12 Medical Management of Medullary and Anaplastic Thyroid Cancer
12.1 Introduction
Although the vast majority of patients with thyroid cancer, particularly differentiated thyroid cancer (DTC), do extremely well, patients with medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC) have a significant risk for morbidity and mortality related to their disease. ATC originates from follicular cells and many times arises from preexisting DTC, particularly foci of papillary thyroid cancer, whereas MTC originates from C cells, which are of neural crest origin and typically reside in the posterolateral aspect of the thyroid gland. 1 , 2 C cells have a distinct function separate from thyroid follicles, producing calcitonin (Ct) and carcinoembryonic antigen (CEA) instead of thyroid hormone and thyroglobulin. MTC was first described in 1906 as “malignant goiter with amyloid.” 3 ATC is an aggressive form of undifferentiated thyroid cancer that tends to grow rapidly, invade local tissues, and metastasize early, and it lacks the ability to concentrate iodine. ATC cells do not secrete thyroglobulin and most commonly present as a giant cell tumor with biphasic spindle cells, although several morphological variations can be encountered.
The treatment of patients with MTC and ATC varies significantly from regimens used to treat DTC. So much so, that the American Thyroid Association provides independent guidelines for the management of both MTC and ATC. Although surgery plays a significant role in MTC and is sometimes indicated in ATC, unlike DTC, radioiodine therapy and TSH suppression have no role. Instead, therapies such as external beam radiotherapy and systemic chemotherapy are standard in cases of ATC and frequently used in cases of MTC, depending on the disease course. Recent advances, particularly in the area of systemic therapy, provide hope for continued improvement in outcomes for patients with both MTC and ATC, though the latter is still associated with a sobering mortality risk.
12.2 Epidemiology
MTC accounts for approximately 4% of all thyroid cancers in the United States. 4 MTC primarily occurs as sporadic disease (75%), with the remainder representing one of the autosomal dominant inherited forms. 4 , 5 Inherited forms of MTC include multiple endocrine neoplasia (MEN) types 2A (80%) and 2B (5%) as well as familial MTC (FMTC) (15%). MEN2A is associated with MTC (~ 100%), pheochromocytoma (50%), and hyperparathyroidism (30%), whereas MEN2B consists of MTC (~ 100%), pheochromocytoma (50%), and cutaneous neuromas, with < 5% exhibiting hyperparathyroidism. Requirements for FMTC, an apparent variant of MEN2A, include the presence of MTC without evidence for pheochromocytoma and primary hyperparathyroidism. Reports do exist of families initially categorized as having FMTC later being found to have MEN2A upon clinical expression of pheochromocytoma or hyperparathyroidism. 6 , 7 Recommendations vary in regard to the number of individuals and generations that must be affected with MTC alone in order to meet the criteria for FMTC. 8 , 9
The prevalence of ATC varies geographically, ranging between 1.3 to 9.8% of all thyroid cancers, and accounts for 1.7% of thyroid cancers in the United States. 10 It tends to occur later in life, at a median age of 69 years, and more so in women (65.8%). 11 Data from the Surveillance, Epidemiology and End Results (SEER) database indicates ATC may occur somewhat more frequently in non-Hispanic Caucasians, but this finding requires additional confirmation. 12 Patients with ATC may present with such findings as an enlarging neck mass, voice changes (e.g., hoarseness or dysphonia), dysphagia, dyspnea, hemoptysis, neck pain, superior vena cava syndrome, and distant metastasis. 12 ATC frequently (> 80%) arises from an abnormal thyroid, such as a goiter, and can arise within the context of a preexisting DTC, although the reported frequency of this occurrence varies widely (7–89%). 1 , 2 , 4 , 13 , 14 , 15 , 16
12.3 Diagnosis
12.3.1 Cytology
MTC cytology consists of polygonal-shaped cells, eccentric nuclei, granular chromatin, amyloid, and azurophilic cytoplasmic granules. 17 Studies report a sensitivity range between 63 and 89% for identifying MTC by FNA cytology, and there are reports of cytological misdiagnosis. 18 In many of these instances, cellular atypia was noted or another form of malignancy suspected, with the diagnosis of MTC being appreciated only on surgical histology. 19
The presence of ATC can many times be surmised by the classic clinical presentation of a rapidly enlarging neck mass that is fixed and hard in texture. Prompt tissue confirmation is essential. Although fine-needle aspiration (FNA) is typically helpful in the evaluation of thyroid nodules/masses, in the case of ATC, extensive fibrosis and cellular necrosis limit the ability to obtain an adequate sample for confirmatory diagnosis. 20 , 21 Use of a core biopsy should be pursued when FNA yields inadequate cellularity, and progression to open biopsy should be considered if the core biopsy is nondiagnostic.
