Laboratory Studies

Most patients who present with a thyroid nodule are euthyroid. The finding of hypothyroidism or hyperthyroidism tends to shift the workup away from thyroid carcinoma to a functional disorder of the thyroid gland, such as Hashimoto’s thyroiditis or a toxic nodule.⁶⁸ Although many thyroid hormone tests are available, few are needed in the initial patient evaluation. TSH measurement serves as an excellent screening test. Full thyroid function tests can be performed if the TSH level is abnormal.

Measurement of thyroglobulin is generally not performed initially because thyroglobulin is secreted by normal and malignant thyroid tissue, and it is not recommended in the 2006 ATA guidelines.⁶⁹ Levels of thyroglobulin cannot differentiate between benign and malignant processes, unless levels are extremely high, as in metastatic thyroid cancer. Antithyroglobulin antibodies can also interfere with the assay. Thyroglobulin levels may be useful in studying patients who have undergone total thyroidectomy for well-differentiated thyroid cancer.

Serum calcitonin levels are not a typical initial test for patients with a thyroid nodule, unless the patient has a family history of MTC or MEN II. If FNAC shows or is suspicious for MTC, however, calcitonin levels should be obtained. In addition, if the patient has RET oncogene mutations, the possibility of a coexisting pheochromocytoma should be evaluated with abdominal magnetic resonance imaging (MRI) and a 24-hour urine collection to measure metanephrines and catecholamines (total and fractionated). The serum calcium level should be measured to exclude hyperparathyroidism.

Fine-Needle Aspiration Cytology

FNAC has become the procedure of choice in the evaluation of thyroid nodules.⁶⁹ The findings are highly sensitive and specific, although the accuracy of FNAC is related to the skill of the aspirator and the experience of the cytopathologist.⁷⁰ The procedure is minimally invasive and may be performed quickly with little patient discomfort. In contrast to large-bore needle biopsies such as the Tru-cut or Vim-Silverman needle, there are fewer complications. With the advent of this technique, the number of patients requiring surgery has decreased by 35% to 75%, and the cost in managing patients with thyroid nodules has been substantially reduced.^71–73 Also, the yield of malignancies has almost tripled in patients who have had thyroid surgery after FNAC.^73,74 The accuracy of FNAC diagnosis of papillary carcinoma is 99% with a false-positive rate of less than 1%.⁷⁵

FNAC should be one of the initial steps in the surgical evaluation of a thyroid nodule. Approximately 15% of all aspirates are inadequate or nondiagnostic, largely because of the sampling from cystic, hemorrhagic, hypervascular, or hypocellular colloid nodules. Repeat aspiration of such a nodule is crucial because a nondiagnostic finding should never be interpreted as a negative finding for carcinoma. Surgical diagnoses after repeated nondiagnostic aspirations revealed malignant nodules in 4% of women and 29% of men.⁷⁶ Nodules that are difficult to localize and nodules that have yielded nondiagnostic aspirates on previous attempts may benefit from ultrasound-guided aspiration. FNAC is increasingly being performed with ultrasound guidance to improve diagnostic accuracy and yield. Cystic nodules with multiple nondiagnostic FNAC studies require close observation or surgical excision. Also, surgery should be more strongly considered for a solid nodule that is cytologically nondiagnostic.⁶⁹

Successful FNAC categorizes a nodule into the following groups: benign, malignant, or suspicious. In 60% to 90% of nodules, FNAC reveals a benign or “negative” diagnosis. The likelihood of malignancy (false-negative rate) is 1% to 6%.^71,77 The diagnosis of malignancy, particularly papillary (including follicular variant), medullary, and anaplastic carcinomas and lymphomas, can be determined in about 5% of nodules. The likelihood of a false-positive finding is less than 5%.^71,77 Frequently, false-positive results occur because of difficulties in interpreting cytology in patients with Hashimoto’s thyroiditis, Graves’ disease, or toxic nodules. A benign cytology is a macrofollicular lesion or a colloid adenomatous nodule. The remaining “suspicious” samples are composed of lesions that contain abnormal follicular epithelium with varying degrees of atypia. This finding needs to be evaluated in the context of patient history and physical findings that may be suggestive of malignancy. A complete report of the FNAC detailing specimen adequacy and pathologic findings is crucial, and efforts have been made to standardize this information.^78,79

Follicular neoplasms cannot be classified by FNAC alone. The presence of hypercellular, microfollicular arrays with minimal colloid increases the concern for carcinoma. The differentiation between follicular adenoma and follicular carcinoma depends on the histologic finding of capsular or vascular invasion, which requires evaluation of the entire thyroid nodule. Occasionally, patients with a diagnosis of follicular neoplasm on FNAC have an iodine-123 (¹²³I) thyroid scan. If the suspicious nodule is “cold,” surgery is indicated. If the nodule is hyperfunctioning compared with the surrounding thyroid, surgery can be avoided. Overall, 20% of nodules diagnosed as follicular neoplasms by FNAC contain thyroid carcinomas.⁸⁰

Similarly, Hürthle cell (oxyphilic) neoplasms can be difficult to evaluate. The presence of Hürthle cells in an aspirate may indicate an underlying Hürthle cell adenoma or carcinoma, but these cells can also be present in thyroid disorders, such as multinodular goiter and Hashimoto’s thyroiditis. Carcinomas can be found in 20% of nodules identified as follicular and oxyphilic neoplasms.⁸¹ Because of the risk of underlying carcinoma in these cases, surgery is recommended.

Imaging

Ultrasonography is tremendously useful and sensitive. These studies detect nonpalpable nodules and differentiate between cystic and solid nodules. Ultrasound detection of subcentimeter nodules is valuable because most are nonpalpable and not detected by other imaging modalities, even though they may harbor malignant disease. In patients with a neck that is difficult to examine (e.g., a patient with a history of head and neck irradiation), ultrasonography can also clarify findings. These studies provide key baseline information regarding nodule size and architecture. Ultrasonography is also a noninvasive and inexpensive method for following changes in the size of benign nodules. Ultrasonography can identify hemiagenesis and contralateral lobe hypertrophy, which may be misdiagnosed as a thyroid nodule. The utility of ultrasound studies has expanded from detection of thyroid nodules to examination of nodal basins for locoregional staging, intraoperative localization of nonpalpable lesions, and routine follow-up examination of the neck after thyroidectomy. Ultrasound examinations are being performed in the office by appropriately trained surgeons. Additionally, ultrasound guidance of FNAC has become integral to the initial workup, resulting in improved target selection and diagnostic yield.

A systematic ultrasound examination can be extremely valuable in the assessment of a patient with thyroid cancer, including color and power Doppler examination of the thyroid, specific nodules, and lymph nodes.^82,83 Examination of the nodal basins should be bilateral and include the jugular, submandibular, supraclavicular, paratracheal, and suprasternal regions. These studies may detect cervical nodes that may contain early clinically occult metastatic disease that would not otherwise have been included in a surgical dissection.^69,84 Characteristics of lymph nodes suspicious for metastatic deposits include loss of the fatty hilum, increased vascularity, rounded node configuration, hypoechogenicity of a solid nodule, and microcalcifications.^83,85,86 Ultrasonography is also useful in the evaluation of cervical lymph nodes in patients with a history of thyroid cancer who present with adenopathy or increasing thyroglobulin levels. These studies are not useful, however, in the evaluation of substernal extent of disease or the involvement of adjacent structures.

In a patient with multiple thyroid nodules, FNAC should be performed in conjunction with a diagnostic ultrasound study. Aspiration of the largest or “dominant” nodule alone may miss a thyroid malignancy. In the presence of two or more thyroid nodules larger than 1 to 1.5 cm, nodules with a suspicious ultrasound appearance should be aspirated preferentially. If none of the nodules has suspicious ultrasound characteristics, and multiple sonographically similar coalescent nodules are present, aspiration of the largest nodule only is reasonable.⁶⁹

Currently, there is no role for ultrasonography in screening asymptomatic patients for thyroid nodules. Preoperative ultrasound evaluation of the lateral cervical lymph nodes is recommended for all patients with papillary and Hürthle cell thyroid cancer before initial thyroidectomy because operative management may be altered in 20% of patients.⁸⁷ In addition, intraoperative ultrasound examination may be useful in the localization of nonpalpable lesions in the thyroid bed or nodal metastases.

Computed tomography (CT) and MRI scans are usually unnecessary in the evaluation of thyroid tumors except for fixed or substernal lesions. Although these studies are not as effective as ultrasonography in the evaluation of thyroid nodules, they are more reliable in evaluating the relationship of the thyroid lesion to adjacent neck structures, such as the trachea and esophagus. These studies are useful in determining substernal extension, identifying cervical and mediastinal adenopathy, and evaluating possible tracheal invasion.⁸⁸ Anatomic imaging should be obtained when visceral compartment invasion is suspected and for localization in patients with nodal disease. Also, CT or MRI can supplement ultrasound imaging, which cannot visualize the regions behind the sternum, trachea, and esophagus. Caution must be exercised in the use of iodine-containing contrast material in patients with multinodular goiter if a hyperthyroid state is suspected, and in patients with well-differentiated thyroid cancer. In the latter group, iodinated contrast media preclude the use of postoperative radioactive iodine therapy for 2 to 3 months. Finally, MRI is more accurate than a CT scan in distinguishing recurrent or persistent thyroid tumor from postoperative fibrosis.

