Evaluation of thyroid nodules - technical
A thyroid nodule is a general term used to describe any mass or growth within the thyroid gland that is distinct from the surrounding thyroid tissue. A solitary nodule is a single nodule that is radiologically distinct from the surrounding thyroid parenchyma, while a multinodular thyroid is one in which there are multiple nodules that are distinct from each other and the surrounding thyroid tissue. Nonpalpable nodules detected on ultrasound or other imaging studies are termed incidentally discovered nodules or “incidentalomas.” Thyroid nodules that produce thyroid hormone in an uncontrolled manner are referred to as autonomous nodules, “hot” nodules, or “toxic” nodules. If the nodule is filled with fluid or blood, it is called a thyroid cyst or hemorrhagic cyst.
Thyroid neoplasms are benign or malignant tumors of the thyroid gland. Benign thyroid neoplasms include follicular and Hurthle cell adenomas. Malignant thyroid nodules are classified by the types of malignant cells they contain: papillary, follicular, medullary, or poorly differentiated (anaplastic) cells.
The prevalence of palpable thyroid nodules is 8.9% but higher in women compared to men living in iodine-sufficient parts of the world (Maia et al. 2011; Karaszewski et al. 2006). The reported prevalence of thyroid nodules is significantly higher on ultrasound examination, ranging from 19% to 67% with higher rates detected in women and the elderly (Maia et al. 2011).
History and Clinical Features
The majority of patients with thyroid nodules are asymptomatic at the time of first presentation. While some nodules are detected by the patient or by a healthcare practitioner, the majority are found incidentally on diagnostic imaging. Frequently, nodules are detected on ultrasound examination of patients referred with head and neck complaints. Incidental nodules are also identified on diagnostic imaging for other indications such as during carotid Doppler examination, breast or chest CT scans, or PET scans.
The reported prevalence of incidentalomas identified by physical examination is 8.9% (Karaszewski et al. 2006), by ultrasound imaging 13.2–14.8% (Karaszewski et al. 2006), and by PET/CT scans 2.2–3.2% (Kim et al. 2005; Zhai et al. 2010).
Occasionally, patients with large thyroid nodules present with symptoms of dysphagia or dyspnea. Pain may be associated with acute thyroiditis or acute hemorrhage into a preexistent thyroid nodule or thyroid cyst. Hyperfunctioning nodules (also referred to as hot or toxic nodules) can cause symptoms of hyperthyroidism. Most patients with malignant nodules present without symptoms. A history of hoarseness should be elicited as this may suggest an invasive malignancy. While vocal cord paralysis may present with obvious hoarseness, voice quality is not a reliable clinical symptom of thyroid malignancy (Hanna and Brooker 2008). Risk factors for thyroid cancer such as a family history of thyroid cancer or a history of radiation exposure should also be elicited.
A full head and neck examination should be performed, with a focus on the thyroid and neck. A palpable nodule should be assessed for size, firmness, and mobility. The neck should be evaluated for lymphadenopathy. The mobility of the vocal cords should be assessed with either mirror examination or, preferably, fiber-optic examination. Clinical signs that raise suspicion of malignancy include the presence of firm fixed masses, lymphadenopathy, and vocal cord paralysis.
When planning how to investigate thyroid lesions, it is important to note that thyroid nodules are extremely common in the general population. Therefore, the aim of the clinician is to identify symptomatic patients or those at risk for thyroid cancer and to manage these patients accordingly, while not over-investigating or treating benign nodules, which constitute the vast majority of thyroid lesions.
At the time of first presentation, patients with thyroid nodules should undergo measurement of serum thyrotropin (TSH) level. If TSH is abnormal, total or free thyroxine (T4) and total triiodothyronine (T3) should be measured to evaluate the hyperthyroid or hypothyroid state. In the patient with a thyroid nodule and suppressed TSH (i.e., hyperthyroidism), a thyroid scan with Natrium-99mTechnetium-Pertechnetat (Na99mTcO4) should be performed to determine if a hyperfunctioning nodule is present. Epidemiological studies have shown that hyperfunctioning nodules are benign in more than 98% of patients (Mukasa et al. 2011), and given such a low rate of malignancy, these nodules do not require further investigation. In patients where hypothyroidism is confirmed, thyroid peroxidase antibodies (TPA) should be measured to diagnose an autoimmune thyroid disease such as Hashimoto’s thyroiditis.
