Chapter 6d. Fine-Needle Aspiration Biopsy of the Thyroid Gland

Chapter 6d. Fine-Needle Aspiration Biopsy of the ThyroidGland

INTRODUCTIONFine-needle aspiration (FNA) biopsy of the thyroid gland is now an established, accu-rate diagnostic test that is routinely used as the first step in the evaluation of nodularthyroid disease (1-4). Epidemiologic studies suggest that nodular thyroid disease isa common clinical problem, with a prevalence of 4% to 7% in the adult population inNorth America and an annual incidence of 0.1%, which translates into approximately300,000 new nodules in the United States (5). A recent survey of clinical members ofthe American Thyroid Association revealed that most (96%) of them would performFNA biopsy for diagnosis of thyroid nodules (6). Therefore, we would estimate thatsomewhere between 250,000 and 300,000 thyroid FNA biopsies will be performedannually in the United States alone. Worldwide, the number of thyroid aspirationswould most likely be in the millions. Thus, the importance of FNA biopsy in thyroidpractice cannot be overemphasized.

This chapter reviews biopsy techniques, cytologic diagnosis, complications, FNA re-sults, diagnostic pitfalls, and other information that may be useful to clinicians whomanage patients with nodular thyroid disease.

DefinitionsIn modern times, diagnosis of thyroid nodules by needle biopsy was first describedby Martin and Ellis (7) in 1930, who used an 18-gauge needle aspiration technique.Subsequently, cutting needle biopsy using Silverman or Tru-Cut needles were usedfor tissue examination. None of these techniques gained wide acceptance becauseof fear of malignant implants in the needle track, false-negative results, and seriouscomplications. However, Scandinavian investigators introduced small-needle aspira-tion biopsy of the thyroid in the 1960s; this became well-accepted but came into wideuse in North America only in the 1980s (8,9).

For FNA biopsy, most use "fine" or "thin" needles ranging from 22 to 27 gauge (com-monly, 25 gauge). As the name indicates, the biopsy technique uses aspiration toobtain cells or fluid from a thyroid mass. In contrast to percutaneous large-needlebiopsy, which obtains tissue specimens and requires histologic fixation, aspirationbiopsy offers cytologic examination of the specimen. Another technique, fine-needlenonaspiration (FNNA) biopsy, avoids aspiration but still permits cytologic review ofthyroid masses.

Although the FNA technique appears simple, considerable time and experience arerequired to acquire and maintain a skillful biopsy technique. Debate continues aboutwho is best qualified to perform FNA biopsy, but it is clear that the best results areobtained if the person performing the biopsy has mastered the technique. In the opin-ion of the author, endocrinologists are best qualified to perform FNA biopsy becausethey are most experienced in thyroid palpation, they acquire and maintain expertisein performing biopsies, and they provide definitive and continued care to patientswith nodular thyroid disease.

EQUIPMENTThe basic equipment needed to perform FNA biopsy is simple and relatively inex-pensive (5,6,8). The following items are essential (Fig. 1):

• A syringe holder or syringe pistol—most commonly used is the Cameco syringepistol (Precision Dynamics Corporation, Burbank, CA) shown in Figure 1. The

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Chapter 6d. Fine-Needle Aspiration Biopsy of the Thyroid Gland

pencil-grip syringe holder is another newly developed syringe holding device (de-veloped by Tao and Tao Technology, Incorporated, Carmel, IN).

• Disposable 10-mL plastic syringes

• Disposable 25- or 27-gauge needles 1 1/2 inches long

• Glass slides, one end frosted on one side, 1.0 mm thin (Gold Seal, Beckton, Dickin-son and Company, Highland Park, IL)

• Alcohol prep sponges

• Alcohol bottles for immediate wet fixation of smears

• Gloves—current regulations of the Occupational Safety and Health Administrationrequire that the person performing a biopsy wear protective gloves

• Containers for cystic fluid collection and transportation to the cytology laboratory

• Laboratory slips with patient’s name, clinic number, biopsy sites, and other rele-vant information to be transferred to the cytology laboratory

• Lidocaine—1% lidocaine local anesthetic should be available for those who preferbiopsy with local anesthesia

Figure 1. FNA biopsy equipment is simple and inexpensive. It includes an alcoholwipe, 4× 4 gauze pads, 10-mL plastic syringes, 25-gauge 1 1/2-inch stiff noncutting,bevel-edged needles, glass slides, alcohol bottles, and a pistol-grip mechanical sy-ringe holder.