12.3.2 Histology
Confirmation of ATC by histology can be challenging because the differential diagnosis includes poorly differentiated thyroid cancer, lymphoma, metastases to the thyroid, sarcoma, squamous cell carcinoma of the thyroid or head/neck, and Riedel’s thyroiditis. 22 Additionally, variations in presenting ATC histology include spindle cell, giant cell, squamoid, and paucicellular forms. 13 , 23 Detailed pathological examination may reveal the presence of areas of DTC or poorly differentiated thyroid cancer in concert with ATC in 20 to 90% of cases. 2 , 4 , 24 Whereas immunostaining for thyroglobulin and Ct tend to be positive in differentiated and medullary thyroid cancer, respectively, such staining is negative in ATC. Testing for P53 and pancytokeratin is usually positive in ATC tissue. Furthermore, positive immunostaining for E-cadherin is common, whereas positivity for PAX8 and TTF-1 is considered uncommon. 25
12.3.3 Biochemical
Although no blood test exists to diagnose ATC, measurement of serum calcitonin can be used to identify cases of MTC, with basal serum Ct levels > 20 to 100 pg/mL being suspicious for MTC. 26 Serum Ct screening yielded an MTC prevalence of 0.40% in a European-based study of 10,864 patients with thyroid nodules. Ct elevation was associated with a better sensitivity and specificity for MTC than cytology as well as earlier diagnosis with improved remission rates (59% vs. 2.7%; p = 0.0001). 27 In the United States, Ct measurement has traditionally been targeted toward at-risk individuals with thyroid nodules, such as those with a family history of MTC or type of thyroid cancer unconfirmed, suspicious cervical lymphadenopathy, a history of parathyroid-related hypercalcemia, or suspicion for pheochromocytoma. However, a U.S.-based study found that Ct screening of thyroid nodules could be cost effective at $11,793 per life-years saved while yielding 113,000 life-years at a cost increase of only 5.3%. 28
Prior to the clinical availability of RET (rearranged during transfection) mutation testing, stimulated Ct levels were used to identify C cell hyperplasia and/or MTC in at-risk individuals. Infusion of calcium and/or pentagastrin stimulates Ct release, with stimulated Ct levels > 100 to 500 pg/mL being suspicious for the presence of C-cell hyperplasia and/or MTC. 29 The sensitivity and specificity of this testing is impacted by the specific Ct cutoff levels applied. 30 However, pentagastrin is no longer available in the United States, and RET oncogene mutation testing is now preferred for identification of at-risk individuals. Preoperative calcitonin levels do provide helpful information to guide the extent of preoperative staging as the probability of extracervical disease rises with calcitonin levels > 400 pg/mL. 8
12.3.4 Mutational Testing
RET oncogene mutation testing allows for identification of individuals with inherited forms of MTC. Initial RET oncogene testing typically involves screening of the more commonly affected exons: 8, 9, 10, 11, 13, 14, and 16. It must be realized that lack of a RET oncogene mutation does not exclude inherited forms of MTC because previously unidentified mutations continue to be discovered. 16 Therefore, full RET oncogene sequencing is recommended when an inherited form of MTC is suspected but initial screening is negative. Identification of RET mutations also holds prognostic value because patients with certain mutations (634, 804, 883, 918) display a more aggressive disease course, whereas those with other mutations (609, 620, 630, 635) display a much more indolent course. 4 In addition to RET mutations, HRAS and KRAS gene mutations have been shown to be present in cases of sporadic MTC and impact tumor behavior, including possibly the response to targeted therapy, such as multikinase inhibitors. 31 , 32
Cutaneous lichen amyloidosis (CLA) is seen with MEN2 and tends to involve the T2 to T6 scapular area dermatomes. Pruritus related to CLA can precede development of MTC and, if recognized, allow for early diagnosis. Hirschsprung’s disease (HD) can also occur and is secondary to a RET gene loss-of-function altered migration of neural crest to enteric submucosa. 33 HD occurs in only about 7% of patients with MEN2A and FMTC, and only 2 to 5% of patients with HD are found to have MTC. 34 , 35
