Thyroid carcinoma is the most common malignancy of the endocrine system. Malignant tumors derived from the follicular epithelium are classified according to histologic features. Differentiated tumors, such as papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC), are often curable, and the prognosis is good for patients identified with early-stage disease. In contrast, anaplastic thyroid cancer (ATC) is aggressive, responds poorly to treatment, and is associated with a bleak prognosis.
The incidence of thyroid cancer is ~12/100,000 per year in the United States and increases with age. Prognosis is worse in older persons (>65 years). Thyroid cancer is twice as common in women as men, but male gender is associated with a worse prognosis. Additional important risk factors include a history of childhood head or neck irradiation, large nodule size (≥4 cm), evidence for local tumor fixation or invasion into lymph nodes, and the presence of metastases (Table 50-3). Several unique features of thyroid cancer facilitate its management: (1) thyroid nodules are amenable to biopsy by FNA; (2) iodine radioisotopes can be used to diagnose (123I) and treat (131I) differentiated thyroid cancer, reflecting the unique uptake of this anion by the thyroid gland; and (3) serum markers allow the detection of residual or recurrent disease, including the use of Tg levels for PTC and FTC, and calcitonin for medullary thyroid cancer (MTC).
TABLE 50-3RISK FACTORS FOR THYROID CARCINOMA IN PATIENTS WITH THYROID NODULE ||Download (.pdf) TABLE 50-3 RISK FACTORS FOR THYROID CARCINOMA IN PATIENTS WITH THYROID NODULE
History of head and neck irradiation, including total-body irradiation for bone marrow transplant and brain radiation for childhood leukemia
Exposure to ionizing radiation from fallout in childhood or adolescence
Age <20 or >65 years
Increased nodule size (>4 cm)
New or enlarging neck mass
Family history of thyroid cancer, MEN 2, or other genetic syndromes associated with thyroid malignancy (e.g., Cowden’s syndrome, familial polyposis, Carney complex)
Vocal cord paralysis, hoarse voice
Nodule fixed to adjacent structures
Lateral cervical lymphadenopathy
Thyroid neoplasms can arise in each of the cell types that populate the gland, including thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal and vascular elements, as well as metastases from other sites (Table 50-2). The American Joint Committee on Cancer (AJCC) has designated a staging system using the tumor, node, metastasis (TNM) classification (Table 50-4). Several other classification and staging systems are also widely used, some of which place greater emphasis on histologic features or risk factors such as age or gender.
TABLE 50-4THYROID CANCER CLASSIFICATIONa ||Download (.pdf) TABLE 50-4 THYROID CANCER CLASSIFICATIONa
|Papillary or Follicular Thyroid Cancers |
| ||<45 Years ||>45 Years |
| Stage I ||Any T, any N, M0 ||T1, N0, M0 |
| Stage II ||Any T, any N, M1 ||T2, N0, M0 |
| Stage III ||— ||T3, N0, M0 |
| || ||T1–T3, N1a, M0 |
| Stage IVA ||— || |
T4a, any N, M0
T1–T3, N1b, M0
| Stage IVB || ||T4b, any N, M0 |
| Stage IVC || ||Any T, any N, M1 |
|Anaplastic Thyroid Cancer |
| Stage IV ||All cases are stage IV || |
|Medullary Thyroid Cancer |
| Stage I ||T1, N0, M0 || |
| Stage II ||T2 or T3, N0, M0 || |
| Stage III ||T1–T3, N1a, M0 || |
| Stage IVA || |
T4a, any N, M0
T1–T3, N1b, M0
| Stage IVB ||T4b, any N, M0 || |
| Stage IVC ||Any T, any N, M1 || |
PATHOGENESIS AND GENETIC BASIS
Early studies of the pathogenesis of thyroid cancer focused on the role of external radiation, which predisposes to chromosomal breaks, leading to genetic rearrangements and loss of tumor-suppressor genes. External radiation of the mediastinum, face, head, and neck region was administered in the past to treat an array of conditions, including acne and enlargement of the thymus, tonsils, and adenoids. Radiation exposure increases the risk of benign and malignant thyroid nodules, is associated with multicentric cancers, and shifts the incidence of thyroid cancer to an earlier age group. Radiation from nuclear fallout also increases the risk of thyroid cancer. Children seem more predisposed to the effects of radiation than adults. Of note, radiation derived from 131I therapy appears to contribute minimal increased risk of thyroid cancer.
