Thyroid nodules are common and usually benign, the risk of malignancy varying from 5 to 10%. Steps to diagnose malignancy should include a careful clinical evaluation, laboratory tests, a thyroid US exam and a fine-needle aspiration (FNA) biopsy. Thyroid FNA biopsy is the most accurate test for determining malignancy, and is an integral part of current thyroid nodule evaluation. Results are superior when FNA is performed with ultrasound-guidance (USFNA). We describe herein techniques for palpation-directed FNA as well as US-directed FNA.
FNA results are classified as diagnostic (satisfactory) or nondiagnostic (unsatisfactory). Unsatisfactory smears (5-10%) result from hypocellular specimens usually caused by cystic fluid, bloody smears, or suboptimal preparation. Diagnostic smears are conventionally subclassified into benign, indeterminate, or malignant categories. Benign cytology (60-70%) is negative for malignancy, and includes cysts, colloid nodule, or Hashimoto thyroiditis. Malignant cytology (5%) is almost always positive for malignancy, and includes primary thyroid tumors or nonthyroid metastatic cancers. Papillary thyroid carcinoma (PTC) is the most common malignancy, characterized by increased cellularity, sheets of cells, and typical nuclear abnormalities.
Indeterminate or suspicious specimens (10-20%) include atypical changes, Hurthle cells or follicular neoplasms, typically with absent or scanty colloid, hypercellularity sometimes with microfollicular arrangement. The new Bethesda Cytologic Classification has a 6-category classification, subdividing indeterminate further by risk factors. Overall, the indeterminate category has anywhere from 15% to 60% risk of malignancy, depending on the specifics of the report. Recent development of molecular markers are hoped to help further separate benign from malignant nodules with an indeterminate cytology. These tests are new and evolving, and no definite recommendations for use can be offered currently.
This chapter also includes recommendations to minimize false-negative FNA results; indications for rebiopsy; use of TSH, TPOAb, & calcitonin; and the application of radioiodine in diagnosis and treatment of goiters.
Fine-needle aspiration (FNA) biopsy of the thyroid gland is an accurate diagnostic test used routinely in the initial evaluation of nodular thyroid disease (1-6). Epidemiologic studies suggest that nodular thyroid disease is a common clinical problem, with a prevalence of 4% to 7% in the adult population in North America and an annual incidence of 0.1%, which translates into approximately 300,000 new nodules in the United States (1). A survey of clinical members of the American Thyroid Association revealed that most endocrinologists (96%) perform FNA biopsy for diagnosis of thyroid nodules (7). In addition, FNA with ultrasonographic guidance (US-FNA) is used routinely in follow-up surveillance of patients with thyroid cancer. Therefore, we estimate that more than 600,000 thyroid FNA biopsies will be performed this year in the United States alone. Worldwide, the number of thyroid aspirations is most likely in the millions. Thus, the importance of FNA biopsy in thyroid practice cannot be overemphasized.
This chapter describes biopsy techniques, cytologic diagnosis, complications, FNA results, diagnostic pitfalls, and other information that may be useful to clinicians who manage patients with nodular thyroid disease.
Diagnosis of thyroid nodules by needle biopsy was first described by Martin and Ellis (8) in 1930, who used an 18-gauge–needle aspiration technique. Subsequently, cutting needle biopsy with Silverman or Tru-Cut needles was used for tissue examination. None of these techniques gained wide acceptance because of fear of malignant implants in the needle track, false-negative results, and serious complications. However, Scandinavian investigators introduced smallneedle aspiration biopsy of the thyroid in the 1960s, and this technique came into widespread use in North America in the 1980s (9).
For FNA biopsy, most use fine or thin (22- to 27-gauge) needles; most commonly used is a 27-gauge needle. As the name indicates, the biopsy technique uses aspiration to obtain cells or fluid from a mass. In contrast to percutaneous largeneedle biopsy, which obtains tissue specimens and requires histologic fixation, aspiration biopsy offers cytologic examination of the specimen. Another technique, fineneedle nonaspiration (FNNA) biopsy, avoids aspiration but still permits cytologic review of thyroid masses.
