Original Article
The Value of Second Opinion in Thyroid Cytology A Review Rene Gerhard, MD, PhD1 and Scott L. Boerner, MD, FRCPC2
BACKGROUND: Second-opinion diagnosis (SOD) on pathological material is an accepted practice before definitive therapy is considered for referred patients. The thyroid gland is an anatomical site prone to diagnostic disagreement between pathologists. We performed a review of the literature that addressed the role of interinstitutional SOD on thyroid fineneedle aspirations (FNAs). METHODS: Nine studies comprising second opinions on thyroid FNAs were selected. The parameters analyzed included: discordances between the initial diagnoses (IDs) and SODs; cytohistologic correlation; changes in the clinical management of the patients with thyroid nodules after SOD. The same parameters were applied to the “indeterminate” diagnostic category comprising cases initially reported as “atypia,” “atypia of undetermined significance/follicular lesion of undetermined significance,” “suspicious for a follicular neoplasm,” “follicular neoplasm,” “suspicious,” and “suspicious for malignancy.” RESULTS: A total of 7154 thyroid FNAs were retrieved, showing an overall discordance rate between ID and SOD of 28.6%. In general, SOD was better supported by clinical follow-up and histological diagnosis, showing higher diagnostic accuracy in comparison with ID. Almost one-third (30.4%) of the discordant cases resulted in changes in the clinical management of patients with thyroid nodules. Numerous thyroid FNAs initially categorized as “indeterminate” were definitively classified as benign or malignant by SOD, with an overall diagnostic resolution rate of 42.5%, sensitivity of 97.9%, and diagnostic accuracy of 73.7%. CONCLUSIONS: Second-opinion review of thyroid FNA improves diagnostic accuracy and potentially changes clinical management. SOD also demonstrates a significative rate of diagnostic resolution for thyroid FNAs originally diagnosed as “indeterminate.” Cancer (Cancer CytoC 2014 American Cancer Society. pathol) 2014;000:000-000. V
KEY WORDS: thyroid fine-needle aspiration; second opinion; cytology; clinical management.
INTRODUCTION Second-opinion or interinstitutional review of pathological material is an accepted practice in many institutions before a definitive therapy is initiated for referred patients.1 Several studies addressed the role of a second opinion in surgical pathology material and analyzed the discordances between the initial (outside) and reviewed (inhouse) diagnoses. According to these studies, diagnostic discrepancies that resulted in change of clinical management and/or therapy for the referred patient ranged from 1.2% to 5.8%.2-6 There are some anatomical sites that are more prone to diagnostic disagreements, including the gastrointestinal,5 genitourinary,6 female genital tract,3-5 hematolymphoid system,4,6 serosal surface,3 skin,5 and breast6,7 sites. The thyroid gland is the anatomic site that showed the highest rate of disagreement in a study that analyzed the second-opinion diagnosis of head and neck lesions.8 In another study, a major discrepancy rate of 8% between the original histological diagnosis and the second opinion was found in the examination of a Corresponding author: Scott L. Boerner, Director of Cytopathology, Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, University of Toronto, University Health Network, 200 Elizabeth Street, 11th Floor, Eaton Wing, Toronto, Ontario M5G 2C4, Canada; [email protected] 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Received: February 26, 2014; Revised: April 10, 2014; Accepted: April 11, 2014 Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cncy.21436, wileyonlinelibrary.com
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Original Article
series consisting of 66 cases of thyroid carcinomas.9 Despite well-defined morphological criteria, considerable inter- and intraobserver variability has been described for the histological diagnosis of follicular thyroid carcinoma10,11 and the follicular variant of papillary thyroid carcinoma.10,12 The type of specimen submitted for review is another factor related to discrepant diagnosis, and cytology is claimed to have a higher discordance rate between the original and the reviewed diagnoses compared withsurgical pathology.2,13 However, studies that evaluated large series of second opinions in the field of cytology found discrepancy diagnostic rates similar to those of surgical pathology reviews.14,15 Regarding the thyroid gland, the cytology of thyroid lesions is also subjected to diagnostic variability and disagreement between pathologists, especially for the diagnosis of follicular lesions and follicular neoplasms.16-18 Recently, a meta-analysis of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC)19 demonstrated wide variation in the use of the diagnostic categories “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS), and “follicular neoplasm/suspicious for a follicular neoplasm” (FN/SFN) among the examined publications.20 The purpose of this study was to perform a review of the published studies that addressed the role of second opinion in the field of thyroid cytology. We examined the discordances between the initial and the reviewed (second-opinion) reported diagnoses, as well as the cytohistological correlation and the impact of the reviewed diagnoses on clinical management of patients with thyroid nodules. We also investigated the effect of second opinion in the “indeterminate” thyroid fine-needle aspiration (FNA) results, comprising diagnoses such as AUS/FLUS, FN/SFN, and suspicious for malignancy.
