Original Article

FNAB of Benign Thyroid Nodules With Papillary Hyperplasia A Cytological and Histological Evaluation Marc P. Pusztaszeri, MD1; Jeffrey F. Krane, MD, PhD2,3; Edmund S. Cibas, MD2,3; Gilbert Daniels, MD2,4; and William C. Faquin, MD, PhD2,5

BACKGROUND: Benign thyroid nodules with papillary hyperplasia (BTN-PH) are sometimes misinterpreted cytologically as papillary thyroid carcinoma (PTC). We evaluated a fine-needle aspiration biopsy (FNAB) series of BTN-PH to identify the causes of diagnostic error and to better define its cytologic criteria. METHODS: A total of 48 FNAB cases of histologically confirmed BTN-PHs from 44 patients were identified from our archives. The available cytological and histological slides were reviewed and scored for 10 cytomorphological features. Fifteen FNAB cases of classical PTC were also reviewed for comparison. RESULTS: The FNAB diagnoses for the 48 BTN-PHs were: benign, 18; suspicious for malignancy (S-PTC), 12); atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 10; follicular neoplasm, 5; malignant (PTC), 2; and nondiagnostic, 1. The extent of PH in the corresponding histology was highest in FNAB cases diagnosed as S-PTC/PTC versus all other categories (54% vs 27%; P 5.0084). Papillary cytoarchitectural features were present in 53% of FNAB cases overall and in 89% of cases diagnosed as S-PTC/PTC (P 5.0093). Nuclei were smaller in FNABs of BTN-PH compared with PTC (mean diameter/range, 8.2/6-12 vs 14.2/7-26 lm, respectively; P 5.0001). Twenty-six percent of BTN-PHs contained cytoplasmic pigment. All FNAB cases diagnosed as S-PTC/PTC had focal nuclear atypia including grooves (87.5%), enlargement and crowding (75%), and chromatin pallor and pseudoinclusions (25%); however, the extent of nuclear atypia was significantly less than in the control group of PTCs (P 10); cellular swirls, a recently described feature of PTC (0, none; 11, rare 1-2; 21, several >2)27; nuclear crowding (0-11, none or minimal; 21, mild to moderate in 50% of cells); nuclear size enlargement (0-11, none or minimal [10 l m in >25% of cells; 31, >10 lm in >50% of cells; 41, >10 lm in >90% of cells); chromatin pallor (0, none; 11, in 50% of cells); nuclear grooves (0, none; 11, in 20% of cells); intranuclear pseudoinclusions (0, none; 11, rare; 21, in several cells; 31, in many cells); and presence or absence of cytoplasmic pigment, psammoma bodies, and giant cells. Of the 28 FNAB cases for which slides were available for review, 19 were liquid based using ThinPrep only, whereas 9 cases included both alcoholfixed smears and liquid-based preparations (ThinPrep or SurePath). The number of slides for each FNAB case ranged from 1 to 12; all cases were alcohol fixed and Papanicolaou stained. Cell-block preparations (hematoxylin and eosin [H & E] stained) were also available in 8 cases. Histological Evaluation

All available histological slides were reviewed to confirm the diagnosis of BTN-PH and correlate the approximate proportion (in 10% increments) of PH present within the corresponding aspirated nodule. PH was defined by the histological presence of fibrovascular cores. From 3 to 52 glass slides stained with H & E were available for review per case. Nuclear Size Evaluation

In a subset of cytological and histological cases from our cohort, nuclei were scored for size using a modification of the technique described previously by Yang et al.28 Nuclear size was estimated on Papanicolaou-stained preparations for cytologic samples and on H & E-stained preparations for histological samples using the red blood cell, which has a mean diameter of 7 lm as the internal reference size. An advantage of this technique is that it avoids the problem of nuclear size variation that can occur 668

secondary to variations in sample fixation and preparation. For the BTN-PH cases in our study, we analyzed the 10 FNAB cases that had the corresponding greatest percentage of PH (>60%) on histology. Nuclear size was measured in whole numbers on a scale from 6 to 28 lm with 2-lm increments. For each of these cases, 100 cells were counted from both the cytological and histological preparations in order to obtain a mean nuclear size (with a range) for each. The same protocol was followed with 10 cases of PTC from the control group in order to obtain a mean nuclear size for the PTC control group for comparison. Immunohistochemistry

Immunohistochemical testing was available for 9 surgical pathology cases. The following primary antibodies were used, alone or in combination: cytokeratin-19 (Leica Microsystems, prediluted antibody), 7; galectin-3 (Leica Microsystems, prediluted antibody), 6; HBME-1 (Dako, 1:50), 5. Statistical Analysis

The statistical significance of differences between study groups was evaluated using the unpaired Student t test (GraphPad Software, La Jolla, CA). P < .05 was considered statistically significant. The study was conducted with the approval of the Partners Institutional Review Board (IRB protocol 2012P-000030/1).