Although the FNA technique appears simple, considerable time and experience are required to acquire and maintain skillful biopsy technique. Debate continues about who is best qualified to perform FNA biopsy, but it is clear that the best results are obtained if the person performing the biopsy has mastered the technique. In the opinion of the authors, endocrinologists are best qualified to perform FNA biopsy because they are most experienced in thyroid palpation, they acquire and maintain expertise in performing biopsies, and they provide definitive and continued care to patients with nodular thyroid disease. Additionally, endocrinologists are now trained to use US-FNA, and therefore can offer an advantage in performing FNA.
The basic equipment needed to perform FNA biopsy is simple and relatively inexpensive (2,6,10). The following items are essential (Table 1):
1. A syringe holder or syringe pistol—most commonly used is the Cameco syringe pistol (Belpro Medical) shown in Figure 1. The pencil-grip syringe holder is another syringe-holding device (Tao and Tao Technology, Incorporated). 2. Disposable 10-mL plastic syringes 3. Disposable 25- or 27-gauge needles, 1.5 inches long 4. Glass slides, with 1 end frosted on 1 side, 1-mm thin (Gold Seal, Erie Scientific Company) 5. Alcohol prep sponges 6. Alcohol bottles for immediate wet fixation of smears 7. Gloves—current regulations of the Occupational Safety and Health Administration require that the person performing a biopsy wear protective gloves 8. Containers for cystic fluid collection and transportation to the cytology laboratory 9. Laboratory slips with the patient’s name, clinic number, biopsy sites, and other relevant information to be transferred to the cytology laboratory 10. Lidocaine—1% lidocaine should be available for those who prefer biopsy with local anesthesia
The thyroid gland should be palpated carefully and the nodule(s) to be biopsied identified. The procedure should be explained carefully to the patient, and all the patient’s questions should be answered completely. We inform our patients that local anesthetic is not used, that the biopsy will take several minutes, that 3 to 6 aspirations are made, and that we expect no serious complications, but there will be slight pain similar to a venipuncture (blood draw for laboratory tests).
The biopsy can be performed with the patient on a hospital bed or in the office on an examining table. In either place, a nurse or clinical assistant should always be available to assist with the procedure. The patient may be seated or supine; we prefer the supine position. The patient is placed supine with the neck hyperextended to expose the thyroid; for support, a pillow is placed under the shoulders (Fig. 2 A). The patient is asked not to swallow, talk, or move during the procedure. It is best to talk to the patient and keep him or her informed of the progress of the biopsy. After the biopsy has been completed, firm pressure is maintained on the biopsy site(s). It is best to observe patients for a few minutes as occasionally, patients have dizziness or pain. If no problems are noted, they are allowed to leave.
Numerous reports, reviews, and even textbooks provide detailed descriptions of various FNA biopsy techniques (10-16). Although most reports agree on the principles of the technique, variations have been described to improve results. It is important to position the patient correctly, identify and locate the mass, provide adequate light during the biopsy, and have a clinical assistant available for help. The physician performing the biopsy should be positioned at the patient’s side, preferably contralateral to the lesion. The nodule(s) to be aspirated is identified, and the overlying skin is cleansed with alcohol. The use of povidone-iodine (Betadine or sterile technique is not necessary. A 10mL plastic syringe is attached to a Cameco syringe holder and held in the right hand by a righthanded operator (Fig. 2 B). Two fingers of the free (left) hand firmly grasp the nodule while the other hand holds a pistol-grip syringe holder (Fig. 2 C). The needle is then rapidly inserted through the skin and into the nodule. Once the needle tip is in the nodule, gentle suction is applied while the needle is moved in and out within the nodule vertically (Fig. 2 D). This maneuver allows the dislodging of cellular material and easy suction into the needle. During this period of 5 to 10 seconds, suction is maintained, and as soon as fluid or aspirate appears in the hub of the needle, the suction is released and the needle is withdrawn. The appearance of fluid suggests that the nodule is cystic; suction is maintained and all the fluid aspirated. It is important to release the syringe plunger and remove the vacuum before withdrawing the needle; this allows the aspirate to remain in the needle and not be sucked into the syringe. Next, the needle is detached from the syringe (Fig. 3 A), and 5 mL of air is drawn into the syringe (Fig. 3 B). The needle is reattached to the syringe, and with the bevel facing down, 1 drop of aspirated material is forced onto each of several glass slides (Fig. 3 C). It is important that all slides be labeled and placed in order on a nearby table before the aspiration. Smears are prepared by using a second glass slide in a manner similar to that of making blood smears (Fig. 3 D). The slides for wet fixation should be placed immediately in 95% alcohol for staining with the Papanicolaou stain. For Giemsa staining, air-dried smears are necessary, and prepared slides are left unfixed and transported to the laboratory.