MATERIAL AND METHODS Selection Criteria
The reviewed studies were selected from the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) using the following key words: “interinstitutional consultation” or “second opinion” combined with “cytology” or “thyroid cytology.” We chose studies containing information related to consultation/second opinions from one 2
institution to a referred institution, so that intradepartmental consultations were excluded. Nine publications written in English were selected; 3 of them analyzed thyroid cytological specimens among other types of cytological material and were cited in the Introduction section of the present article.13-15 The other 6 publications specifically evaluated second opinions from thyroid FNA specimens.21-26 General Parameters Analyzed
Selected data were extracted from the publications for further analysis. The parameters that were reported by the studies and that were examined in the present study include: 1) characteristics of the reviewed study (duration of the study, number of cases for each study); 2) the diagnostic discordances between the initial diagnosis (ID) and the second opinion (number of discordant cases, overall discordance rate, discordance rates for specific diagnostic category); 3) correlation with histological diagnosis and clinical follow-up; 4) second-opinion diagnostic performance; 5) changes or potential changes in the clinical management of the patients with thyroid nodules after the second-opinion diagnoses (SODs); and 6) the clinical impact of SOD. “Indeterminate” Diagnostic Category
In the present study, we examined the results of SOD for nondefinitive ID of thyroid FNA specimens. For the purpose of this study, the nondefinitive diagnosis was defined as “indeterminate.” Excluding the nondiagnostic/unsatisfactory results, the following reported IDs were pooled from the reviewed studies to establish the “indeterminate” category: “atypia,” “atypia of undetermined significance/ follicular lesion of undetermined significance” (AUS/ FLUS), “suspicious for a follicular neoplasm” (SFN), “follicular neoplasm” (FN), “suspicious,” and “suspicious for malignancy” (SFM). We further investigated several parameters for the “indeterminate” cytological category: 1) overall discordance rates between ID and SOD; 2) diagnostic resolution rate (number of cases definitively reclassified as benign or malignant on SOD); 3) SOD performance; and 4) potential changes in the clinical management after SOD. Statistical Analysis
Statistical analysis was performed on the data extracted from the reviewed studies. True positives (TPs) were Cancer Cytopathology
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TABLE 1. Summary of the Literature Review Authors
Focus of the Study
Baloch et al Layfield et al Tan et al Lueck et al Bomeisl et al Davidov et al Bajaj et al Park et al Olson et al Total
Thyroid FNAs Cytology specimens Thyroid FNAs Cytology specimens FNAs Thyroid FNAs Thyroid FNAs Thyroid FNAs Thyroid FNAs
No. of Thyroid FNAs
Duration of Study (Years)
Number of Discordant Cases
Rate of Discordance
183 14 147 N/A 173 331 922 1499 3885 7154
1.5 2.0 3.8 1.6 4.3 5.0 2.0 1.0 2.8
110 4 27 9 28 113 122 394 1238 2045
60% 29% 18% N/A 16% 34% 13% 26% 32% 28.6%
Abbreviation: FNAs, fine-needle aspiration biopsies.
