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Anatomic Pathology / INTEROBSERVER VARIABILITY IN THYROID FNA INTERPRETATION

Interobserver Variability in Thyroid Fine-Needle Aspiration Interpretation of Lesions Showing Predominantly Colloid and Follicular Groups Edward B. Stelow, MD,1 Ricardo H. Bardales, MD,2 Gretchen S. Crary, MD,2 H.Evin Gulbahce, MD,3 Michael W.Stanley, MD,4 Kay Savik, MS,5 and Stefan E. Pambuccian, MD3 Key Words: Adenoma; Carcinoma; Cytology; Fine-needle aspiration; Follicular; Interobserver; Lesion; Neoplasm; Thyroid DOI: 10.1309/P5MFMA7UMFUL2KWT

Abstract We studied interobserver variability in the assessment of thyroid fine-needle aspiration (FNA). We limited our cases to those showing predominantly colloid and follicular cell groups. Twenty cases of thyroid FNA diagnosed by 1 experienced cytopathologist were reviewed by 4 other cytopathologists who made their own diagnoses while unaware of the original diagnoses. Two cytopathologists then assessed the cytologic features of the 20 cases. Interobserver variability was calculated for noncollapsed and collapsed diagnoses. Diagnoses and observer agreement were compared with cytologic features. There was little correlation among observers regarding the diagnosis of follicular “lesion” vs “neoplasm.” Interobserver variability was somewhat poor before data were collapsed (κ = 0.35) but was relatively good when data were collapsed to treatment recommendations (κ = 0.65). Cellularity, cyst change, and amount of colloid correlated with treatment recommendations; no specific features correlated with poor performance. Thyroid FNA shows good interobserver agreement in the diagnoses of lesions showing predominantly colloid or follicular cells (when collapsed). We speculate that interobserver variability is poor in some cases owing to difficulty assessing thin colloid, some lack of agreement regarding criteria for adequacy, and a possible “gray zone” that might exist with lesions showing colloid and abundant follicular cells.

Fine-needle aspiration (FNA) has been shown to be an effective method for the preliminary interpretation and triaging of thyroid lesions.1-9 Recently, it has become clear that even the “gold standard” for diagnosing follicular-patterned thyroid lesions, surgical pathology, shows considerable interobserver variability.10-12 Also, it has been shown that thyroid pathology contributes significantly to second-opinion discrepancies for surgical pathology and cytopathology specimens.13-16 Because of the “gray zone” that exists in the interpretation of cytologic samples of thyroid lesions composed predominantly of colloid and follicular groups, we speculated that considerable interobserver variability might exist for the interpretation of these cases.17-21 Colloid nodule (CN) is the most common diagnosis made with thyroid FNA, and it represents, by far, the most common thyroid nodule.1,6,7,9,22,23 The differential diagnosis for CN most often includes other follicular-patterned thyroid lesions, generally diagnosed as follicular “lesions” (FLs) or follicular “neoplasms” (FNs) by FNA. Because thyroid pathology is vast, we limited our study to this common diagnostic dilemma. Therefore, we reviewed interobserver variability with thyroid FNA of specimens that showed predominantly colloid and follicular groups.

Materials and Methods The cytology files of 1 cytopathologist who reviews more than 600 thyroid FNA specimens per year were reviewed. All slides from 10 consecutively diagnosed CNs and 10 consecutively diagnosed FLs or FNs were retrieved. Each case was placed into a separate folder and was accompanied with a Am J Clin Pathol 2005;124:239-244

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DOI: 10.1309/P5MFMA7UMFUL2KWT

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generic history (ie, 40-year-old woman with a 2.5-cm thyroid nodule) to avoid bias from clinical details. Each case had only conventional-type smears with 2 to 18 slides per case. The vast majority of slides were air-dried and rapid Romanowsky stained. No liquid-based preparations were evaluated. Four pathologists with special interest in cytopathology, each with more than 5 years of experience, 2 with and 2 without cytopathology fellowship training, were informed of the purpose of the study and given the cases to review while unaware of the original diagnoses. All diagnoses (including those of the original reviewing cytopathologist) were recorded, and interobserver variability was calculated using the multirater κ described by Siegel and Castellan24 for diagnoses made and for diagnoses collapsed to triaging recommendations (nondiagnostic and CN, nonsurgical triage; FL and FN, surgical triage). In general, the diagnosis of CN is used by members of our group to connote cytologic changes that are consistent with nonneoplastic, hyperplastic changes. The diagnosis of FL is used when the features are worrisome for a follicular-patterned neoplasm (adenoma or carcinoma) but the case does not have cytologic features of papillary carcinoma. The diagnosis of FN is used when the cytologic features are believed most likely to signify a true neoplasm. Thus, this diagnosis is used when the cytologic features are believed to be “more” worrisome than those of FL. Cytologic features, including presence and quantity of thick colloid and thin colloid, overall quantity of follicular epithelium, sheets of follicular epithelium, microfollicles, Hürthle-cell change, and cystic change were assessed semiquantitatively

