Barbara A. Crothers, DO
Michael J. Henry, MD
Manon Auger, MD, FRCP(C)
Thyroid fine-needle aspiration (FNA) is now well established as a highly successful triaging tool for surgery for patients harboring potentially malignant thyroid nodules. The widespread use of imaging studies, however, has led to the detection of an increasing number of incidental thyroid nodules that are often investigated by FNA. This has shifted the focus of thyroid specialists to also include prevention of unnecessary surgical procedures in this setting. Paramount to these efforts are a greater understanding of the current science of thyroid pathology, development of a common reporting language, and collaborative management paradigms to ensure the success of future concerted efforts.
The National Cancer Institute, under the skillful coordination of Andrea Abati, MD, sponsored a “State of the Science” Conference for Thyroid Fine-Needle Aspiration, held Oct. 22–23, 2007 in the Natcher Auditorium in Bethesda, Md. The goal of this effort was to “encourage interdisciplinary dialogue and education”1 regarding the evaluation, management, and interpretive reporting of thyroid nodules.
The conference was prefaced by several months of online Web discussion of six general topics under the guidance of committees entrusted with reviewing current scientific evidence for specific practices. Each committee hosted a discussion forum by posting questions under its topic. The committee members consisted of recognized experts in the field of thyroid pathology. The discussions at the conference were efficiently and tactfully co-moderated by Ed S. Cibas, MD, and Susan J. Mandel, MD. What follows is a summary of the discussions and of the recommendations of this State of the Science Conference. The final draft of the review and conclusions of the conference are posted on the Web site http://thyroidfna.cancer.gov. The definitive version of the final conclusions of the conference will soon be published in articles in Diagnostic Cytopathology.
Indications for thyroid FNA and pre-FNA requirements
Nodules discovered by palpation. Levels of thyroid stimulating hormone (TSH) should be measured and should be normal or elevated prior to aspirating a clinically palpable thyroid nodule (typically ≥1 cm diameter). Patients with depressed TSH levels should be referred for radionuclide thyroid scan. Ultrasound is strongly suggested either before or in conjunction with the FNA to identify those nodules meeting echographic criteria for the procedure. A family history or clinical factors that increase the likelihood of malignancy should be considered in the decision to aspirate even in the absence of the above indications. It is acceptable to perform FNA of all clinically palpable nodules if ancillary resources (for example, ultrasound) are limited, since it may prove diagnostic. Contraindications for thyroid FNA are few but include uncooperative patients and those with a severe bleeding diathesis.
Nodules discovered incidentally. More controversial are the indications for FNA of lesions discovered incidentally through imaging procedures undertaken for purposes other than investigation of the thyroid. The risk for malignancy in such “incidentalomas” is around 10 to 16 percent,2,3 and subsequent action is dependent on initial imaging methodology. Nodules under 1 cm should be referred to ultrasound to detect suspicious echographic characteristics that would warrant FNA. Focal thyroid uptake on PET scans, though uncommon, also warrants FNA because of the relatively high risk of primary thyroid malignancy in that setting (14 to 50 percent).4–6 Similarly, thyroid nodules detected on sestamibi scans and confirmed by ultrasound to be a discrete nodule should be aspirated, since the incidence of primary malignancy is also high (up to 66 percent).7 In contrast, CT and MRI are relatively insensitive for the detection of primary thyroid carcinoma, and there are little data to support FNA of nodules detected primarily through these modalities. It is suggested that these patients also be referred for ultrasound to search for suspicious features (Table 1). In fact, any thyroid lesion with suspicious features on ultrasound should be considered for FNA, as should nodules larger than 1 to 1.5 cm, even in the absence of suspicious features.
In many instances, ultrasound-guided FNA is preferable to palpation-guided FNA largely because of the additional information derived from the ultrasound imaging, especially the appearance of the nodule to determine the need for FNA and to confirm needle placement in small lesions. Nodules that are primarily cystic (less than 25 percent solid component) should be aspirated under ultrasound guidance to ensure sampling of solid components. In addition, prior “unsatisfactory” or “nondiagnostic” FNA results should be repeated with ultrasound-guided procedures. FNA is also considered desirable in all patients with significant risk factors for thyroid carcinoma, regardless of the size of the lesion or of ultrasound characteristics.8 When FNA is performed without ultrasound guidance, nodules targeted should preferably be easily palpable, discrete, larger than 1 cm, and predominantly solid.