Many differentiated thyroid cancers express TSH receptors and, therefore, remain responsive to TSH. Higher serum TSH levels, even within normal range, are associated with increased thyroid cancer risk in patients with thyroid nodules. These observations provide the rationale for T4 suppression of TSH in patients with thyroid cancer. Residual expression of TSH receptors also allows TSH-stimulated uptake of 131I therapy (see below).
Oncogenes and tumor-suppressor genes
Thyroid cancers are monoclonal in origin, consistent with the idea that they originate as a consequence of mutations that confer a growth advantage to a single cell. In addition to increased rates of proliferation, some thyroid cancers exhibit impaired apoptosis and features that enhance invasion, angiogenesis, and metastasis. Thyroid neoplasms have been analyzed for a variety of genetic alterations, but without clear evidence of an ordered acquisition of somatic mutations as they progress from the benign to the malignant state. On the other hand, certain mutations are relatively specific for thyroid neoplasia, some of which correlate with histologic classification (Table 50-5).
TABLE 50-5GENETIC ALTERATIONS IN THYROID NEOPLASIA ||Download (.pdf) TABLE 50-5 GENETIC ALTERATIONS IN THYROID NEOPLASIA
|Gene/Protein ||Type of Gene ||Chromosomal Location ||Genetic Abnormality ||Tumor |
|TSH receptor ||GPCR receptor ||14q31 ||Point mutations ||Toxic adenoma, differentiated carcinomas |
|GSα ||G protein ||20q13.2 ||Point mutations ||Toxic adenoma, differentiated carcinomas |
|RET/PTC ||Receptor tyrosine kinase ||10q11.2 ||Rearrangements ||PTC (more common in radiation-induced tumors) |
| || || ||PTC1: inv(10)(q11.2q21) || |
| || || ||PTC2: t(10;17)(q11.2;q23) || |
| || || ||PTC3: ELE1/TK || |
|RET ||Receptor tyrosine kinase ||10q11.2 ||Point mutations ||MEN 2, medullary thyroid cancer |
|BRAF ||MEK kinase ||7q24 ||Point mutations, rearrangements ||PTC, ATC |
|TRK ||Receptor tyrosine kinase ||1q23-24 ||Rearrangements ||Multinodular goiter, papillary thyroid cancer |
|RAS ||Signal transducing p21 ||NRAS 1p13.2 (most common); HRAS 11p15.5; KRAS 12p12.1 ||Point mutations ||Follicular thyroid cancer, PTC follicular variant, adenomas |
|p53 ||Tumor suppressor, cell cycle control, apoptosis ||17p13 ||Point mutations Deletion, insertion ||Anaplastic cancer |
|APC ||Tumor suppressor, adenomatous polyposis coli gene ||5q21-q22 ||Point mutations ||Anaplastic cancer, also associated with familial polyposis coli |
|p16 (MTS1, CDKN2A) ||Tumor suppressor, cell cycle control ||9p21 ||Deletions ||Differentiated carcinomas |
|p21/WAF ||Tumor suppressor, cell cycle control ||6p21.2 ||Overexpression ||Anaplastic cancer |
|MET ||Receptor tyrosine kinase ||7q31 ||Overexpression ||Follicular thyroid cancer |
|c-MYC ||Receptor tyrosine kinase ||8q24.12-13 ||Overexpression ||Differentiated carcinoma |
|PTEN ||Phosphatase ||10q23 ||Point mutations ||PTC in Cowden’s syndrome (multiple hamartomas, breast tumors, gastrointestinal polyps, thyroid tumors) |
|CTNNB1 ||β-Catenin ||3p22 ||Point mutations ||Anaplastic cancer |
|Loss of heterozygosity (LOH) ||? Tumor suppressors ||3p; 11q13, other loci ||Deletions ||Differentiated thyroid carcinomas, anaplastic cancer |
|PAX8-PPARγ1 ||Transcription factor-nuclear receptor fusion ||t(2;3)(q13;p25) ||Translocation ||Follicular adenoma or carcinoma, rare PTC follicular variant |
As described above, activating mutations of the TSH-R and the GSα subunit are associated with autonomously functioning nodules. Although these mutations induce thyroid cell growth, this type of nodule is almost always benign.
