTC (> 90% of affected patients will develop MTC during their lifetime). MEN 2A is the more common syndrome, accounting for more than 90% of hereditary cases. Other features of MEN 2A are unilateral or bilateral pheochromocytoma (40–50% penetrance), and hyperparathyroidism (10–30% penetrance); less common findings include a cutaneous condition (lichen planus amyloidosis) or Hirschprung’s disease. ^{20 , 21 , 22}

MEN 2B patients develop MTC in 100% of cases, and pheochromocytoma in 40%, but this group of patients is distinguished by different comorbid conditions, which include multiple mucosal neuromas, “marfanoid” habitus, intestinal ganglioneuromatosis, medullated corneal nerve fibers, and megacolon. ²³ MEN 2B accounts for approximately 5% of patients with familial disease, and these MTC tumors are often present at birth. MTC in MEN 2B is a more aggressive variant, with early metastasis, making early diagnosis and treatment critical for successful management. Thyroidectomy is recommended in infancy, when possible (Fig. 17.2). ²¹ Lastly, FMTC is a variant of MEN 2A characterized by predisposition to MTC only, though caution is warranted because some kindreds designated as FMTC have subsequently developed pheochromocytoma and parathyroid abnormalities.

17.5 Genetic Analysis

The RET (rearranged during transfection) proto-oncogene on chromosome 10q11.2 plays a critical role in the understanding of MTC, both in diagnosis and in familial screening. RET encodes a tyrosine kinase receptor protein that is composed of an extracellular domain containing a ligand-binding site with a cysteine-rich region, a transmembrane domain, and two intracellular tyrosine kinase domains. ^{3 , 24} All of the hereditary MTC syndromes are caused by missense germline mutations in RET. Interestingly, these mutations are “gain of function” mutations as opposed to “loss of function” germline mutations seen in all other hereditary cancer syndrome genes. Somatic (non-germline) mutations of RET have also been identified in 40 to 50% of sporadic MTC cases. ²⁵ In sporadic MTC, patients with somatic codon 918 RET mutations have been found to have more aggressive disease progression and worse prognosis. ²⁵

There are strong genotype–phenotype correlations in the MEN 2 syndromes. Disease severity and expression of associated pathologies (pheochromocytoma, hyperparathyroidism, Hirschprung’s disease, lichen planus amyloidosis, and MEN2B phenotype) correlate with the codon and functional domain of mutation within the RET protein. For virtually all MEN 2A patients, the mutation occurs within the cysteine-rich extracellular domain, which results in ligand-independent receptor dimerization and constitutive activity. ²⁶ In the FMTC variant, mutations are usually similar to those in MEN 2A, but some families have mutations in the intracellular domain. Unlike MEN 2A and FMTC, MEN 2B nearly always involves the same codon 918 mutation, in the intracellular tyrosine kinase domain. ²⁷

The increasing availability of genetic analysis over the last 20 years has revolutionized treatment of patients with hereditary syndromes. Now, based on identification of a mutated RET allele, tumor aggressiveness and disease course can be much more clearly predicted, and this greater knowledge of genotype–phenotype correlations translates into timely and appropriate patient counseling. The ATA recommends RET testing as early as possible to patients with family history consistent with MEN 2 or FMTC; for MEN 2B, this should occur shortly after birth, and for MEN 2A and FMTC, testing should be performed before 5 years of age. ²⁸ In families with a known specific RET mutation, a targeted approach can be employed to detect its presence. For patients with newly diagnosed MTC or in families with uncharacterized RET mutations, the usual strategy currently employed is to sequence exons 10 and 11 (codons 609, 611, 618, 620, 634) and exons 13, 14, 15, and 16 where the majority of mutations are found.