Serum thyroglobulin levels may be elevated in most thyroid diseases and is thus considered an insensitive and nonspecific test for thyroid cancer (Cooper et al. 2009). Blood calcium testing is not part of the workup of patients with thyroid nodules. Measurement of basal plasma calcitonin levels is indicated only in patients with a positive family history for medullary thyroid carcinoma, multiple endocrine neoplasia types (MEN) 2a or b or pheochromocytoma (Cooper et al. 2009), or who have a fine-needle aspiration (FNA) suspicious or diagnostic for medullary thyroid carcinoma.
Ultrasound imaging of the neck and particularly of the thyroid should be performed in all patients presenting with a thyroid nodule, goiter, or thyroid incidentaloma (Cooper et al. 2009). The following features should routinely be assessed and reported in ultrasonographic evaluation of thyroid nodules: dominant nodule location, size, volume, echogenicity, presence or absence of a halo sign, solid and/or cystic, hypervascularity, shape, irregular margins, and calcifications (Cooper et al. 2009). In addition, the presence of other thyroid nodules and their sonographic features should be reported, as should the presence of lymphadenopathy. This information can be used to identify nodules that require further investigation with FNA, as well as to identify features that increase the suspicion of malignancy and which may help management in cases where FNA is nondiagnostic or even benign.
Certain ultrasound characteristics of thyroid nodules have been associated with higher or lower risk of malignancy (Eng et al. 2010). In particular, comet tail sign, halo sign, and coarse calcification all suggest benign disease, whereas hypoechoicity and absent halo with indistinct margins are more frequently seen in malignant nodules. In a recently published review (Sheth 2010) that included six large studies on the association between ultrasound features and malignancy, hypoechogenicity of thyroid nodules was found to have a sensitivity and specificity of approximately 85% and 60%, respectively. The positive predictive value was approximately 30%, and the negative predictive value was 55%. Some studies have demonstrated that an elongated shape (i.e., length: width ratio of 1) is highly specific (91.4%) for malignancy (Sheth 2010).
Data on the relationship between speculated margins and malignancy show sensitivity between 47.8% and 77.5%, specificity between 63% and 91.8%, negative predictive value between 70.7% and 93%, and positive predictive value between 16.4% and 81.3%. The presence of microcalcifications is highly suggestive of papillary carcinoma. A recently published study on 600 patients with thyroid nodules showed that microcalcification was detected on ultrasound more than twice as often in malignant nodules as in benign nodules (Raza et al. 2008). Sheth showed that the presence of microcalcifications in solid nodules had a high specificity of 91.3–96.3% and a positive predictive value for malignancy of 74.8%, but the sensitivity was only 29–51.4%. The size of thyroid nodes as a cancer-predictive characteristic is highly controversial, with some studies reporting that the risk of malignancy increases with increasing nodule size (Maia et al. 2011) and others reporting no such association (Sheth 2010).
While no single ultrasound feature can predict malignancy, the presence of several high-risk ultrasound characteristics increases the probability of malignancy (Lew and Solorzano 2010). Maia and colleagues have compared ultrasound features and demographic data that predict malignancy in thyroid nodules. Multivariate analysis of the data showed that age (greater than 39 years), margin irregularity, microcalcifications, and nodule diameter greater than 2 cm were highly accurate indicators of malignant thyroid nodules. Irregular margins and microcalcifications were found to be the strongest predictors of malignancy (Maia et al. 2011).
Radioisotope imaging is a very reliable and useful scanning technique to determine the functional status of the thyroid gland. The radioisotopes Tc99m, I123, and I131 have all been used in clinical practice. The vast majority of thyroid nodules (80–85%) are hypofunctioning, of which only 10% are malignant. In contrast, less than 5% of all nodules are hyperfunctioning and less than 5% of these are malignant (Bomeli et al. 2010). Because the specificity of thyroid scans is 5% and the positive predictive value for malignancy is only 10%, radioisotope scanning is rarely included in the initial workup of a thyroid nodule (Bomeli et al. 2010). Currently, the main indication for nuclear imaging of the thyroid is to determine if a nodule is hyperfunctioning in a patient with low TSH levels (i.e., clinical or subclinical hyperthyroidism). If the nodule is hyperfunctioning, then the probability of malignancy is very low and no further workup is required.