Activation of the RET-RAS-BRAF signaling pathway is seen in up to 70% of PTCs, although the types of mutations are heterogeneous. A variety of rearrangements involving the RET gene on chromosome 10 bring this receptor tyrosine kinase under the control of other promoters, leading to receptor overexpression. RET rearrangements occur in 20–40% of PTCs in different series and were observed with increased frequency in tumors developing after the Chernobyl radiation accident. Rearrangements in PTC have also been observed for another tyrosine kinase gene, TRK1, which is located on chromosome 1. To date, the identification of PTC with RET or TRK1 rearrangements has not proven useful for predicting prognosis or treatment responses. BRAF V600E mutations appear to be the most common genetic alteration in PTC. These mutations activate the kinase, which stimulates the mitogen-activated protein MAP kinase (MAPK) cascade. RAS mutations, which also stimulate the MAPK cascade, are found in about 20–30% of thyroid neoplasms (NRAS > HRAS > KRAS), including both PTC and FTC. Of note, simultaneous RET, BRAF, and RAS mutations rarely occur in the same tumor, suggesting that activation of the MAPK cascade is critical for tumor development, independent of the step that initiates the cascade.
RAS mutations also occur in FTCs. In addition, a rearrangement of the thyroid developmental transcription factor PAX8 with the nuclear receptor PPARγ is identified in a significant fraction of FTCs. Overall, about 70% of follicular cancers have mutations or genetic rearrangements. Loss of heterozygosity of 3p or 11q, consistent with deletions of tumor-suppressor genes, is also common in FTCs.
Most of the mutations seen in differentiated thyroid cancers have also been detected in ATCs. BRAF mutations are seen in up to 50% of ATCs. Mutations in CTNNB1, which encodes β-catenin, occur in about two-thirds of ATCs, but not in PTC or FTC. Mutations of the tumor-suppressor P53 also play an important role in the development of ATC. Because P53 plays a role in cell cycle surveillance, DNA repair, and apoptosis, its loss may contribute to the rapid acquisition of genetic instability as well as poor treatment responses (Chap. 26) (Table 50-5).
The role of molecular diagnostics in the clinical management of thyroid cancer is under investigation. In principle, analyses of specific mutations might aid in classification, prognosis, or choice of treatment. Although BRAF V600E mutations are associated with loss of iodine uptake by tumor cells, there is no clear evidence to date that this information alters clinical decision making. Higher recurrence rates have been variably reported in patients with BRAF-positive PTC, but the impact on survival rates is unclear. Sequencing of thyroid cancers as part of the Cancer Genome Atlas (TCGA) is likely to lead to new classification schemes based on molecular abnormalities in tumors.
MTC, when associated with multiple endocrine neoplasia (MEN) type 2, harbors an inherited mutation of the RET gene. Unlike the rearrangements of RET seen in PTC, the mutations in MEN 2 are point mutations that induce constitutive activity of the tyrosine kinase (Chap. 52). MTC is preceded by hyperplasia of the C cells, raising the likelihood that as-yet-unidentified “second hits” lead to cellular transformation. A subset of sporadic MTC contains somatic mutations that activate RET.
WELL-DIFFERENTIATED THYROID CANCER
PTC is the most common type of thyroid cancer, accounting for 70–90% of well-differentiated thyroid malignancies. Microscopic PTC is present in up to 25% of thyroid glands at autopsy, but most of these lesions are very small (several millimeters) and are not clinically significant. Characteristic cytologic features of PTC help make the diagnosis by FNA or after surgical resection; these include psammoma bodies, cleaved nuclei with an “orphan-Annie” appearance caused by large nucleoli, and the formation of papillary structures.