17.6 Diagnostic Evaluation

In the initial consultation of a patient presenting with MTC, a full patient and family history should be obtained, and particular attention should be placed on the history of any thyroid or parathyroid disease, uncontrolled hypertension, sudden death, or adrenal tumors. Every patient should be considered to have possible familial MTC until proven otherwise, and genetic screening should be offered to patients with MTC or with other associated features, including lichen planus amyloidosis or Hirschprung’s disease. ^{3 , 22} On physical exam, any palpable mass should be assessed for size or fixation to surrounding structures, and the presence of multiple nodules, lymphadenopathy, or evidence of distant metastases should be noted. Computed tomography of the neck and chest is especially helpful. Particularly in MEN 2B patients, several overt clinical features, such as tongue nodules or a prominent mid-upper lip, may be present. In patients presenting with symptoms of respiratory difficulty or hoarseness, direct laryngoscopy for examination of the vocal cords should be done as this could indicate extensive local disease and possible involvement of the recurrent laryngeal nerve. Patients with high levels of calcitonin or metastatic disease may also present with symptoms of flushing, diarrhea, and weight loss.

Diagnostic workup should proceed with fine-needle aspiration (FNA) biopsy of the dominant nodule and include immunohistological staining for calcitonin. This has been shown to be successful in diagnosing MTC in approximately 50 to 80% of patients. ^{9 , 29 , 30}

Preoperative laboratory testing should include measurement of serum calcitonin, CEA, metanephrines, normetanephrines, and calcium levels. RET proto-oncogene analysis should be performed for any newly diagnosed MTC patient. Serum calcitonin has proven to be a sensitive and cost-efficient marker in detecting MTC; however, routine measurement in patients with nodular thyroid disease has remained controversial. Several studies have demonstrated an incidence of MTC in 0.5 to 2% of patients without suspected malignancy, and the benefit in reaching an earlier diagnosis and subsequent treatment suggests that implementation of routine calcitonin measurement may be an effective surveillance option. ^{30 , 31 , 32} Though calcitonin levels may be mildly elevated in other clinical conditions (e.g., renal insufficiency, neuroendocrine tumors), a basal or stimulated calcitonin level > 100 pg/mL strongly suggests the presence of MTC, and the extremely elevated level alone is an indication for surgery. Similarly, a basal level > 10 to 20 pg/mL necessitates further workup of possible MTC. ^{23 , 30 , 31 , 32 , 33 , 34}

Serum CEA levels are also helpful in the risk stratification of patients with MTC. Preoperative levels > 30 ng/mL have been shown to portend a poor prognosis for surgical curability and are associated with involvement of local lymph nodes in approximately 70% of patients; at levels > 100 ng/mL, 90% of patients had contralateral neck lymph node involvement, and 75% were found to have distant metastases. ³⁵ All MTC patients > 8 years of age should undergo biochemical testing for pheochromocytoma with plasma metanephrines and catecholamines or 24-hour urine collection for metanephrines or catecholamines. If positive, the patient should undergo treatment for the pheochromocytoma prior to definitive thyroidectomy for MTC. Finally, hyperparathyroidism found by elevated calcium and parathyroid hormone levels is managed with concurrent parathyroidectomy at the time of surgery for MTC.

Imaging plays a vital role in the assessment of MTC and first involves a neck ultrasound with lymph node mapping of the cervical compartments. This is critical in the preoperative setting because the sensitivity of intraoperative palpation to detect nodal metastases is only 64%, even when performed by experienced surgeons. ¹⁰ Sonographic findings of MTC commonly include hypoechogenicity, internal vascularity, and calcifications similar to other thyroid malignancies. ³⁶ In MTC patients presenting with a palpable thyroid nodule, more than 75% will have associated nodal metastases, and 10 to 15% will also demonstrate evidence of distant disease. ^{10 , 37} MTC does not concentrate iodine and will appear as a cold nodule on thyroid scintigraphy. Computed tomographic (CT) imaging of the neck, chest, and abdomen may reveal distant sites of involvement, particularly in the lungs, liver, and mediastinal lymph nodes, and local mass effects (Fig. 17.3). Primary tumors have relatively nonspecific CT features but generally appear as nodules with calcifications. As mentioned earlier, lung and liver metastases can be quite small, numerous, and have a miliary appearance. Magnetic resonance imaging (MRI) with contrast administration can also be used in evaluation of metastatic disease and is considered the most sensitive imaging technique for detecting liver metastases. Bone lesions are typically best seen either on axial MRI or on bone scintigraphy. ³⁸ Use of fludeoxyglucose positron emission tomography (FDG-PET) remains controversial because some studies have shown FDG-PET to have low sensitivity. ^{38 , 39 , 40} Serum calcitonin levels have been shown to correlate well with tumor volume, and distant metastases are generally associated with elevated calcitonin levels; imaging is therefore recommended for these patients and for those with local lymph node metastases. ⁴¹