CT and MRI have a limited role in the initial workup of patients with thyroid nodules. However, both imaging techniques are excellent for determining the size and extent of large and particularly substernal multinodular goiters. Other indications for CT or MR imaging are for the assessment of invasion by firm fixed tumors. In patients with vocal cord paralysis, cross-sectional imaging should be strongly considered to assess for extrathyroidal extension and tracheal and/or laryngeal invasion. Similarly, in cases where lymphadenopathy is present, further evaluation should be performed with either CT or ultrasound. The use of iodinated contrast materials and CT scans in patients with thyroid nodules remains controversial. It has become axiomatic that administration of iodinated contrast interferes with subsequent radioactive iodine scintigraphy or radioactive iodine therapy for a period of 1–2 months. However, there is no evidence-based literature to support this axiom. Moreover, many contrast agents currently in use are non-iodinated. The benefit of using contrast-enhanced CT is that nodal metastases with papillary carcinoma typically demonstrate contrast enhancement. In the presence of nodal metastases, CT imaging allows assessment for nodal metastases to the upper mediastinum which typically cannot be assessed with ultrasound.
18F-fluorodeoxyglucose positron emission tomography-CT (PET/CT) is an imaging technique for staging cancer patients, evaluating their treatment response, and screening for recurrent disease. PET is used to evaluate many different malignancies, and incidental thyroid nodules have been noted frequently to take up FDG. A recent review concluded that the pattern of abnormal FDG uptake is the most important factor in discriminating benign and malignant nodules (Lang and Law 2011). Thyroid nodules with focal multifocal, or diffuse with focal uptake carry 14–68.8% malignancy, whereas diffuse uptake is considered a normal variant or physiological uptake (Lang and Law 2011). Kim and colleagues showed that the incidence of focal 18FDG-PET/CT in 159 patients without known thyroid disease was 1.36% and the cancer risk was 23.3%.
Furthermore, malignant thyroid incidentalomas show significantly higher SUVmax values than do benign nodules (Kim et al. 2005). Zhai found focal 18FDG uptake into thyroid nodules in 115 of 3,600 patients. Of these 115 patients, 96 nodules were further investigated and 48 were shown to be malignant (Zhai et al. 2010). A small number of studies have investigated the value of 18FDG-PET/CT in patients who presented with indeterminate thyroid lesions on FNA biopsy. Although the number of patients in these studies is limited between 15 and 51 patients, most of the studies showed sensitivity and negative predictive values of 100%. However, the cost and limited access to PET does not justify its current use in the diagnosis of a thyroid nodule. Although 18FDG-PET/CT is not yet included in the workup of a nodule, any nodules that do show nondiffuse 18FDG-PET/CT uptake should undergo a thorough workup to exclude malignancy.
Fine-needle aspiration biopsy (FNAB) is the most important tool for diagnosing thyroid nodules. FNAB is cost-effective, widely available, well tolerated, and carries a low risk for complications. Various classification schemes have been devised for FNAB results, with the National Institutes of Health system being most commonly used. This system uses a six-category diagnostic scheme: benign, follicular lesion (atypia) of undetermined significance, follicular neoplasm, suspicious for malignancy, malignant, and unsatisfactory (Baloch et al. 2008). Benign lesions include nodular goiter, chronic lymphocytic thyroiditis, and hyperplastic/ adenomatoid nodule in goiter. Follicular lesions of undetermined significance or atypia are nodules showing neither benign nor malignant cells.
The risk of malignancy in these lesions is low, between 5% and 10%. Follicular neoplasm represents a diagnosis of low to intermediate (20–30%) risk of malignancy. This category includes nonpapillary follicular patterned neoplasms and Hurthle cell lesions, where the diagnosis of carcinoma is made based on vascular and capsular invasion. The term suspicious for malignancy is typically used to report cytology findings suspicious for papillary carcinoma. The probability of malignancy in these cases is between 50% and 75%. Nondiagnostic results represent specimens that were processed and examined but were not diagnostic due to limited cellularity, absence of follicular cells, or poor fixation and preservation (Baloch et al. 2008). Among thyroid nodules that undergo successful FNAB, approximately 60% are benign and less than 10% are malignant (Tallini and Gallo 2011). The remaining 30% are neither benign nor malignant and classified as “lesion of undetermined significance,” or “suspicious for malignancy” (Tallini and Gallo 2011), reflecting a significant limitation of thyroid FNAB.
