Thyroid Ultrasound: Thyroid ultrasound is becoming more and more popular in the first-line evaluation of thyroid nodules. Good technique demonstrates nodules, if they are larger than 3 mm; indicates cystic areas; and may reveal a capsule around the nodule and the size of the lobes. It often displays multiple nodules when only one is noted clinically, and it allows the discovery of suspicious lymph nodes in the neck. This technique is more sensitive than thyroid scan, is noninvasive, involves less time, allows serial examination, and usually is less expensive. From 3% to 20% of lesions are found to be totally or partially cystic. Purely cystic lesions are reported to have a lower incidence of malignancy than do solid tumors (3% vs. 10%), and diagnosis of a cyst raises the possibility of aspiration therapy.⁵⁶ Some specific features (e.g., hypoechoic, solid, irregular halo, microcalcifications, shape) are indicative, although not diagnostic, of malignant nodules. The study of blood flow by Doppler ultrasonography may provide indicative information, and, very recently, a new technique called “elastographic ultrasound” was applied to the differential diagnosis with great specificity and sensitivity.^57,58

Isotope Scans and Other Imaging Techniques: Isotope scintiscans provide only functional information regarding activity of the nodules; their use has been much reduced since neck ultrasound was introduced,^59,60 because the same functional information is revealed by measurement of serum TSH levels. In cases of multinodular goiter, scintiscan is still useful in distinguishing the nodules to be submitted to FNAC (the cold one). Nodules that are hyperfunctional and that produce hyperthyroidism are rarely malignant, and those that accumulate iodide in concentrations equal to the surrounding normal thyroid tissue are usually but not always benign^61,62 (Fig. 18-2). Cold nodules are typically benign, but when viewed the other way, most thyroid cancers are seen as inactive areas on thyroid scan. In practice, except for the specific case of a toxic nodule, scans are probably of little help in the differential diagnosis, and the tendency to omit scanning from diagnostic maneuvers is growing. Scintiscans can confirm the diagnosis of multinodular goiter and can show the presence of diffuse disease (e.g., Hashimoto’s thyroiditis) in some patients when nodularity is suspected.

Other scanning techniques have not found a place in routine preoperative evaluation (Fig. 18-3). Computed tomography (CT) is expensive but occasionally useful, especially in unusually large substernal glands. Magnetic resonance imaging (MRI) is rarely necessary but is useful for identifying abnormal nodes. Fluorine-18-fluoro-deoxyglucose (FDG)–positron emission tomography (PET) is generating great interest in general oncology but has no particular role in the diagnosis of thyroid nodules, even if sporadic reports of positive uptake in malignant nodules have been published.^63,64

Chest radiograph and soft tissue x-ray films of the neck are useful for ascertaining the presence of compression signs (e.g., indentation or deviation of the trachea), which are particularly common when the tumor is larger than 3 or 4 cm in diameter. Fine, stippled calcifications through the tumor (psammoma bodies) are virtually pathognomonic of papillary cancer. Patchy or “signet ring” calcification occurs in old cysts and degenerating adenomas and has no such connotation. The presence of such signs is very well detected by thyroid ultrasound.

Fine-Needle Aspiration Cytology: Although all the above mentioned procedures may provide some indication, only the results of FNAC can give a definitive answer regarding the nature of a thyroid nodule. FNAC has now been widely adopted after initial favorable reports by Walfish and colleagues⁶⁵ and Gershengorn and colleagues.⁶⁶ It has replaced the core needle biopsy previously used to provide a histologic diagnosis.⁶⁷ In expert hands, adequate specimens can be obtained in more than 90% of patients, with a diagnostic sensitivity and specificity near or superior to 95%. Willems and Lowhagen, in reviewing a collected series of nearly 4000 surgically proven fine-needle aspiration (FNA) studies, found that 11.8% were considered malignant lesions.⁶⁸ False-negative diagnoses of cancer were made in 6.6% to 27.5%, and false-positive diagnoses in only 0% to 2%. Currently, the results of FNAC are viewed as the “gold standard” for diagnosis in most cases, and they play a crucial role in the selection of patients for surgery,^69–71 Gharib and coworkers analyzed data on 10,000 FNA procedures and found it to be the preferred first step in diagnosis.⁷² Diagnostic accuracy was nearly 98%, with fewer than 2% false positives and false negatives. Miller and colleagues compared FNA, large-needle aspiration, and cutting needle biopsy.⁷³ They found that FNAC examination was able to detect almost all carcinomas, but they believe that cutting needle biopsy is a useful additional procedure, especially with larger (more than 2 to 3 cm) nodules.