THE PATIENTThe thyroid gland should be palpated carefully and the nodule(s) to be biopsied iden-tified. The procedure should be explained carefully to the patient, and all the patient’squestions should be answered completely. We inform our patients that local anes-thetic is not used, that the biopsy will take several minutes, that 2 to 4 aspirations are

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made, and that we expect no significant complications, but there will be slight painwith minor hematoma or swelling at the biopsy site(s).

The biopsy can be performed with the patient on a hospital bed or in the office onan examining table. In either place, a nurse or clinical assistant should always beavailable to assist with the procedure. The patient may be seated or supine; we preferthe supine position. The patient is placed supine with the neck hyperextended toexpose 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 totalk to the patient and keep him/her informed of the progress of the biopsy. Afterthe biopsy has been completed, firm pressure is maintained on the biopsy site(s).The patient is then asked to sit for a few minutes. Occasionally, patients complain ofdizziness or pain. It is best to observe patients for a few minutes, and if no problemsare noted, they are allowed to leave. We prefer that a nurse or clinical assistant bepresent for help during the procedure.

Figure 2. A, Position of patient during FNA. Note: supine position and pillow un-der patient’s shoulder to allow hyperextension of the neck and maximal exposure.B, Syringe is placed in syringe-holder. C, Nodule is identified and stabilized withoperator’s "nonaspirating" hand. The operator stands on the side of the patient op-posite to that of the thyroid nodule. Current OSHA regulations require the use ofgloves because of concern about blood-borne diseases. D, With a quick motion,the needle passes through the skin and enters the nodule. Immediate mild suctionfollows. As soon as aspirate appears, suction is released and the needle is with-drawn.

FNA BIOPSYNumerous reports, reviews, and even textbooks provide detailed descriptions of var-ious FNA biopsy techniques (10-15). Although most reports agree on the principlesof the technique, variations have been described to improve results. It is importantto position the patient correctly, to identify and locate the mass, to provide adequatelight during the biopsy, and to have a clinical assistant available for help. The physi-cian performing the biopsy should be positioned at the patient’s side, preferably con-tralateral to the lesion. The nodule(s) to be aspirated is identified, and the overlying

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skin is cleansed with alcohol. The use of betadine or sterile technique is not neces-sary. A 10-mL plastic syringe is attached to a Cameco syringe holder and held in theright hand by a right-handed operator (Fig. 2 B). Two fingers of the free (left) handfirmly 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. Oncethe needle tip is in the nodule, gentle suction is applied while the needle is movedback and forth within the nodule vertically (Fig. 2 D). This maneuver allows the dis-lodging of cellular material and easy suction into the needle. During this period of5 to 10 seconds, suction is maintained, and as soon as fluid or aspirate appears inthe hub of the needle, the suction is released and the needle is withdrawn. The ap-pearance of fluid suggests that the nodule is cystic; suction is maintained and all thefluid aspirated. It is important to release the syringe plunger and remove the vacuumbefore withdrawing the needle; this allows the aspirate to remain in the syringe andnot be sucked into the syringe. Next, the needle is detached from the syringe (Fig. 3A), and 5 mL of air is drawn into the syringe (Fig. 3 B). The needle is reattached tothe syringe, and with the bevel pointing down, 1 drop of aspirated material is forcedonto each of several glass slides (Fig. 3 C). It is important that all slides be labeled andplaced in order on a nearby table before the aspiration. Smears are prepared by usinga 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 stainingwith the Papanicolaou stain. For Giemsa staining, air-dried smears are necessary, andprepared slides are left unfixed and transported to the laboratory.

Figure 3. A, The needle is removed quickly from syringe. B, Five milliliters of airis aspirated into the syringe, and the needle placed back on the syringe. C, Withneedle bevel pointing down, one drop of aspirated material is expelled onto eachof several glass slides. Slides are labeled and placed on the table before aspiration,ready for use. D, With a second slide, smears are prepared in a manner similar tothat for blood smears. Slides are then immediately wet-fixed by placing them inalcohol bottle.