The number of negative results has been decreased by performing FNAB under ultrasound guidance (Bomeli et al. 2010), and this procedure is recommended for all nonpalpable nodules and is highly recommended when the initial FNAB done by palpation is insufficient or nondiagnostic. FNAB is particularly suited to diagnosing papillary thyroid cancer on the basis of cytologic features such as nuclear enlargement, nuclear overlapping, powdery chromatin, pseudoinclusions, nuclear grooves, and psammoma bodies (McKee 1998). FNAB is also very reliable in diagnosing medullary and anaplastic carcinoma and lymphoma. However, FNAB has limited diagnostic potential for differentiating benign and malignant follicular and oncocytic neoplasias. To accurately diagnose malignancy, the pathologist needs to evaluate tissue architecture, in particular the existence of capsular or angiolymphatic invasion (Bomeli et al. 2010). Interestingly, the rate of falsenegative samples increases significantly with the size of the thyroid nodules. Recently published studies showed that FNAB of solid thyroid nodules of 3 cm and larger had a 17% false-negative rate, whereas this rate for cystic lesions up to 3 cm was 30%. Thus, most endocrine surgeons recommend diagnostic hemithyroidectomy for nodules larger than 3 cm.
Other studies demonstrate that the combination of FNAB and ultrasound increases the diagnostic accuracy; therefore, recommendations for a diagnostic hemithyroidectomy can be expanded to nodules larger than 4 cm (Cooper et al. 2009). In clinical practice, the endocrine surgeon’s decision to perform a diagnostic hemithyroidectomy must consider not only the size of the nodule but also the patients’ risk factors, demands, and concerns. An algorithm for thyroid workup and in particular for the FNAB diagnosis is summarized and presented in Fig. 1. The ATA 2009 guidelines strongly recommend FNAB in patients whose thyroid nodules have suspicious ultrasound features such as microcalcifications, hypoechogenicity, increased nodular vascularity, infiltrative margins, and taller than wide size on transverse view. Additionally, FNAB is strongly recommended if the patient has a high-risk history of thyroid cancer in one or more first-degree relatives, exposure to external beam radiation as a child or ionizing radiation in childhood or adolescence, prior thyroid cancer, 18FDG avidity on PET scanning, MEN2 mutation, or familial medullary thyroid cancer (Cooper et al. 2009). According to the ATA guidelines, the size of a nodule at which FNA is warranted depends upon the history and ultrasound features (Table 1) (Cooper et al. 2009).
FNAB and Molecular Analysis
Over the last decade, molecular studies have contributed significantly to the understanding of genetic alterations in thyroid cancer. Currently, the most advanced molecular testing in thyroid patients is RET mutation analysis for medullary thyroid carcinoma (Al-Rawi and Wheeler 2006). In particular, missense mutations in the extracellular and intracellular domains of RET tyrosine kinase are encoded by the RET proto-oncogene on chromosome 10; these findings reflect the tremendous advances in DNA analysis and testing that facilitate identification of family members at risk. Mutations in the BRAF and RAS oncogenes play a key role in papillary thyroid carcinoma, and both genes are mutated in 80% of these carcinomas. Besides their role in tumorigenesis, BRAF and RAS mutations have potential as diagnostic markers in combination with FNAB.
Two prospective studies showed that in indeterminate FNA specimens, the presence of BRAF and RAS mutations predicted malignancy with 100% specificity and positive predictive value (Nikiforov et al. 2009). These studies also demonstrated that patients positive for the RAS mutations carry an 87.5% risk for malignancy (Nikiforov et al. 2009), and even when defined as benign, mutated RAS-positive follicular adenomas are likely precursor lesions to follicular carcinoma. As a result of these findings, many authors have suggested that patients carrying BRAF mutations should undergo a total thyroidectomy. However, one case report identified a patient with a false-positive BRAF mutation, whose final diagnosis of atypical nodular hyperplasia may be a premalignant lesion (Bomeli et al. 2010).
Two drawbacks to the use of diagnostic molecular analysis are that the cost is high and molecular testing is not established in all institutions. In summary, molecular testing should be reserved for high-risk patients and for cases where FNAB shows an intermediate or suspicious cytology. Nevertheless, further studies are warranted to evaluate cost efficiency and the power of molecular analysis in combination with FNAB and imaging to predict tumor behavior and thus clinical outcome.
For the vast majority of patients, the cause of thyroid nodules remains unknown. However, several studies have shown that iodine deficiency, diet, radiation exposure, autoimmunity, and familial disorders can all increase the risk of developing thyroid nodules.