MEN2B occurs as a de novo mutation in > 50% of cases, with the M918T RET mutation (exon 16) being found in > 95% and another 2 to 3% exhibiting the A883F (exon 15) mutation. 36 MEN2B–associated MTC tends to exhibit more aggressive behavior and present about a decade earlier than that associated with MEN2A. MEN2B is associated with several phenotypic findings, including Marfanoid habitus; pectus excavatum; pes cavus; neuromas of the lips, tongue, and cornea; and gastrointestinal disorders, such as constipation (sometimes complicated by megacolon), vomiting with dehydration, intestinal ganglioneuromatosis, and obstruction. 37 Additional findings in young children include an inability to generate tears when crying, severe constipation, and feeding-related issues. 38
RET oncogene testing allows for potential early recognition of at-risk family members prior to the development of MTC, even prior to evidence of Ct elevation. With the natural course of MTC associated with various RET mutations being better understood, the timing for prophylactic thyroidectomy can be individualized based on the mutation present. The American Thyroid Association (ATA) MTC guidelines divide RET oncogene mutations into groups that represent severity of disease and expected time of onset. 16 With MEN2B mutations exhibiting a trend for an aggressive disease pattern with early onset, surgical intervention should be considered within the first year of life. 39 Those with MEN2A–related mutations with higher-risk MTC are recommended to undergo thyroidectomy with evidence of Ct elevation or prior to 5 years of age, whereas those with less concerning mutations can potentially be followed with serial neck ultrasound (US) imaging and Ct levels. 40 Thyroidectomy should be considered for development of Ct elevations or in childhood when lengthy serial follow-up is not preferred by the patient and/or parents. 16
Pheochromocytoma screening should begin by age 16 years. Because primary hyperparathyroidism (HPT) frequently occurs in association with MEN2A kindreds, screening for this entity should occur prior to thyroid surgery. Laboratory testing consistent with primary HPT should precipitate additional evaluation for confirmation of the diagnosis. Localization testing should be interpreted with caution because multigland disease is common, but not all involved parathyroid glands may be noted on sestamibi parathyroid scanning or neck US.
Microscopic evaluation reveals most ATC samples to be aneuploid in nature and contain significant abnormalities in chromosomal numbers and structure. 41 , 42 The evident mutational progression and evolution of chromosomal changes progressing from PTC to poorly differentiated thyroid cancer and then to ATC supports the concept of multistep mutation-driven dedifferentiation. 43 , 44 , 45 Mutations commonly found in both well-differentiated DTC and ATC include BRAF, RAS, phosphoinositide-3-kinase (PIK3-α), as well as RET/PTC3 rearrangement. 46 , 47 In a report of 652 ATC cases, the following prevalence of genetic mutations was noted: RAS 60%, TP53 48%, PI3KCA 24%, BRAF 23%, PTEN 16%, and RET/PTC 4%. 48 Other mutations noted in ATC include axin, TP53 and β-catenin, anaplastic lymphoma kinase (ALK), and adenomatous polyposis coli (APC). 26 , 49 , 50 A significant amount of gene mutations and microRNA alterations leads to protein expression changes impacting critical cellular roles. These changes are summarized in Table 12.1.
12.3.5 Staging
Staging for MTC is based on the American Joint Committee on Cancer (AJCC). 51 Stage I consists of tumors < 2 cm and stage II includes tumors between 2 and 4 cm, both without evidence of extraglandular disease. Stage III encompasses any tumors > 4 cm, level VI nodal metastases or microscopic extrathyroidal invasion irrespective of tumor size. The presence of any distant metastases, lymph node involvement beyond level VI, or gross soft tissue extension qualifies as stage IV. The reported associated mortality by stage is stage I, 0%; stage II, 13%; stage III, 56%; and stage IV, 100%. 52
Correct initial staging of patients with ATC provides information that plays an important role for both assessment of prognosis and therapeutic decision planning. All cases of ATC are considered stage IV and are subdivided as follows: IVA, primary tumor limited to thyroid; IVB, extrathyroidal extension; and IVC, distant metastases. The preponderance of data indicates that patients with ATC tend to present with more advanced disease burden: stage IVC (~ 45%), IVB (~ 40%), and IVA (~ 10%). 2 , 53 , 54 , 55 , 56 The reported median survival in months by stage are IVA, 7.3; IVB, 3.9; and IVC, 1.7, with respective 1-year survival rates of 72.7%, 24.8%, and 8.2%. 2 , 10
12.4 Preoperative Assessment
The surgical management of MTC and ATC is thoroughly reviewed in Chapters 17 and 18, respectively, and the reader is referred to these sections for detailed discussion of this area. This section is limited to surgical issues pertinent to the discussion of medical management.