Usually, 2 to 4 aspirations are made (10,12,13), although some authors suggest at least6 punctures should be made (16). Frequently, 8 to 10 slides are made for each nodule.Preferably, the aspirates should be obtained from the peripheral areas and differentparts of the nodule, in a sequential manner, to ensure representative sampling (10,12).

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For larger nodules, the deep center of the mass should be avoided because it is morelikely to contain degeneration and fluid, decreasing the chance of a diagnostic speci-men. For cystic lesions, the fluid should be completely aspirated and FNA attemptedon residual tissue. Aspirated fluid should be placed in a plastic cup and saved forcytologic evaluation. We use a new needle and syringe for each biopsy.

FNNA BIOPSYFine-needle nonaspiration (FNNA) technique has been described by several authors(1,12,17). This technique is thought to minimize trauma to thyroid tissue and to re-duce blood contamination. For this technique, patient preparation is similar to thatfor FNA. However, no syringe or suction is necessary. The hub of a 25-gauge needleis held in a pencil-grip fashion, and the needle is gently inserted into the nodule andthen moved in and out over 5 to 10 seconds (Fig. 4). Aspirate flows into the needlethrough capillary action, and as soon as aspirate appears in the hub, the needle iswithdrawn and attached to the syringe with air inside. Next, the plunger is used toexpel the material onto glass slides. The procedure is repeated several times, and theslides are prepared as described above for FNA.

Figure 4. Fine-needle nonaspiration (FNNA) biopsy showing needle, position, anddirection for biopsy. After needle is placed into target tissue, it is moved with shortback-and-forth movements until aspirate appears in hub. The needle is then with-drawn.

After the biopsy has been completed, firm pressure is applied to biopsy site(s) witha 4 × 4 gauze pad. Once bleeding has stopped, an adhesive bandage (Band-Aid) isplaced on the puncture site(s) and the patient is observed for a few minutes and, ifthere are no problems, allowed to leave (Fig. 5).

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Figure 5. Immediately after FNA, firm pressure is applied to biopsy sites. After theprocedure is finished, adhesive bandage is applied and patient is allowed to sit fora few minutes before dismissal.

COMPLICATIONSThyroid FNA biopsy is very safe. No serious complications such as tumor seeding,nerve damage, tissue trauma, or vascular injury have been reported (10-14). Nee-dle puncture may cause slight pain and some skin discoloration at the aspirationsite(s). However, even a minor hematoma is not common. The use of anticoagulantsor salicylates does not preclude FNA biopsy. Needle tract implantation of thyroidcarcinoma is extremely rare; it has been poorly documented and is not considered areal problem by most experts (18). Post-aspiration hemorrhage within a cystic lesioncan occur, and the author has seen one patient who, within several hours after FNAbiopsy, developed severe pain from bleeding into the nodule that warranted surgi-cal excision. The specimen contained fresh blood consistent with hemorrhage causedby biopsy. However, this is the only example we have had among more than 15,000biopsies performed at our institution.

CYTOLOGIC DIAGNOSISAspirates from normal glands often have scant thyroid follicular cells and colloid.Wet-fixed smears are usually prepared with a modified Papanicolaou stain, whichshows nuclear detail. Air-dried smears are often prepared with a Romanovsky stain.May-Grunwald-Giemsa (MGG) is a modified Romanovsky staining procedure that issometimes used in thyroid cytologic preparations. The cytologic diagnosis includesfour categories: benign (negative), suspicious (indeterminate), malignant (positive),or unsatisfactory (nondiagnostic).

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Benign CytologyAspirates obtained from multinodular goiters, benign microfollicular adenoma, ornormal thyroid are referred to as "colloid nodules" and show loosely cohesive sheathsof follicular epithelium, colloid, blood, and rare macrophages. Colloid nodules con-tain an abundance of colloid with sparse follicular cells. There is considerable vari-ation in the number of cells as well as the type and amount of colloid present (Fig.6).

Figure 6. Colloid nodule. Sheath of normal thyroid epithelium showing uniformnuclei and pale cytoplasm. (Papanicolaou; ×100.)

Another benign diagnosis is Hashimoto’s thyroiditis; it has a fairly characteristic pat-tern on FNA smears, showing hypercellularity with lymphocytes, Hürthle cells, andminimal or no colloid (Fig. 7).