Informed consent. Regulations regarding the need for informed consent prior to procedures vary greatly between states. Therefore, physicians are encouraged to develop policies for consent in accordance with state and local guidelines. Ethically, patients must be informed, at least verbally, of the nature and purpose, risks, and benefits and complications of those procedures, of reasonable alternative options with their concomitant risks and benefits, and of the likely outcome of declining a proposed procedure. The patient must be able to comprehend the information provided, whether written or oral. Written information materials allow patients to engage family members or others in their care and may facilitate comprehension.
Although uncommon, hematoma and infections, the most frequent complications of thyroid FNA, should be mentioned. There are no convincing data to suggest that adding information to consent forms or to written materials concerning procedural false-negative and false-positive rates is valuable to patients.
Information required for requisition form. Requisitions submitted to the laboratory for interpretation of FNA material are subject to the same regulations as all other laboratory requisitions, requiring accurate identification of the patient or unique patient identifier, age or date of birth, gender, name and contact information of the individual requesting the test, specimen source, requested test, date of specimen collection, and any “clinically relevant” information. Clinically relevant information is indeed essential for accurate interpretation of thyroid FNA by pathologists. It is this last item that generates controversy and requires interdisciplinary cooperation. As a minimum, clinical information relevant to thyroid pathology should be annotated on the requisition (Table 2). Additional useful information includes ultrasound, CT, MRI, or nuclear imaging findings; TSH levels; concurrent levothyroxine therapy; and history of prior FNA. All of these factors can influence the interpretation of a thyroid FNA because they convey situations that change expectations for a specific morphologic pattern or for the probability of disease. For example, low serum TSH levels are associated with a lower risk of thyroid carcinoma.9 Cellular changes that mimic malignant processes occur with I131 therapy, external beam radiation, prior FNA, autoimmune thyroiditis, and Graves’ disease.
Thyroid FNA training and credentialing
Initial fellowship or residency training in FNA suffices for initial credentialing and privileging. The controversy arises when trying to determine the number of FNA procedures necessary for an individual to remain proficient. Not all specialists performing FNA list it as a separate procedure requiring credentialing. There is no magical number that implies proficiency, but the quality of aspiration can be evaluated by measuring the “unsatisfactory” rate. Therefore, it is suggested that credentialing bodies document the total number of FNAs performed annually by a provider and require an unsatisfactory rate of less than 10 percent. In general, evidence suggests that individuals performing large numbers of procedures, and individuals who both procure and interpret the specimen, have the highest diagnostic and lowest unsatisfactory rates. At least 50 percent of diagnostic failures are the result of unsatisfactory specimens, with the other 50 percent owing to either diagnoses rendered on unsatisfactory specimens or to erroneous interpretations on adequate samples.10,11 A significant problem arises when FNA procurement is spread among multiple providers, thereby diluting the total number of cases that each performs annually. In two studies, unsatisfactory rates were reduced to less than 10 percent when an FNA clinic was established in which a smaller number of physicians both procured and interpreted the specimens.12,13 Appropriately trained teams also perform better if on-site evaluation is performed routinely, preferably by a pathologist, provided the necessary changes in the sampling/collecting techniques are made based on the feedback received. In one report, the presence of a cytotechnologist alone providing adequacy evaluation resulted in no improvement in adequacy,14 possibly because no corrective advice was offered to the procurer.
One of the major obstacles in obtaining quality FNA specimens is the misconception that performing FNA is easy and requires little, if any, training. “See one, do one, teach one” is not effective in producing adequate samples. Furthermore, performing high numbers of procedures does not necessarily guarantee diagnostic material. All aspiring procurers, regardless of specialty, benefit from practice sessions on technique before facing a live patient. Indeed, it seems that focused training by an experienced practitioner with immediate feedback on technique is more important than the number of procedures performed.
The importance of slide preparation is frequently overlooked. It is critical to master techniques of slide preparation—in particular, making conventional smears, which generally have been shown to be of superior quality for diagnosis than other types of preparation. FNA cytology is clinically useful only if an interpretation can be provided with confidence. Skillful preparation of that material is one of the three critical components that inspire confidence in pathologists interpreting thyroid FNAs, along with sufficient procurement of diagnostic material and high-quality staining.