defined as SODs of abnormal cytology (“indeterminate” or malignant) and a corresponding histological diagnosis of malignancy. The “indeterminate” category was considered a positive result because this diagnostic category, as defined in the present study, most probably leads to surgical management of the thyroid nodule. On the other hand, true negatives (TNs) were defined as a SODs reported as negative with corresponding benign histology. False-positive (FP) results corresponded to SODs of abnormal cytology in a histologically benign lesion and false-negative (FN) results as SODs reported as negative in a proven malignant lesion by histology. For SODs of “indeterminate” ID, diagnostic performance was calculated according to the following parameters: sensitivity 5 (TP/[TP1FN]); specificity 5 (TN/[TN1FP]); positive predictive value (PPV) 5 (TP/[TP1FP]); negative predictive value (NPV) 5 (TN/[TN1FP]); and accuracy 5 ([TP1TN]/[TP1TN1FP1FN]). These calculations were only performed for the 3 large series that applied the BSRCT terminology to report the SODs.24-26
RESULTS A total of 7154 thyroid FNAs were retrieved from all but 1 of the reviewed studies, ranging from a minimum of 1413 to a maximum of 388526 specimens. In the study of Lueck et al,14 SOD was performed for 499 cytological specimens, including thyroid FNAs, but an actual number of thyroid specimens was not reported. The mean duration of the studies was 2.7 years (range, 15-5.0 years); see Table 1). There were a total of 2045 cases with discordant diagnosis between ID and SOD. The discordance rates were highly variable among the examined studies, ranging Cancer Cytopathology
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from 13%24 to 60%,21 with an overall discordance rate of 28.6% (Table 1). The discordance rates between ID and SOD for specific cytological diagnostic categories were reported by few studies22,23,25 as follows: nondiagnostic, ranging from 12%25 to 33%22; benign, ranging from 9%22 to 23%25; indeterminate, ranging from 21%22 to 87%25; suspicious for malignancy, ranging from 38%22 to 76%25; and malignant, ranging from 5%22 to 14%.23 The discordance rate for the diagnostic category of follicular neoplasm was 70% and was reported only in the study of Park et al.25 Statistically significant changes in the cytological diagnostic categories after SOD were found in the study of Olson et al,26 with an increased number of nondiagnostic, benign, and malignant diagnoses and a decreased number of indeterminate and suspicious categories. Correlation of the cytological findings with the histological diagnosis was reported for 2011 cases, corresponding to 28.1% of the total number of thyroid FNA specimens. The studies of Tan et al22 and Davidov et al23 showed increased numbers of TNs and lower FP results with subsequent improvement in specificity and PPV after SOD. Increased numbers of TPs and higher PPV (with a value of 99.2%) after SOD were found in the study of Olson et al.26 The accuracy of thyroid FNA was improved with SOD: increment rates of 12% (from 73% to 85%) and 14% (from 60% to 74%) in diagnostic accuracy were detected in the studies of Baloch et al21 and Davidov et al,23 respectively. In general, for the discordant diagnosis, SOD was better supported by histological diagnosis and/or clinical follow-up in comparison with ID. In the studies of Bomeisl et al15 and Park et al25 SOD was better supported by surgical or clinical follow-up in 62% and 68.8% of the discordant cases, respectively. 3
Original Article TABLE 2. Clinical Impact and Changes in Clinical Management of Patients With Thyroid Nodules After SOD Parameters Number of thyroid FNA cases Number of discordant cases Number of cases that changed management % Changed patient management Clinical impact of SOD
Tan et al
Lueck et al
Bomeisl et al
Bajaj et al
Park et al
Total
147 27 4 14.8% 2.7%
N/Aa 9 3 33.3% N/Aa
173 21 13 61.9% 7.5%
922 122 75 61.5% 8.1%
1499 394 79 20.1% 5.3%
2741 573 174 30.4% 6.2%
Abbreviations: SOD, second-opinion diagnosis; FNA, fine-needle aspiration biopsy. a Because it was not possible to calculate the clinical impact of the 3 discordant cases reported in the study of Lueck et al, they were excluded from the analysis of the overall clinical impact: 171 discordant cases were included, resulting in an overall clinical impact rate of 6.2%.
TABLE 3. Discordances Between ID and SOD and Diagnostic Resolution Rate Regarding “Indeterminate” Diagnostic Categorya
Authors Baloch et al Layfield et al Tan et al Lueck et al Bomeisl et al Davidov et al Bajaj et al Park et al Olson et al Total
ID 5 “Indeterminate”a
SOD 6¼ “Indeterminate”a
Discordance Rate
Definitively Classified by SOD
Diagnostic Resolution Rate
97 3 81 6 17 129 82 393 1484 2292
74 3 N/Ab 6 N/Ab 81 N/Ab 300 867 1331
76.3% 100.0% N/Ab 100.0% N/Ab 62.8% N/Ab 76.3% 58.4% 63.0%
27 2 N/Ab 6 13 59 39 248 546 940
27.8% 66.7% N/Ab 100.0% 76.5% 45.7% 47.6% 63.1% 36.8% 42.5%
Abbreviations: ID, nitial diagnosis; bSOD, second-opinion diagnosis. a “Indeterminate” diagnostic category includes cases originally classified as “atypia”; “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS); “suspicious for a follicular neoplasm” (SFN); “follicular neoplasm” (FN); “suspicious”; “and suspicious for malignancy” (SFM). b N/A, data not available for the studies of Tan et al, Bomeisl et al, and Bajaj et al.