Figure 7. Hashimoto’s thyroiditis. A, Group of Hürthle cells, with large cytoplasmand prominent nuclei, surrounded by a teratogeneous population of lymphocytes.(Papanicolaou; ×60.) B, Hypercellular aspirate with lymphocytes and Hürthlecells. (May-Grünwald-Giemsa; ×250.)

Subacute (granulomatous) thyroiditis is a rare condition with a benign aspirate. Typ-ically, the smear shows multinucleated giant cells, epithelioid histiocytes, and scat-

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tered inflammatory cells (Fig. 8).

Figure 8. Subacute thyroiditis. Large multinucleated giant cells in a mixed inflam-matory background. Absence of colloid is noticeable. (Papanicolaou; ×64.)

Malignant CytologyPapillary carcinoma, the most common thyroid malignancy, is readily diagnosed byFNA. Typically, cytology shows a papillary configuration, large irregular nuclei, andnuclear grooves. Psammoma bodies may or may not be present, but if present, theyare highly suggestive of papillary thyroid carcinoma (Fig. 9).

Figure 9. Papillary thyroid carcinoma. A, Follicular cells with large irregular nuclei,nuclear grooving, and pale chromatin. (Papanicolaou; ×400.) B, Histologic prepa-ration showing typical papillary configurations. (Hematoxylin-eosin; ×50.)

Medullary thyroid carcinoma accounts for 5% to 10% of thyroid cancers and maypresent as a thyroid nodule or neck mass. Typically, aspirates from a medullary thy-roid carcinoma are hypercellular, composed of large poorly cohesive cells, and are

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predominantly spindle-shaped. Amyloid is often, but not invariably, present, andthere is no colloid (Fig. 10).

Figure 10. Medullary thyroid carcinoma. A, Cellular specimen staining positivelyfor calcitonin with immunoperoxidase. (×100.) B, Loosely cohesive fragments ofspindle-shaped cells; amyloid is present as amorphous blue material intimatelyassociated with neoplastic cells. (Papanicolaou; ×400.)

High-grade carcinoma can be diagnosed cytologically but distinguishing betweenprimary and metastatic cancer is not easy.

FNA RESULTSThe accumulated experience of the past 2 decades has confirmed the reliability andusefulness of FNA as a diagnostic test (11-14,16,19-24). The role of FNA biopsy in theevaluation of thyroid nodules is now firmly established, and FNA has become theinitial test because it is both safe and cost-effective. In most clinics, FNA has becomea standard test, performed most often by an endocrinologist.

Diagnostic CytologyAn adequate specimen of good technical quality is considered diagnostic or satisfac-tory and may be "benign," "suspicious," or "malignant." A benign cytologic diagnosisis reported for 50% to 90% of the specimens (average, 70%) (10,14,22,25,26). From10% to 30% of FNA cytologic specimens may be suspicious for malignancy or inde-terminate (average, 20%) (25,26). A malignant or positive cytologic diagnosis variesfrom 1% to 10% (average, 5%). For example, Caruso and Mazzaferri (25) reportedthe following results from 9 series that included more than 9,000 patients: benign,74%; malignant, 4%; inadequate and suspicious, each 11%. We reviewed more than18,000 specimens from seven large series and obtained similar cytologic results: be-nign, 69%; malignant, 4%; suspicious, 10%; and nondiagnostic, 17% (26).

False-Negative DiagnosesFalse-negative results mean missed malignancy. False-negative rates generally varyfrom 1.5% to 11.5% (average, <5%) (16,19,25,26). The false-negative rate is definedas the percentage of patients with "benign" cytology in whom malignant lesions arelater confirmed on thyroidectomy. The frequency of false-negative cytologic diagno-sis depends on the number of patients who subsequently have surgery and histo-logic review. In most retrospective series, less than 10% of patients with a benign cy-tologic diagnosis subsequently have thyroid surgery, suggesting that false-negativerates should be interpreted with some skepticism (25,26). Despite this note of caution,most authorities agree that the true false-negative rate is less than 5% if all patients

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have thyroid surgery. False-negative rates are lower in centers experienced with theprocedure and with cytologic interpretation by expert cytopathologists.