17.7 Initial Surgical Approach

Surgery for MTC is the most important initial patient treatment, and early intervention is of paramount importance due to the more aggressive nature of MTC and the higher rates of recurrence and mortality when compared to differentiated thyroid cancer. Surgery also offers the only possible definitive cure for MTC and is a very effective option for palliation. Systemic therapies, while showing promise, are not curative. ⁴² Outcomes are improved in patients with complete remission following surgical resection when compared to patients with biochemically persistent disease (i.e., persistent elevation of calcitonin levels) or to those with distant metastatic disease.

For patients with familial syndromes, the best curative option is complete surgical resection before malignant transformation or before spread beyond the thyroid gland. ^{3 , 43} Per the ATA, prophylactic thyroidectomy should be recommended to all patients with positive genetic testing for hereditary MTC who have not yet developed clinically apparent disease. ²⁸ Timing of surgery differs based on the genotype–phenotype correlations, and risk levels developed by the ATA regarding aggressiveness of disease are used as guidelines for patients with hereditary syndromes. For instance, patients with mutations involving codon 918, associated with MEN 2B and the youngest age of onset of MTC, highest risk of metastases, and disease-specific mortality, are given an ATA level D and are recommended to undergo prophylactic total thyroidectomy in infancy. This is in contrast to patients with ATA level A mutations, considered at lowest risk, who are advised to undergo thyroidectomy prior to 5 years of age but who may consider the option to delay surgery beyond age 5 years if certain screening criteria are met (i.e., normal annual basal serum calcitonin, normal annual neck ultrasound, less aggressive MTC family history). ²⁸

In our 2005 study of children with MEN 2A RET mutations, no evidence of persistent or recurrent MTC (as indicated by elevated serum calcitonin levels) was found in 44 of the 50 children who underwent total thyroidectomy and central lymph node dissection before age eight years. ⁴³ A European series of 207 patients with MEN 2A reported that none of the children younger than 14 years of age developed lymph node metastases. ⁴⁴ We have treated bulky nodal metastatic disease in a 9-year-old index MEN 2A patient, and cervical lymph node metastases developed in a teen 10 years after a preventive thyroidectomy. The performance of a central neck lymph node dissection should be based on the calcitonin level and the preoperative physical exam and ultrasound. Current recommendations for MEN 2A patients advise total thyroidectomy alone prior to age 5 years if preoperative ultrasound demonstrates thyroid nodules < 5 mm and the basal serum calcitonin level is < 40 pg/mL. Current ATA guidelines suggest that central neck dissection should be done in patients with a basal serum calcitonin > 40 pg/mL, and/or clinical evidence of cervical lymph node involvement. ^{28 , 43 , 44 , 45 , 46}