There are numerous ways to train individuals in FNA procurement, and a combination of techniques is probably optimal. Teaching aids, such as videos and DVDs, are available. The Papanicolaou Society of Cytopathology’s Web site offers free instruction on technique and slide preparation at http://papsociety.org. Bench practice with bovine liver, with or without the use of ultrasound, provides the added advantage of being able to practice smears. For trainees, it is best to start with the largest and most superficial and easily palpable lesions in patients. Experienced providers may want to first obtain diagnostic specimen from patients before allowing trainees to collect. Each subsequent pass will tend to induce greater hemorrhage and edema, thereby decreasing the likelihood of obtaining diagnostic material. Trainees should also have the ability to view their collected material; immediate feedback allows the facts to speak for themselves. In the future, it will be possible to practice FNA with “virtual” patients through simulation programs that are in developmental stages now in the United States. They could provide an excellent way to measure and ensure proficiency as well as train individuals in the FNA technique.
Thyroid fine-needle aspiration techniques
A variety of FNA techniques are effective in the thyroid. The thyroid is a highly vascular, superficial organ with overlying muscle. As a result, FNA of the thyroid tends to induce significant hemorrhage, thereby diluting the specimen, and may result in a painful aspirate if the needle passes through or repetitively into the neck muscles. In general, smaller gauged needles reduce trauma, so it is helpful to start with a smaller gauge (27 g) and work up to a larger gauge needle (22 g) if necessary. Needles with a long beveled edge are ideal, since it is the cutting surface of the bevel that produces a cellular specimen and not the use of aspiration. The subsequently obtained “shaved” material moves into the needle bore through capillary action. Use of an aspiration device with which to provide suction is optional. Many experienced operators have found that the Zajdela technique, using only the needle without an attached syringe or aspiration device, is highly effective in the thyroid. If suction is needed to drain cyst contents, a section of IV tubing with a syringe can be attached to the needle hub and an assistant can provide the necessary suction. Alternatively, a larger needle with a syringe can be inserted and the contents aspirated. A dwell time of two to five seconds within a nodule, with three oscillations per second, will provide an adequate specimen, provided the needle enters the lesion. There is no need to adhere to strict aseptic techniques; alcohol wipes to clean the aspiration site are sufficient if the patient is not immunocompromised.
Use of anesthetic is optional, but many procurers use it routinely to maximize patient comfort. If incorrectly injected, anesthetics can cause more discomfort than the procedure itself. Anesthetic can also obscure landmarks when palpation is used and, if injected into the lesion itself, may affect the morphology and properties of aspirated cells. When introducing anesthesia, it is important to use a small-gauge needle and inject slowly and intradermally without producing a skin wheal. Alternative anesthetics include local application of ice packs, four percent lidocaine spray, and lidocaine gel.
Cystic change is the primary characteristic of aspirated thyroid nodules that adversely affects adequacy. Frates, et al. recommend against aspirating nodules with a cystic component greater than 75 percent15 because of lower diagnostic yield. Cystic contents should be drained and the remaining solid component sampled. Ultrasound is a key factor in assessing the character of the nodule before and after cyst content aspiration and ensuring placement of the needle into the residual lesion. All nodules clearly visible on ultrasound are viable candidates for FNA, but it is the echographic characteristics rather than the mere presence of a nodule that should guide the decision to biopsy.
The use of core needle biopsies for the diagnosis of thyroid lesions is controversial. Core needle biopsies are preferably obtained by using a short throw device or one with a non-advancing cutting edge (Temno needle) to prevent damage to local structures because the superficial location of the thyroid and its proximity to neurovascular bundles in the neck present hazards for the procurer. Large bore needles (Tru-cut) have not been widely used due to the greater risk of complication, the difficulty of sampling small lesions, and the high rate of unsatisfactory samples. Documented cases of tumor-seeding along needle tracts are almost exclusively associated with large bore needles. All core biopsy techniques suffer from limited ability to sample multiple areas within large lesions without causing undue hemorrhage. In addition, core biopsies do not add any advantage to the interpretation of most follicular lesions because capsular invasion, which is one of the defining criteria for distinguishing adenoma from carcinoma, requires histological examination of the entire capsule. In contrast, thyroid FNA benefits from a very low (less than one percent) morbidity rate and a very high (90 to 100 percent) rate of diagnostic accuracy. FNA is less expensive, easier to use, and more comfortable for patients than core needle biopsy. In conclusion, FNA remains the best technique for initial investigation of thyroid nodules. Core biopsies should be seen as a complementary investigational tool having a role primarily in situations where cytopathology expertise is unavailable for interpretation of FNA cytology, providing a tissue sample for histological examination.