RESULTS Clinical Findings

Forty-eight cases of BTN-PH were identified from 44 patients with a mean age of 43 years (range, 16-73 years). Patients with BTN-PH were predominantly female (36 of 44; 82%). In 20 cases (45.5%), only a single nodule was present (size range, 0.6-8.5 cm; mean, 2.6 cm; median, 1.6 cm), whereas in 24 cases (54.5%), the BTN-PH represented a dominant nodule (size range, 0.5 to 4.9 cm; mean, 1.8 cm; median, 1.6 cm) in a multinodular thyroid. Management of the 44 patients included either thyroid lobectomy in 25 patients (57%)—right lobe, n 5 14; left lobe, n 5 11)—or total thyroidectomy in 19 patients (43%). With 1 exception, all patients with a diagnosis of S-PTC or PTC on FNAB (14 of 15; 93%) underwent a total thyroidectomy. In contrast, only 20% of patients (6 Cancer Cytopathology

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Benign Nodule With Papillary Hyperplasia/Pusztaszeri et al

TABLE 1. Cytological Diagnoses of BTN-PH Cases Cytological Diagnosis Non diagnostic Benign AUS/FLUS Suspicious for FN Suspicious for HCN Suspicious for malignancy Malignant (PTC) Total

Total, n (%) 1 18 10 3 2 12 2

(2%) (38%) (21%) (6%) (4%) (25%) (4%) 48

Available for Review 1 8 8 1 2 7 1 28

Abbreviations: AUS/FLUS, atypia of undetermined significance/follicular €rthle lesion of undetermined significance; FN, follicular neoplasia; HCN, Hu cell neoplasia; PTC, papillary thyroid carcinoma

of 29) diagnosed as benign, undetermined significance/ follicular lesion of undetermined significance (AUS/ FLUS), or suspicious for a follicular/H€ urthle cell neoplasm underwent a total thyroidectomy (P < .0001). Cytological Evaluation

Tables 1 and 2 detail the original cytological diagnoses (according to the the BSRTC2,3,26) and the specific cytomorphologic features evaluated and scored semiquantitatively relative to a control group of classical PTCs. The estimated proportion of PH present within the corresponding resected thyroid nodules (Table 2) was higher in the S-PTC and PTC groups (mean, 54%; SD, 30.5) than in the other FNAB diagnostic categories (mean, 27%; SD, 28; P 5 .0084). Papillary structures were identified in 53% of the FNAB cases and were more frequent in the cases in which the extent of PH in the corresponding resected nodule was greatest (P 5 .0052). In the S-PTC and PTC FNAB groups, papillary structures were identified in 89% of cases; the 1 FNAB case in this group without papillary structures was hypocellular. In the other diagnostic cytology categories, only 38% contained papillary structures (P 5 .0093; Table 2). Although papillary structures showed cytomorphologic overlap with those seen in the control group of classical PTC, they were significantly fewer in number (P 10 lm) with nuclear pallor, numerous grooves (n 5 15, 100%) and pseudoinclusions (n 5 14, 93%); see Table 2. Among the subset of BTN-PH having a diagnosis of S-PTC/PTC, however, all cases had at least one or more focal nuclear features of PTC including rare nuclear grooves (87.5%), nuclear enlargement and crowding (75%), chromatin pallor, and rare intranuclear pseudoinclusions (25%); see Figure 2. When scored semiquantitatively, all nuclear features examined were more marked in cases of classical PTC than in the BTN-PH group, regardless of the diagnostic category (P < .0001 Table 2). When papillary structures were identified in BTN-PH, they were always admixed with a nonpapillary component composed of a variable amount of macrofollicles and microfollicles in a cystic background with histiocytes and/ or siderophages. Occasional cases of BTN-PH had moderate amounts of oncocytic cytoplasm (Fig. 1). In 1 of the 2 BTN-PH cases diagnosed as PTC, the smear was cellular and contained an admixture of microfollicles, macrofollicles, and papillary structures. Most nuclei (70%) were small, dark, and regular, but several groups of cells had enlarged, irregular nuclei with grooves and rare pseudoinclusions (Fig. 2). The atypical cells in this case were among the 10% of FNAB cases that contained brown granular intracytoplasmic pigment (Figs. 1 and 2). In the corresponding cell block, there were several papillae lined by cells with round and regular, focally overlapping nuclei and chromatin clearing. In addition, these cells showed apical snouting that was not apparent in the corresponding smears. Immunohistochemistry performed on the cell block was negative for HBME-1 and predominantly negative for galectin-3 and cytokeratin-19. The second case diagnosed as PTC was not available for cytologic review. In that case, evaluation was limited by partially obscuring blood, and a single papillary 669