Iodine deficiency is linked to the development of thyroid nodules. Physiologically, the thyroid gland adapts to the availability of iodine by regulating thyroid hormone production. However, such adaptive mechanisms can lead to thyroid hyperactivity, which when sustained is associated with thyroid growth, and with follicular cell proliferation that leads to multifocal autonomous growth and function. In geographic regions where there is mild to moderate dietary iodine deficiency, such multifocal autonomous thyroid function is a common cause of hyperthyroidism and the prevalence of thyroid enlargement and nodularity is correspondingly high (Laurberg et al. 2010). Other studies have suggested that individuals with low serum selenium levels have a significantly increased risk for thyroid enlargement and development of multiple nodules (Rasmussen et al. 2011) and that thyroid nodules are significantly more frequent in patients with metabolic syndrome and insulin resistance (Ayturk et al. 2009).
Studies have shown that ionizing radiation induces RET chromosomal rearrangements, which are involved in the pathogenesis of thyroid carcinomas (Elisei et al. 2001). Ron and colleagues reviewed combined studies of 120,000 people, approximately 58,000 exposed to a wide range of radiation doses and 61,000 nonexposed subjects. They found the excess relative risk of developing thyroid cancer was 7.7 per Gy for patients exposed to radiation before the age of 15 (Ron et al. 1995). Another recent prospective analytic cohort study included 12,514 people who resided in three contaminated states of Ukraine during the Chernobyl accident and who underwent up to four thyroidscreening examinations between 1998 and 2007. I-131 thyroid doses were estimated on the basis of individual radioactivity measurements. The excess relative risk per Gy was 1.91 for developing thyroid cancer, indicating that the thyroid cancer risk persisted for two decades following exposure with no evidence of decrease during the observation period (Brenner et al. 2011).
Recent reports have shown that patients with Hashimoto’s thyroiditis have a significantly higher prevalence of thyroid nodules compared with patients without Hashimoto’s thyroiditis. Erdogan et al. showed that 483 of 769 (63%) patients with Hashimoto’s disease have either single or multiple nodules, while another study showed that Hashimoto’s thyroiditis patients had a significantly higher rate of thyroid carcinoma (Erdogan et al. 2009). In the latter study, the prevalence of malignant thyroid nodules was 45.7% among 92 patients with Hashimoto’s thyroiditis, whereas the rate was significantly lower (29%) in patients without Hashimoto’s thyroiditis. In addition, the prevalence of Hashimoto’s thyroiditis was higher in patients with thyroid cancer (21.8%) than in patients without malignant thyroid disease (11.9%) (Gul et al. 2010).
The greatest clinical concern with thyroid nodules is the likelihood of a thyroid carcinoma. A less frequent concern is whether the nodule or nodules are causing symptoms such as dysphagia and/or dyspnea. When warranted, the primary modality of treatment of thyroid nodules is surgical removal with either a hemi- or total thyroidectomy. Suppression therapy with levothyroxine has been used in the past to help differentiate benign from malignant nodules and to treat benign nodules although it is no longer recommended in these situations. Several meta-analyses have been performed in the last 10 years, which have shown a trend between suppressive thyroid hormone therapy of longer than 6-month duration and greater than 50% reduction in the volume of benign thyroid nodules.
However, long-term treatment was shown to be less effective, and regrowth was likely following cessation of therapy (Castro et al. 2002). Bennedbaek et al. showed that levothyroxine therapy does not significantly reduce nodule volume but was subjectively satisfactory in a subgroup of patients, probably due to concomitant reduction of the perinodular thyroid volume (Bennedbaek et al. 1998). Given the risks of treating patients with levothyroxine, particularly patients over 60 years of age and postmenopausal women (Cooper et al. 2009), routine use is not recommended for benign nodules (Sdano et al. 2005).
The majority of thyroid nodules are asymptomatic, and since only 5–15% are malignant, the decision to operate is made on diagnostic or therapeutic principles or on patients’ concerns and demands. In an asymptomatic patient with thyroid nodules, the goal of treatment is first to differentiate benign from malignant nodules and thus prevent unnecessary thyroidectomies. The risk of malignancy is determined by a number of the investigations discussed above, including history, physical examination, ultrasound findings, and most importantly, the results of FNAB. In the majority of patients without risk factors for malignancy, ultrasound and FNAB are primarily used to determine the risk of malignancy and guide treatment decisions. The following approaches to management of thyroid nodules are based on FNAB results and ultrasound findings and are consistent with the 2009 ATA guidelines.