Is there a particular specialist who is most qualified to perform FNA? The evidence suggests that the ideal individual is not associated with a particular specialty. Rather, he or she has the depth of experience to obtain adequate samples consistently and prepare excellent slides and repeatedly demonstrates good clinical judgment in performing the procedure.
Ideally, experienced personnel should process the material collected. Solid or semi-solid material should be prepared to produce air-dried smears for Romanowsky stain, alcohol wet-fixed smears for Papanicolaou stain, along with needle rinses for liquid-based cytology or cell block, or both, if necessary. Cyst fluid should be prepared with one to two smeared slides, with the rest collected for later processing in the laboratory for cytospin or other liquid-based cytology methods (SurePath, ThinPrep). Where experienced personnel are not available on site for slide preparation, an alternative is to provide a liquid preservative into which each collected sample can be placed for further preparation. Options include RPMI or balanced saline solutions, formalin, or liquid-based collection vials.
There is insufficient evidence to provide a recommendation for the optimal number of passes necessary to collect an adequate sample from a thyroid lesion. However, the consensus opinion is that procurers should not exceed five passes, even for cystic lesions, as there is very little diagnostic gain beyond five samples. In general, two FNAs from different areas in a lesion are sufficient if a cyst is completely drained without a residual mass, if malignancy is represented, or if the FNA appears adequate as per on-site assessment. Additional FNA passes may be indicated when these conditions are not met or when a need for a cell block is anticipated. In solid lesions that show little colloid and mostly follicular cells, one should collect a minimum of five to six groups with at least 10 cells each on a single slide.
Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions
The main task of this committee was to evaluate diagnostic terminology and classification schemes for thyroid FNAs. Although outlining the morphologic criteria for the cytological diagnostic categories was also mandated, this particular aspect was not covered in the conference because of time restrictions. Several pathology and clinical organizations have suggested classification schemes. They include, among others, those proposed by the Papanicolaou Society of Cytopathology16 and the American Association of Clinical Endocrinologists,17 but none of these systems is widely accepted for the reporting of thyroid FNA specimens. Though there are diagnostic schemes of three to more than 10 categories, the one that the participants at the conference favored (after lengthy discussion) consists of seven categories. These generic categories are displayed in Table 3.
In many ways, the topic of diagnostic terminology and classification schemes was the most controversial and complex of all; it certainly engendered the most heated discussions, both online and at the conference. Most of the discussion centered on three areas: 1) the nondiagnostic specimens, 2) the “atypical” category, and 3) the terminology for follicular/Hurthle cell neoplasms.
Nondiagnostic specimens. The discussion of nondiagnostic specimens centered on what to do with cystic lesions and colloid nodules. There was agreement that specimens of limited cellularity, no follicular epithelium, or poor preservation precluding cellular evaluation may be considered unsatisfactory or nondiagnostic. Some participants used these terms interchangeably, but others indicated that a specimen may be satisfactory but also not diagnostic of a particular entity, and that “unsatisfactory” determines the quality or adequacy of the preparation. In such cases, colloid only or sheets of macrophages could be considered “nondiagnostic.” There was agreement that a minimum of six groups of 10 follicular cells should be present for an FNA to be considered adequate or satisfactory (see exception, in paragraph below, for FNAs containing abundant colloid).
The discussion was heated with regard to the placement of cystic specimens in the diagnostic scheme (in the benign versus the nondiagnostic versus another category by itself). In view of the fact that a small but significant percentage of cystic specimens may represent sampling from a cystic papillary carcinoma, it was decided that reassurance with a “benign” category would be inappropriate. The conclusion was that cystic specimens containing macrophages only (or macrophages with less than six groups of follicular cells) should be included in a separate category titled “cyst fluid only” with a recommendation that correlation be made with the ultrasound findings. An optional disclaimer that cystic carcinoma cannot be excluded can be added.
After much consideration, the committee concluded that an exception to the minimum number of follicular cells could be made in the FNA composed of abundant colloid. Because such FNAs most likely represent colloid nodules and carry an insignificant risk of malignancy, they can be included in the benign category as being “suggestive of colloid nodule.”