0 (0%) 3 (37%)

4 (50%)

0 (0%) 1 (50%)

6 (86%)

1 (100%)

15 (100%)

Cytological Diagnosis

Nondiagnostic Benign

AUS/FLUS

Suspicious for FN Suspicious for HCN

Suspicious for malignancy

Malignant (PTC)

PTC control group

0 (7; 100%)

0 (1; 100%) 0 (3; 20%) 11 (5; 33%) 21 (7; 47%)

11 (1; 14%) 21 (4; 58%) 31 (1; 14%) 31 (1;100%)

11 (1; 7%) 21 (2; 13%) 31 (12; 80%)

0 (1; 100%) 0 (2; 100%)

0 (8; 100%)

N.A. 0 (8; 100%)

Cellular Swirls Score (n; %)

0 (1; 100%) 0 (1; 50%) 11 (1; 50%) 0 (1; 14%)

N.A 0 (5; 63%) 11 (3; 37%) 0 (4; 50%) 11 (2; 25%) 21 (2; 25%)

Papillary Structure Core (n; %)

41 (15)%

21 (1; 100%)

21 (4; 57%) 41 (1; 14%)

N.A. 0 (2; 25%) 11 (6; 75%) 0 (1; 12.5%) 11 (2; 25%) 21 (4; 50%) 31 (1; 12.5%) 21 (1; 100%) 21 (1; 50%) 31 (1; 50%) 11 (2; 29%)

Nuclear Enlargement Score (n; %)

31 (15; 100%)

21 (1; 100%)

21 (4; 57%) 31 (1; 14%)

11 (2; 28%)

11 (1; 100%) 0 (2; 100%)

N.A. 0 (5; 63%) 11 (3; 37%) 0 (1; 12.5%) 11 (4; 50%) 21 (3; 37.5%)

Nuclear Crowding Score (n; %)

31 (15; 100%)

11 (1; 100%)

11 (4; 57%) 21 (2; 29%)

0 (1; 14%)

0 (1; 100%) 0 (2; 100%)

N.A. 0 (7; 87.5%) 11 (1; 12.5%) 0 (6; 75%) 11 (1; 12.5%) 21 (1; 12.5%)

Nuclear Pallor Score (n; %)

21 (5, 33%) 31 10; 67%)

11 (1; 100%)

11 (6; 86%)

0 (1; 14%)

0 (1; 100%) 11 (2; 100%)

0 (6; 75%) 11 (1; 12.5%) 21 (1; 12.5%)

N.A. 0 (8; 100%)

Nuclear Grooves Score (n; %)

0 (1; 7%) 11 (3; 21%) 21 (4; 28%) 31 (7; 44%)

11 (1; 100%)

11 (1; 14%)

0 (6; 86%)

0 (1; 100%) 0 (2; 100%)

0 (8; 100%)

N.A. 0 (8; 100%)

Nuclear Pseudoinclusions Score (n; %)

GC (1; 100%) CP (1; 100%) GC (7; 44%) PB (1; 7%)

GC (1; 50%) CP (1; 50%) CP (3; 43%)

N.A. GC (1; 12.5%) CP (1; 12.5%) GC (1; 12.5%) CP (1; 12.5%)

Other Features Present (GC, CP, PB [n; %])

N.A.

65 (2;50-80)

51 (9;10-90)

23 (3;10-50) 35 (2;10-60)

38 (9;10-80)

50 (1;50) 18 (15;10-90)

Proportion of PH in Corresponding Histology Mean % (n; range %)

€rthle cell neoplasia; PTC, papillary thyroid carcinoma; PH, papillary hyperplasia; GC, giant Abbreviations: AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FN, follicular neoplasia; HCN, Hu cells; CP, cytoplasmic pigment; PB, psammoma body; N.A., not assessable.