FNAC should always be performed with ultrasound guidance, especially in smaller (or less discrete) or partially cystic nodules. It is demonstrated that, with respect to pre-FNAC years, various centers using the results of FNAC for therapeutic decisions have observed a 35% to 75% reduction in the number of patients sent to surgery; a twofold to threefold increase in the percentage of cancers found at surgery; and a variable, but constant, reduction in the cost of thyroid nodule management.

FNAC is performed with a 22 to 25 gauge needle. Specimen adequacy requires a minimum of two slides (from separate aspirates) showing at least six to eight cell clusters.⁷⁴ The method is simple, inexpensive, and very well tolerated and, if necessary, may be repeated several times. Complications are very rare and consist mainly of hematomas. In several large series, it has been found that around 70% (range, 53% to 90%) of aspirates are classified as benign; 4.0% (1% to 10%) as malignant or suspicious for malignancy; 10% (5% to 23%) as indeterminate, mainly represented by “follicular neoplasia”; and 17% (15% to 20%) as inadequate for diagnosis.^75–78 When the sample obtained is of good quality (i.e., high cellularity), the cytologic diagnosis of thyroid carcinoma, especially in the case of a papillary histotype, is highly reliable, and false-negative or false-positive results are very rare. Medullary thyroid carcinoma is diagnosed easily by cytology in classic cases, but sometimes the cellular pattern is atypical and can be interpreted as follicular and even papillary proliferation. Problems may arise in the case of thyroid lymphoma, because the smear may be composed of follicular cells mixed with lymphocytes, which can mimic chronic lymphocytic thyroiditis or may be confused with anaplastic carcinoma. Cytology of cystic nodules shows the presence of colloid, necrotic material, macrophages, and rare epithelial cells. In most cases, these lesions are benign, but the possibility of cystadenocarcinoma must be considered. The cytologic diagnosis of follicular or Hürthle cell neoplasia is particularly challanging. A variety of techniques have been applied to improve the accuracy of interpretation of FNA cytology in this setting, including staining with antibodies to thyroid peroxidase (TPO) and the search for MUC1 gene expression and telomerase activity, as well as galectin-3 expression.^79–85 However, none of these potential markers has been entered into clinical practice because of conflicting results or low sensitivity.

The major limitation of FNAC is the inadequacy of specimens, even after repeat attempts. The rate of inadequacy is variable among different centers, with a realistic estimation of between 15% and 25%.75–76 Inadequacy raises the question of therapy for the nodule with nondiagnostic FNAC. Some authors recommend surgical treatment for all these nodules, whereas others select for surgery only those suspicious by other clinical or laboratory features. Even if only the most suspicious nodules with inadequate FNAC are selected for surgery, the yield of malignancy at histology is relatively low and ranges from 8% to 19%.^74,86,87 In any case, patients should be carefully monitored by repeat FNAC and referred to a surgeon in the event that a nodule increases in size.

An additional indication for FNAC is the diagnostic evaluation of cervical nodes, both at initial evaluation and when a diagnosis of thyroid cancer has already been established. In the case of lymph nodes suspected of being of thyroid metastatic origin, FNAC may be integrated with the measurement of Tg in the liquid recovered when the needle used for the aspiration is washed. As is shown in Fig. 18-4, in the case of a metastatic lesion from differentiated thyroid carcinoma, this technique demonstrates the presence of high levels of Tg.^88,89

In conclusion, FNAC should be performed on any thyroid nodule. In the case of multinodular goiter, FNAC should be performed on as many nodules as possible. The largest nodule is not necessarily the one associated with malignancy; thus, FNA should be performed under the guidance of sonographic features rather than on the basis of size.¹² In dubious cases, FNAC may be repeated immediately or over the years, if the final decision is to not operate on the patient. It is worth mentioning that the preoperative diagnosis of thyroid carcinoma is useful not only for selecting patients to be operated on, but also for planning in advance the most appropriate surgical procedure.