The “atypical” category. By far the most controversial area of discussion revolved around the terminology for an “atypical” category. It was recognized that there are FNAs with cytological features that are more than benign but insufficient for an interpretation of follicular or Hurthle neoplasia. Though some elect to make a definitive call of either “benign” or “neoplasm” in these borderline cases, others use terms such as “indeterminate” or “follicular lesion.” A poll taken at the conference revealed that the majority of participants were in favor of an “atypical” category as long as it was reasonably well defined and that its use was minimized. Recent studies have shown that the risk of malignancy in this group is low (10 to 15 percent) and that these patients should, in general, be followed with repeat FNA rather than surgery. No consensus was achieved at the conference on the exact terminology that should be used for this category; acceptable suggested terminology included “follicular lesion of undetermined significance,” with the following as possible alternatives: “atypia of undetermined significance,” “atypical follicular lesion,” and “cellular follicular lesion.” The final conclusions of the committee on suggested terminology of the atypical category will be in the Diagnostic Cytopathology articles.
Terminology for follicular and Hurthle cell neoplasms. Finally, there was debate about whether to use the term “suspicious for follicular or Hurthle cell neoplasm.” The histological followup of the majority of FNAs diagnosed as follicular or Hurthle cell neoplasms indeed reveal neoplasms, most of which are follicular or Hurthle cell adenomas. Because only approximately 20 percent of those cases prove to be malignant on histological followup, many cytopathologists do not like to use the term “suspicious” in the context of an FNA diagnosis of follicular or Hurthle cell neoplasm because the term “suspicious” usually connotes a strong concern for malignancy. In the case of thyroid FNAs in this context, the concern is not so much about malignancy but whether these cellular FNAs represent a true neoplasm (that would require surgery) or simply a cellular adenomatoid nodule (which can be followed conservatively). The two preferred terms for these aspirates were “follicular/Hurthle neoplasm” or “suspicious for follicular/Hurthle neoplasm” and appear as the final proposals. These terms are intended to apply only to nonpapillary patterns in cytology.
In contrast, there was general agreement on terms such as “benign,” “negative for malignancy,” or “non-neoplastic” for use in FNA reporting with specimens that show the features of nodular goiter or lymphocytic thyroiditis. Long descriptive diagnoses of these lesions may confuse clinicians, especially when terms such as “follicular lesion” are used. There was also general agreement that the cytological characteristics of malignant lesions of the thyroid are sufficiently well defined to allow specific diagnoses of many lesions—for example, papillary carcinoma, medullary carcinoma, and anaplastic carcinoma, as well as lymphoma and others. Because many surgeons will perform a total thyroidectomy with a diagnosis of papillary carcinoma, special care should be taken when making this definitive interpretation on thyroid FNA.
Use of ancillary studies in thyroid FNA
The committee evaluated the use of ancillary studies in thyroid FNA, investigating three separate issues: 1) the indications for ancillary studies on thyroid FNAs, 2) specific ancillary studies to be performed for each indication, and 3) sample preparation for each type of study.
Indications for ancillary studies. Indications for ancillary testing depend on the morphology of the specimen, the clinical information provided, and the likelihood that these tests might add diagnostic information. Most of the ancillary tests used routinely in thyroid FNA are aimed at specific malignancies, such as medullary carcinoma, lymphoma, or possible metastases. More controversial areas involve the use of ancillary studies to re-classify an indeterminate/suspicious FNA into a benign or malignant category or to refine the risk of malignancy within this category.
Specific ancillary studies. Specific ancillary tests include routine immunohistochemistry (IHC) and more cutting-edge molecular markers. IHC is most often used on cell blocks or core biopsies obtained in conjunction with the FNA. Although pathologists may use IHC on smears, cytospins, or other liquid-based cytology preparations, these procedures need to be carefully validated.
An IHC panel for suspected medullary carcinoma cases may include calcitonin, thyroglobulin, carcinoembryonic antigen, and chromogranin. This panel allows for the distinction of medullary carcinoma from neoplasms derived from the follicular epithelium. Immunohistochemistry to differentiate anaplastic carcinoma from metastatic carcinoma is often not useful because most anaplastic carcinomas lose specific thyroid markers. Because it can be extremely difficult to differentiate between parathyroid and thyroid follicular cells, an IHC panel that contains TTF-1, parathyroid hormone, and chromogranin can be used.