Optimal surgical management is essential in patients with MTC. MTC tumors are known to often invade perithyroidal soft tissue structures and also frequently spread to central and lateral cervical lymph nodes. Therefore, preoperative anatomical imaging is essential and includes detailed cervical lymph node mapping with neck US or computed tomographic (CT) scanning, the latter allowing detailed central node assessment despite an intact thyroid. 57 Aerodigestive tract involvement can occur, and the presence of hoarseness, dysphagia, or other upper respiratory complaints should precipitate upper respiratory tract and vocal cord visualization. Additionally, contrast CT of the chest is useful for identification of metastases to the mediastinum and lungs, whereas CT of the abdomen and pelvis should be pursued when calcitonin levels are > 400 pg/mL. 16 Contrast-enhanced three-phase liver CT and magnetic resonance imaging (MRI) are more sensitive than conventional CT for detection of liver metastases. Preoperative laparoscopic liver screening for micrometastases was advocated but now is rarely performed, because extensive cervical microdissections are no longer recommended given that sustained clinical benefit was infrequent. 58
Preoperative identification of MEN is important because pheochromocytoma occurs in 50% of MEN2A and MEN2B cases. Identification and treatment of pheochromocytoma is essential to avoid perioperative morbidity and mortality related to this entity. 59 MEN-related pheochromocytomas are typically benign, multicentric, intraglandular, and bilateral. 60 Preoperative screening for pheochromocytoma may include plasma metanephrines, 24-hour urine catecholamines, and metanephrines with creatinine or CT of the adrenal glands.
Patients with ATC frequently present with signs or symptoms indicating upper airway involvement (hoarseness, stridor, dysphagia, hemoptysis, etc.). Mirror or fiberoptic visualization allows assessment of the larynx and vocal cords for evidence of invasion or vocal cord dysfunction. Follow-up bronchoscopy for further tracheal inspection is recommended in cases with evidence of any upper airway involvement, which necessitates prompt intervention to secure it.
Initial laboratory testing upon diagnosis of ATC includes a complete blood count and metabolic profile. Hypocalcemia secondary to tumor-related hypoparathyroidism may be encountered and, rarely, humoral-induced hypercalcemia may occur. 61 , 62 , 63 Thyroid function status should be assessed with TSH and free T4 levels because hypothyroidism or thyrotoxicosis may be present. 64
Imaging to assess the primary tumor and metastatic burden is integral in treatment planning, including determining the potential for tumor resection. The preferred imaging modality is 18-fludeoxyglucose positron emission tomography (18-FDG-PET) CT scanning is the preferred imaging modality for ATC cases, allowing for both anatomical assessment of the neck and chest and screening for extracervical 18-FDG avid metastases. If PET-CT is unavailable then cross-sectional imaging of the neck, chest, and abdomen should be obtained. 44 , 65 Metastases from ATC may occur in the lungs, mediastinum, liver, kidneys, heart, adrenal glands, brain, and bones. 22 Additional targeted imaging with neck US and MRI or bone scan may be clinically useful. 22 Radioactive iodine scanning does not have a role because ATC tumors do not concentrate iodine.
12.5 Treatment
In the context of inherited forms of MTC, prophylactic thyroidectomy should occur prior to the expected onset of cancer based on the RET oncogene mutation present. Total thyroidectomy with central lymph node dissection is recommended in patients > 8 years old with MEN2A or FMTC, and at any age for patients with MEN2B. However, total thyroidectomy alone is considered appropriate in children < 5 years old with MEN2A or FMTC without cervical lymphadenopathy. 16 Patients with local cervical metastases (≥ 10 lymph nodes) tend not to achieve biochemical cure, with only approximately 10% cured despite extensive surgical interventions. 66 However, patients with persistent postoperative Ct elevations exhibit reasonable survival rates of 80.2% at 5 years and 70.3% at 10 years. 67
When MTC is diagnosed following hemithyroidectomy, completion thyroidectomy and cervical lymph node dissection should be considered. Potential indications for additional surgery include the presence of multifocal MTC, cervical lymphadenopathy, and postsurgical Ct levels. Multifocal MTC is more common in familial forms (~ 75% in MEN2A) in comparison to sporadic MTC (0–22%). 68 Although Ct elevations indicate persistent MTC, there is no definitive cutoff for pursuing additional surgery. 13 If serial follow-up is elected, Ct levels should be closely monitored, with any rise prompting reevaluation.