False-Positive DiagnosesFalse-positive rates vary from 0 to 8% (average, 3%) (19,25,26). A false-positive diag-nosis indicates that a patient with "malignant" FNA results was found on histologicexamination to have benign lesions.

Causes of False DiagnosesInterpretive or sampling errors account for false diagnoses (12,13,26,27). Hashimoto’sthyroiditis probably is the most common cause of false-positive cytology. Misclassi-fication of follicular and Hürthle cell adenomas as papillary carcinomas accounts forother errors. FNA biopsy of thyroid lymphomas may produce lymphocytes that canbe interpreted as Hashimoto’s thyroiditis, accounting for a false-negative diagnosis.Inadequate or improper sampling accounts for some false-negative errors. For exam-ple, nodules smaller than 1 cm in size may be too small for accurate needle placement,and nodules larger than 4 cm in diameter are too large to allow proper sampling fromall areas, thereby increasing the likelihood of misdiagnosis. Finally, the cytopatholo-gist should establish and observe criteria to exclude a diagnosis of malignancy (5).

The Problem of Cellular TumorsHypercellular specimens from follicular or Hürthle cell lesions may have featuressuggestive of, but not diagnostic for, malignancy (8,10,12,13,28). Thus, the cytopathol-ogist labels these "suspicious for malignancy" because cytologic features neither con-firm nor rule out malignancy. Histologic examination is necessary for definitive di-agnosis. Hypercellularity may be seen with non-neoplastic lesions, and Hürthle cellchanges may be seen in patients with lymphocytic thyroiditis. The diagnosis of follic-ular neoplasm is indicative of an underlying malignancy in 14% of cases and Hürthlecell neoplasm in 15% (20,26). Kini (29) believes that follicular adenomas and follicu-lar carcinomas usually can be differentiated on the basis of nuclear size but Hürthlecell lesions are problematic to diagnose cytologically. Other pathologists maintainthat benign and malignant follicular/Hürthle cell tumors cannot be distinguished onthe basis of aspirated cells only and the lesion must be removed for histopathologicexamination (8,12,13,28).

Several authors have discussed the problem of follicular neoplasm. In a study of 149patients with the cytologic diagnosis of follicular neoplasm, Tuttle et al. (30) reportedthat risk of malignancy was higher for males, solitary nodules, and nodules largerthan 4 cm. In a study of 219 patients with follicular neoplasm, Schlinkert et al. (31)showed that nodules are more likely malignant in younger patients, in males, if thenodule is solitary, and if it is larger than 4 cm. Recently, Baloch et al. (32) studied 184cases of follicular neoplasm and reported that risk factors for malignancy includedmale sex, older age (> 40 years), and larger nodules (> 3 cm). Overall, they found that70% of these lesions are benign.

Recent studies suggest that immunohistochemical and genetic markers may be use-ful in improving diagnostic accuracy in this group. Two such markers, HBME-1 andgalectin-3, have shown most promise in reliably distinguishing between benign andmalignant follicular neoplasms. In one report (33) all papillary (145/145) and follicu-lar (27/27) cancers showed staining not present in normal thyroid tissue. Galectin-3is also reported as staining positive for papillary/follicular cancers but not for nodu-lar hyperplasia (34). Further studies are needed to validate these results before theirroutine clinical application is recommended.

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Nondiagnostic CytologyInadequate specimens are labeled "nondiagnostic" or "unsatisfactory" and accountfor 2% to 20% of specimens (average, 15%) (19,25,26). Several factors influence non-diagnostic rates for FNA results, including the skill of the operator, vascularity of thenodule, criteria used to judge adequacy of the specimen, and the cystic component ofthe nodule (35-37). Overall, a satisfactory smear contains at least six clusters of well-preserved cells, with each group consisting of at least 10 to 15 cells. Reaspirationyields satisfactory specimens in at least 50% of cases that are considered nondiagnos-tic on initial FNA (16,28). Although it has been suggested that more aspirations willincrease the diagnostic rates, the optimal number of aspirations is a matter of debate.In general, most reports indicate that two to four aspirates per nodule are adequate(12,13,28).