Benign Thyroid Nodule
Patients who receive a benign diagnosis after FNAB may undergo active surveillance or surgery. Active surveillance with physical exam, thyroid function tests, and ultrasound scans at regular intervals is a reasonable option for patients who have FNAB biopsies showing a benign thyroid nodule and no clinical symptoms or clinical or radiographic features suggestive of malignancy. No further treatment beyond careful monitoring and routine checkups is necessary if the thyroid nodule remains unchanged. Most studies suggest no benefit to repeat FNAB unless there is nodule growth. According to the ATA guidelines 2009, significant nodule growth is defined as a 50% change in volume or a 20% increase in at least two nodule dimensions, with a minimal increase of 2 mm in solid nodules or in the solid portion of mixed cystic–solid nodules (Cooper et al. 2009).
Repeat examination intervals typically should be not less than 6 months and are usually between 6 months and 1 year, depending on the clinical concern of a false-negative result. There are no specific guidelines as to when monitoring can cease; this decision will depend on the clinician’s and patient’s concerns for an underlying malignancy, the size of the nodule and its ultrasound features, and whether there has been nodule growth. Similarly, there are no guidelines as to which changes in the benign nodule should initiate intervention. Clinicians are usually guided by nodule growth or change in appearance to determine if further investigations, such as a repeat FNAB or surgery, are warranted. While growth does not necessarily imply malignancy nor stability implies benign disease, diagnostic thyroidectomy is recommended if there is demonstrated growth on repeat examinations and a repeat benign FNAB, particularly if there are suspicious features on ultrasound.
Surgery may be considered in patients with benign nodules based on FNAB. Surgery may be considered for large thyroid nodules despite a benign FNAB because of the risk of a false-negative result. There is no clear consensus as to a nodule size cutoff that requires thyroidectomy. Surgery may also be considered in those patients with a benign FNAB with suspicious ultrasound features, or risk factors for malignancy or in those with nodules causing compressive symptoms. If thyroidectomy is indicated in a patient with a benign nodule, the extent of surgery will depend on several factors, including the number of nodules, age of patient, suspicion for malignancy, and the presence of dysphagia and dyspnea.
The general principle is to be as conservative as possible. Theminimal extent of surgery should be a hemithyroidectomy. There is no role in any patient for subcapsular hemithyroidectomy, nodulectomy, or enucleation of the nodule. In patients with a solitary nodule, a hemithyroidectomy is often sufficient; this will preserve the contralateral lobe and in the majority of patients will not require thyroid hormone replacement. Patients should be made aware of the potential need for completion thyroidectomy if the final pathology comes back as carcinoma. In patients with contralateral nodules, the decision for a total thyroidectomy depends on the patient’s wishes as well as the workup of the contralateral nodules. If the nodules in the opposite lobe are also considered benign based on FNAB and ultrasound findings, then a hemithyroidectomy may still be performed and a total thyroidectomy is not always required.
FNAB should be repeated in patients with an initial nondiagnostic FNAB, particularly if ultrasound guidance was not used. Repeat FNAB should be performed under ultrasound guidance and where available with on-site cytologic evaluation to obtain a biopsy that meets specific criteria for cytologic adequacy of ultrasound- guided FNAB (Cooper et al. 2009). Studies also have shown that repeated FNAB will yield a diagnostic cytology specimen in 75% of solid nodules and 50% of cystic nodules (Cooper et al. 2009). However, up to 7% of nodules continue to yield nondiagnostic cytology results despite repeated biopsies and may be malignant at the time of surgery (Cooper et al. 2009). Partially cystic nodules that repeatedly yield nondiagnostic aspirates need close observation or surgical excision. The downside to early repeat FNAB is reactive nuclear atypia which has been demonstrated to be a significant diagnostic challenge for pathologists (Anderson et al. 2004). Therefore, when clinically possible, the repeat FNAB should be delayed (i.e., >6 months) in order to potentially avoid reactive atypia (Cooper et al. 2009).