Clinical Presentation

A thyroid adenoma is a true benign neoplasm derived from follicular cells. These follicular lesions are occasionally multiple and may arise in the setting of a normal thyroid, nodular goiter, toxic goiter, or thyroiditis. They occur most commonly in women older than 30 years. Patients usually present with a solitary, mobile thyroid nodule. The thyroid mass is often found incidentally on a routine physical examination and is frequently not associated with any other signs or symptoms. Sudden hemorrhage into the adenoma may cause a sudden increase in size and associated pain.

Pathology

The revised histologic classification of thyroid tumors divides epithelial tumors into the categories of follicular adenoma and other rare tumors (Table 124-4). Follicular adenomas are the most common benign thyroid lesions. Atypical follicular adenomas may show atypical microscopic features, including excess cellularity, increased mitotic figures, and necrotic foci. Although most of these lesions are benign, they may metastasize even in the absence of microinvasion.⁹¹

Table 124-4 World Health Organization Revised Histologic Classification of Thyroid Tumors

From Hedinger C, ed. Histological Typing of Thyroid Tumours. 2nd ed. Berlin: Springer-Verlag; 1988.

On gross examination, thyroid nodules and adenomas are well circumscribed and demarcated from adjacent normal thyroid tissue. The classic adenoma is fleshy and pale, although areas of necrosis, hemorrhage, and cystic change may be readily apparent. Microscopic findings include large and small follicles with abundant colloid. Cells may be flat, cuboidal, or columnar. The nuclei are small and round with an even chromatin pattern. Mixed populations of macrophages and lymphocytes, and fibrosis, hemosiderin, and calcification may be visible. Cystic areas may be present near areas of abundant papillae formation. Adenomas that exhibit pseudopapillary structures need to be distinguished from papillary carcinoma. Oxyphilic (Hürthle) cell adenoma contains mitochondria-rich eosinophilic cells. Thyroglobulin immunohistochemical staining can distinguish a clear cell adenoma from a parathyroid adenoma and metastasis from a renal carcinoma. This adenoma also needs to be differentiated from the clear cell variant of follicular carcinoma.

Nodules within a nodular goiter occasionally may be hyperfunctional or “hot.” These lesions are termed autonomously hyperfunctioning thyroid adenomas, and may or may not cause thyrotoxicosis. These lesions often occur in women, and nodules associated with thyrotoxicosis are frequently in patients older than 40 years.

Management and Prognosis

Thyroid nodules that are determined to be benign require follow-up because of a low false-negative rate (approximately 5%) with FNAC.^92,93 Nodule growth alone is not an indication of malignancy, but growth is an indication for repeat biopsy. The 2006 ATA guidelines recommend serial clinical examination for easily palpable benign nodules at 6- to 18-month intervals.⁶⁹ All other benign nodules should be followed with serial ultrasound examinations 6 to 18 months after initial FNAC. Patients with nodules that remain stable in size may have subsequent examinations at longer time intervals. Patients with evidence of nodule growth should have repeat FNAC, preferably with ultrasound guidance.

The surgical evaluation of a thyroid nodule begins with FNAC that shows follicular neoplasm. Distinguishing follicular or Hürthle cell adenoma from carcinoma depends on histopathologic analysis after surgical excision. Concern for a potential malignancy increases with highly cellular findings or pseudopapillary structures on FNAC. The lack of tumor capsule and vascular invasion is characteristic of a follicular adenoma.

Surgical excision involves a thyroid lobectomy. A unilateral partial thyroid lobectomy is no longer an acceptable standard of care. Patients with a history of radiation to the head and neck, other head and neck cancers, potential high-risk factors, and comorbidities may benefit from a total thyroidectomy. Risk of surgical morbidity at the initial surgery must be balanced with the potential risks of reoperation. In most patients, thyroid hormone administration is unnecessary when the patient has undergone resection of a single thyroid lobe for a thyroid adenoma.

Autonomously hyperfunctioning thyroid adenomas are usually anatomically and functionally stable. Although most patients do not develop thyrotoxicosis, 20% of patients with lesions greater than 3 cm may develop thyrotoxicosis. Surgery and radioiodine therapy can be used to manage these lesions, although many physicians prefer surgery for patients younger than 40 years. These patients may require preoperative medications to control thyrotoxic symptoms. The lesions are typically removed with a unilateral thyroid lobectomy. The remaining thyroid tissue typically returns to normal function after several months. Ethanol injection has become increasingly common, especially in Europe, to manage these lesions.⁹⁴

Clinical Presentation

Although a thyroid cyst is not a specific diagnosis, this entity is frequently encountered in clinical practice. Approximately 15% to 25% of all thyroid nodules are cystic or have a cystic component.⁴⁷ The presence of a cyst does not signify a benign lesion because papillary carcinomas and parathyroid tumors may manifest with cystic masses. Papillary carcinoma may be present in 14% to 32% of all cystic nodules, although most of these lesions are benign adenomas or colloid nodules.^95,96

Pathology

A thyroid cyst can result from congenital, developmental, or neoplastic causes.⁹⁵ Many cysts result from intranodular ischemia causing tissue necrosis and liquefaction. True epithelial-lined cysts are rare. Occasionally, parathyroid or thyroglossal duct cysts can be mistaken for thyroid nodules. A parathyroid cyst contains high parathyroid hormone levels within the clear fluid, and a thyroglossal duct cyst contains columnar epithelium. These lesions may also be differentiated by ultrasound imaging.

Management and Prognosis

When encountered during FNAC, a thyroid cyst should be drained completely. This procedure may prove curative in most simple cysts, although one or two additional drainage procedures may be required. If a cyst persists after three drainage attempts or reaccumulates quickly, the suspicion for carcinoma should increase. Brown fluid withdrawn from a cyst may represent old hemorrhage into an adenoma, but red fluid is more suspicious for carcinoma.⁶⁴ Clear, colorless fluid may be withdrawn from a parathyroid cyst and can be assessed for parathyroid hormone.⁹⁷ In suspicious cases, the surgeon and patient should consider ultrasound-guided FNAC to sample a solid component of the lesion or a unilateral thyroid lobectomy to obtain a definitive diagnosis. Because of the potential for thyroid carcinoma in cystic lesions, surgical excision for diagnosis is preferable to the injection of sclerosing agents.

Clinical Presentation

Papillary carcinoma is the most common form of thyroid malignancy, accounting for 60% to 70% of all thyroid cancer.^58,98 This lesion typically occurs in patients 30 to 40 years old, and is more common in women, with a female-to-male ratio of 2 : 1. This ratio has decreased steadily over the past 40 years as the incidence in men has increased.⁹⁹ Papillary carcinomas are the predominant thyroid malignancy in children (75%). Although children more commonly present with advanced disease, including cervical and distant metastases, their prognosis remains quite favorable.

Most cases of papillary carcinoma occur spontaneously. Patients with a history of low-dose radiation exposure tend to develop papillary carcinomas (85% to 90%).¹⁰⁰ These lesions also are more common in patients with Cowden’s syndrome (familial goiter and skin hamartomas), Gardner’s syndrome (familial colonic polyposis), and familial polyposis. Only 6% of papillary carcinomas are associated with familial disease.

Papillary carcinoma can be classified into three categories based on size and extent of the primary lesion.^101,102 Minimal carcinoma or occult carcinoma/microcarcinoma tumors are 1.5 cm or smaller in size, and show no evidence of invasiveness through the thyroid capsule or to cervical lymph nodes. These lesions are typically nonpalpable and are usually incidental findings during operative or autopsy examination. Intrathyroid tumors are greater than 1.5 cm in diameter, but are confined to the thyroid gland with no evidence of extrathyroid invasion. Extrathyroid tumors extend through the thyroid capsule to involve the surrounding viscera. This latter form of papillary carcinoma is associated with substantial morbidity and decreased survival.^7,101

Most patients present with a slow-growing, painless mass in the neck and are often euthyroid. Often, the primary lesion is confined to the thyroid gland, although 30% of patients may have clinically evident cervical nodal disease.^103,104 Histologic studies have shown the strong lymphotropic nature of papillary carcinoma, leading to multifocal disease within the thyroid and regional lymphatics. Microscopic disease has been identified in the cervical nodes of 50% to 80% of patients and in the contralateral lobe in 80% of patients with papillary carcinoma at the time of surgery.¹⁰⁵ The significance of this microscopic disease is unclear, however, because clinical recurrences in the neck and in the contralateral lobe occur in less than 10% of patients.¹⁰⁶ More likely, the prevalence of microscopic disease suggests that most papillary carcinomas have an indolent course that only occasionally becomes clinically evident. Definite predictors of the clinical course for papillary carcinoma are not well defined, however.

Advanced disease may be associated with symptoms of local invasion, including dysphagia, dyspnea, and hoarseness. Occasionally, cervical nodal involvement may be more apparent than the thyroid nodule. Distant metastases, especially to the lungs, are more commonly encountered in children, although 10% of all patients may ultimately develop distant disease.⁸¹

Thyroid cancer is often suspected in these patients after a thorough history and physical examination. The diagnosis is usually established by FNAC. Thyroid function tests are done routinely in the preoperative assessment. Radiographic imaging (CT or MRI) is selectively performed to define extensive local or substernal disease and to evaluate possible lymph node involvement.