Surgery for Nodules With FNAC Indicative of Malignancy: When the malignant nature of a nodule has been established by FNAC, the recommended surgical procedure should be total (or near-total) thyroidectomy regardless of the size of the nodule, without the need for frozen section examination, which has a rate of false-negative results in excess of false-positive results for FNAC (near zero). This procedure decreases the risk for local recurrence and is performed with almost no morbidity under expert hands. Moreover, it facilitates postsurgical radioiodine ablation and adequate follow-up.90–92 Surgery should be preceded by careful staging of the disease in the neck. This is accomplished by thyroid and neck ultrasound. Any suspicious lymph node must be submitted to confirmatory FNAC to alert the surgeon of the presence of metastatic disease. If positive nodes are seen, the surgeon should perform the most appropriate dissection of lymph node chains (central compartment, homolateral modified neck dissection, or bilateral). The need for routine dissection of the central node compartment in the absence of suspicious ultrasonographic findings is debated. Recent European and American guidelines^53,54a suggest that the central neck should be explored and all nodes removed by the surgeon in cases of papillary and Hürthle cell thyroid cancer, but not follicular thyroid cancer. However, the benefits of prophylactic “en bloc” central node dissection in the absence of preoperative or intraoperative evidence of nodal disease are controversial. No evidence suggests that it improves recurrence or mortality rates, but it does permit accurate staging of the disease that may guide subsequent treatment and follow-up.

This approach, which emphasizes more extensive nodal surgery and less use of ¹³¹I, represents an interesting return to concepts in vogue and discarded five decades ago. Bonnet et al.^54b reported a series of 115 patients with papillary tumors of 1 to 2 cm and no preoperatively recognized cervical nodes, whose surgery arbitrarily included en bloc dissection of midcervical (level VI) nodes and lateral (level III and IV) nodes, and sometimes level II and V nodes. Patients probably had more advanced tumors than are seen in average cases, in that 29% were invasive and 37% multifocal. This extensive nodal surgery changed therapy in 11%, in whom no nodes were found, and who therefore received no ¹³¹I. Complications included hypoparathyroidism and vocal cord paralysis (0.9% each). Certainly this “prophylactic” node dissection may preclude discovery of nodes at a later date, thus preventing a small number of patients from being exposed to 30 mCi of ¹³¹I. Whether this is a fair trade for the certain increase in side effects that would follow application of the approach in general practice remains very uncertain, and this approach cannot be recommended at present.

Surgery for Nodules With Indeterminate or Suspicious FNAC: Among solitary thyroid nodules with an indeterminate (“suspicious,” “follicular neoplasm,” or Hürthle cell neoplasm) biopsy, the risk for malignancy is approximately 20%.93–95 For solitary nodules that are repeatedly nondiagnostic on biopsy, the risk for malignancy is unknown but is probably closer to 5% to 10%.⁹⁶ In these cases, the surgical procedure should be discussed with the patient. For those who prefer a more limited surgical procedure, thyroid lobectomy associated with frozen section examination is the recommended initial surgical approach.

Because of increased risk for malignancy, total thyroidectomy is indicated in patients with large tumors (>4 cm) when marked atypia is seen on biopsy, when the biopsy reading is “suspicious for papillary carcinoma,” in patients with a family history of thyroid carcinoma, in patients with a history of radiation exposure,97–99 in patients with bilateral nodular disease, and in those who prefer to undergo bilateral thyroidectomy to avoid the possibility of requiring a future surgery.

Surgery for Differentiated Thyroid Cancer Detected at Final Histology Without Total Thyroidectomy Performed: If a patient is referred after less than near-total thyroidectomy, completion thyroidectomy should be proposed in the case of a large tumor, multifocality, extrathyroidal extension, and/or vascular invasion or evidence of local or distant metastases, previous history of radiation exposure, or unfavorable histology.^96,101 In cases of primary tumors between 10 and 20 mm in diameter that have been diagnosed at postoperative definitive histopathology, the indication for completion thyroidectomy should be discussed with the patient on the basis of the risks and benefits of reoperative surgery, including the potential risk for surgical morbidity. Depending on the size of the thyroid remnant, an effective alternative to completion thyroidectomy when the risk for persistent disease is low may be radioiodine ablation of residual thyroid tissue.¹⁰²