(except for cystic change and Hürthle-cell change, which were assessed as present or absent) together by 2 pathologists. Thick colloid was defined as distinct blobs of colloid and was scored as 0 (none present), 1 (1-5 blobs), and 2 (>5 blobs). Thin colloid was scored as 0 (not identified), 1 (present but not abundant), and 2 (abundant, ie, >50% coverage of any single slide). Overall numbers of follicular cells, microfollicles, and sheets of follicular cells were scored as 0 (not identified), 1 (15 groups), 2 (6-25 groups), 3 (26-100 groups), and 4 (>100 groups). Cytologic features were compared with agreement (presence or absence of complete agreement among the 5 pathologists as to surgical triage) and treatment plan using a Mann-Whitney U test for ranked data and a χ2 test of association for categorical data. Results were considered significant at a P value of less than .05.

Results Individual diagnoses are given in ❚Table 1❚. Interobserver variability was high when FL and FN were considered separate diagnoses (κ = 0.35), with 6 cases having consensus diagnoses and 9 having diagnoses agreed on by at least 4 observers. When FL and FN were considered equivalent, interobserver variability decreased (κ = 0.57), and 10 cases had consensus diagnoses and 15 cases were agreed on by at least 4 observers. If cases were further collapsed into those requiring surgery vs those not requiring surgery, interobserver variability decreased even more (κ = 0.65).

❚Table 1❚ Observer Diagnoses of 20 Selected Thyroid Fine-Needle Aspiration Specimens* Observer Case No. 1 2 3 4 5 6 7† 8 9 10 11 12 13 14 15 16 17 18 19 20 * †

1 Colloid nodule Colloid nodule Follicular neoplasm Colloid nodule Colloid nodule Nondiagnostic Follicular neoplasm Nondiagnostic Follicular neoplasm Colloid nodule Colloid nodule Follicular lesion Follicular neoplasm Colloid nodule Follicular lesion Follicular lesion Colloid nodule Colloid nodule Colloid nodule Nondiagnostic

2 Colloid nodule Colloid nodule Follicular lesion Colloid nodule Colloid nodule Follicular lesion Follicular neoplasm Follicular lesion Follicular neoplasm Colloid nodule Colloid nodule Follicular neoplasm Follicular lesion Colloid nodule Follicular neoplasm Follicular lesion Colloid nodule Colloid nodule Colloid nodule Follicular lesion

3 Colloid nodule Colloid nodule Follicular neoplasm Colloid nodule Colloid nodule Colloid nodule Follicular neoplasm Follicular neoplasm Follicular neoplasm Colloid nodule Colloid nodule Follicular neoplasm Follicular neoplasm Colloid nodule Follicular neoplasm Colloid nodule Colloid nodule Colloid nodule Colloid nodule Colloid nodule

4

5

Follicular lesion Colloid nodule Follicular lesion Colloid nodule Follicular lesion Follicular lesion Papillary carcinoma Follicular lesion Follicular lesion Colloid nodule Colloid nodule Follicular lesion Follicular lesion Colloid nodule Follicular lesion Colloid nodule Colloid nodule Colloid nodule Colloid nodule Colloid nodule

Colloid nodule Colloid nodule Follicular neoplasm Colloid nodule Follicular lesion Colloid nodule Papillary carcinoma Follicular lesion Colloid nodule Colloid nodule Nondiagnostic Follicular neoplasm Follicular lesion Colloid nodule Follicular lesion Follicular lesion Nondiagnostic Colloid nodule Colloid nodule Colloid nodule

Cases interpreted as follicular lesions or neoplasms and papillary carcinoma were deemed to require resection; others were not. The 3 observers for case 7 who diagnosed it as follicular neoplasm noted that they found the features suggestive of papillary carcinoma.

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Cytologic features for individual cases are noted in ❚Table 2❚. The presence of increasing thin colloid correlated with nonsurgical triage (P = .002), as did the presence of cyst change (P = .02), whereas increasing numbers of overall follicular cells and microfollicles correlated with the diagnosis of FL/FN and surgical triage (P = .005 and P = .001, respectively). Three cases “performed” poorly after data were collapsed based on surgical triage recommendations with only 3 of 5 pathologists agreeing as to proper treatment. No specific cytologic features, however, could be found that correlated with poor performance (ie, P > .05 for all comparisons).