Papillary Structures Present, n (%)

TABLE 2. Cytological Features of Benign Thyroid Nodules With Papillary Hyperplasia

Benign Nodule With Papillary Hyperplasia/Pusztaszeri et al

Figure 1. FNAB features of benign thyroid nodules with papillary hyperplasia (BTN-PH). (A) Low-magnification view showing the simple papillary architecture in BTN-PH. (B) Although a papillary pattern is present, nuclei are predominantly small and round with regular dark chromatin. (C) A higher-magnification view shows the evenly spaced round nuclei in cells with small amounts of delicate cytoplasm. (D) Some cases of BTN-PH show mild anisonucleosis and slight nuclear crowding, but other features of papillary carcinoma are absent. (E) A subset of cases contain fine brown granular cytoplasmic pigment as well as occasional background histiocytes. (F) Apical snouting (arrows) identified in a rare case of BTN-PH. (G) Occasional cases with moderate amounts of granular oncocytic cytoplasm with round nuclei and a small eccentric nucleolus (Papanicolaou stain).

fragment with cytological features compatible with PTC was described. Histological Features

The diagnosis of BTN-PH was confirmed in all 40 histopathology specimens and at least focal PH was identified in the corresponding resected nodules of all cases by our review (Table 2). The extent of PH varied, with 80% in 17.5% of cases (n 5 7). Nodules were well circumscribed by variably thin to thick fibrous capsules and were readily distinguished from the surrounding thyroid parenchyma. Tumors with non-PH areas exhibited an admixture of micro- and macrofollicles. The size and shape of the follicular cells lining the papillae ranged Cancer Cytopathology

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from cuboidal cells to more elongated cells (Fig. 3). The follicular cells had a fine granular apically oriented cytoplasm reminiscent of apical snouting in 78% of cases (n 5 31; Fig. 3), and in cystic areas, the cytoplasm often contained finely granular brown pigment. As seen in the corresponding FNAB specimens and in contrast to the nuclei of PTC, the follicular cell nuclei in the BTN-PH group were generally small (mean diameter, 8.6 lm; range, 6-11 lm) and round with dark granular chromatin. Only rare welldefined nuclear grooves were present, and intranuclear pseudoinclusions were not identified histologically. In addition, rare psammomatous calcifications were observed in 4 cases (10%). There were no multinucleated giant cells. A subset of BTN-PH cases (n 5 9) underwent immunohistochemical staining for markers typically 671

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Figure 1. (Continued)

associated with PTC. None were positive for galectin-3 (n 5 6; Fig. 3) or HBME-1 (n 5 5), and 1 of 7 was positive for cytokeratin-19.

DISCUSSION To the best of our knowledge, this represents the largest reported analysis of FNAB findings in surgically resected BTN-PH. BTN-PH can pose a diagnostic challenge in cytology as well as in surgical pathology by mimicking classical PTC,7–17 particularly when papillary hyperplasia comprises the majority of the nodule. In this study, we have shown that FNAB interpretations of BTN-PH can encompass all 6 diagnostic categories of the BSRTC. Thirty percent were diagnosed as either S-PTC or PTC, a rate that is significantly higher than the overall rates for FNAB of thyroid nodules.2,4,29–31 By requiring histological confirmation as an inclusion criterion for our study, 672

however, we selected for cases of PH that were “overcalled” by FNAB, because many cases correctly identified as benign would not have been resected. Benign thyroid nodules with extensive papillary hyperplasia (so-called papillary adenomas) are uncommon. For tumors with a minor component of PH, however, it is likely that the true prevalence is underestimated or underreported. In a retrospective histological study of thyroid nodules in adults including follicular adenomas and multinodular goiter, Mai et al found an average prevalence of PH of 10%; PH often posed a diagnostic challenge even in resection specimens.7 Similarly, Harach et al found papillary structures in the FNABs of 17% of BTNs in nodular goiter.19 In another retrospective histological study by Perez-Montiel et al, florid PH was found in 13% of 300 surgical resection cases of nodular goiter.32 Florid PH in surgical specimens was characterized by uniform simple branching papillae often with well-formed fibrovascular Cancer Cytopathology

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Benign Nodule With Papillary Hyperplasia/Pusztaszeri et al