Pathology

On gross examination, papillary carcinoma is firm, white, and not encapsulated. The lesion tends to remain flat on sectioning, rather than bulging the way normal thyroid tissue or benign nodular lesions do. Macroscopic calcifications, necrosis, or cystic changes may be readily apparent.¹⁰⁷

Histologically, these lesions arise from thyroid follicular cells and contain papillary structures that consist of a neoplastic epithelium overlying a true fibrovascular stalk.¹⁴ Cells are cuboidal with a pale, abundant cytoplasm. Large, crowded nuclei with folded and grooved nuclear margins may have intranuclear cytoplasmic inclusions. Prominent nucleoli account for the “Orphan Annie eye” appearance. Laminated calcium densities, psammoma bodies, are likely the remnants of necrotic calcified neoplastic cells and are present in 40% of cases.

Although a follicular component may predominate, lesions with any papillary features behave clinically as papillary carcinomas. The designation of “papillary carcinoma” includes mixed papillary follicular carcinoma and the follicular variant of papillary carcinoma. A more unfavorable prognosis is associated with certain histologic forms of papillary carcinoma, including diffuse sclerosing and tall-cell variants.^14,108 The tall-cell variant is characterized by well-formed papillae covered by cells that are twice as tall as they are wide. The rarer columnar cell variant is characterized by the presence of prominent nuclear stratification.¹⁰⁹

Papillary carcinomas have a strong tendency for lymphatic spread within the thyroid and to local lymph nodes in the paratracheal and cervical regions. The tendency for intraglandular spread may lead to the multifocal disease often present in patients. Discrete lesions may be due to de novo formation, however, especially in patients previously exposed to ionizing radiation.¹¹⁰

Local invasion occurs in 10% to 20% of these tumors, leading to involvement of the overlying strap muscles, laryngeal and tracheal framework, RLNs, pharynx, and esophagus. This extension may evolve from the primary lesion or from extracapsular extension of metastatic nodes. Angioinvasion is a clear harbinger of increased risk for recurrence and worse prognosis.⁵⁸ A coexisting lymphocytic thyroiditis has been correlated with decreased recurrence and better overall prognosis.

Management and Prognosis

Most patients with papillary carcinoma do well regardless of treatment. Prolonged survival, even with recurrent disease, has led to controversy regarding the extent of thyroidectomy for patients with well-differentiated thyroid carcinomas (see section on extent of surgery under surgical management and technique). A balance must be achieved between an effective surgical treatment for these malignancies and the potential morbidity of this surgery. Numerous studies have attempted to categorize patients by their risk factors and to justify more aggressive surgical intervention for high-risk patients (see section on tumor staging and classification). The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology provides specific recommendations for evaluation and management of well-differentiated thyroid carcinomas.¹¹¹

Incidental micropapillary thyroid carcinoma is usually identified in a thyroid specimen removed for other reasons. Unilateral thyroid lobectomy and isthmectomy is usually sufficient surgical treatment, unless there is angioinvasion or tumor at the margins of resection. These patients can be treated with thyroid hormone to suppress TSH and closely followed up with ultrasonography. In patients with a small, encapsulated papillary thyroid carcinoma (<1 cm in diameter), a total lobectomy is sufficient.

When patients present with biopsy-proven disease or indications of disease in both lobes, total or near-total thyroidectomy is the procedure of choice. Additionally, patients stratified into high-risk categories in any of the classification schemes previously described (see section on tumor staging and classification) would probably benefit from a more extensive surgical procedure that includes paratracheal lymph node dissection. This procedure would permit possible thyroid hormone suppression therapy and radioiodine ablation of remaining disease.

Multifocal disease is present in 80% of patients in some reports.^104,108 This percentage may represent de novo multicentric tumor formation or intraglandular metastasis. The prevalence of multifocal disease lends credence to the argument for more complete surgical removal of the thyroid gland in patients with papillary thyroid cancer. Patients with partial thyroidectomy had higher local recurrence rates and increased pulmonary and cervical metastases.^33,112 Controversy remains, however, because this increased local recurrence did not compromise disease survival in some studies.^53,113

Generally, invasive tumors are associated with a compromise in survival. Woolner and colleagues¹⁰⁷ reviewed 1181 thyroid cancer patients and found that no patient died of papillary cancer when the lesion was less than 1.5 cm in size. Only 3% of patients died when the lesion was larger but remained intrathyroid. Mortality increased to 16% of patients when extrathyroid disease was present.

After total thyroidectomy, patients may be monitored by following thyroglobulin levels, which should remain undetectable, and by neck ultrasonography to evaluate the central and lateral cervical compartments. Any increase in thyroglobulin levels is suspicious for disease recurrence and requires appropriate screening. Approximately 12% of patients with papillary carcinoma are not cured by initial treatment, leading to a prolonged clinical course.¹¹⁴ Recurrent disease may occur after many years, involving the thyroid bed (5% to 6%), regional lymphatics (8% to 9%), or distant sites (4% to 11%).¹¹⁵ Successful treatment of recurrence varies by site of involvement and the patient’s initial risk classification.

Local recurrence is a serious complication and is associated with a disease-related mortality of 33% to 50%.¹¹⁵ Typically, patients with nodal recurrence fare better than patients with tumor recurrence in the thyroid bed or distant sites. Studies have been inconsistent regarding the impact of cervical metastases on survival. Patients older than 40 years may have clinically evident nodal disease in 36% to 75% of cases and overall increased mortality.^6,99 Some studies suggest prognosis is better with more cervical node involvement.^56,116 Although the role of cervical metastasis in survival may be controversial, there is an association with an increased recurrence rate, especially in elderly patients.^114,116,117 Generally, lymph node metastases do not seem to have an impact on overall survival in most patients with low-risk and intermediate-risk disease.^101,118 Cervical recurrences occur in 20% of patients with low-risk disease, however, and 59% of patients with high-risk disease.^53,119 The continuing debate regarding extent of lymphadenectomy at the time of thyroidectomy reflects a shift in focus from overall survival to recurrence-free survival.

Because of these findings and the overall prevalence of microscopic cervical disease with uncertain prognostic implications, management of cervical metastasis tends to be conservative. There is no role for elective neck dissection in the clinically disease-free neck, especially considering the effectiveness of radioiodine therapy in ablating microscopic disease.¹⁰⁶ The central compartment from hyoid bone to mediastinum between the internal jugular veins (levels VI and VII) should be carefully inspected and palpated. The 2006 ATA management guidelines recommend considering routine central compartment (level VI) neck dissection for patients with papillary thyroid carcinoma and suspected Hürthle cell carcinoma, although postoperative radioiodine therapy may provide an alternative approach.⁶⁹

Elective dissection of the pretracheal and ipsilateral paratracheal nodes may be reasonable, especially in patients with high-risk factors. Additionally, elective removal may potentially decrease nodal recurrence in this region and the need for reoperation. In patients with palpable or visible neck disease, a comprehensive neck dissection (levels II-V) should be performed, as opposed to selective cervical lymph node excision or “berry-picking.” Although level I is seldom involved, metastatic disease is frequently noted on histologic examination of nodal levels II through V.¹²⁰ In addition, because the incidence of contralateral subclinical metastasis is less than 20%, elective treatment of the contralateral neck is not advocated.

The presence of distant metastasis is associated with a worse prognosis. Approximately 10% of patients with papillary thyroid carcinoma develop distant metastasis at some point during their disease course.⁸¹ Most commonly, the lungs are involved, although bone sites and the central nervous system may also be affected.

In nearly every study, patient age at the time of diagnosis is an important prognostic variable.^6,116,121 Older patients (especially >40 years old) with papillary carcinoma have a worse prognosis. Extrathyroidal invasion seems to be more common in older patients. The prognosis for men younger than 40 years is comparable to women of the same age. Overall survival is worse for men, however, and the risk of death from papillary thyroid carcinoma may be twice as great.^53,116 In the last 40 years, the increase in incidence of papillary thyroid carcinoma in men has decreased the gender ratio of men to women with the disease from 1 : 4 to 1 : 2.⁹⁹

Children fare better with this disease. Among patients younger than 15 years, 90% show cervical metastasis at some time during their disease course.¹²² Twenty percent of children may present with pulmonary metastases.¹²³ Neither cervical nor pulmonary metastases seem to have any impact on survival, however. Perhaps these differences may be related to biologic differences in the disease process or between age groups.

Finally, the tall-cell variant of papillary thyroid carcinoma is different from other forms of this disease. A review of patients with tall-cell variant papillary carcinoma showed a more aggressive natural history in all age groups and a worse prognosis.¹²⁴

Clinical Presentation

Follicular carcinomas represent 10% of thyroid malignancies. The mean age of presentation is 50 years compared with 35 years mean age of patients with papillary carcinoma. Women more commonly have this lesion, with a female-to-male ratio of 3 : 1.¹²⁵ These lesions occur more frequently in iodine-deficient areas, especially areas of endemic goiter. Follicular carcinomas have been correlated with pregnancy and with certain HLA subtypes (DR1, DRw, and DR7). Also, a rare form of familial follicular carcinoma is reported in patients with dyshormonogenesis. The overall incidence of follicular carcinoma in decreasing in the United States.

Patients usually present with a solitary thyroid nodule, although some patients may have a history of long-standing goiter and recent rapid increase in size. These lesions are typically painless, although hemorrhage into the nodule may cause pain. Cervical lymphadenopathy is uncommon at initial presentation, although distant metastases are more frequently encountered than with papillary carcinomas. In rare cases (1%), the follicular carcinoma may be hyperfunctioning, and the patient presents with signs and symptoms of thyrotoxicosis.