Usually, 3 to 6 aspirations are made (11,13,14), and some authors suggest at least 6 (17). Frequently, 8 to 10 slides are made for each nodule. Preferably, the aspirates should be obtained from the peripheral areas and different parts of the nodule in a sequential manner to ensure representative sampling (11,13). For larger nodules, the deep center of the mass should be avoided because it is more likely to contain degeneration and fluid, decreasing the chance of a diagnostic specimen. For cystic lesions, the fluid should be completely aspirated and FNA attempted on residual tissue. Aspirated fluid should be placed in a plastic cup and saved for cytologic evaluation. We use a new needle and syringe for each biopsy.
The FNNA technique has been described by several authors (6,13,18). This technique is thought to minimize trauma to thyroid tissue and to reduce blood contamination. For this technique, patient preparation is similar to that for FNA. However, no syringe or suction is necessary. The hub of a 27-gauge needle is held in a pencil-grip fashion, and the needle is gently inserted into the nodule and then moved in and out for 5 to 10 seconds (Fig. 4). Aspirate flows into the needle through capillary action, and as soon as aspirate appears in the hub, the needle is withdrawn and attached to a syringe with air inside. Next, the plunger is used to expel the material onto glass slides. The procedure is repeated several times, and the slides are prepared as described above for FNA.
After the biopsy has been completed, firm pressure is applied to the biopsy site(s) with a 4×4-inch gauze pad. Once bleeding has stopped, an adhesive bandage is placed on the puncture site(s), and the patient is observed for a few minutes. If there are no problems, the patient is allowed to leave (Fig. 5).
Thyroid FNA biopsy, particularly under US-FNA, is very safe. No serious complications such as tumor seeding, nerve damage, tissue trauma, or vascular injury have been reported (10-16). Needle puncture causes slight pain and some skin discoloration at the aspiration site(s). However, even a minor hematoma is uncommon. Patient use of anticoagulants or salicylates does not preclude FNA biopsy. Needle track implantation of thyroid carcinoma is extremely rare; it has been poorly documented and is not considered a real problem by most experts (19). Post-aspiration hemorrhage within a cystic lesion can occur, and the author has seen 1 patient who, within several hours after FNA biopsy, developed severe pain from bleeding into the nodule that warranted surgical excision. The specimen contained fresh blood consistent with hemorrhage caused by biopsy. However, this is the only example we have had among more than 40,000 biopsies performed at our institution during the past 4 decades.
Aspirates from normal glands often have scant thyroid follicular cells and colloid. Wetfixed smears are usually prepared with a modified Papanicolaou stain, which shows nuclear detail. Air-dried smears are often prepared with a Romanovsky stain. MayGrünwald-Giemsa is a modified Romanovsky staining procedure that is sometimes used in thyroid cytologic preparations. The conventional cytologic diagnosis includes 4 categories: benign (negative), suspicious (indeterminate), malignant (positive), or unsatisfactory (nondiagnostic). The new Bethesda Classification has 6 categories, further expanding the indeterminate cytologies (Table 9).
Aspirates obtained from multinodular goiters, benign microfollicular adenoma, or normal thyroid are referred to as colloid nodules and show loosely cohesive sheaths of follicular epithelium, colloid, blood, and rare macrophages. Colloid nodules are the most common cytology and contain an abundance of colloid with sparse follicular cells. There is considerable variation in the number of cells as well as the type and amount of colloid present (Fig. 6).