PTC tends to be multifocal and to invade locally within the thyroid gland as well as through the thyroid capsule and into adjacent structures in the neck. It has a propensity to spread via the lymphatic system but can metastasize hematogenously as well, particularly to bone and lung. Because of the relatively slow growth of the tumor, a significant burden of pulmonary metastases may accumulate, sometimes with remarkably few symptoms. The prognostic implication of lymph node spread is debated. Lymph node involvement by thyroid cancer can be well tolerated but appears to increase the risk of recurrence and mortality, particularly in older patients. The staging of PTC by the TNM system is outlined in Table 50-4. Most papillary cancers are identified in the early stages (>80% stages I or II) and have an excellent prognosis, with survival curves similar to expected survival (Fig. 50-2). Mortality is markedly increased in stage IV disease, especially in the presence of distant metastases (stage IVC), but this group comprises only about 1% of patients. The treatment of PTC is described below.
Survival rates of patients with different stages of papillary cancer. (Adapted with permission from Edge SB, Byrd DR: Thyroid, in Compton CC, Fritz AB, Greene FL, Trotti A [eds]: AJCC Cancer Staging Manual, 7th ed. New York, Springer, 2010, pp 87–92.)
The incidence of FTC varies widely in different parts of the world; it is more common in iodine-deficient regions. Currently, FTC accounts for only about 5% of all thyroid cancers diagnosed in the United States. FTC is difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures. FTC tends to spread by hematogenous routes leading to bone, lung, and central nervous system metastases. Mortality rates associated with FTC are less favorable than for PTC, in part because a larger proportion of patients present with stage IV disease. Poor prognostic features include distant metastases, age >50 years, primary tumor size >4 cm, Hürthle cell histology, and the presence of marked vascular invasion.
TREATMENT Well-Differentiated Thyroid Cancer Surgery
All well-differentiated thyroid cancers should be surgically excised. In addition to removing the primary lesion, surgery allows accurate histologic diagnosis and staging, and multicentric disease is commonly found in the contralateral thyroid lobe. Preoperative sonography should be performed in all patients to assess the central and lateral cervical lymph node compartments for suspicious adenopathy, which if present, can undergo FNA and then be removed at surgery. Bilateral, near-total thyroidectomy has been shown to reduce recurrence rates in all patients except those with T1a tumors (≤1 cm). If cytology is diagnostic for thyroid cancer, bilateral surgery should be done. If malignancy is identified pathologically after lobectomy, completion surgery is recommended unless the tumor is T1a or is a minimally invasive follicular cancer. Bilateral surgery for patients at higher risk allows monitoring of serum Tg levels and administration of radioiodine for remnant ablation and potential treatment of iodine-avid metastases, if indicated. Therefore, near-total thyroidectomy is preferable in almost all patients; complication rates are acceptably low if the surgeon is highly experienced in the procedure. TSH Suppression Therapy
Because most tumors are still TSH-responsive, levothyroxine suppression of TSH is a mainstay of thyroid cancer treatment. Although TSH suppression clearly provides therapeutic benefit, there are no prospective studies that define the optimal level of TSH suppression. The degree of TSH suppression should be individualized based on a patient’s risk of recurrence. It should be adjusted over time as surveillance blood tests and imaging confirm absence of disease or, alternatively, indicate possible residual/recurrent cancer. For patients at low risk of recurrence, TSH should be suppressed into the low but detectable range (0.1–0.5 mIU/L). If subsequent surveillance testing indicates no evidence of disease, the TSH target may rise to the lower half of the normal range. For patients at high risk of recurrence or with known metastatic disease, TSH levels should be kept to <0.1 mIU/L if there are no strong contraindications to mild thyrotoxicosis. In this instance, unbound T4 must also be monitored to avoid excessive treatment. Radioiodine Treatment
After near-total thyroidectomy, substantial thyroid tissue often remains, particularly in the thyroid bed and surrounding the parathyroid glands. Postsurgical radioablation of the remnant thyroid eliminates residual normal thyroid, facilitating the use of Tg determinations and radioiodine scanning for long-term follow-up. In addition, well-differentiated thyroid cancer often incorporates radioiodine, although less efficiently than normal thyroid follicular cells. Radioiodine uptake is determined primarily by expression of the NIS and is stimulated by TSH, requiring expression of the TSH-R. The retention time for radioactivity is influenced by the extent to which the tumor retains differentiated functions such as iodide trapping and organification. Consequently, for patients at risk of recurrence and for those with known distant metastatic disease, 131I ablation may also potentially treat residual tumor cells. Indications