Other than characterization of a follicular neoplasm, a definitive preoperative diagnosis is usually impossible by FNAC. Differentiation between follicular adenoma and follicular carcinoma requires an evaluation of the thyroid capsule for invasion or identification of vascular invasion. Typically, about 20% of thyroid nodules showing follicular neoplasm cytology contain carcinoma.

In contrast to papillary carcinoma, follicular thyroid carcinomas are less likely to metastasize via lymphatic pathways (found in <10% of patients).⁸⁸ More commonly, follicular carcinomas spread through local extension and hematogenous spread. Often, the presence of cervical lymph node disease indicates significant local disease and visceral invasion.^99,126 Distant metastasis is also more common in follicular cancers than papillary cancers, especially at presentation.^127,128 A pathologic bone fracture may be the initial presentation of follicular carcinoma. Other common sites include liver, lung, and brain.

Pathology

Follicular thyroid carcinoma tends to manifest as solitary, encapsulated lesions. Cytologic analysis of follicular neoplasms reveals small follicular arrays or solid sheets of cells.¹⁴ The follicular structures have lumens that do not contain colloid, and the overall architectural pattern depends on the degree of tumor differentiation. Increased cellularity may increase the suspicion for carcinoma, but cytology alone is insufficient to distinguish between a follicular adenoma and carcinoma.

Histologic findings are necessary to distinguish benign and malignant lesions. Malignant lesions are differentiated by the identification of capsular invasion and potential microvascular invasion of vessels along the tumor capsule.^91,129 Complete capsular evaluation must be performed. Frozen-section analysis is often inadequate, and definitive diagnosis requires complete assessment of permanent sections.

The degree of capsular invasion is important for patient prognosis. Follicular carcinomas can be divided into two broad categories. Minimally invasive tumors show evidence of invasion into, but not through, the tumor capsule at one or more sites. These lesions do not exhibit small-vessel invasion. Frankly invasive tumors show invasion through the tumor and often exhibit vascular invasion.¹³⁰ Tumor infiltration and invasion may be apparent at surgery, with tumor present in the middle thyroid or jugular veins.

Many other factors have been investigated as means to differentiate between adenomas and carcinomas. To date, no molecular markers have been clinically useful. DNA ploidy varies in adenomas and carcinomas with considerable overlap.¹³¹ Aneuploid follicular carcinomas are noted to behave in a more aggressive manner.

Management and Prognosis

Patients diagnosed with a follicular lesion by FNAC should have a thyroid lobectomy with isthmectomy performed. The pyramidal lobe, if present, should be included in the resection. As described previously, cytologic findings alone cannot determine the presence of adenoma or carcinoma. Intraoperative frozen-section analysis is not helpful because of the incomplete assessment of the tumor capsule. Frozen sections should be analyzed, however, to confirm gross evidence of adjacent cervical lymphadenopathy. A total thyroidectomy is recommended if carcinoma is identified. In patients with a clinical suspicion for follicular carcinoma, the tendency is to perform a more complete resection. Total thyroidectomy is performed in older patients with a nodule greater than 4 cm in size diagnosed by FNAC as follicular neoplasm. In these patients, the risk of carcinoma is approximately 50%.¹¹² Additional factors that may favor a total thyroidectomy as the initial surgical procedure include a family history of thyroid carcinoma, history of radiation exposure, and patient preference.⁶⁹

A diagnosis of follicular carcinoma after a thyroid lobectomy usually necessitates a completion thyroidectomy. Patients with minimally invasive follicular cancer have a very good prognosis, and the initial thyroid lobectomy may be sufficient treatment. Invasiveness of follicular carcinoma correlates directly with decreased survival, however. In patients with invasive follicular carcinomas, many surgeons tend toward completion and total thyroidectomy to permit radioiodine scanning for detection and ablation of metastatic disease. More aggressive surgical intervention does not improve survival because invasiveness already indicates the increased likelihood of distant metastasis. Neck dissection is performed if cervical lymphadenopathy is present. When cervical disease is present, consultation with the pathologist is warranted because the patient may have a follicular variant of papillary thyroid carcinoma. Elective neck dissections are unwarranted because nodal involvement is unlikely.¹⁰

The recurrence rate after initial management is approximately 30%.¹³² Recurrence is related to the degree of invasiveness of the initial lesion, not the extent of initial thyroid surgery. Minimally invasive disease behaves similarly to follicular adenoma and is typically cured with conservative surgical procedures (thyroid lobectomy).¹³³ Recurrence of minimally invasive follicular carcinoma is approximately 1%. About 15% of patients with recurrent or metastatic disease can be cured. The prognosis of these patients relates to the site of recurrence and the patient’s initial risk stratification. Survival outcomes are significantly poorer in patients with capsular invasion and angioinvasion.¹³⁴ Patients with cervical node recurrence have a 50% cure rate, whereas patients with distant metastases have a cure rate of about 9%.^115,132

Overall, 5-year survival is 70% and decreases to 40% at 10 years for patients with follicular carcinoma. The presence of distant metastasis diminishes 5-year survival to 20%.¹³⁵ Factors that worsen prognosis include age older than 50 years at presentation, tumors greater than 4 cm in size, higher tumor grade, marked vascular invasion, extrathyroidal invasion, and distant metastasis at the time of diagnosis.¹⁰ Extrathyroidal invasion beyond the capsule and into the thyroid parenchyma and local structures is the key factor decreasing patient survival. Risk stratification shows marked differences in patient survival. In one study, the low-risk group had a 5-year survival rate of 99% and a 20-year survival rate of 86%. In the high-risk group, the 5-year survival rate was only 47%, and this decreased to a 20-year survival rate of 8%.¹²⁵

The prognosis for patients with follicular carcinoma has typically been reported to be worse than for patients with papillary carcinoma. Some reports that matched age, sex, and stage at time of diagnosis suggest that patients with papillary and follicular carcinomas have similar survival patterns.^6,8 The poor prognosis of patients with follicular carcinoma may be related to the increased number of patients who present at an older age and a more advanced disease stage. Also, in contrast to papillary carcinoma, mortality is directly related to recurrence in patients with follicular carcinoma.⁹⁹

Clinical Presentation

According to World Health Organization classification, Hürthle cell tumor is a subtype of follicular cell neoplasm. Hürthle cell tumor nodules can be found in patients with Hashimoto’s thyroiditis or Graves’ disease or within a nodular goiter. These tumors are derived from oxyphilic cells of the thyroid gland. Although the precise function of these cells is unknown, Hürthle cells express TSH receptors and produce thyroglobulin.

Hürthle cell neoplasms are typically diagnosed by FNAC. Approximately 20% of these lesions are malignant. Similar to follicular lesions, histologic criteria are required to diagnose carcinomas. Hürthle cell carcinomas represent approximately 3% of all thyroid malignancies. The mean age of presentation for patients with Hürthle cell carcinoma may be older than for follicular carcinoma.^80,136 Hürthle cell carcinomas are more aggressive than follicular carcinomas. They are often multifocal and bilateral at presentation. These malignancies also are more likely to metastasize to cervical nodes and distant sites.¹³⁷

Pathology

FNAC of Hürthle cell tumor typically shows hypercellularity and the presence of eosinophilic cells. These neoplasms are characterized by sheets of eosinophilic cells packed with mitochondria. Cytologic differentiation between adenoma and malignant tumor by FNAC is extremely difficult. Histologic findings of capsular or vascular invasion confirm the presence of Hürthle cell carcinoma.

Management and Prognosis

The clinical approach to Hürthle cell tumors is similar to that for follicular neoplasms. With Hürthle cell adenoma, resection of the affected lobe and isthmus is sufficient. Invasive findings for Hürthle neoplasms on formal pathology warrant a total or completion thyroidectomy. Hürthle cell carcinomas tend to be more aggressive than other follicular carcinomas, and they are less amenable to radioiodine therapy because of their decreased tendency to uptake radiolabeled iodine. Because locoregional nodal metastases may occur, careful examination for local disease extension or adjacent cervical lymphadenopathy should be performed. The paratracheal region should be carefully palpated and examined. The paratracheal nodes should be removed if disease is obvious during inspection. Also, a comprehensive neck dissection should be undertaken if lateral neck nodes are palpable.

Postoperative management should include TSH suppression and thyroglobulin monitoring, and periodic ultrasound evaluation of the central and lateral cervical compartments. A ^99mTc scan may be useful for detecting persistent local or metastatic disease. A ¹²³I scan and ablation can be performed to remove any residual normal thyroid tissue to allow for better surveillance. This therapy is unlikely to be effective in tumor ablation, however, because few (approximately 10%) Hürthle cell carcinomas uptake radioiodine.¹³⁸

Overall, survival rates for Hürthle cell carcinoma are significantly worse than for follicular thyroid cancer. The number of patients who die of Hürthle cell carcinoma is greater than the number who die of papillary or follicular carcinoma.¹³⁹ Additionally, Hürthle cell carcinoma is associated with the highest incidence of distant metastases among the well-differentiated thyroid carcinomas.¹⁴⁰

Clinical Presentation

MTCs are a distinct category of disease and represent approximately 5% of all thyroid carcinomas. These malignancies arise from parafollicular C cells and may secrete calcitonin, carcinoembryonic antigen (CEA), histaminidases, prostaglandins, and serotonin. Measurement of secreted calcitonin is useful for the diagnosis of MTC and for postsurgical surveillance for residual and recurrent disease.