Whenever surgery is performed for nodules with no suspicion of malignancy, the usual procedure is lobectomy, which is relatively harmless and has an incidence of complications approaching zero. Usually, patients are discharged within 2 to 3 days. Complications are more common when more extensive dissection is done, as will be discussed subsequently. The thyroid specimen itself, any abnormal areas in the gland, and any abnormal appearing lymph nodes should be examined immediately by frozen section. Differentiating benign from malignant thyroid lesions is admittedly difficult, especially with frozen sections, but experienced pathologists can make the distinction with a high degree of reliability. Occasionally, follicular lesions are believed by the pathologist to be benign at surgery, but permanent sections reveal changes that indicate malignancy. Reoperation with near-total thyroidectomy is probably desirable in these patients, because up to one third can be expected to have residual tumor in the contralateral lobe.¹⁰³ To avoid these second operations, we recommend lobectomy and contralateral subtotal resection for very cellular follicular lesions as the initial procedure. Occasionally, a small papillary or follicular cancer is found in the pathologic specimen after the operation has concluded. If this cancer is less than 1 cm and has a well-demarcated single focus, and the patient is younger than 45 years, nothing further need be done therapeutically, but follow-up by periodic thyroid ultrasound is recommended. After surgery, all patients are maintained on replacement levothyroxine therapy in the hope of preventing recurrence of other nodules. Serum TSH should be maintained in the low-normal range.

Benign Solid Cold Nodule: Appropriate management of these nodules is strongly debated. A meta-analysis¹⁰⁴ has indicated that about 25% respond to thyroxine treatment with a decrease in size, whereas the remainder remain unchanged, at least over several months. Some physicians believe that once malignancy has been ruled out, medical therapy is indicated for solid cold nodules with normal or subnormal thyroid function, especially when associated with thyroid enlargement. The drug of choice is levothyroxine. Some physicians advocate a dose sufficient to suppress pituitary TSH secretion as demonstrated by a serum TSH level less than 0.1 µU/mL. The rationale for this therapy is the unequivocal observation that TSH is, to some extent, a growth factor not only for the normal thyroid but also for thyroid nodules. Experimental and clinical evidence has shown that even mild iodine deficiency elicits subminimal increases in TSH levels, which leads first to glandular hyperplasia and later to multinodular goiter. On the other hand, the functional heterogeneity and the variable degree of mitogenicity of follicular cells upon stimulation by TSH offer an explanation for the appearance of a nodule without diffuse goiter. When the nodule and/or the goiter is of recent origin, suppression of TSH stimulation by levothyroxine is often sufficient to eliminate the nodule, or at least to reduce its size and that of the thyroid gland. In long-standing cases, both the nodules and the goiter are seldom cured, but a significant reduction in size and arrest of the progression are likely to occur.

Once instituted, levothyroxine therapy must go on for years to be effective.¹⁰⁶ Age is very important in the selection of patients to be treated. Treatment is indicated in young patients and in adults up to about 45 to 50 years of age. In older patients, the opportunity to initiate suppressive therapy must be considered on an individual basis after other underlying diseases such as heart problems are excluded. However, if a patient is already receiving levothyroxine treatment and shows good compliance and no side effects, treatment can be continued after age 50 years and even after age 60 years with the daily dosage slightly decreased.

An alternative approach is to aim for a TSH of 0.3 to 1 µU/mL, because this level will have some suppressive effect, perhaps will inhibit the growth of nodules over subsequent years, and is free of the minimal risk for mild thyrotoxicosis.

At the other end of the spectrum of opinion are physicians who believe that thyroxine therapy is useless and who simply offer continued observation without treatment.

Another aspect to be considered is functional thyroid status. Before instituting levothyroxine therapy, to avoid iatrogenic thyrotoxicosis, one must be certain that the patient is perfectly euthyroid, and that serum TSH, measured with an ultrasensitive assay, is not already suppressed, as so often can happen in multinodular goiters with areas of functional autonomy.

The last important aspect is the dose to be given. The usual suppressive dose is between 1.5 and 2 µg/kg/day, administered in the morning. The dose is checked after 3 to 4 months by measuring FT₃, which should stay in the normal range, and TSH, which should be in the range selected, with an FT₄ value usually in the upper limit of the normal range. If results show that TSH is not suppressed, or that the patient has been overtreated, an appropriate dosage modification will be made, with another hormonal control determined 3 to 4 months later and then yearly.