Another benign diagnosis is Hashimoto thyroiditis. It has a fairly characteristic pattern on FNA smears, showing hypercellularity with lymphocytes, Hürthle cells, and minimal or no colloid (Fig. 7).
Subacute (granulomatous) thyroiditis is a rare condition with a benign aspirate. Typically, the smear shows multinucleated giant cells, epithelioid histiocytes, and scattered inflammatory cells (Fig. 8).
Papillary carcinoma, the most common thyroid malignancy, is readily diagnosed by FNA. Typically, cytology shows a papillary configuration, large irregular nuclei, and nuclear grooves. Psammoma bodies may or may not be present, but if present, they are highly suggestive of papillary thyroid carcinoma (Fig. 9).
Medullary thyroid carcinoma accounts for 5% to 10% of thyroid cancers and may present as a thyroid nodule or neck mass. Typically, aspirates from a medullary thyroid carcinoma are hypercellular, composed of large, poorly cohesive cells, and predominantly spindle shaped. Amyloid is often, but not invariably, present, and there is no colloid (Fig. 10).
High-grade carcinoma can be diagnosed cytologically, but distinguishing between primary and metastatic cancer is not easy.
The accumulated experience of the past 4 decades has confirmed the reliability and usefulness of FNA as a diagnostic test (1,2,6,10-15,17,20-25). The role of FNA biopsy in the evaluation of thyroid nodules is now firmly established, and FNA has become the initial test because it is both safe and cost effective. In most clinics, FNA has become a standard test, performed most often by an endocrinologist.
An adequate specimen of good technical quality is considered diagnostic or satisfactory and may be benign, suspicious, or malignant. A benign (negative) cytologic diagnosis is reported for 50% to 90% of the specimens (average, 70%) (11,15,23,26,27). Ten percent to 30% of FNA cytologic specimens may be suspicious for malignancy (indeterminate) (average, 20%) (26,27). A malignant (positive) cytologic diagnosis varies from 1% to 10% (average, 5%). For example, Caruso and Mazzaferri (26) reported the following results from 9 series that included more than 9,000 patients: benign, 74%; malignant, 4%; inadequate, 11%; and suspicious, 11%. We reviewed more than 18,000 specimens from 7 large series and obtained similar cytologic results: benign, 69%; malignant, 4%; suspicious, 10%; and nondiagnostic, 17% (27).
False-negative results mean missed malignancy. False-negative rates generally vary from 1.5% to 11.5% (average, <5%) (17,20,26,28). The false-negative rate is defined as the percentage of patients with benign cytology in whom malignant lesions are later confirmed on thyroidectomy. The frequency of false-negative cytologic diagnosis depends on the number of patients who subsequently have surgery and histologic review. In most retrospective series, less than 10% of patients with a benign cytologic diagnosis subsequently have thyroid surgery, suggesting that false-negative rates should be interpreted with some skepticism (26,27). Despite this note of caution, most authorities agree that the true false-negative rate is less than 5% if all patients have thyroid surgery. False-negative rates are lower in centers experienced with the procedure and with cytologic interpretation by expert cytopathologists.
False-positive rates vary from 0% to 8% (average, 3%) (20,26,27). A falsepositive diagnosis indicates that a patient with a malignant FNA result was found on histologic examination to have benign lesions.
CAUSES OF FALSE DIAGNOSES
Interpretive or sampling errors account for false diagnoses (13,14,27,28). Hashimoto thyroiditis is probably the most common cause of falsepositive cytology. Misclassification of follicular and Hürthle cell adenomas as papillary carcinomas accounts for other errors. FNA biopsy of thyroid lymphomas may produce lymphocytes that can be interpreted as Hashimoto thyroiditis, accounting for a falsenegative diagnosis. Inadequate or improper sampling accounts for some false-negative errors. For example, nodules smaller than 1 cm may be too small for accurate needle placement, and nodules larger than 4 cm are too large to allow proper sampling from all areas, thereby increasing the likelihood of misdiagnosis. Finally, the cytopathologist should establish and observe criteria to exclude a diagnosis of malignancy (2,6,10,25).