MTC shows an intermediate behavior between well-differentiated thyroid cancers and anaplastic carcinomas. Women and men are equally affected by MTCs.¹⁴¹ Patients usually present with a neck mass associated with palpable cervical lymphadenopathy (≤20%).¹⁴² Local pain is more common in these patients, indicating the presence of local invasion, and may be associated with dysphagia, dyspnea, or dysphonia. MTC may manifest along with papillary thyroid carcinoma because related mutations in RET are present in both diseases. Although MTC spreads initially to cervical nodes, distant metastases may be found in the mediastinum, liver, lung, and bone, and are present in 50% of patients at diagnosis.¹⁴³

Most (70%) MTCs are spontaneous unifocal lesions in patients 50 to 60 years old without an associated endocrinopathy.¹⁴² The remaining 30% of cases affecting younger patients are familial. These hereditary MTCs are inherited as autosomal dominant traits with nearly 100% penetrance. MTC in these patients is preceded by multifocal C-cell hyperplasia and leads to disease that is multicentric and bilateral in 90% of cases.^144,145 Familial MTC is not associated with any other endocrine pathology. Two forms of MEN syndrome are associated with MTC. Patients with MEN IIA exhibit MTC, pheochromocytoma, and hyperparathyroidism.^144,146 Patients with MEN IIB have a marfanoid body habitus and may have MTC, pheochromocytoma, or mucosal neuromas. Although penetrance for MTC approaches 100% in these patients, expression of other features varies.^145,147

FNAC diagnosis of MTC is confirmed by elevated serum calcitonin. These patients also should have testing for mutation of the RET proto-oncogene. Genetic screening has replaced provocative pentagastrin-stimulation testing. Careful screening for hereditary diseases is also necessary when a patient is diagnosed with MTC. Hyperparathyroidism can be assessed by serum calcium levels and appropriate imaging studies. Patients should also be screened for the presence of a pheochromocytoma with 24-hour urinary levels for catecholamines and metanephrines, and should undergo abdominal MRI. An undiagnosed pheochromocytoma could lead to an intraoperative hypertensive crisis and death. Additionally, the detection of any hereditary form of MTC in a patient should lead to family screening. Affected family members can often be identified and treated at earlier stages of disease with improved survival.^148,149

Pathology

MTC originates from parafollicular C cells of neuroectodermal origin.¹⁵⁰ The cells descend to join the thyroid gland proper and are concentrated mainly in the lateral portions of the superior poles. Most MTC lesions are located in the middle and upper thyroid poles. In patients with hereditary forms of MTC, the disease is often multifocal. Grossly, the tumor is solid and firm, and has a gray cut surface. The lesion is nonencapsulated, but well circumscribed.

These lesions are composed of sheets of infiltrating neoplastic cells that are heterogeneous in shape and size. The cells are separated by collagen, amyloid, and dense irregular calcification. The amyloid deposits are likely polymerized calcitonin and are virtually pathognomonic for MTC, although not all MTCs contain amyloid.¹⁵¹ More aggressive tumors typically have increased mitotic figures, nuclear pleomorphism, and areas of necrosis. Immunohistochemistry for calcitonin and CEA are useful diagnostic studies.

Management and Prognosis

Specific guidelines were recently published by the American Thysoid Association regarding the management of MTC.^151a

Preoperative workup includes measurement of calcitonin and serum CEA. Patients with germline RET mutations should be screened for pheochromocytoma (MEN IIA/IIB) and hyperparathyroidism (MEN IIA). CT scan of the chest and mediastinum and ultrasound examination of the neck are recommended.

Total thyroidectomy is the treatment of choice in patients with MTC because the lesions have a high incidence of multicentricity and an aggressive disease course. Patients with familial MTC or MEN II should have the entire gland removed, even in the absence of a palpable mass.

Because of the frequent involvement of cervical nodes, initial surgical management should include bilateral central compartment neck dissection. When central compartment nodes are involved, or when palpable lateral cervical nodes are present, treatment including an ipsilateral or bilateral comprehensive neck dissection (levels II-V) should be considered. When the primary lesion is greater than 1 cm (>0.5 cm for MEN IIB patients), or when central compartment lymph node metastases are present, elective ipsilateral comprehensive neck dissection should be considered because nodal metastases may be present in more than 60% of these patients.^111,152,153 The superior mediastinal lymph nodes (level VII) should be routinely removed as well.

Potentially associated conditions, such as hyperparathyroidism and pheochromocytoma, must be carefully evaluated and, if necessary, treated before thyroidectomy. A pheochromocytoma may need to be removed before treatment of the thyroid lesion. Alternatively, preoperative treatment with α-adrenergic blockade (phenoxybenzamine) or α-methyltyrosine is necessary to avoid a hypertensive crisis during surgery. In the presence of hypercalcemia, the parathyroid glands need to be identified during thyroidectomy. If the parathyroid glands are abnormal, they should be removed. Otherwise, they should be adequately marked to facilitate future identification, especially in patients with MEN IIA.

Children with any of the genetic disorders leading to MTC need to be treated aggressively. Typically, a total thyroidectomy should be performed by the time the patient is 2 to 3 years old, or before C-cell hyperplasia occurs. Removal of the thyroid gland should prevent development of MTC in these patients and improve survival. MTC has been diagnosed in MEN IIB patients 7 months old, however.¹⁵⁴

After surgery, patients require close follow-up and monitoring of serum calcitonin and CEA levels. Calcitonin is more sensitive for detecting persistent or recurrent disease, but CEA levels seem to be predictive for survival.¹⁵³ Increasing or persistent calcitonin levels should increase suspicion for residual or recurrent disease. Localization studies should be performed to identify potential sites of disease involvement. Tumor debulking for metastatic disease or local recurrence can decrease symptoms of flushing and diarrhea, and may reduce the risk of death resulting from recurrent central neck disease.^143,155 MTCs do not respond to radioiodine therapy or TSH suppression therapy, however, because of their parafollicular C-cell origin.¹⁴⁹ External-beam radiation therapy (EBRT) has been controversial for patients with positive tumor margins or unresectable tumor, and there is no effective chemotherapy regimen.

Prognosis for patients with MTC is directly related to disease stage. The overall 10-year survival rate is 61% to 75%, but decreases to 45% if cervical nodes are involved.^149,156 The best outcome is for patients with familial MTC, then MEN IIA, sporadic disease, and MEN IIB.

Clinical Presentation

Anaplastic thyroid carcinomas are one of the most aggressive malignancies, with few patients surviving 6 months beyond initial presentation.^62,157 These lesions represent less than 5% of all thyroid carcinomas.¹⁵⁸ These tumors affect patients 60 to 70 years old; presentation before age 50 years is extremely rare. Women are more commonly affected than men, with a ratio of 3 : 2. Of these malignancies, 80% may occur with a coexisting carcinoma and may represent transformation of a well-differentiated thyroid cancer.^157,159

Typically, patients have a long-standing neck mass that enlarges rapidly. This sudden change is often accompanied by pain, dysphonia, dysphagia, and dyspnea. Often the mass is quite large and fixed to the tracheolaryngeal framework, resulting in vocal cord paralysis and tracheal compression. More than 80% have jugular lymph node involvement at the time of presentation, and greater than 50% have systemic metastases.¹⁶⁰ Most patients die of superior vena cava syndrome, asphyxiation, or exsanguination.

Pathology

In the case of anaplastic thyroid carcinoma, the gross specimen shows areas of necrosis and macroscopic invasion of surrounding tissues, often with lymph node involvement. Microscopically, sheets of cells with marked heterogeneity are present. Spindle, polygonal, and giant, multinucleated cells are present with occasional foci of differentiated cells. These cells do not produce thyroglobulin, do not transport iodine, and do not express thyroid hormone receptors.¹⁵⁷ These findings can often be established on FNAC, although a formal biopsy is occasionally necessary to exclude a diagnosis of lymphoma.

Management and Prognosis

Management of anaplastic carcinoma is extremely difficult, requiring a multidisciplinary approach and close consultation with the patient and family. Surgical debulking may be performed for palliation. Initial therapy should ensure airway protection with a tracheostomy and nutritional support. All treatment forms are disappointing, and median survival is 2 to 6 months.^158,161 One current treatment protocol involves doxorubicin, hyperfractionated radiation therapy, and potential surgical debulking.^162,163 Although survival beyond 2 years is only 12%, this is one of the only regimens currently available for these patients.

Retrospective evaluation of various treatment strategies identified a subset of patients who have had long-term survival.^5,86,164 Independent prognostic variables include resectability of local disease, absence of distant metastasis at diagnosis, and adjuvant treatment with radiation therapy. Additionally, many long-term survivors had small areas of anaplastic foci within well-differentiated carcinoma.

Insular Thyroid Carcinoma

Insular carcinoma was named for the clusters of cells that contain small follicles resembling pancreatic islet cells.¹⁶⁵ These tumors are very rare and manifest as an independent lesion or concomitantly with papillary or follicular thyroid carcinomas. These cells stain with thyroglobulin antibodies, but not for calcitonin. Typically, capsular and vascular invasion is present at the time of diagnosis.