Flow cytometry is the standard method for characterizing lymphoma and may be used in thyroid FNA. One should use caution when interpreting these results, since clonal B-cell lymphoid populations may be detected in the background of Hashimoto’s thyroiditis without concomitant lymphoma.18 Thus, the indication for flow cytometric analysis should be based on cytomorphologic or clinical features that raise the suspicion of lymphoma. Flow cytometric analysis should not be used routinely when lymphoid material is obtained. In addition, immunophenotyping results from thyroid FNA samples should be interpreted with caution since Hashimoto’s thyroiditis may yield κ/λ ratios that are skewed beyond normal values associated with reactive lymph nodes.19
One of the most problematic areas in thyroid FNA is the atypical or suspicious follicular lesion. Problems include distinguishing neoplastic from non-neoplastic follicular lesions, as well as distinguishing benign from malignant neoplasms. The use of either IHC or molecular techniques in this setting remains controversial. Several different molecular markers exist that have been associated with thyroid carcinomas, including galectin-3, cytokeratin-19, HBME-1, thyroid peroxidase, and DAP IV. Genetic mutations (BRAF, RAS) and chromosomal rearrangements (RET/PTC, PAX8/ PPARG) are also being studied. Of these, the detection of BRAF mutation appears particularly promising because the BRAF mutation is highly specific for papillary thyroid carcinoma and the test can be performed by removing cells from direct smears;20,21 however, further validation is required for routine clinical use.
Sample preparation. The final area of consideration was sample preparation for ancillary studies. It was recognized that preanalytical sampling, processing protocols, and variables are very important in the interpretation of results from any ancillary study. It remains a challenge to triage the relatively limited cells of many thyroid FNAs when any of these tests may be necessary without compromising the cytomorphologic analysis of the specimen.
Most IHC testing is done on cell block preparations from a portion of the FNA sample. In some cases, entire passes are dedicated to the cell block preparation. IHC on other types of preparations should be carefully validated. Flow cytometry requires live cells suspended in a supportive medium, preferably from at least one dedicated pass. Ancillary studies to detect genetic alterations may require dedicated passes and special processing protocols, depending on the analyte.
Post-FNA testing and treatment options
There are several management issues following a diagnosis by thyroid FNA. The strategies discussed closely followed existing recommendations made by various professional associations, including the American Thyroid Association, the American Association of Clinical Endocrinologists with the American Association of Endocrine Surgeons, and the British Thyroid Association in conjunction with the Royal College of Physicians.8,22,23
Nondiagnostic specimens. Thyroid FNAs may be reported as nondiagnostic because of qualitative or quantitative reasons. Unless there is a strong suspicion for malignancy, a waiting period of at least three months should elapse between an initial “nondiagnostic” aspirate and the repeat FNA to prevent interpretive errors related to reparative changes. Solid nodules with inadequate sampling should be re-aspirated with ultrasound guidance and on-site adequacy assessment whenever possible. If the repeat FNA is also “nondiagnostic,” surgery should be strongly considered. Close clinical followup with ultrasound examination is a reasonable alternative to surgery provided the patient is reliable and likely to return for clinical followup and that the nodule is 1 cm or less in size. When growth of the nodule is detected during ultrasound surveillance, excision is recommended.
Nondiagnostic cystic lesions should undergo a repeat FNA if an ultrasound examination demonstrates suspicious areas. The repeat FNA should be under ultrasound guidance, with on-site assessment whenever possible. The cyst should be completely drained and well sampled. When the repeat FNA yields “nondiagnostic” material, correlation with family history and close clinical and ultrasound followup should be performed. Repeat FNA can be performed in six to 18 months at the clinician’s discretion.
Benign aspirates. This category includes specimens diagnosed as a colloid nodule, benign thyroid nodule (goiter), or inflammatory lesions such as Hashimoto’s thyroiditis. Followup of these patients depends on the clinical findings and level of suspicion. The use of hormone suppressive therapy is controversial but ethanol ablation may be considered in selected patients.
There is a low but definite false-negative rate for thyroid FNA. Consequently, thyroid nodules interpreted as “benign” require careful clinical followup. Easily palpable thyroid nodules may be followed clinically at six to 18-month intervals. Nodules that are not readily palpable should receive serial ultrasound examinations at six to 18-month intervals. The duration of the followup period is not fully defined but should be at least three to five years following the initial “benign” cytologic diagnosis. If a 20 percent increase in nodule diameter or a minimum of a 2-mm increase in two dimensions is detected either by palpation or ultrasound, repeat FNA is appropriate. Repeat FNA should also be performed if ultrasound abnormalities develop; in such cases, the repeat FNA should be performed under ultrasound guidance.