All patients with MTC, both sporadic and hereditary, who present with palpable disease should undergo total thyroidectomy with varying extents of concurrent systematic lymph node dissection and parathyroid autotransplantation. Given that lymph node metastases may be difficult or impossible to detect either by imaging or by palpation, selective node dissection (“berry picking”) is discouraged because this has been shown to have higher rates of recurrence, lower rates of biochemical cure, and worse survival when compared to meticulous compartment-oriented dissection (Fig. 17.4). ^{10 , 47} In a series of 73 patients treated at the authors’ institution who had presented with an initial palpable mass, 80% were found to have central node (level VI) involvement, 75% had ipsilateral jugular node (levels II–IV) involvement, and 47% had contralateral jugular node involvement. ¹⁰ Therefore, at a minimum, central and ipsilateral lateral compartment node dissection should be performed at the time of thyroidectomy in patients with a palpable primary tumor. Further compartment-oriented dissection may be warranted based on preoperative imaging, calcitonin and CEA levels, and intraoperative findings. ^{3 , 10} Of note, in patients with sporadic MTC, the incidence of bilateral tumor is relatively low, and a 2002 study examined the utility of total versus unilateral thyroidectomy in patients with sporadic MTC and no identified RET germline mutation. ⁴⁸ With 22 patients in retrospective review and 15 patients treated prospectively, unilateral thyroidectomy with isthmusectomy, systematic bilateral central lymph node dissection, and ipsilateral modified radical neck dissection was performed. The prospective population was found to have a biochemical cure rate of 80%, with no recurrences in the remaining thyroid lobe. ⁴⁸ Although unilateral thyroidectomy offers the advantages of lower risks of hypoparathyroidism and recurrent nerve injury and no need for thyroid supplementation, further investigation will be needed to elucidate the risks and benefits of unilateral thyroidectomy in comparison to removal of all thyroid tissue. Current recommendations remain that the operative procedure should remove all thyroid and nodal tissue from the level of the hyoid bone superiorly to the innominate vessels inferiorly and to the carotid arteries laterally. ⁴⁹

Ultrasound mapping of regional lymph nodes prior to surgery is particularly useful, and suspicious nodes can be marked on the skin preoperatively, which is helpful to the surgeon in planning extent of surgery, and whether contralateral level II through V node dissection will be necessary. In a study of 195 patients with MTC, it was found that as the number of central node metastases increased, the frequency of ipsilateral and contralateral lateral compartment lymph node metastases also increased in direct relation. When 10 or more central compartment lymph nodes were involved, nearly all patients had ipsilateral node involvement, and 77% had contralateral metastases, which supports undertaking bilateral lateral compartment dissection during thyroidectomy when numerous central node metastases are identified. ⁵⁰ Discontinuous lymphatic spread (“skip metastases”) have also been described in the literature and underscores the importance of a thorough preoperative evaluation to determine lymph node involvement sites. ^{10 , 51}

Preoperative basal serum calcitonin levels are also useful in estimating the extent of possible nodal involvement and need for dissection. A report of 300 patients with MTC treated by compartment-oriented surgery identified different thresholds at which lymph node metastases were found in different compartments; none of the patients with calcitonin levels < 20 pg/mL had evidence of lymph node involvement, which contrasted sharply with patients with calcitonin levels > 10,000 pg/mL, who demonstrated > 80% with lymph node involvement in the neck, > 50% in the upper mediastinum, and > 70% prevalence of distant metastases. ⁵² This can assist decision making in operative planning for the index procedure, and, in patients with elevated basal calcitonin levels > 200 pg/mL, contralateral lateral neck dissection is recommended as well.

Careful management of the parathyroids is critical to preserve function during total thyroidectomy and neck dissection. The extent of surgical manipulation has been controversial because the adequacy of central compartment dissection is arguably compromised by leaving the parathyroids in place with sufficient blood supply. The previous approach at the authors’ institution included routine four-gland parathyroidectomy with autotransplantation during central neck dissection; however, our current practice entails resection and autotransplantation of one or two parathyroids on the side of the primary tumor and the contralateral lower parathyroid, if it is not able to be preserved on a viable vascular pedicle. The contralateral upper parathyroid is left in place on its native vascular supply. Preservation of parathyroid function can then be accomplished by transplanting minced 1 mm fragments of the removed parathyroid tissue into individual muscle pockets created in the sternocleidomastoid muscle or a forearm muscle. ^{1 , 53} Due to the risk of subsequent graft-dependent hyperparathyroidism, a nondominant forearm muscle may be used for MEN 2A patients, whereas the sternocleidomastoid is usually used for patients with sporadic disease, MEN 2B, or FMTC. All parathyroid tissue should be left in the patient if possible, and transplantation of whole glands is not advised. If a patient has already developed primary hyperparathyroidism before thyroidectomy, appropriate parathyroidectomy should be performed. Surgical options include intraoperative parathyroid hormone monitoring with removal of only visibly enlarged glands, subtotal parathyroidectomy leaving one gland or a piece of one gland in situ, or total parathyroidectomy with forearm autotransplantation.