These lesions are very aggressive when compared with follicular and papillary carcinoma, and seem to have an increased recurrence and mortality rate when present as an independent process.¹⁶⁶ Insular carcinoma located within follicular or papillary thyroid cancer does not seem to affect the clinical course adversely, however. Many insular thyroid carcinomas are able to concentrate radioiodine.

Lymphoma

Primary thyroid lymphoma is unusual and represents less than 5% of all thyroid malignancies.¹⁶⁷ Women are more commonly affected at a ratio of 3 : 1, and lymphoma typically manifests in patients older than 50 years. Patients may present with symptoms similar to anaplastic carcinoma, although the rapidly enlarging mass is often painless. Symptoms may also include regional adenopathy, dysphagia, and vocal cord paralysis caused by RLN invasion. Many affected patients are clinically hypothyroid or already receiving thyroid replacement therapy for conditions such as Hashimoto’s disease.¹⁶⁸ Non-Hodgkin B-cell type lymphoma is most common, although Hodgkin’s disease and plasmacytomas occur.¹⁶⁹ Thyroid lymphoma can arise as part of a generalized lymphomatous condition because many of these patients have Hashimoto’s disease. A current hypothesis as to why this occurs is chronic antigenic lymphocyte stimulation that results in lymphocyte transformation.

A definite diagnosis needs to be made and frequently can be established by FNAC. Occasionally, a needle-core or open cervical lymph node biopsy may be necessary. Because of the rare incidence of primary thyroid lymphoma, a comprehensive survey must be done to exclude the presence of lymphoma at other sites.

Patients typically respond rapidly to chemotherapy, especially CHOP (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone).^170,171 Combined radiation and chemotherapy regimens have also been developed and have been promising. Thyroidectomy and nodal resection may be considered to alleviate symptoms of airway obstruction in patients who do not respond rapidly to treatment, but surgical options are not primary treatment modalities.

The prognosis depends on the histologic grade of the tumor and the presence of extrathyroidal disease. Overall, 5-year survival is about 50%. Intrathyroid disease survival is 85% and decreases to 40% for patients with extrathyroid disease.

Metastatic Carcinoma

The thyroid is a rare site for metastases from other cancers. Metastasis can occur, however, from primary lesions in the kidney, breast, lung, and skin (i.e., melanoma). The most common metastatic tumor to the thyroid is from a hypernephroma. Also, approximately 3% of bronchogenic carcinomas metastasize to the thyroid, but account for 20% of all metastases to the thyroid.¹⁷²

Typically, the history and physical examination identify the source of the metastasis. FNAC is performed for definitive diagnosis. Thyroidectomy may be considered for palliation, especially when the primary lesion is very slow growing (e.g., renal cell carcinoma).¹⁷³

Squamous Cell Carcinoma

Squamous cell carcinoma of the thyroid is very rare, representing less than 1% of thyroid cancers.¹⁷⁴ Older patients are most commonly affected, and the disease can progress rapidly with local invasion and metastasis. During the workup, metastasis from another site within the upper aerodigestive tract needs to be excluded. Early detection and aggressive surgical treatment seems to represent the best option for palliation and cure. As with other squamous cell carcinomas of the head and neck, radiation therapy is probably important, although not well characterized.¹⁷⁵

Management of Regional Lymphatics

Management of the neck in patients with well-differentiated thyroid carcinomas is typically conservative. Cervical node disease is rare in follicular carcinomas, but more common in papillary carcinomas. There is currently no role for elective neck dissection in cases of follicular carcinoma. Current ATA guidelines recommend consideration of central compartment (level VI) neck dissection for patients with papillary thyroid carcinoma and suspected Hürthle cell carcinoma.⁶⁹ If disease is present by palpation or visible inspection, patients with papillary or Hürthle cell thyroid carcinoma have a concurrent central compartment lymph node dissection with total thyroidectomy or the completion thyroid lobectomy.

Because of the higher frequency of microscopic tumor spread in MTCs and their lack of radioiodine uptake, elective central compartment lymph node dissection is commonly performed. When these patients present with palpable anterior lymph node disease, bilateral central compartment dissection is performed with the total thyroidectomy, and the lateral cervical nodes are carefully inspected. Central compartment dissection should include the Delphian, paratracheal lymphatic, and lymph nodes of the upper mediastinum. The RLN, inferior thyroid artery, and parathyroid glands should be clearly identified, and the lymphatics should be removed en bloc from the level of the cricoid to the innominate artery.

When performing bilateral central compartment dissection, preservation of the parathyroid glands can be difficult. Attempts should be made in the dissection, especially contralateral to the thyroid lesion, to identify and preserve the ascending branch of the inferior thyroid artery that supplies the superior parathyroid gland. If the vascular supply to the parathyroid gland is compromised, a biopsy specimen of the gland should be obtained to confirm the presence of parathyroid tissue and placed into a pocket in the sternocleidomastoid muscle. The gland should be minced into 1-mm pieces, and the implantation site should be marked with vascular clips.

When palpable lateral cervical nodes are present, and metastatic disease is confirmed by FNAC, a selective neck dissection, including levels II through V, should be performed. The submandibular and submental nodes (level I) are rarely involved and should be dissected only when there is clinically positive disease in this region.^105,181 Cervical involvement is frequently ipsilateral to the primary thyroid lesion.¹⁸² Extension of the collar incision superior to the mastoid tip provides adequate exposure of the lateral neck if palpable disease is present. Careful inspection and dissection should be performed along the spinal accessory nerve because this is a frequent site of metastatic thyroid disease.¹⁰ A more extensive modified radical neck dissection may be necessary to remove gross disease. Radioiodine ablation is an important adjunctive therapy for the management of cervical disease in these patients.

In patients with MTC, lymph node metastasis can occur in 81% of cases.¹⁸³ Retrospective analysis revealed a 10-year survival rate of 67% for patients with MTC treated with neck dissection versus 43% for patients who were not treated with neck dissection.¹⁵² Palpable cervical disease necessitates central compartment and comprehensive neck dissection. In patients with clinically negative neck disease, surgical treatment should include total thyroidectomy, central compartment dissection, and elective, ipsilateral comprehensive neck dissection. Dissection of the contralateral neck in all patients should be considered, especially when the primary thyroid lesion is 2 cm or greater in size because bilateral neck dissection may be necessary to maximize regional control.¹⁸³

Intrathoracic Goiter

Less than 1% of patients may have a thyroid gland that is partially or completely intrathoracic.^184,185 In most of these patients, the intrathoracic goiter can be removed via a collar incision in the neck without resorting to a sternotomy. The vascular supply, typically originating in the neck, is identified, ligated, and divided. Division of the isthmus may facilitate mobilization of the substernal goiter from beneath the sternum. Large sutures can be placed deeply into the goiter to facilitate traction and blunt dissection to permit delivery of the thyroid through the neck.

Patients with substernal goiters who have had previous thyroid operations, some patients with invasive malignant tumors, and patients with no thyroid tissue in the neck may require a median sternotomy. Occasionally, the substernal goiter may simply be too large to deliver through a cervical incision. In these cases, the thyroidectomy is usually performed in collaboration with a thoracic surgeon.

Recurrent Laryngeal Nerve Invasion

Surgical situations necessitating the sacrifice of the RLN are uncommon. If preoperative vocal cord paralysis is present, and carcinoma invasion is seen intraoperatively, the nerve may be sacrificed. More commonly, the RLN should be dissected free of gross disease. Among patients with well-differentiated thyroid carcinomas, there is no survival difference between patients with RLN sacrifice and patients treated postoperatively with radioiodine for gross disease left on the nerve.¹⁷¹ Because of the lack of response by MTC to postoperative radioiodine treatment, RLN sacrifice must be considered to achieve complete removal of gross disease.

Sacrifice of the RLN requires the exclusion of nerve infiltration by benign disease processes. Graves’ disease, Hashimoto’s thyroiditis, and Reidel’s thyroiditis can involve the RLN with or without vocal cord paralysis. Benign processes can cause stretch injuries to the RLN that resolve with surgical removal of the mass. Finally, lymphomas can involve the RLN, but treatment is rarely surgical and should not involve excision of the nerve.

Extended Surgical Resection

Surgical treatment of thyroid carcinomas should remove all gross disease, especially in patients with MTC. Fixation to the thyroid cartilage or trachea may require partial-thickness to full-thickness removal of those structures (Fig. 124-6). A thyroid cartilage lamina can be removed without major morbidity if the internal thyroid perichondrium is left intact. The trachea can be partially resected and repaired to permit en bloc tumor removal. Primary anastomosis can be performed for resections involving up to four tracheal rings.¹⁸⁶ Additionally, tracheal shaving can be performed, leaving the internal mucosa intact. Isolated full-thickness defects can be repaired with composite mucosal-cartilage grafts from the nasal septum. In patients with more extensive skeletal involvement, a partial laryngectomy may be required and has shown improvements in survival.^187,188 Total laryngectomy should be performed in only the most extreme cases of extensive intraluminal invasion, substantial cricoid involvement, or bilateral RLN dysfunction. Typically, this procedure would be done after the failure of radioiodine treatment, EBRT, or both. Pharyngeal and esophageal local invasion typically requires resection of the immediate area and primary closure (Fig. 124-7).

Figure 124-6. A, Lateral view of the neck shows a large, compressive thyroid mass. B, Axial CT scan reveals extensive local invasion by the thyroid lesion involving the thyroid cartilage, larynx, and esophagus.