Discussion Cramer3 and numerous others have pointed out that although there may be between 10 and 20 million clinically evident thyroid nodules in the United States at any one time, only 17,000 or so cases of thyroid cancer are diagnosed within the United States per year. Because almost all thyroid diseases may manifest as a solitary thyroid nodule and the specific diagnosis of these nodules most often cannot be made clinically, FNA has an important role in the specific diagnosis of the lesions and the proper triaging of patients. Although thyroid pathology is in some ways straightforward, there are numerous problems that occur in the diagnosis of thyroid disease. Two of the more common pathologies (nodular hyperplasia and chronic lymphocytic thyroiditis) occur together and with other pathologies and are even risk

factors for those pathologies.25-29 Criteria for specific histologic diagnoses might require extensive sampling and be based on minute, focal findings (eg, vascular invasion or capsular penetration used for the diagnosis of minimally invasive follicular carcinoma).12 Criteria for other diagnoses might be subject to a high degree of interobserver variability (eg, the assessment of nuclear features for the diagnosis of follicular variant of papillary carcinoma [FVPC]).10,11 Other criteria might be defined poorly and, because of a good deal of histologic overlap and even true disease overlap, difficult to apply (eg, criteria for differentiating cellular adenomatoid nodules from follicular adenomas).11 Recently, it has been shown that a high degree of interobserver variability exists with the histologic diagnosis of FVPC.10,11 The original investigators and others have shown that interobserver variability exists for the diagnosis of other follicular-patterned lesions.11,12 Because some but not all of the same dilemmas that face surgical pathologists with histologic diagnoses face cytopathologists with cytologic diagnoses, we speculated that considerable interobserver variability might exist with the interpretation of thyroid FNA specimens. By far, the most common nodule of the thyroid is the dominant nodule in an otherwise hyperplastic thyroid.1,6,7,9,22,23 That said, CNs also make up the vast majority of solitary thyroid nodules in otherwise normal-appearing thyroid glands.22,23,30 The cytologic findings of FNA specimens from CNs have been well described. In general, thick and thin colloid is present with groups of follicular cells. The follicular cells can be arranged in small groups or in recognizable

❚Table 2❚ Cytologic Features of 20 Selected Thyroid Fine-Needle Aspiration Specimens With Treatment Recommendations and Number of Observers in Agreement* Colloid Case No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 *

Thick 2 1 0 0 2 0 1 0 1 2 0 1 1 1 1 0 0 1 2 1

Follicular Cell Groups Thin 2 2 0 2 2 1 0 1 1 2 2 1 1 2 1 2 2 2 2 2

Cyst Change

Overall

Microfollicles

Sheets

Hürthle-Cell Change

Resect?

No. Who Agree

No Yes No Yes Yes No No No No Yes Yes Yes No Yes No No Yes Yes No No

2 2 4 1 4 2 4 3 2 2 0 4 4 1 4 3 1 3 3 3

2 1 4 0 2 0 4 3 2 2 0 4 4 0 4 1 0 2 0 2

0 2 2 1 3 2 0 0 2 0 0 1 2 1 2 2 0 3 3 1

Yes Yes Yes No Yes No No Yes No No No Yes No No Yes No No No No No

No No Yes No No No Yes Yes Yes No No Yes Yes No Yes Yes No No No No

4 5 5 5 3 3 5 4 4 5 5 5 5 5 5 3 5 5 5 4

See the “Materials and Methods” section for a description of the scoring used.

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follicles and can focally show Hürthle-cell change. In general, the follicles should be polymorphic and should be less abundant than colloid. Features of cystic degeneration are often also present. Histologically and cytologically, other follicular-patterned lesions present the most common differential diagnoses. These include follicular adenoma, follicular carcinoma, and FVPC. As the criteria for distinguishing follicular adenomas from carcinomas are defined histologically, cytopathologists are mostly unable and usually do not attempt to distinguish the two. FVPC, however, is defined by cytologic findings, and the specific diagnosis often can be made with cytologic material. Follicular-patterned neoplasms are distinguished from nonneoplastic CNs cytologically by less abundant colloid (at least relative to the amount of follicular epithelium). Follicular groups should, in general, be more abundant and often are monomorphic, especially microfollicular. Hürthle-cell change can be present and might be the overwhelming cell type (we diagnose these lesions as Hürthle-cell lesions and did not include such cases in this study). Cystic change usually is not present. The amount and quantity of colloid, proportion of follicular cells forming microfollicles, and the overall cellularity required for these diagnoses are debated, and some authors are willing to make the diagnosis of FL or FN with very low cellular FNA specimens.18 Whether cytopathologists diagnose these cases as FLs or FNs is a matter of some debate.31-33 Theoretically, the use of both terms might represent an attempt to distinguish FNA specimens that show findings more consistent with a neoplasm from those that might have some cytologic overlap with more cellular adenomatoid nodules, ie, lesions more suggestive of neoplasia and, thus, carcinoma from those that appear more “indeterminate.” Because both diagnoses might indicate a need for surgery and both might show rather extensive overlap in cytologic and histologic features, it might be wondered why such attempts should be made. Furthermore, our data suggest that the terms are used somewhat haphazardly, and there seems to be little correlation with the use of the different terms between different cytopathologists. The use of different terms to connote the same diagnosis might only increase the confusion of those who read our reports. Our data show that the amount of colloid and number of follicular groups and microfollicles correlate with diagnoses (when collapsed to surgical triage recommendations), as would be expected. Cyst change, most commonly seen in CNs, also was shown to correlate with nonsurgical triage. No other cytologic features correlated with suggested triage based on diagnosis, but this might represent the relatively small number of cases included in our study, which had not actually been designed to define cytologic features of these lesions. 242 242