In a recent report, Chow et al. (38) found a 7% malignancy rate in 153 patients withinitial nondiagnostic smears. Among 27 patients treated surgically, 37% had cancer.Reaspiration with ultrasonographic (US) guidance was diagnostic in 66% and 56%without US; overall, 62% of reaspirations were diagnostic.

Diagnostic AccuracyAnalysis 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%) (19,25). The pre-dictive value of a positive or suspicious cytologic result is approximately 50%. Theoverall accuracy for cytologic diagnosis approaches 95%.

FNA GuidelinesGuidelines have been published to help improve the adequacy and accuracy of cy-tology specimens (39). FNA biopsy should be performed by individuals who havehad training in both thyroid examination and thyroid biopsy. Thyroid FNA in thehands of experienced operators achieves high diagnostic accuracy. Aspirates shouldbe obtained from different portions of the nodule, preferably peripheral areas, in anorganized and sequential manner. It is essential to ensure that an adequate num-ber of follicular cells is present. A cytopathologist, preferably one with experience inthyroid cytology, should review and interpret the slides. If reaspiration yields insuf-ficient material, US-guided FNA (US-FNA) biopsy is the next test. In the event thatthe final result is still insufficient, surgical excision is warranted for most nodules.

Several authors have offered suggestions to minimize false-negative rates (1,3,10,16).In a recent review of thyroid FNA, Belfiore and La Rosa (40) suggested the followingsteps to reduce false-negative results:

• Acquire and maintain adequate biopsy expertise

• Avoid making a diagnosis with a suboptional sample

• Be cautious with cystic degeneration, Hurthle cells, or lymphocytes

• Repeat FNA at least once during follow-up

• Repeat FNA or recommend surgery when nodule is suspicious by clinical or USexamination

To minimize false-negative results, we follow the guidelines summarized in Table 1.

Table 1. Steps That Improve Accuracy of Fine-Needle Aspiration (FNA) and Leadto Better Nodule Management*

Step Explanation

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Step ExplanationEndocrinologist performs biopsy Offers better thyroid examination;

accumulates experience with FNA

Experienced cytopathologist reviewsslides

Improves cytologic interpretation

Careful with small (< 1 cm) or large (> 4cm) nodules

Increased chance of misdiagnosis;US-FNA improves accuracy

2-4 aspirates from different nodule sites Improves cytologic sampling

Rebiopsy if cytology is nondiagnostic One-half will be diagnostic onreaspiration

Nondiagnostic cytology is not negative 5%-10% of nondiagnostic nodulesharbor malignancy

Aspirates with no follicular cells arenondiagnostic

These should not be considered"negative for malignancy"

Excise large (> 4 cm) or recurrent cysts Higher likelihood of malignancy

Excise nodules yielding "suspicious"cytology

10%-30% chance of malignancy

Excise clinically suspicious,cytologically benign nodules

Consider cytology false-negative untilproved otherwise

US-FNA, ultrasound-guided FNA.*Modified from Gharib (5). By permission of Mayo Foundation for Medical Educa-tion and Research.

ULTRASOUND-GUIDED FNA BIOPSYHigh-frequency sonography demonstrates the anatomy of the neck and morphologyof the thyroid in exquisite detail (1). Current US equipment is sensitive, portable,adaptable to office use, simplified for use by nonradiologists, and less costly thanprevious machines. As a result, an increasing number of endocrinologists are nowusing US in the setting of an office practice. Widespread use of US has resulted in thediscovery of unsuspected nodules, often smaller than 1 cm, referred to as "thyroidincidentalomas." Endocrinologists are seeing an increase in referrals for incidentallydiscovered micronodules (41).

Indications for US use are multiple. US can be used to supplement the physical ex-amination when neck palpation is difficult because the neck is short, full, or fat. USexamination may not only detect impalpable small (< 1 cm) nodules, it may also showa 2.0- to 3.0-cm nodule that may be impalpable because of its location or because ofthe anatomy of the neck. US may also be used to evacuate cystic fluid or to reaspiratea nodule found to be nondiagnostic on initial palpation-guided biopsy. Finally, USshould be used for alcohol ablation (41,42).