Not all patients benefit from radioiodine therapy. Neither recurrence nor survival rates are improved in stage I patients with T1 tumors (≤2 cm) confined to the thyroid. However, in higher risk patients (larger tumors, more aggressive variants of papillary cancer, tumor vascular invasion, presence of large-volume lymph node metastases), radioiodine reduces recurrence and may increase survival. 131I Thyroid ablation and treatment
As noted above, the decision to use 131I for thyroid ablation should be coordinated with the surgical approach, because radioablation is much more effective when there is minimal remaining normal thyroid tissue. Radioiodine is administered after iodine depletion (patient follows a low-iodine diet for 1≤2 weeks) and in the presence of elevated serum TSH levels to stimulate uptake of the isotope into both the remnant and potentially any residual tumor. To achieve high serum TSH levels, there are two approaches. A patient may be withdrawn from thyroid hormone so that endogenous TSH is secreted and, ideally, the serum TSH level is >25 mIU/L at the time of 131I therapy. A typical strategy is to treat the patient for several weeks postoperatively with liothyronine (25 μg qd or bid), followed by thyroid hormone withdrawal for 2 weeks. Alternatively, recombinant human TSH (rhTSH) is administered as two daily consecutive injections (0.9 mg) with administration of 131I 24 h after the second injection. The patient can continue to take levothyroxine and remains euthyroid. Both approaches have equal success in achieving remnant ablation.
A pretreatment scanning dose of 131I (usually 111–185 MBq [3–5 mCi]) or 123I (74 MBq [2 mCi]) can reveal the amount of residual tissue and provides guidance about the dose needed to accomplish ablation. However, because of concerns about radioactive “stunning” that impairs subsequent treatment, there is a trend to avoid pretreatment scanning with 131I and use either 123I or proceed directly to ablation, unless there is suspicion that the amount of residual tissue will alter therapy or that there is distant metastatic disease. In the United States, outpatient doses of up to 6475 MBq (175 mCi) can be given at most centers. The administered dose depends on the indication for therapy with lower doses of 1850–2775 MBq (50–75 mCi) given for remnant ablation but higher doses of 3700–5500 MBq (100–150 mCi) used as adjuvant therapy when residual disease may be present. A WBS following radioiodine treatment is used to confirm the 131I uptake in the remnant and to identify possible metastatic disease. Follow-up whole-body thyroid scanning and thyroglobulin determinations
Serum thyroglobulin is a sensitive marker of residual/ recurrent thyroid cancer after ablation of the residual postsurgical thyroid tissue. However, newer Tg assays have functional sensitivities as low as 0.1 ng/mL, as opposed to older assays with functional sensitivities of 1 ng/mL, reducing the number of patients with truly undetectable serum Tg levels. Because the vast majority of papillary thyroid cancer recurrences are in cervical lymph nodes, a neck ultrasound should be performed about 6 months after thyroid ablation; ultrasound has been shown to be more sensitive than WBS in this scenario.
In low-risk patients who have no clinical evidence of residual disease after ablation and a basal Tg <1 ng/mL on levothyroxine, an rhTSH-stimulated Tg level should be obtained 6–12 months after ablation, without WBS. If stimulated Tg levels are low (<1 ng/mL) and, ideally, undetectable, the risk of recurrence is <5% at 5 years. Newer data indicate that rhTSH stimulation may not be required for patients with undetectable basal Tg levels in sensitive assays, if there is documented absence of Tg antibodies. These patients can be followed with unstimulated Tg every 6–12 months and neck ultrasound as indicated. Levothyroxine dosing may then be titrated to a higher TSH level of 0.5–1.5 mIU/L.
The use of WBS is reserved for patients with known iodine-avid metastases or those with elevated serum thyroglobulin levels and negative imaging with ultrasound, chest CT, and neck cross-sectional imaging who may require additional 131I therapy.
In addition, most authorities advocate radioiodine treatment for scan-negative, Tg-positive (Tg >5–10 ng/mL) patients, as many derive therapeutic benefit from a large dose of 131I. For such patients, rhTSH preparation is not FDA approved for the treatment of metastatic disease, and the traditional approach of thyroid hormone withdrawal should be followed. This involves switching patients from levothyroxine (T4) to the more rapidly cleared hormone liothyronine (T3), thereby allowing TSH to increase more quickly. Whenever 131I is administered, posttherapy WBS is the gold standard to assess iodine-avid metastases.