It is interesting to note that no specific features seemed to correlate with cases that performed poorly, namely the 3 cases with only 3 of 5 cytopathologists agreeing about treatment. This might be due to actual interobserver variability of the assessment of the cytologic features themselves. Observers were not asked to actually quantify features, but we have noticed anecdotally that interobserver variability seems to exist with the assessment of thin colloid, especially with smears that show significant background blood. This seems to be true for even experienced cytopathologists and might represent a true interpretive difficulty. Although most of our smears were air-dried and rapid Romanowsky–stained, we suspect that the same difficulty is present, if not worse, with alcohol-fixed, Papanicolaou-stained material. Finally, it should be noted that occasional somewhat paradoxical diagnoses were made compared with the noted cytologic features. Although interpretation might even have some role here, one must remember that interpretation does not account for all interobserver variability, especially when numerous slides must be assessed. It should not be surprising that occasional cases were considered “nondiagnostic” or “inadequate” by different cytopathologists. Although some have tried to define quantifiable criteria for adequacy for thyroid FNA, the Papanicolaou Society has taken a more pragmatic approach and suggests that hard and fast criteria should not be used for the assessment of adequacy, but instead the criteria should be more qualified and based on the individual’s interpretation of the case.4,34 Given this, occasional cases, especially low-cellular cases, obviously will be considered inadequate by some, whereas others might consider them “diagnostic.” Indeed, as was mentioned, some might even be willing to diagnose lowcellular FNA specimens as FLs or FNs, whereas others might consider them nondiagnostic.18 Overall, we would have to conclude that once data are collapsed into diagnoses requiring resection and diagnoses not requiring resection, there is relatively good agreement between cytopathologists when they are faced with FNA samples that show predominantly colloid and follicular groups. This suggests to us that simplifying one’s diagnostic terminology in the diagnosis of these lesions (eg, not using FL and FN, but instead using only the term FL) might be prudent. Even when this is done, however, occasional cases will present diagnostic difficulty because of the difficulty assessing certain cytologic features and because occasional cases truly might represent gray-zone cases for which a definitive separation of a nonneoplastic adenomatoid nodule from a neoplastic follicular-patterned lesion becomes more difficult. This is the area in which individual pathologists define their threshold for the diagnosis of an FL as they try to achieve 100% sensitivity for the diagnosis of thyroid cancers while maintaining the greatest specificity possible. Although © American Society for Clinical Pathology

Anatomic Pathology / ORIGINAL ARTICLE

the literature shows some variation, nearly a third of the cases diagnosed as FLs might show nonneoplastic pathologic features at resection, likely depending on the skill of the cytopathologist interpreting the FNA specimens and the threshold at which the surgical pathologist diagnoses follicular neoplasia and differentiates it from nodular hyperplasia.17,35 At least in the small group we reviewed, cases falling into this gray zone do not seem to be that common. This study included a limited number of cases, investigated a single diagnostic difficulty, and used cytopathologists from only 2 institutions from the same geographic area. A larger study with a more diverse group of cytopathologists might be needed to investigate the true interobserver variability in the interpretation of these lesions and to explain the reported differences in the rates of malignancy and even neoplasia that have followed the cytologic diagnosis of FL or FN.17,36-39 From the Departments of Pathology and Laboratory Medicine, 1University of Virginia, Charlottesville; 2Hennepin County Medical Center, Minneapolis, MN; 3University of Minnesota, Minneapolis; 4Abbott Northwestern Hospital, Minneapolis; and 5School of Nursing, University of Minnesota, Minneapolis. Data from this study were presented in abstract form at the fall meeting of the American Society of Cytopathology, Chicago, IL, November 15, 2004. Address reprint requests to Dr Stelow: University of Virginia Health Sciences, Box 800214, Charlottesville, VA 22908.

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