Figure 2. FNAB features of BTN-PH interpreted as “suspicious for malignancy” or “malignant.” (A) Cells are arranged in a papillary pattern, and nuclei are crowded, but most nuclei are small and round. (B) This FNAB case containes areas in which nuclei are enlarged, pale, and oval with occasional grooves (arrow). (C) Rare FNAB cases contain a well-defined intranuclear pseudoinclusion (arrow). (D) Nuclei in this case are suggestive of papillary carcinoma, with granular cytoplasmic pigment also present (Papanicolaou stain)

cores that architecturally resembled the papillary structures of PTC but lacked the diagnostic nuclear features of PTC.32 Given these documented estimates and that the vast majority of thyroid nodules are benign, it is apparent that the combined incidence of all forms of BTN-PH is substantial. The surgical approach to patients with an FNAB diagnosis of S-PTC typically ranges from lobectomy to total thyroidectomy. Although a limited diagnostic surgical procedure such as thyroid lobectomy is sometimes used for isolated solitary nodules that are diagnosed as S-PTC on cytology,1,24,25 many endocrinologists recommend a total thyroidectomy, given the high risk of malignancy associated with S-PTC (60%-75% in the BSRTC2). This is particularly true when the nodule is large, when it is associated with other risk factors, or when contralateral nodules are present. The latter approach is Cancer Cytopathology

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followed at our 2 institutions. This is reflected in our cohort, in which 93% of patients with an FNAB diagnosis of S-PTC or PTC had a total thyroidectomy. This contrasted with the more conservative approach (lobectomy) for the lesser diagnostic categories, in which only 20% of patients were managed by a total thyroidectomy. The most common form of BTN-PH has only a minor (10% of the cells, the 674

specificity for PTC increases to 80%.28,33,34 Histological studies of nuclear changes in neoplastic thyroid lesions (including papillary and nonpapillary lesions) suggest that thyroid lesions with fewer than 33% of nuclei with nuclear grooves or optically clear nuclei (limited nuclear features of PTC) are likely to be benign (ie, evidence of malignancy was not demonstrated in these lesions).7,35 Several case reports and smaller series have also reported cytological and histological findings similar to those found in our study.9–13 Faser et al described 3 FNAB cases of BTN-PH with surgical follow-up. Their cases were diagnosed as S-PTC (n 5 1) and S-FN (n 5 2), although no nuclear grooves or pseudoinclusions were identified.10 Powari et al described a single case of BTNPH diagnosed as Thy5, consistent with PTC on FNAB and treated by total thyroidectomy.9 Baloch et al studied Cancer Cytopathology

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Benign Nodule With Papillary Hyperplasia/Pusztaszeri et al

3 pediatric cases of BTN-PH (including 2 with evidence of hyperfunction)13 and 8 cases in adults.12 They also found mild nuclear atypia that included rare nuclear grooves in their FNAB cases, but no intranuclear pseudoinclusions were identified. A potentially helpful diagnostic feature in their pediatric series13 was the presence of “fire flares,” secretory vacuoles extruded from follicular cells, reflecting hyperfunction.36,37 None of our BTN-PH cases were hyperfunctioning nodules, and fire flares were not found in any cases. Apical snouting was a useful distinguishing feature histologically within areas of PH in most of our BTN-PH patients (31 of 40; 78%); unfortunately, this feature was very rarely seen by cytological examination (1 of 28; 3.5%). It is likely that our inability to detect apical snouting in our FNAB cohort was related to the lack of air-dried cytology preparations, in which apical snouting is more prominent. The same is also true of fire flares. Interestingly, 4 cases (10%) of BTN-PH in our study had rare psammomatous calcifications on histological review. These psammomatous calcifications were poorly formed, however, and other diagnostic features of PTC were absent in these nodules. Importantly, psammoma bodies were not present in the corresponding FNAB. Although isolated psammoma bodies in an otherwise normal thyroid gland (or within a cervical lymph node) is a feature that should prompt a search for an occult PTC within the thyroid gland, as suggested by Hunt and Barnes,38 it is also recognized that psammomatous calcifications can be found within a wide range of benign and malignant lesions.39 When present as an isolated finding, the positive predictive value of psammoma bodies for PTC in thyroid FNABs is only 50 %.40 It is not surprising that psammomatous calcifications could occur within a BTN-PH, where true fibrovascular cores are present, the tips of which can calcify. An important clinical dilemma is how to classify specimens such as BTN-PH that fall within the indeterminate categories of the BSRTC. According to the BSRTC,2 a “suspicious for malignancy” (S-PTC) interpretation should be rendered when nuclear changes of PTC make the diagnosis of PTC likely, but some of the diagnostic features of PTC are either absent or equivocal. In other words, a strong suspicion of malignancy is required. Indeed, the positive predictive value for PTC in the S-PTC category should be greater than 50% and generally in the range of 60%-75%. This is particularly important at institutions (such as ours) where surgeons are likely to perform a total thyroidectomy based on this Cancer Cytopathology