Indeterminate Cytology Follicular Neoplasm, Hurthle Cell Neoplasm, or Atypia of Undetermined Significance
Indeterminate cytology is reported as a follicular neoplasm, Hurthle cell neoplasm, or atypia of undetermined significance (AUS). Specifically, follicular or Hurthle cell neoplasms are found in 15–30% of FNAB specimens (Cooper et al. 2009) and carry a 20–30% risk of malignancy, while lesions reported as AUS have a 5–10% risk of malignancy (Cooper et al. 2009). A recent study revealed a risk of malignancy for FNAB-reported AUS (n ¼ 376) or follicular neoplasm (n ¼ 116) of 6% and 22%, respectively (Her-Juing et al. 2011). These authors strongly support repeating FNAB in patients with AUS, as recommended by the ATA guidelines (Cooper et al. 2009). In contrast, Vander Laan conducted a retrospective study of 4,691 patients who had undergone thyroid FNAB (Vander Laan et al. 2011), of whom 512 (10.9%) had a diagnosis of AUS.
Of the 331 cases (64.6%) for which cytologic or histologic outcome data were available, 240 (72.5%) were benign and 91 (27.5%) were malignant. Although AUS confers an intermediate risk of malignancy, the authors concluded that guidelines recommending repeated FNAB for AUS should be reevaluated. At the Princess Margaret Hospital, FNAB will be repeated due to the experience that the risk of malignancy is low in patients with AUS. Furthermore, certain clinical features can improve the diagnostic accuracy for malignancy in patients with indeterminate cytology, including male sex, nodule size (>4 cm), or advancing patient age (Cooper et al. 2009).
The predictive value of indeterminate cytology can also be improved by including genetic and protein analyses. Although not yet widely applied in clinical practice, large prospective studies have shown that typing of genetic and/or proteins markers (such as BRAF, RAS, RET, and galectin-3) improves preoperative diagnostic accuracy for patients with indeterminate thyroid nodules. It is likely that in the future, some combination of molecular markers will be used to optimize management of patients with indeterminate cytology on FNA specimens. Clinicians have also used 18FDG-PET scanning to better distinguish benign indeterminate nodules from those that are malignant. Unfortunately, 18FDG-PET scans have a relatively high sensitivity for malignancy but appear to have low specificity (Cooper et al. 2009).
Nodule Suspicious for Papillary Thyroid Malignancy
For patients presenting with FNAB showing “suspicious for papillary carcinoma,” either lobectomy or total thyroidectomy is recommended depending on the lesion’s size and additional risk factors (Cooper et al. 2009). Patients may be offered a diagnostic lobectomy if the lesion is strictly circumscribed within one lobe and less than 4 cm in size. However, they must be informed of the high probability of requiring a completion thyroidectomy should the final pathology demonstrate a malignancy. On the other hand, patients can be offered a total thyroidectomy, particularly those with a history of thyroid carcinoma or radiation exposure, suspicious nodules in the contralateral gland, or those patients who do not want to undergo a second procedure. Patients undergoing total thyroidectomy must be made aware of the possibility that the nodule may be considered benign on final pathology.
Frozen section may be performed at some centers for patients undergoing diagnostic thyroidectomy for a benign, insufficient, or indeterminate result. Frozen section is not uniformly used among endocrine surgeons as an intraoperative diagnostic tool in thyroid management and is also a controversial topic in the current literature with respect to cost effectiveness and reduction of completion thyroidectomies (Lai et al. 2009). The diagnosis of thyroid malignancy is primarily based on cytologic features and on invasion of the tumor capsule or blood vessels in paraffin-embedded sections. Because making a diagnosis based on frozen sections alone is often unreliable, the accuracy of an intraoperative diagnosis is improved by combining the evidence of papillary or follicular growth pattern in the frozen section specimen with the cytologic features in cytology touch or scrape preparations (Tallini and Gallo 2011).
A recent study showed frozen sections to be very useful in cases that are suspicious for papillary carcinoma on FNAB and in selected cases with an indeterminate cytologic diagnosis (Lumachi et al. 2009). However, it should be borne in mind that even with good cytology smears, the diagnosis of the follicular carcinoma in the absence of invasion remains a difficult intraoperative diagnosis. The most significant disadvantage of frozen sections is the potential to create cytologic artifact and to waste valuable diagnostic material, especially for small (<1 cm) lesions. Loss of nuclear detail or artifactual nuclear clearing in frozen sections may be mistaken for papillary thyroid carcinoma, leading to a false-positive intraoperative diagnosis (Baloch and LiVolsi 2006). However, a clear advantage of frozen sections in thyroid carcinoma is in avoiding a completion thyroidectomy (Tallini and Gallo 2011; Lai et al. 2009).