Atypical. An atypical diagnosis is essentially an equivocal diagnosis. It is, therefore, difficult to know how to clinically manage these patients. What constitutes an atypical specimen? Because of the wide variability of morphologic features in this diagnostic category, it is associated with a low specificity and a low positive predictive value. Most “atypical” aspirates prove to be dominant nodules in a multinodular goiter.
Whenever the atypical category is used, the type of atypical cells should be specified, since followup recommendations may vary depending on the nature of the lesion. For example, an FNA with cytological features between a benign thyroid nodule and follicular neoplasm might be re-aspirated, whereas a specimen with atypical lymphocytes might require special studies such as flow cytometry.
In general, a conservative approach should be adopted for atypical thyroid FNAs. The majority of these lesions should be re-aspirated in an attempt to define them more clearly. In most instances, after a single “atypical” interpretation, a repeat FNA should be considered in three to six months. If the repeat FNA is atypical, surgical consultation should be considered.
Suspicious for follicular or Hurthle cell neoplasm. The majority of patients in this category will have a neoplasm on surgical followup, with an overall 20 percent to 30 percent risk of malignancy. The malignancies include follicular carcinoma, Hurthle cell carcinoma, and follicular variant of papillary carcinoma. Because of the risk of malignancy, these patients should have surgery, most often a lobectomy.
Opinions vary about the use of intraoperative frozen section for these lesions. There is little peer-reviewed data supporting the use of intraoperative frozen section to separate follicular adenomas from follicular carcinomas, and the majority of the participants at the NCI conference recommended against it. However, some surgeons elect to ask for an intraoperative frozen section evaluation of the nodule and will proceed to complete total thyroidectomy if a diagnosis of malignancy can be made intraoperatively.
Suspicious for malignancy. This diagnosis is made when cytological features are suggestive but not diagnostic of malignancy. It is limited to cases where the features suggest a specific malignancy such as papillary carcinoma (PTC), medullary carcinoma, or other primary or metastatic carcinoma; it should not be used for follicular or Hurthle cell lesions. The vast majority of the thyroid FNAs in this category fall into the “suspicious but not diagnostic of PTC” subcategory. Studies have shown a 60 percent to 75 percent positive predictive value for a diagnosis of “suspicious for PTC.”24,25
Patients with a diagnosis of “suspicious for malignancy” should be referred for surgery, generally a lobectomy. Since most of these cases are potential papillary carcinomas, intraoperative evaluation is more useful to determine whether a lobectomy or a total thyroidectomy is required. A total thyroidectomy would be performed if a definitive diagnosis of carcinoma can be reached intraoperatively. Also, because of the increased risk of malignancy in this category, total thyroidectomy should be considered in patients with large tumors (>4 cm) and in patients with a history of radiation exposure. Patients with bilateral nodular disease or those who prefer to undergo bilateral thyroid lobectomy to avoid the possibility of future thyroid surgery on the contralateral lobe can also be considered for total thyroidectomy.
Positive for malignancy. The type of malignancy identified determines followup. By far the most common malignancy in the thyroid is papillary carcinoma. Studies show an approximate 99 percent predictive value for a diagnosis of PTC on FNA. It is important to exclude other types of primary thyroid carcinomas or metastatic neoplasms because treatment will vary with the specific diagnosis.
Controversy does exist as to whether total thyroidectomy or lobectomy should be performed in some cases of PTC. The selection of lobectomy versus thyroidectomy depends on the evaluation of the patient’s clinical status, as well as the size and nature of the tumor. Papillary carcinomas under 1–1.5 cm in diameter and without unfavorable prognostic features may be best treated by simple lobectomy. Patients with larger carcinomas, especially those over 4 cm, should probably have a total or near total thyroidectomy.
The National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference was a timely and successful interdisciplinary dialogue and educational forum on the evaluation, interpretation, and reporting of thyroid FNAs. In particular, the improved standardization of the diagnostic terminology for thyroid FNA that is likely to follow from this concerted effort will most certainly have a positive impact on the entire field of thyroid pathology that will ultimately translate into improved patient diagnosis and care.
1. Abati A. Letter to Thomas M. Sodeman, MD, and the College of American Pathologists. Dated Feb. 16, 2007.
2. Shetty SK, Maher MM, Hahn PF, et al. Significance of incidental thyroid lesions detected on CT: correlation among CT, sonography, and pathology. AJR Am J Roentgenol. 2006;187:1349–1356.