When feasible, complete excision of the thyroid/anaplastic tumor should occur because survival is significantly impacted by extent of resection. The extent of invasion, the specific cervical structures involved, and the presence of distant metastases are the main factors that impact tumor resectability. If surgery is deemed appropriate, then surgical goals include total thyroidectomy with central and lateral lymph node resection. The degree of tumor resection is divided into four levels: R0, no residual tumor; R1, microscopic residual tumor; R2, macroscopic residual tumor; and RX, presence of residual tumor cannot be assessed. 51
Available data indicate improvement in survival with complete resection, whether or not additional chemotherapy and/or radiotherapy are being considered. Additionally, incomplete tumor resection is preferred over lesser resection or no surgery at all. 10 , 44 , 69 , 70 , 71 , 72 , 73 In an effort to achieve disease-free margins, en bloc resection of tumor may be appropriate, but tumor debulking has not been associated with an improvement in outcomes. 22 Of interest, neoadjuvant therapy with combination chemotherapy and radiotherapy can result in originally unresectable tumors meeting criteria for potential resection. 74
Management of airway issues is particularly challenging in patients with ATC. Although avoidance of tracheostomy placement is preferred, if necessary, it is best to perform the procedure in an operating room under controlled circumstances and avoid emergent placement. 75 To successfully place the tracheostomy, an isthmusectomy or debulking of tumor anterior to the trachea may be required when thyroidectomy is not feasible.
12.5.1 Radiation Therapy
Because C cells do not concentrate iodine, postoperative radioactive iodine (RAI) ablation is not used except possibly in rare occasions when coincident DTC is diagnosed. The role of external beam radiation therapy (EBRT) in the treatment of MTC remains controversial because prospective data for a survival benefit are lacking. EBRT may improve local disease control, but Ct levels rarely become undetectable. EBRT has not uniformly been shown to affect locoregional recurrence rates, although cases with persistent microscopic disease, extrathyroidal extension, or positive lymphadenopathy displayed a better 10-year local relapse-free rate with EBRT than without (86 vs. 52%; p = 0.049). Similar results were noted in another, much smaller study. 76 No consensus exists in regard to the use of EBRT for persistent Ct elevation following successful resection of macroscopic disease. A study of 207 patients with persistent Ct elevation without distant metastases revealed a reduced recurrence rate. 77 However, measurable postoperative Ct levels may represent either persistent local microscopic disease or unidentified distant metastases, with EBRT therapy holding no significant benefit in the latter scenario.
Because surgical resection of recurrent MTC is an effective alternative for local control and because radiation changes make future surgery much more challenging, EBRT is best reserved for cases where only incomplete resection is feasible and gross residual disease remains. The ATA MTC guidelines suggest the potential use of postoperative adjuvant EBRT of the neck or mediastinum following surgery in cases of high-volume disease, particularly with microscopically positive margins. 17 Evidence of extranodal extension and persistently measurable Ct postoperatively are other possible indications for EBRT. Of note, the latter two indications are only supported by a grade C rating and reflect expert opinion rather than conclusive data.
EBRT plays an integral role in the management of patients with ATC. Radiotherapy can slow the growth of locoregional disease, and in combination with prior successful surgical resection (R0 and R1) and chemotherapy is associated with the best local control and survival rates. 1 , 54 , 78 , 79 A multivariate analysis of 516 ATC cases noted that only patient age and combined surgery with radiotherapy were reliable survival predictors. 13
Because ATC tumors display very rapid growth, hyperfractionated or accelerated treatment protocols are preferred over conventional techniques, although these protocols are associated with a rise in adverse effects. 80 Intensity-modulated radiation therapy (IMRT), which enables concentration of treatment to tumor tissue while minimizing exposure to adjacent normal tissue, is most commonly used. 81 , 82 , 83 Outcomes appear to improve when at least 40 Gy is delivered, as observed in two studies with extension in survival from 3.2 to 11.1 months and 1.7 to 5.4 months. 1 , 56 Another report noted improved median survival at 1 year (54% vs. 17%) with a treatment dose > 45 Gy. 74 There has been some debate as to whether radiotherapy should be delivered pre- or postoperatively. 84 , 85 , 86 The ATA ATC guidelines advise that, for patients with resectable disease, radiotherapy after surgery is appropriate, and that treatment should begin about 2 to 3 weeks postoperatively to allow for resolution of swelling and adequate healing. 22
Available data indicate that better results occur with a combination of surgery and radiation than radiotherapy alone. 53 , 54 , 85 , 87 , 88 However, in cases where tumors are unresectable, radiotherapy, particularly combined with systemic therapy, should be considered in patients who prefer aggressive treatment, have been educated on potential risks and benefits, and are deemed fit to undergo such treatment. Palliative radiation therapeutic regimens can be considered in patients with poor performance status who are unfit for more aggressive intervention but have local symptoms and are interested in receiving at least some therapy. Radiation therapy may also be considered beyond the region of the neck and mediastinum for distant metastases to locations such as the brain or bone. 22 Complications from EBRT can be clinically significant and include odynophagia, dysphagia, anorexia with weight loss, radiation burns, fatigue, and poor nutritional state.
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