The Multinodular Goiter
In the past, it was generally agreed that multinodular goiters that lack a dominant nodule or a solitary cyst likely represent benign disease. However, a recently published study showed that malignant tumor was found in 10 (12.6%) of 79 patients with multinodular goiter and nondiagnostic FNAB (Akgul et al. 2011). This study additionally showed that male gender and nodules greater than 4 cm are particularly significant predictors of malignant disease. Patients with a positive history for radiation exposure and family history for thyroid carcinoma also harbor a significant risk for developing thyroid carcinoma. In the setting of the multinodular thyroid, an FNAB should be performed on the dominant nodule or any nodule with suspicious ultrasonographic features.
Management of Thyroid Nodules in Children
The incidence of thyroid nodules in children is very low, accounting for only 1–1.5% of all nodules (Josefson and Zimmerman 2008). However, the risk for developing malignant thyroid disease is fourfold greater in children than in adults (Josefson and Zimmerman 2008; Scholz et al. 2011). The initial workup should include physical examination and thorough history, particularly family history for thyroid carcinoma and MEN. According to the ATA guidelines (Cooper et al. 2009) and confirmed in most clinical centers (Scholz et al. 2011), FNAB biopsy is sensitive and specific in the diagnosis of childhood thyroid nodules and is therefore highly recommended. In a recent retrospective chart review of 175 children less than 18 years old, surgical complications were rare but permanent hypocalcemia and unilateral vocal cord paralyses were observed in 2 (4.7%) of 43 patients who underwent bilateral resection for malignant thyroid nodules. Here too, the authors recommended routine use of FNAB to guide the extent of initial surgical resection (Scholz et al. 2011).
Management of Thyroid Nodules in Pregnant Women
Thyroid nodules discovered during pregnancy are a particular challenge for both patients and physicians. There remains an ongoing debate as to whether pregnancy affects the development of thyroid disease or the clinical outcome after diagnosis of thyroid malignancy (Cooper et al. 2009; Scholz et al. 2011). However, it is widely accepted that pregnancy is favorable for the growth of thyroid nodules, possibly due to the presence of several growth factors (Vannucchi et al. 2010; Stagnaro-Green et al. 2011). The initial workup of pregnant women with thyroid nodules is the same as described and discussed earlier for children and adults. Nodules with either a benign, indeterminant, or insufficient FNAB should be followed with serial ultrasound (Stagnaro-Green et al. 2011).
Thyroidectomy may be considered if FNAB cytology shows papillary thyroid carcinoma. However, there is no consensus regarding the optimal timing of surgery, in particular whether it should be performed during pregnancy or after delivery. To minimize the risk to the fetus and for miscarriage, thyroidectomy if contemplated should be performed in the second trimester before 24 weeks’ gestation (Cooper et al. 2009). In most cases, thyroidectomy may be deferred until after delivery. The ATA guidelines discuss administering levothyroxine to maintain TSH in the range of 0.1–1 mU/L in pregnant women who have a FNAB suspicious for, or confirmed papillary thyroid carcinoma (Cooper et al. 2009). Furthermore, nodules with cytology indicating papillary thyroid carcinoma discovered early in pregnancy should be monitored sonographically and surgery performed at 24 weeks if substantial growth is observed before then.
However, if the nodule remains stable by mid-gestation or if it is diagnosed in the second half of pregnancy, surgery may be performed after delivery. In patients with more advanced disease, surgery in the second trimester is a reasonable option (Stagnaro-Green et al. 2011). In a recent study, 123 women were divided into three groups according to the time of thyroid nodule diagnosis (group 1, at least 1 year after delivery; group 2, during pregnancy or within the first year after delivery; and group 3, nulliparity). The authors showed that thyroid cancer diagnosed in group 2 patients was significantly associated with poorer outcome and persistent disease (Vannucchi et al. 2010). Moreover, expression of the estrogen receptor was significantly increased in group 2 compared with groups 1 and 3, suggesting that the poor outcome in this group may be related to estrogen-stimulated tumor growth (Vannucchi et al. 2010).
In contrast, other studies have shown no difference in the outcome of disease after treatment of pregnant woman and age-matched controls (Stagnaro-Green et al. 2011). These authors concluded that treatment of thyroid cancer occurring during pregnancy can be delayed until after delivery in most patients (Stagnaro-Green et al. 2011). In situations where thyroidectomy is performed during pregnancy, it is recommended that surgery be performed at an institution with a high-risk obstetrical unit.
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