Figure 124-7. A, Axial CT scan shows a large, locally invasive thyroid mass. B, The large thyroid mass has been dissected free from adjacent structures, but involves the esophagus. C, Resection of the thyroid mass required excision of a portion of the esophagus. The esophagus was closed primarily. D, Postoperative barium swallow study showed that the esophagus was intact, and the patient was able to tolerate a regular diet.

(From Lai SY, Weber RS. Thyroid cancer. In Ensley JF, Gutkind JS, Jacobs JR, et al, eds. Head and Neck Cancer: Emerging Perspectives. San Diego: Academic Press; 2002:424.)

Reoperative Thyroid Surgery

Reoperative thyroid surgery may be required in various clinical situations. A patient may have had a previous thyroid lobectomy and require a completion thyroidectomy. Recurrence of disease may require re-exploration of the thyroid bed or dissection of the cervical lymph nodes, including the central compartment (level VI). In addition, previous neck surgery, such as a parathyroidectomy, may have involved the thyroid bed.

Reoperative surgery has been associated with a higher incidence of complications than initial thyroid surgery. Scarring and fibrosis from prior surgery may cause difficulty in identifying tissue planes, resulting in an increased risk of injury to the RLN. Potential injury or devascularization of the parathyroid glands on one side of the neck creates increased concern for preservation of the glands on the contralateral side. Older series reported a high incidence of complications in reoperative surgery.^106,189 More recent reports indicate, however, that the risk of permanent hypoparathyroidism or RLN injury is less than 2%.^190–193

Although reoperative thyroid surgery cannot be completely avoided, steps may be taken to minimize the need for reoperation. Before the initial surgery, preoperative preparation should include a thorough evaluation for thyroid mass fixation or RLN palsy or paralysis. In these patients, preoperative imaging and potential coordination with other surgeons help to prevent unexpected intraoperative findings.

The minimum adequate surgical treatment for a thyroid nodule is a thyroid lobectomy and isthmectomy. A unilateral subtotal thyroidectomy may encompass a suspected thyroid nodule, but leave residual disease behind. En bloc resection of the thyroid lobe can be performed safely, and often eliminates the need to return to the original surgical bed for re-exploration.

The effectiveness of FNAC has also directed surgeons to perform the appropriate surgery for a particular disease. The presence of a follicular or Hürthle cell adenoma should direct a surgeon to perform a unilateral thyroid lobectomy, avoiding exploration of the contralateral lobe. In cases of carcinoma, reoperation is safer because the contralateral lobe has been left undisturbed. When a patient has significant comorbidities that may preclude reoperation, the contralateral side can be addressed at the initial surgery by performing a total or near-total thyroidectomy. FNAC that shows papillary carcinoma prepares a surgeon for total thyroidectomy or more comprehensive surgery for MTC. Although intraoperative frozen-section analysis is controversial, frozen-section analysis in conjunction with cytologic examination can be valuable for cases diagnosed on preoperative FNAC as suspicious for papillary thyroid carcinoma.^194,195 Finally, ultrasound evaluation of the thyroid bed and lateral neck provides improved preoperative assessment of the extent of disease and facilitates surgical planning. Even in patients with palpable lymph node recurrences, ultrasound evaluation of the lateral and central compartments may change the extent of the surgical procedure in 40% of patients undergoing reoperative surgery.⁸⁷

Typically, reoperation should be performed within 3 to 4 days of the initial operation, if definitive pathology is available, or after 3 months. Healing and inflammation during the early and late time points are typically manageable for reoperation. No control studies to date have addressed the issue of the degree of inflammation in the neck encountered during repeat surgery.

Before reoperation, the vocal cords should be visualized to identify any potential RLN injury. Imaging studies can be useful in cases of disease recurrence to identify local invasion or cervical disease and potential involvement of the RLN or parathyroid glands. During surgery, the RLN should be followed from a previously undissected area into the surgical bed. The surgeon should be familiar with numerous techniques to identify the RLN. A lateral approach from the medial border of the sternocleidomastoid, a low anterior neck approach, and a medial approach to the superior pole of the thyroid have been described.¹⁹² Intraoperative monitoring of the RLN can be helpful, and an electrophysiologic nerve stimulator can facilitate and confirm nerve identification. Visualization of the RLN is crucial, and the use of loop magnification may be helpful to identify the RLN and parathyroid glands.

Because of the difficulties associated with permanent hypoparathyroidism, preservation of the parathyroid glands is crucial in reoperative surgery. As described for initial thyroid surgery, extracapsular thyroid dissection and close vessel ligation aid in preserving parathyroid gland vascular supply. Prior surgery may have disrupted the normal anatomic locations of the gland or created scarring that makes gland localization difficult. In these cases, all perithyroidal fat should be carefully mobilized and preserved. When reoperation includes central compartment dissection, the parathyroid glands may be removed en bloc with the disease.

The surgical specimen needs to be inspected carefully, and biopsy specimens of potential parathyroid tissue should be obtained. Identified parathyroid tissue should be reimplanted into the sternocleidomastoid muscle. All parathyroid tissue should be preserved when possible. The combination of parathyroid preservation in situ and autotransplantation of devascularized parathyroid tissue significantly reduces the risk of permanent hypoparathyroidism.¹⁹⁶ Parathyroid tissue that has been reimplanted functions even when other parathyroid glands have been left intact and in the absence of hypocalcemia.¹⁹⁷

Intraoperative ultrasound may be useful for the resection of radiographically identified, nonpalpable lesions within the thyroid bed or nodal basins. The technique may be particularly helpful in patients who have had EBRT or for lesions that are smaller than 2 cm, locally invasive, or adherent to the airway. Ultrasound can be performed through the strap muscles in an open wound, and a needle can be placed in the target lesion as a guide.

Children

In children, nodular thyroid disease is uncommon, with an incidence of 0.2% to 1.8%.²¹¹ Most neck masses occurring in children are due to congenital or inflammatory causes. Malignant neck masses may be due to lymphoproliferative disorders, sarcomas, or thyroid carcinomas. Less than 6% of pediatric neck tumors are thyroid malignancies.²¹² Approximately 10% of all thyroid carcinomas occur in patients younger than 21 years.²¹³

Most children with thyroid neoplasms present with an asymptomatic mass within either the thyroid or the lateral neck. The lesions are often asymptomatic and frequently noted by a parent or pediatrician during a routine physical examination. A complete history should include special attention to family history and radiation exposure. The physical examination should carefully evaluate potential fixation of the thyroid gland to surrounding neck structures. Vocal cord mobility should be documented by indirect fiberoptic nasolaryngoscopy. The central compartment and lateral necks also should be carefully palpated. Lymph node metastases are present in more than 50% of children with differentiated thyroid cancer.²¹⁴ Local extension was reported in 18%. In addition, 15% of patients have distant metastasis, frequently identified with postoperative radioiodine.^215,216 A chest radiograph may be normal or may show a fine interstitial reticular pattern, potentially mistaken for miliary tuberculosis. Children with extensive pulmonary involvement may present with dyspnea on exertion.

The diagnostic workup in children should include FNAC and ultrasonography. An uncooperative child may require sedation and ultrasound guidance for FNAC. Because an advanced stage of disease is common in children at initial presentation, ultrasonography provides valuable information regarding the size and consistency of the thyroid mass. Ultrasound examination also can identify potential regional involvement of the paratracheal or cervical lymphatics.

Although the most common cause of a solitary thyroid nodule in children is a follicular adenoma (68.9%), malignancies are found in 16% to 25% of the nodules.^217,218 The most common malignant histologic type is papillary carcinoma, present in more than 80% of these cases. In contrast to thyroid carcinoma in adults, papillary carcinomas are usually follicular in pattern, and tall-cell and columnar-cell variants do not occur in children.^219,220 Hürthle cell carcinomas may manifest with multiple lesions and a papillary architecture as a familial syndrome.²²¹ MTCs constitute about 10% of pediatric thyroid carcinomas, and all family members need to be carefully evaluated for possible familial MTC or MEN syndromes.

Management of a child with thyroid carcinoma must balance the potential morbidity associated with treatment against the low probability that the patient will die of this disease. The primary goal of surgery is to remove gross disease completely at the primary and regional metastatic sites. A total or near-total thyroidectomy is recommended.^{213,214,222,223} Multifocal disease is present in 10% to 30% of patients. In addition, a total or near-total thyroidectomy allows the use of serum thyroglobulin to monitor disease recurrence, and facilitates the use of radioiodine to identify and treat distant metastases. More recent studies have shown a low incidence of permanent hypoparathyroidism and RLN injury after total thyroidectomy. The recurrence rate is lower for patients undergoing total thyroidectomy than for patients undergoing lesser procedures.²²⁴

Children often present with cervical nodal metastases requiring therapeutic lymphadenectomy. In patients with nodal disease, the paratracheal and pretracheal lymph nodes are involved in 90% of cases.³² The metastatic deposits are frequently compressive rather than infiltrative with respect to adjacent neck structures. Radical neck dissection is rarely necessary. Patients should have central compartment dissections when cervical disease is present, rather than simple node plucking. Care should be taken to identify and preserve the blood supply to the parathyroid glands. Also, lateral neck disease requires a comprehensive lateral neck dissection (levels II-V).