THE PROBLEM OF CELLULAR TUMORS
Hypercellular specimens from follicular or Hürthle cell lesions may have features suggestive of, but not diagnostic for, malignancy (1,4,10,14,23). Thus, the cytopathologist labels these suspicious for malignancy because cytologic features neither confirm nor rule out malignancy. Histologic examination is necessary for definitive diagnosis (Fig. 11). Hypercellularity may be seen with nonneoplastic lesions, and Hürthle cell changes may be seen in patients with lymphocytic thyroiditis. The diagnosis of follicular neoplasm is indicative of an underlying malignancy in 14% of cases and Hürthle cell neoplasm in 15% (21,27). Many pathologists maintain that benign and malignant follicular or Hürthle cell tumors cannot be distinguished on the basis of aspirated cells only, and the lesion must be removed for histopathologic examination (2,13,14,29). However, Kini (30) believes that follicular adenomas and follicular carcinomas usually can be differentiated on the basis of nuclear size, but Hürthle cell lesions are difficult to diagnose cytologically.
INSERT FIGURE 11
Figure 11. Follicular neoplasm. A, Cytology shows hypercellularity, dispersed microfollicular pattern, and absent colloid. B, Thyroidectomy shows benign follicular adenoma.
Several authors have discussed the problem of follicular neoplasm. In a study of 149 patients with the cytologic diagnosis of follicular neoplasm, Tuttle et al (31) reported that risk of malignancy was higher in men, solitary nodules, and nodules larger than 4 cm. In a study of 219 patients with follicular neoplasm, Schlinkert et al (32) showed that nodules are more likely malignant in younger patients, in men, if the nodule is solitary, and if it is larger than 4 cm. More recently, Baloch et al (33) studied 184 cases of follicular neoplasm and reported that risk factors for malignancy included male sex, older age (>40 years), and larger nodules (>3 cm). Overall, they found that 70% of these lesions are benign.
Recent studies suggest that immunohistochemical and genetic markers may be helpful in separating benign from malignant follicular lesions (1, 4,34,35). Although results have been mostly discordant and variable, 2 of those markers, HBME-1 (human bone marrow endothelial cell) and galectin-3 have shown promise in predicting malignancy (34, 35). HBME-1 is a monoclonal antibody against the microvillous surface of mesothelial cells; galectin-3 is a protein involved in cell-matrix interactions. Both have been reported to have adequate sensitivity and specificity in predicting malignancy. However, results have not been consistent (5), and “no markers have high sensitivity and specificity for correctly diagnosing thyroid cancer.” Other molecular markers, such as gene expression classifier or mutation panel tests, are now available for clinical use. Despite advances in molecular testing, these new techniques have limitations and cannot be recommended for routine use at present. We await additional trials and data to determine if new tests are helpful in separating benign from malignant or suspicious cytology (1).
Inadequate specimens are labeled nondiagnostic or unsatisfactory and account for 2% to 20% of specimens (average, 10%) (2,6,26,27). Several factors influence nondiagnostic rates for FNA results, including the skill of the operator, vascularity of the nodule, criteria used to judge adequacy of the specimen, and the cystic component of the nodule (3639). Overall, a satisfactory smear contains at least 6 clusters of wellpreserved cells, with each group consisting of at least 10 to 15 cells. Reaspiration with US-FNA yields satisfactory specimens in more than 50% of cases with nondiagnostic initial FNA (17,29). A solid, hypoechoic nodule, repeatedly nondiagnostic by FNA, should undergo surgical excision. A primarily cystic lesion with repeatedly nondiagnostic FNA should be monitored by ultrasonography (US).
Chow et al (40) found a 7% malignancy rate in 153 patients with initial nondiagnostic smears. Among 27 patients treated surgically, 37% had cancer. Reaspiration with US-FNA was diagnostic in 66% and 56% without US; overall, 62% of reaspirations were diagnostic.