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FNAB interpretation. Although some studies have found that FNAB cases with focal nuclear features of PTC are significantly associated with PTC at resection (39%, especially with the follicular variant),41,42 this malignancy risk falls short of the level expected for the S-PTC category. Similarly, cases of BTN-PH with indeterminate features are more suitable to classification as AUS/FLUS or S-FN than as S-PTC. Our study demonstrates that BTN-PH should be considered when an FNAB identifies papillary structures but nuclear features of PTC are sparse or the features are admixed with an otherwise benign-appearing follicular component. The key diagnostic problem of BTN-PH on cytology is that any papillary architecture (especially when combined with any degree of nuclear atypia) can lead the unsuspecting cytologist to a diagnosis of PTC. The primary cause for misinterpreting a case of BTN-PH as PTC is not the minimal nuclear atypia; it is first and foremost the presence of papillary structures. A key point of our study is that papillary structures within a thyroid FNAB should not be overinterpreted, particularly when any perceived nuclear atypia is minimal. This is also the reason that BTN-PH lesions are not within the differential diagnosis of the follicular variant of PTC, another problematic entity for which diagnostic concerns are based principally on nuclear atypia, not papillary structures. Therefore, in cases in which BTN-PHs are suspected, it may be better to classify them as either benign, AUS/FLUS, or S-FN, depending on other diagnostic features and sample quality in order to avoid the possibility of total thyroidectomy for benign disease. Because BTN-PHs are true variants of follicular adenomas despite their variable papillary architecture, it is reasonable for management purposes that a subset will be classified as S-FN. Importantly, the S-FN category of the BSRTC does not exclude cases with papillary architecture such as BTN-PH as long as nuclear features of PTC are not present. Although papillary architecture should certainly raise concern for PTC, in and of itself, it does not warrant a diagnosis of S-PTC in the absence of supportive nuclear features, as our series of BTN-PH demonstrates. Recognizing that the nuclear features of PTC are absent or minimal in BTN-PH should help to lead one toward a classification within the BSRTC other than S-PTC. Immunocytochemistry may also help to distinguish BTN-PH from PTC on FNAB. All cases examined in our study were negative for both HBME-1 and galectin-3, although it is important to point out that only a minority 675

Original Article

were actually tested. This is also consistent with the results of previous studies on BTN-PH.8,12 In contrast, most classical PTCs are positive for these markers on cytology.43,44 Conversely, CD117 (c-kit) expression is present in BTN and typically absent in classical PTC, as shown by our group recently.45 Therefore, CD117 may serve as a positive marker for BTN. Although our study did not address the potential use of molecular testing for BTN-PH, there is also a role for such testing in the cytologic and histological assessment of these nodules. The molecular profile of BTN-PH is not well characterized, but given that the presence of papillary structures raises a differential diagnosis of classical PTC, testing to exclude a BRAF mutation or RET/ PTC rearrangement might be useful.46,47 Alternatively, a gene-expression classifier with a high negative predictive value (Afirma, Veracyte, Inc., South San Francisco, CA) might be useful, but it is not known if the Afirma test identifies BTN-PH as “benign.”48 Finally, if there are no worrisome clinical or sonographic features, clinical follow-up with a repeat FNAB may provide a more definite diagnosis. In conclusion, the diagnosis of BTN-PH in a thyroid nodule should be considered for FNAB cases containing papillary structures when the typical nuclear features of PTC are not well developed, when they are not extensive, or when they are admixed with a benign-appearing follicular component. Other cytological clues to the diagnosis of BTN-PH include small nuclear size, cytoplasmic pigment, and absence of cellular swirls. The suspicious for malignancy/S-PTC diagnostic category should be avoided under these circumstances and a lesser category preferred, perhaps supported by immunocytochemical and/or molecular findings.

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FUNDING SUPPORT No specific funding was disclosed.

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CONFLICT OF INTEREST DISCLOSURES

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Marc P. Pusztaszeri received support from the Nuovo-Soldati Foundation for a visiting fellowship to Massachusetts General Hospital, Boston, Massachusetts.

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FNAB of benign thyroid nodules with papillary hyperplasia: a cytological and histological evaluation.

Benign thyroid nodules with papillary hyperplasia (BTN-PH) are sometimes misinterpreted cytologically as papillary thyroid carcinoma (PTC). We evaluat...
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