In addition to radioiodine, external beam radiotherapy is also used to treat specific metastatic lesions, particularly when they cause bone pain or threaten neurologic injury (e.g., vertebral metastases).
New potential therapies Kinase inhibitors are being explored as a means to target pathways known to be active in thyroid cancer, including the RAS, BRAF, EGFR, VEGFR, and angiogenesis pathways. A multicenter randomized controlled trial of the multikinase inhibitor sorafenib in 417 patients with progressive metastatic thyroid cancer reported a doubling of progression-free survival to 10.8 months in the treatment group compared with the placebo group. Ongoing trials are exploring whether differentiation protocols with kinase inhibitors or other approaches might enhance radioiodine uptake and efficacy.
ANAPLASTIC AND OTHER FORMS OF THYROID CANCER
Anaplastic thyroid cancer
As noted above, ATC is a poorly differentiated and aggressive cancer. The prognosis is poor, and most patients die within 6 months of diagnosis. Because of the undifferentiated state of these tumors, the uptake of radioiodine is usually negligible, but it can be used therapeutically if there is residual uptake. Chemotherapy has been attempted with multiple agents, including anthracyclines and paclitaxel, but it is usually ineffective. External beam radiation therapy can be attempted and continued if tumors are responsive.
Lymphoma in the thyroid gland often arises in the background of Hashimoto’s thyroiditis. A rapidly expanding thyroid mass suggests the possibility of this diagnosis. Diffuse large-cell lymphoma is the most common type in the thyroid. Biopsies reveal sheets of lymphoid cells that can be difficult to distinguish from small-cell lung cancer or ATC. These tumors are often highly sensitive to external radiation. Surgical resection should be avoided as initial therapy because it may spread disease that is otherwise localized to the thyroid. If staging indicates disease outside of the thyroid, treatment should follow guidelines used for other forms of lymphoma (Chap. 16).
MEDULLARY THYROID CARCINOMA
MTC can be sporadic or familial and accounts for about 5% of thyroid cancers. There are three familial forms of MTC: MEN 2A, MEN 2B, and familial MTC without other features of MEN (Chap. 52). In general, MTC is more aggressive in MEN 2B than in MEN 2A, and familial MTC is more aggressive than sporadic MTC. Elevated serum calcitonin provides a marker of residual or recurrent disease. All patients with MTC should be tested for RET mutations, because genetic counseling and testing of family members can be offered to those individuals who test positive for mutations.
The management of MTC is primarily surgical. Unlike tumors derived from thyroid follicular cells, these tumors do not take up radioiodine. External radiation treatment and chemotherapy may provide palliation in patients with advanced disease (Chap. 52).
APPROACH TO THE PATIENT: Thyroid Nodules
Palpable thyroid nodules are found in about 5% of adults, but the prevalence varies considerably worldwide. Given this high prevalence rate, practitioners commonly identify thyroid nodules either on physical examination or as incidental findings on imaging performed for another indication (e.g., carotid ultrasound, cervical spine MRI). The main goal of this evaluation is to identify, in a cost-effective manner, the small subgroup of individuals with malignant lesions.
Nodules are more common in iodine-deficient areas, in women, and with aging. Most palpable nodules are >1 cm in diameter, but the ability to feel a nodule is influenced by its location within the gland (superficial versus deeply embedded), the anatomy of the patient’s neck, and the experience of the examiner. More sensitive methods of detection, such as CT, thyroid ultrasound, and pathologic studies, reveal thyroid nodules in up to 50% of glands in individuals over the age of 50. The presence of these thyroid incidentalomas has led to much debate about how to detect nodules and which nodules to investigate further.