Analysis of the data reveals that the sensitivity of FNA ranges from 65% to 98% (mean, 83%), and specificity ranges from 72% to 100% (mean, 92%) (11,20,26). The predictive value of a positive or suspicious cytologic result is approximately 50%. The overall accuracy for cytologic diagnosis approaches 95% (Table 2).
Table 2. Summary Data From Literature Survey on Thyroid FNA*
|Likelihood that patient who has disease has positive test results|
|Likelihood that patient without disease has negative test results|
Positive predictive value, %
|Fraction of patients who have positive test who have disease|
False-negative rate, %
|FNA negative; histology positive for cancer|
FNA, fine-needle aspiration.
*From Gharib et al (2). Used with permission.
Guidelines have been published to help improve the adequacy and accuracy of cytology specimens (2). FNA biopsy should be performed by individuals who have had training in both thyroid examination and thyroid biopsy. Thyroid FNA in the hands of experienced operators achieves high diagnostic accuracy. Aspirates should be obtained from different portions of the nodule, preferably peripheral areas, in an organized and sequential manner. It is essential to ensure that an adequate number of follicular cells are present. A cytopathologist, preferably one with experience in thyroid cytology, should review and interpret the slides. If reaspiration yields insufficient material, US-FNA biopsy is the next test. In the event that the final result is still insufficient, surgical excision is warranted for most nodules.
Several reports have offered suggestions to minimize false-negative rates (1,2,6,17). In a review of thyroid FNA, Belfiore and La Rosa (10) suggest the following steps to reduce false-negative results (Table 3).
1. Acquire and maintain adequate biopsy expertise 2. Avoid making a diagnosis with a suboptimal sample 3. Be cautious with cystic degeneration, Hürthle cells, or lymphocytes 4. Repeat FNA at least once during follow-up 5. Repeat FNA or recommend surgery when nodule is suspicious by clinical or US examination
To minimize falsenegative results, we follow the steps summarized in Table 4.
Table 4. Steps to Improve Accuracy of FNA and Lead to Better Nodule Management*
|Endocrinologist performs biopsy||Offers better thyroid examination; accumulates experience with FNA|
|Experienced cytopathologist reviews slides||Improves cytologic interpretation|
|Careful with small (<1 cm) or large (>4 cm) nodules||Increased chance of misdiagnosis; US FNA improves accuracy|
|3-6 aspirates from different nodule sites||Improves cytologic sampling|
|Rebiopsy if cytology is nondiagnostic||One-half will be diagnostic on reaspiration|
|Nondiagnostic cytology is not negative||Risk of cancer is low but not ruled out|
|Aspirates with no follicular cells are nondiagnostic||These should not be considered negative for malignancy|
|Excise nodules yielding suspicious cytology||20% chance of malignancy|
|Excise clinically suspicious, cytologically benign nodules||Clinical impression overrides FNA diagnosis|
FNA, fine-needle aspiration; US-FNA, FNA with ultrasonographic guidance.
*Modified from Gharib (6). By permission of Mayo Foundation for Medical Education and Research.
Published thyroid guidelines and reviews state that thyroid US should not be used as a screening test in the general population (1,2). However, US is recommended for all patients with a single palpable nodule or a multinodular goiter or in a patient suspected of having a nodule (1) (Table 5). Current US machines are safe, easy to use, relatively inexpensive, have high resolution, and are widely available. It is important to note that US results are quite operator dependent.
Table 5. Indications for Thyroid Ultrasound Examination*
Palpable solitary nodule
|Palpable multinodular goiter|
|Suspicion of nodule in patient with difficult neck palpation|
|Prior history of neck radiation|
|Family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, or papillary thyroid carcinoma|
|Unexplained cervical adenopathy|
|Preoperative thyroidectomy for cancer; long-term postoperative surveillance|
|*Data from Gharib et al (2).|
An ever-increasing number of practicing endocrinologists are training to use US in routine practice. US is now used to supplement physical examination when neck palpation is difficult, a thyroid mass is present, a nodule needs careful measurement, or an impalpable thyroid lesion is suspected. As a result of this widespread use, many small (<1.5 cm) thyroid incidentalomas are noted, creating what has been referred to as a “thyroid epidemic” (1,41,42). Such a finding has been an unintended consequence of thyroid US use and has created a management dilemma for the clinician.