Once the few precautions described above are observed, levothyroxine treatment is generally useful and safe. Our own experience and data from the literature indicate that significant shrinkage is obtained in 15% to 50% of the nodules, and that many others do not progress. Side effects on the heart and bone, described by some authors, are not observed when careful avoidance of subclinical thyrotoxicosis is maintained.¹⁰⁷

When clinical signs of hyperthyroidism suddenly develop during levothyroxine therapy, one must suspect the occurrence of functional autonomy of the nodule(s), and levothyroxine treatment must be withdrawn immediately. An indication for referring the patient to a surgeon is an increase in size of the nodule during levothyroxine therapy. Such a situation is not unusual and, although regarded as suspicious, does not constitute definite evidence of malignancy.

Autonomously Functioning Thyroid Nodule: The incidence of cancer in an autonomously functioning thyroid nodule (AFTN) (hot nodule) is so low that the therapeutic approach is dictated mainly by the presence of thyrotoxicosis and/or the size of the nodule. Sometimes hot nodules are found in the presence of detectable TSH, with the extranodular uptake being reduced but not suppressed. Many AFTNs are associated with subclinical thyrotoxicosis, the only abnormality being a low or undetectable serum TSH. Overt thyrotoxicosis is present in the remaining cases. AFTNs tend to occur in young adults, and they are usually smaller than 3 cm.

AFTNs of small dimension (<3 cm), without thyrotoxicosis, can be left untreated and observed. About 20% to 30% of the nodules, and a greater percentage when they are larger than 3 cm, evolve to thyrotoxicosis, sometimes decades after discovery. In the case of thyrotoxicosis, three therapeutic options are available: (1) surgery, (2) radioiodine, and (3) ethanol injection. Radioiodine is a very effective therapy and is the treatment of choice in many patients with AFTNs. Euthyroidism and a variable degree of tumor shrinkage are always attained after ¹³¹I treatment, but a hard nodule usually persists for life. No agreement has been reached on the best activity of ¹³¹I to be administered. In our experience, standard doses of 15 mCi usually are sufficient to abolish the function of the nodule, although they induce late hypothyroidism in about 20% of patients.¹⁰⁸ Surgery is an acceptable alternative therapy and is indicated for large nodules (>3 cm) and for patients who refuse to be treated with radioiodine. Surgery consists of total lobectomy and, in the case of thyrotoxicosis, must be performed after normal thyroid function has been restored by adequate preparation with antithyroid drugs (methimazole or propylthiouracil). The development of hypothyroidism after treatment is unusual after surgery and occurs in about 10% of cases after radioiodine therapy. Replacement therapy probably is indicated, also in patients who remain euthyroid, to avoid late compensatory hyperplasia of the remaining lobe.

A third therapeutic option for the treatment of AFTN has been proposed by Italian authors and consists of percutaneous intranodular ethanol injection (PEI).^109,110 The mechanism of action of ethanol is based on induction of cellular dehydration, followed by coagulative necrosis and vascular thrombosis and occlusion. The technique, when performed by well-trained staff, is effective and safe. Transient local pain is the most common side effect. PEI may be considered a possible alternative to surgery and radioiodine in selected cases (i.e., small nodules easily accessible to palpation). This method has now been used for several years, and so far evaluation has not revealed long-term complications. Recently, the indication for PEI therapy has been extended successfully by an Italian group to the treatment of large AFTN in conjunction with radioiodine therapy.^111,112

Thyroid Cysts: Thyroid cysts are managed easily by aspiration, but recurrence of the cyst is very common. Suppressive therapy with levothyroxine may reduce the risk for relapse, especially if aspiration is performed after a few months of levothyroxine treatment, but the risk for relapse remains significantly high. An emerging alternative therapy is cyst sclerotherapy by ethanol injection into the nodule after complete aspiration of the cystic fluid.¹¹³ The technique appears to be effective and safe: It might become the treatment of choice for thyroid cysts. When the above mentioned therapy fails to avoid cyst recurrence, or when the size of the nodule is too large, surgery is necessary.

A small proportion (about 3%) of cystic nodules diagnosed as thyroid cysts do not originate from the follicular epithelium but rather from the parathyroids. These cysts may be suspected from the color of the cystic fluid, which usually, but not always, is transparent like water. The final diagnosis is achieved easily by a finding of high concentrations of parathyroid hormone and low or undetectable concentrations of Tg in the fluid aspirate.¹¹⁴ Most of the time, calcemia is normal. The differential diagnosis between thyroid and parathyroid cysts has important therapeutic implications in that parathyroid cysts do not tend to recur after FNA and of course do not respond to levothyroxine treatment.