3. Youserm DM, Huang T, Loevner LA, et al. Clinical and economic impact of incidental thyroid nodules found with CT and MR. AJNR Am J Neuroradiol. 1997; 18: 1423– 1428.
4. Are C, Hsu JF, Schoder H, et al. FDG-PET detected thyroid incidentalomas: need for further investigation? Ann Surg Oncol. 2007;14:239–247.
5. Chu QD, Conner MM, Lilien DL, et al. Positron emission tomography (PET) positive thyroid incidentaloma: the risk of malignancy observed in a tertiary referral center. Am Surg. 2006; 72:272–275.
6. Kresnik E, Gallowitsch HJ, Mikosch P, et al. Fluorine-18-fluorodeoxyglucose uptake in thyroid from positron emission tomography in the preoperative assessment of thyroid nodules in endemic goiter area. Surgery. 2003;133:294–299.
7. Kresnik E, Gallowitsch HJ, Mikosch P, et al. Technetium-99M-MIBI scintigraphy of thyroid nodules in endemic goiter area. J Nucl Med. 1997;38:62–65.
8. Cooper DS, Doherty GM, Haugen BR, et al. The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16:109–142.
9. Boelaert K, Horacek J, Holder RL, et al. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab. 2006;91:4295–4301.
10. Raab SS, Vrbin CM, Grzybicki DM, et al. Errors in thyroid gland fine-needle aspiration. Am J Clin Pathol. 2006; 125: 873– 882.
11. de Vos tot Nederveen Cappel RJ, Bouvy ND, Bonjer HJ, et al. Fine needle aspiration cytology of thyroid nodules: how accurate is it and what are the causes of discrepant cases? Cytopathology. 2001; 12: 399– 405.
12. Bakshi NA, Mansoor I, Jones BA. Analysis of inconclusive fine-needle aspiration of thyroid follicular lesions. Endocr Pathol. 2003;14:167–175.
13. Mayall F, Denford A, Chang B, et al. Improved FNA cytology results with a near patient diagnosis service for non-breast lesions. J Clin Pathol. 1998; 51: 541– 544.
14. Kocjan G. Evaluation of the cost effectiveness of establishing a fine needle aspiration cytology clinic in a hospital out-patient department. Cytopathology. 1991;2:13–18.
15. Frates MC, Benson CB, Charboneau JW, et al. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology. 2005;237: 794–800.
16. Guidelines of the Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration specimens from thyroid nodules. The Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Diagn Cytopathol. 1996;15(1):84–89.
17. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract. 2006;12 (1): 63– 102.
18. Saxena A, Alport EC, Moshynska O, et al. Clonal B cell populations in a minority of patients with Hashimoto’s thyroiditis. J Clin Pathol. 2004;57:1258–1263.
19. Chen HI, Akpolat I, Mody DR, et al. Restricted kappa/lambda light chain ratio by flow cytometry in germinal center B cells in Hashimoto thyroiditis. Am J Clin Pathol. 2006;125:42–48.
20. Cohen Y, Rosenbaum E, Clark DP, et al. Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid: a potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res. 2004; 10: 2761–2765.
21. Jin L, Sebo TJ, Nakamura N, et al. BRAF mutation analysis in fine needle aspiration (FNA) cytology of the thyroid. Diagn Mol Pathol. 2006; 15: 136– 143.
22. Thyroid Carcinoma Task Force. AACE/ AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract. 2001; 7: 202– 220.
23. British Thyroid Association and Royal College of Physicians. Guidelines for the management of thyroid cancer in adults. http://www.british-thyroid-association.org/complete%20guidelines.pdf. Published March 2002. Accessed Nov. 21, 2005.
24. Wang HH. Reporting thyroid fine-needle aspiration: literature review and a proposal. Diagn Cytopathol. 2006; 34 (1): 67– 76.
25. Yang J, Schnadig V, Logrono R, et al. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer. 2007; 111 (5): 306– 315.
Dr. Crothers is director of cytopathology, Walter Reed Army Medical Center, Washington, DC; Dr. Henry is director of cytopathology, Mayo Clinic, Rochester, Minn.; and Dr. Auger is associate professor, Department of Pathology, McGill University, and director of cytopathology, McGill University Health Center, Montreal. All are members of the CAP Cytopathology Committee.