Sonographic characteristics of thyroid nodules include the following:
1 Echogenicity: hypo- or hyperechoic 2 Calcifications: micro- or eggshell 3 Margins: well-defined or irregular 4 Vascularity: high or low 5 Shape: tall or wide
The overall predictive value of US for malignancy is summarized in Table 7. Although no single US feature is diagnostic for malignancy, the specificity is highest for microcalcifications and lowest for echogenicity. The presence of at least 2 suspicious US criteria reliably identifies 85% to 93% of thyroid malignancies (1).
Table 7. Value of US Features Predicting Thyroid Malignancy*
Positive Predictive Value, %
Negative Predictive Value, %
Irregular margins or no halo
More tall than wide
*From Frates et al (43). Used with permission.
Recent reports and reviews confirm that sensitivity, positive predictive value, and negative predictive value increase significantly with US-FNA (1,44-47). US can be used to assist or guide FNA, the latter being more accurate. US-FNA permits precise needle placement in a nodule, thereby increasing both the rate of satisfactory aspirates and the diagnostic accuracy (1,2,44,47). Although US-FNA is useful for small (<1.5-1.0 cm) thyroid nodules, many endocrinologists currently use US-FNA for larger, easily palpable lesions.
It is now established that neither nodule size nor number can preclude or predict malignancy (1,43). Patients with multiple nodules have the same risk of thyroid cancer as those with a solitary nodule. Moreover, approximately 50% of patients with a single nodule on palpation have additional thyroid nodules on thyroid US examination (41). US-FNA helps select the nodule or nodules that need biopsy. Recent American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi guidelines (2) suggest selection of nodules for FNA on the basis of US features, whereas the Society of Radiologists in Ultrasound recommends FNA for nodules larger than 1.0 to 1.5 cm in diameter (43). This issue remains controversial.
Percutaneous ethanol injection (PEI) during US guidance was first used for recurrent or persistent hyperparathyroidism, especially in surgically high-risk patients. More recently, alcohol therapy has been applied to thyroid nodules (1,2,48-52). Lippi and colleagues (50) reported results of a large multicenter Italian study that included 429 patients: 56% had toxic nodules and 44% had hyperfunctioning but nontoxic nodules. Under US guidance, ethanol was injected into the nodules and 12 months after treatment, 74% of the patients were biochemically euthyroid. Papini and coworkers (49) reviewed the role of PEI in the treatment of benign thyroid nodules. They found indications for treatment of patients with toxic hot nodules, nontoxic hot nodules, toxic multinodular goiters, and thyroid cysts. In patients with solitary nodules, nodules with a volume less than 10 mL were more likely to respond to treatment with complete remission than were nodules with a large volume. PEI is performed on outpatients. The procedure is short, never exceeding 10 minutes, and requires no local or general anesthesia. US-guided PEI is safe and effective in centers with experience. Valcavi and Frasoldati (53) used PEI to treat benign thyroid cysts. Complications included transient dysphonia and pain; no permanent injuries were recorded. Two-thirds of the patients required only 1 injection to reduce nodule size. Of note, there is often an acute, marked increase in the serum level of thyroglobulin but only a slight increase in the serum level of thyroid hormones. There is no evidence that injected ethanol enters the circulation, because serum levels of ethanol do not increase after PEI.
Zingrillo and colleagues (54) treated large (>10 mL) cold benign thyroid nodules in 41 patients with PEI. Follow-up ranged from 12 to 36 months. Symptoms were markedly reduced. The authors concluded that PEI is a safe and effective treatment of symptomatic, large, cold, benign nodules and should be considered an alternative treatment for high-risk surgical patients or when patients refuse surgical treatment.
In a prospective randomized trial, Bennedbaek and colleagues (55) compared the effect of a single PEI treatment with suppressive doses of thyroxine in euthyroid patients with a single solid colloid thyroid nodule. The thyroid nodules were small (estimated volume, <10 mL). After 12 months, the median nodule reduction in the PEI group was greater than in the thyroxine group, indicating that a single PEI treatment is more effective than thyroxine therapy.