An approach to the evaluation of a solitary nodule is outlined in Fig. 50-3. Most patients with thyroid nodules have normal thyroid function tests. Nonetheless, thyroid function should be assessed by measuring a TSH level, which may be suppressed by one or more autonomously functioning nodules. If the TSH is suppressed, a radionuclide scan is indicated to determine if the identified nodule is “hot,” as lesions with increased uptake are almost never malignant and FNA is unnecessary. Otherwise, the next step in evaluation is performance of a thyroid ultrasound for three reasons: (1) Ultrasound will confirm if the palpable nodule is indeed a nodule. About 15% of “palpable” nodules are not confirmed on imaging, and therefore, no further evaluation is required. (2) Ultrasound will assess if there are additional nonpalpable nodules for which FNA may be recommended based on imaging features and size. (3) Ultrasound will characterize the imaging features of the nodule, which, combined with the nodule’s size, facilitate decision making about FNA. Evidence-based guidelines from both the American Thyroid Association and the American Association of Clinical Endocrinologists provide recommendations for nodule FNA based on sonographic imaging features and size cut offs, with lower size cut offs for nodules with more suspicious ultrasound characteristics. FNA biopsy, ideally performed with ultrasound guidance, has good sensitivity and specificity when performed by physicians familiar with the procedure and when the results are interpreted by experienced cytopathologists. The technique is particularly useful for detecting PTC. However, the distinction between benign and malignant follicular lesions is often not possible using cytology alone. In several large studies, FNA biopsies yielded the following findings: 65% benign, 5% malignant or suspicious for malignancy, 10% nondiagnostic or yielding insufficient material for diagnosis, and 20% indeterminate. The Bethesda System is now widely used to provide more uniform terminology for reporting thyroid nodule FNA cytology results. This six-tiered classification system with the respective estimated malignancy rates is shown in Table 50-6. Specifically, the Bethesda System subcategorized cytology specimens previously labeled as indeterminate into three categories: atypia or follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm, and suspicious for malignancy.
Cytology results indicative of malignancy mandate surgery, after performing preoperative sonography to evaluate the cervical lymph nodes. Nondiagnostic cytology specimens generally result from cystic lesions but may also occur in fibrous long-standing nodules. Ultrasound-guided FNA is indicated when a repeat FNA is necessary. Repeat FNA will yield a diagnostic cytology in about 50% of cases. Benign nodules should be monitored by ultrasound for growth, and repeat FNA should be considered if the nodule enlarges. The use of levothyroxine to suppress serum TSH is not effective in shrinking nodules in iodine-replete populations, and therefore, levothyroxine should not be used. The three new cytology classifications introduced by the Bethesda System are associated with different risks of malignancy (Table 50-6). For nodules with suspicious for malignancy cytology, surgery is recommended after ultrasound assessment of cervical lymph nodes. Options to be discussed with the patient include: (1) lobectomy with intraoperative frozen section; (2) near-total thyroidectomy; and (3) mutational analysis mainly for BRAF V600E, which is virtually diagnostic of PTC, and bilateral rather than unilateral thyroid surgery is required.
On the other hand, the majority of nodules with AUS/FLUS and follicular neoplasm cytology results are benign; only 10–30% are malignant. The traditional approach for these patients is diagnostic lobectomy for histopathologic diagnosis. Therefore, up to 85% of patients undergo surgery for benign nodules. A high-sensitivity (~90%) novel molecular test using gene expression profiling technology may reduce the need for unnecessary surgery in these two groups. In a multicenter trial of over 265 such nodules, a negative gene expression classifier test reduced the risk of malignancy to about 6%, leading to clinical recommendations for follow-up rather than surgery.
The evaluation of a thyroid nodule is stressful for most patients. They are concerned about the possibility of thyroid cancer, whether verbalized or not. It is constructive, therefore, to review the diagnostic approach and to reassure patients when no malignancy is found. When a suspicious lesion or thyroid cancer is identified, the generally favorable prognosis and available treatment options can be reassuring.
Approach to the patient with a thyroid nodule. See text and references for details. FNA, fine-needle aspiration; LN, lymph node; PTC, papillary thyroid cancer; TSH, thyroid-stimulating hormone; US, ultrasound.
TABLE 50-6BETHESDA CLASSIFICATION FOR THYROID CYTOLOGY ||Download (.pdf) TABLE 50-6 BETHESDA CLASSIFICATION FOR THYROID CYTOLOGY
|Diagnostic Category ||Risk of Malignancy |
|Nondiagnostic or unsatisfactory ||1–5% |
|Benign ||2–4% |
|Atypia or follicular lesion of unknown significance (AUS/FLUS) ||15–20% |
|Follicular neoplasm ||20–30% |
|Suspicious for malignancy ||60–75% |
|Malignant ||97–100% |