Several studies have suggested that the diagnostic accuracy of US-FNA is superior tothat of palpation-guided FNA (43-46). A satisfactory biopsy rate for US-FNA rangesfrom 80% to 95%. By means of US guidance, the biopsy site(s) can be precisely se-lected and the needle correctly positioned, allowing sampling of the cyst wall orsolid component and thereby providing enhanced diagnostic accuracy (43-45). Fur-thermore, US-FNA permits complete evacuation of cystic material, resulting in near-collapse of cystic lesions. Some reports have suggested that with the combined useof FNA and US, thyroid cancers are detected more frequently and at earlier stages.

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Percutaneous ethanol injection (PEI) during US guidance was first used for recurrentor persistent hyperparathyroidism, especially in surgically high-risk patients. Morerecently, alcohol therapy has been applied to thyroid nodules (47-51). Lippi and col-leagues (49) reported results of a large multicenter Italian study that included 429patients: 56% had toxic nodules and 44% had hyperfunctioning but nontoxic nod-ules. Under US guidance, ethanol was injected into the nodules and 12 months aftertreatment, 74% of the patients were biochemically euthyroid. Papini and coworkers(48) recently reviewed the role of PEI in the treatment of benign thyroid nodules.They found indications for treatment of patients with toxic hot nodules, nontoxichot nodules, toxic multinodular goiters, and thyroid cysts. In patients with solitarynodules, nodules that had a volume less than 10 mL were more likely to respond totreatment with complete remission than were nodules with a large volume. PEI isperformed on outpatients. The procedure is short, never exceeding 10 minutes, andrequires no local or general anesthesia. US-guided PEI is safe and effective in centerswith experience. Valcavi and Frasoldati (52) used PEI to treat benign thyroid cysts.Complications included transient dysphonia and pain; no permanent injuries wererecorded. Two-thirds of the patients required only one injection to reduce nodulesize. Of note, there is often an acute, marked increase in the serum level of thyroglob-ulin but only a slight increase in the serum level of thyroid hormones. There is noevidence that injected ethanol enters the circulation, because serum levels of ethanoldo not increase after PEI.

Zingrillo and colleagues (53) treated large (>10 mL) cold benign thyroid nodules in41 patients with PEI. Follow-up ranged from 12 to 36 months. Symptoms were sig-nificantly reduced. The authors concluded that PEI is a safe and effective treatmentof symptomatic large cold benign nodules and should be considered an alternativetreatment for high-risk surgical patients or when patients refuse surgical treatment.

In a recent prospective randomized trial, Bennedbaek and colleagues (54) comparedthe effect of a single PEI treatment with suppressive doses of thyroxine (T4) in eu-thyroid patients with a single solid colloid thyroid nodule. The thyroid nodules weresmall (estimated volume, <10 mL). After 12 months, the median nodule reduction inthe PEI group was greater than in the T4 group, indicating that a single PEI treat-ment is more effective than thyroxine therapy. Clearly, additional studies with longerfollow-up are needed.

FNA PITFALLSThe experience as well as the expertise of the cytopathologist is critical in avoidingpitfalls. Determining the adequacy of an aspirate, cellular atypia, application andinterpretation of immunostains, and differentiation of lymphocytic thyroiditis fromlymphoma are but a few of these problems. Larger nodules are more likely to yieldfalse-negative results. To improve sampling, aspirates should be obtained from mul-tiple sites of the nodule rather than repeatedly from one spot. The absence of malig-nant cells in an otherwise acellular specimen does not exclude malignancy. It is goodpractice to biopsy all accessible nodules in a multinodular gland.

REBIOPSYIndications for rebiopsy include an enlarging nodule, recurrent cyst after aspiration,initial nondiagnostic FNA, and persistent nodule after suppressive T4 therapy. Ingeneral, routine rebiopsy of cytologically benign nodules is not suggested. However,for those who begin FNA biopsy in their practice, rebiopsy in 6 to 12 minutes is help-ful to provide data on biopsy results, to minimize false-negative rates, and to improvequality of care. In a recent report, Chehade et al. (55) showed that repeated biopsy candecrease the rate of false-negative FNA to < 1.3%. Thus, reaspiration biopsy may be asafeguard against a high rate of missed cancer (false-negative), which is a recognizedlimitation of FNA.

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Chapter 6d. Fine-Needle Aspiration Biopsy of the Thyroid Gland

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Transcript of Chapter 6d. Fine-Needle Aspiration Biopsy of the Thyroid Gland