The experience as well as the expertise of the cytopathologist is critical in avoiding pitfalls. Determining the adequacy of an aspirate, cellular atypia, application and interpretation of immunostains, and differentiation of lymphocytic thyroiditis from lymphoma are but a few of these problems. Larger nodules are more likely to yield falsenegative results. To improve sampling, aspirates should be obtained from multiple sites of the nodule rather than repeatedly from a single spot. The absence of malignant cells in an otherwise acellular specimen does not exclude malignancy. It is good practice to biopsy all accessible nodules in a multinodular gland. In patients with multiple nodules, US-FNA is the method of choice for selecting nodules for FNA when US features are suspicious (1,2).
Opinions on indications for reaspiration are divided, some favoring (10,56), others not favoring (2,6,57), routine rebiopsy. Lucas et al (57) reported no advantage in routine rebiopsy, whereas Chehade et al (56) found that repeated biopsy may decrease the rate of false-negative FNA from an average of 5.2% to less than 1.3%. Recent thyroid nodule guidelines from the American Association of Clinical Endocrinologists and the Associazione Medici Endocrinologi (2) did not suggest routine rebiopsy of FNA-benign nodules.
Indications for rebiopsy are listed in Table 8 and include an enlarging FNA-benign nodule or a nodule that does not shrink on thyroxine -suppressive therapy. Additional indications are recurrent cysts or an initial FNA that is not diagnostic. In the opinion of this author, in clinics or centers with FNA experience, routine rebiopsy is not necessary. However, for those who begin FNA biopsy in their practice, rebiopsy in 12 to 18 months may provide reassurance to the physician as well as the patient that cancer was not missed and false-negative rates remain low.
Table 8. When to Repeat FNA
|Enlarging FNA-benign nodule|
|Initial FNA nondiagnostic|
|Large (>4 cm) nodule|
|Follow-up of FNA-benign nodule|
|FNA, fine-needle aspiration|
The new Bethesda System for Thyroid Cytopathology offers a 6-category classification that further subdivides the indeterminate category in 3 classes: atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS); follicular neoplasm; and suspicious for malignancy (58). AUS and FLUS have low risk for malignancy, and currently are subjected to molecular testing before surgery. Details of this new cytologic classification and implications for decision making and clinical management in each group are summarized in Tables 9 & 10.
Table 9. The Bethesda System for Reporting Thyroid Cytopathology: Recommended Diagnostic Categories
|I.||Nondiagnostic or unsatisfactory|
- Cyst fluid only
- Virtually acellular specimen
- Other (obscuring blood, clotting artifact, etc.)
- Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule, etc)
- Consistent with lymphocytic thyroiditis (Hashimoto) in the proper clinical context
- Consistent with granulomatous thyroiditis (subacute)
III.Atypia of undetermined significance or follicular lesion of undetermined significanceIV.Follicular neoplasm or suspicious for a follicular neoplasm
- Specify if Hürthle cell type (oncocytic)
V.Suspicious for malignancy
- Suspicious for papillary carcinoma
- Suspicious for medullary carcinoma
- Suspicious for metastatic carcinoma
- Suspicious for lymphoma
- Papillary thyroid carcinoma
- Poorly differentiated carcinoma
- Medullary thyroid carcinoma
- Undifferentiated carcinoma (anaplastic)
- Squamous cell carcinoma
- Carcinoma with mixed features (specify)
- Metastatic carcinoma
- Non-Hodgkin lymphoma
*Adapted with permission from Cibas and Ali (58).
Table 10. The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management
Risk of Malignancy (%)
|Nondiagnostic or unsatisfactory||
|Repeat FNA with ultrasound guidance|
|Atypia of undetermined significance or follicular lesion of undetermined significance||
|Follicular neoplasm or suspicious for a follicular neoplasm||
|Near total thyroidectomy|
FNA-fine needle aspiration
*Adapted with permission from Cibas and Ali (58).
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