Although children and adolescents commonly present with more advanced disease than adults, their prognosis remains excellent. In several series, young patients have a 10-year survival near 100% and a 2- to 5-year survival rate near 90%.²²⁵ Relapse is most common in the cervical lymphatics, and is more common in children than in adults. Recurrence seems to be more common in younger patients and patients with papillary histology.²²⁶ Cervical disease can be surgically excised, and pulmonary recurrence is responsive to radioiodine therapy.²²⁷

Pregnancy

Because thyroid neoplasms occur more commonly in women and often during their childbearing years, physicians occasionally need to manage this disease in pregnant women. The incidence of thyroid nodules during pregnancy has been reported as 2% to 10%.^228,229 Management of these patients must protect the well-being of the mother and fetus, and minimize the risks of preterm labor or abortion. A crucial difference in thyroid nodule management during pregnancy and breastfeeding is the absolute contraindication for the use of radioactive iodine.²³⁰

During pregnancy, the thyroid gland physiology is markedly altered. The gland can increase significantly in size because of a relative iodine insufficiency and hormonal changes.^231,232 These physiologic and hormonal changes may increase the incidence of thyroid nodules or cause the enlargement of existing thyroid nodules.

The presence of any discrete thyroid nodule should be evaluated by FNAC.²³³ Some authors argue that a pregnant patient beyond 20 weeks of gestation should have FNAC deferred until after the pregnancy to reduce patient anxiety.^229,234 These authors argue that treatment would likely occur after surgery, and they advocate FNAC only when the nodule shows continued growth or other suspicious features. Other authors advocate immediate FNAC at any stage of pregnancy.²³⁰

Ultrasonography may be used for initial assessment and continued monitoring. Ultrasound evaluation is effective for the evaluation of thyroid and cervical involvement. CT scans during pregnancy are not recommended, although MRI, if necessary, may be performed safely.

When FNAC is benign, the patient should be reassured, and ultrasonography can monitor the nodule for possible growth during pregnancy. A follicular neoplasm may be monitored closely or surgically explored. If FNAC is suspicious or shows thyroid carcinoma, surgery is recommended at the safest time possible.²²⁸ Thyroid carcinomas identified late in pregnancy should be treated in the immediate postpartum period. Carcinomas diagnosed during the first and early second trimesters may be surgically treated during the 22nd through 26th gestational weeks, when the risk to fetal development and for preterm labor is lowest. The patient can be reassured that thyroidectomy and even cervical lymphadenectomy at midtrimester do not carry significant risks for the fetus. Maternal complications are similar to nonpregnant patients. A more recent study suggests, however, no difference in the natural history and prognosis of pregnant patients with a thyroid carcinoma diagnosed early in gestation who defer surgery until after labor.²³⁵ Most patients would likely experience too much stress and anxiety to have an untreated cancer present throughout gestation.

Aggressive thyroid carcinomas that grow rapidly or invade adjacent cervical structures may demand immediate surgical attention. Additionally, a diagnosis of medullary or undifferentiated carcinoma in pregnant patients requires prompt treatment. These tumors are rare and often affect older women. Before starting treatment in these cases, the pregnancy should be terminated.

Bleeding Complications

Hemorrhage is uncommon when surgery is performed with meticulous hemostasis. Bleeding may occur, however, because of an undetected coagulopathy or a technical mishap. Significant hemorrhage in the immediate postoperative period can lead to life-threatening airway compression. A rapidly expanding hematoma requires immediate opening of the surgical incision and evacuation of blood. Airway control can be established, and the patient can be returned to the operating room for complete exploration to identify bleeding sites. A wound seroma may occur, especially after the removal of a large goiter. If a fluid collection is present, simple needle aspiration should manage the problem and prevent the risk of infection.

Superior Laryngeal Nerve Injury

Injury to the external branch of the SLN is believed to be rare, but the exact frequency is unknown. Often disturbance of SLN function is temporary and unrecognized by the patient and the surgeon.²³⁶ Injury to the SLN alters function of the cricothyroid muscle. Patients may have difficulty shouting, and singers find difficulty with pitch variation, especially in the higher frequencies. The external branch of the SLN is not often visualized and lies near the superior pole vessels. Adequate exposure of the superior thyroid pole and close ligation of the individual vessels on the thyroid capsule may prevent SLN injury. Voice therapy may help patients to compensate in cases of SLN injury.

Recurrent Laryngeal Nerve Injury

Injury to the RLN has a much greater impact and is more noticeable than SLN injury. The incidence of permanent RLN paralysis is approximately 1% to 1.5% for total thyroidectomy and less for near-total procedures.^101,237,238 Temporary dysfunction because of nerve traction occurs in 2.5% to 5% of patients.¹⁷⁶ Incidence increases with second and third procedures. RLN injury is also more common in thyroidectomy with neck dissection, although this may reflect more advanced disease states.²³⁹ Disease-specific risk factors for permanent nerve damage include recurrent thyroid carcinoma, substernal goiter, and various thyroiditis conditions. Vocal cord function should be evaluated and documented by indirect laryngoscopy, especially in patients who have had previous surgery.

Unilateral RLN injury leads to a vocal cord in the paramedian position, and the voice may be breathy and lack volume. Concurrent injury of the SLN results in a more laterally positioned vocal cord and worsens voice quality and glottic competence.²⁴⁰ Occasionally, patients may have difficulty with aspiration and pneumonia.²³⁹

Bilateral RLN injury may manifest very dramatically. Immediate postoperative stridor and dyspnea may require immediate reintubation and a possible tracheostomy. Occasionally, bilateral RLN injury may not be immediately noticeable, and patients may adapt to the reduced airway. Over time, the vocal cords move to the midline compromising the airway.

Identification and careful dissection along the course of the RLN decreases the incidence of permanent injury. The surgeon should also be aware of the possibility of a nonrecurrent nerve, most commonly on the right side. If the nerve is transected during surgery, microsurgical repair of the nerve is recommended. Although the repair is unlikely to restore normal function, reanastomosis of the RLN may decrease the extent of vocal cord atrophy.²⁴¹ Some surgeons advocate anastomosis of the ansa hypoglossal nerve to the distal end of the severed RLN to prevent laryngeal synkinesis and possible vocal cord hyperadduction.^242,243

Comprehensive management of vocal cord injury is beyond the scope of this chapter. In most cases, RLN injury is detected postoperatively. Management is supportive, although some surgeons favor re-exploration when vocal cord paralysis is noted in the immediate postoperative period. Return of normal vocal cord function occurs 6 to 12 months after temporary RLN injury occurs. Speech therapy can be valuable. Serial examinations should document a potential return of function or compensation by the contralateral vocal cord. In patients with continued vocal incompetence or aspiration, treatment directed toward vocal cord medialization may consist of vocal cord injection, thyroplasty, or arytenoid medialization. In cases of bilateral RLN injury, management is directed at improving the airway, while not completely sacrificing airway quality, and may involve arytenoidectomy or transverse cordotomy.

Hypocalcemia

Transient symptomatic hypocalcemia after total thyroidectomy occurs in approximately 7% to 25% of cases, but permanent hypocalcemia is less common (0.4% to 13.8%).^244,245 The risk of hypoparathyroidism is related to the size and degree of invasion of the tumor, pathology, and extent of procedure and surgeon experience.^55,246 Changes in serum calcium levels are often transient and may not always be related to parathyroid gland trauma or vascular compromise.

Parathyroid autotransplantation may be considered when the risk of postoperative hypocalcemia is increased.^247,248 These situations may include thyroid carcinoma requiring total thyroidectomy with central neck dissection, en bloc resections that require removal of the parathyroid glands, and reoperation after previous thyroid or parathyroid surgery. Autotransplantation is commonly performed in the sternocleidomastoid muscle, although various locations, including the brachioradialis muscle of the nondominant forearm, have been used.²⁴⁹

Transient hypocalcemia is often related to variations in serum protein binding caused by perioperative alterations in acid-base status, hemodilution, and albumin concentration. These changes do not produce hypocalcemic symptoms. Sudden changes in levels of ionized serum calcium can result in perioral and distal extremity paresthesias, however. As calcium levels continue to decline, patients may experience tetany, bronchospasm, mental status changes, seizures, laryngospasm, and cardiac arrhythmias. Chvostek’s sign and Trousseau’s sign may develop with increased neuromuscular irritability as serum calcium levels decrease to less than 8 mg/dL.

Typically, serum calcium levels are measured in the immediate postoperative period and the next morning for patients with a total or completion thyroidectomy. Patients should have a stable or increasing serum calcium level. Patients undergoing a thyroid lobectomy do not usually require serum calcium monitoring. Findings that should be worrisome for hypoparathyroidism include hypocalcemia, hyperphosphatemia, and metabolic alkalosis. PTH levels may also be measured to predict potential hypocalcemia.²⁵⁰

Treatment for hypocalcemia is typically initiated if the patient is symptomatic or serum calcium levels decrease to less than 7 mg/dL. In these patients, cardiac monitoring is warranted. Patients should receive 10 mL of 10% calcium gluconate and 5% dextrose in water intravenously, titrated to symptom resolution and subsequent serum calcium level tests. Oral calcium supplementation should begin with 2 to 3 g of calcium carbonate per day. Calcitriol (1,25-dihydroxycholecalciferol) also should be initiated. Adjustments in supplemental calcium and vitamin D should be done in consultation with an endocrinologist.