Data extracted from 5 studies demonstrated that from a total of 573 discordant cases, 30.4% (174 cases) resulted in changes or potential changes in the clinical management of patients with thyroid nodules after SOD.14,15,22,24,25 However, the rates of changes (or potential changes) in the clinical management for the discordant cases were variable among the examined studies: the minimum rate, 14.8%, was found in the study of Tan et al,22 and rates above 60% were encountered in the studies of both Bomeisl et al15 and Bajaj et al24 (Table 2). In their series, Park et al25 carefully analyzed the type of changes in clinical management after SOD: 44% of the patients were changed from surgical to medical management; 25% from medical to surgical management; 22% had changes in the type of medical management (clinical follow-up or repeat FNA); and 9% had changes in the type of surgical procedure (lobectomy vs total thyroidectomy). In another study, an alteration from medical to surgical procedure was observed in 54% of the patients who underwent a change in clinical management after SOD.15 The clinical impact of SOD was calculated as the ratio between the number of discordant cases that resulted 4
in changes or potential changes in clinical management and the total number of concordant and discordant cases. Regarding the studies of Tan et al,22 Bomeisl et al,15 Bajaj et al,24 and Park et al,25 the overall clinical impact of SOD was 6.2%, corresponding to 171 discordant cases that resulted in modifications of clinical management in a total series of 2741 thyroid FNAs. The highest clinical impact rate was 8.1%,and was found in the series of Bajaj et al,24 in which from a total of 922 patients with thyroid FNAs, 75 had discordances between ID and SOD that resulted in some kind of change of medical or surgical management (Table 2). As defined in the present study, there were 2292 IDs that fitted in the “indeterminate” diagnostic category, corresponding to 32% of the total number of thyroid FNA specimens. With the exception of 3 studies,15,22,24 it was possible to calculate the discordance rate for the “indeterminate” diagnostic category: from a total of 2112 IDs in this diagnostic category, 1331 cases were discordant according to SOD, resulting in an overall discordance rate of 63% (Table 3). We also verified that for all but 122 of the examined studies, comprising 2211 IDs categorized Cancer Cytopathology
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TABLE 4. Distribution of Reclassified Diagnoses (SODs) according to BSRTC Terminology BSRTC Diagnostic Category Nondiagnostic Benign AUS/FLUS FN/SFN SFM Malignant Total
TABLE 5. Cytohistological Correlation for Thyroid FNAs with ID Classified in the “Indeterminate” Diagnostic Categorya
n
%
106 579 530 332 303 361 2211
4.8 26.2 24.0 15.0 13.7 16.3 100.0
Abbreviations: SOD, second-opinion diagnosis; BSRTC, Bethesda System for Reporting Thyroid Cytopathology; AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FN/SFN, follicular neoplasm/suspicious for a follicular neoplasm; SFM, suspicious for malignancy.
as “indeterminate,” 940 cases were definitively classified as benign (579 cases, 26.2%) or malignant (361 cases, 16.3%) by SOD, with an overall diagnostic resolution rate of 42.5% (Table 3). SOD was not definitively diagnostic for the remaining cases that were reclassified as nondiagnostic (106 cases, 4.8%) or persisted as “indeterminate” (1165 cases, 52.7%). The detailed distribution of the reclassified diagnoses according to BSRTC terminology is shown in Table 4. However, as shown in Table 3, both the discordance and diagnostic resolution rates for the “indeterminate” diagnostic category were highly variable among the examined studies. It was possible to outline SOD performance for the “indeterminate” diagnostic category according to data pooled from the 3 studies with the largest series of thyroid FNAs.24-26 The cytohistological correlation of 702 cases with IDs classified in the “indeterminate” diagnostic category showed a malignant rate of 65.1% (Table 5). From these 702 cases, SOD showed a sensitivity of 98.7% and a specificity of 32.7%, with a FN rate of 0.9% and a FP rate of 23.5%. The PPV, NPV and overall accuracy for SOD were 73.2%, 93.0%, and 75.6%, respectively (Table 6). We also stratified the “indeterminate” diagnostic category into 3 subcategories: atypia/AUS/FLUS (151 cases, 21.5%), SFN/FN (161 cases, 22.9%), and suspicious/ SFM (390 cases, 55.6%), as shown in Table 5. Next, we calculated the SOD performance for each of the 3 diagnostic subcategories (Table 6). Potential changes in the clinical management of patients with thyroid FNA results classified as “indeterminate” were also investigated. Data from 6 studies,14,15,22,24-26 comprising 893 patients with IDs fitted in the “indeterminate” diagnostic category, showed that after SOD 508 patients (56.9%) would be clinically Cancer Cytopathology
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Total ID Atypia/AUS/FLUS SFN/FN Suspicious/SFM Total
Benign Histology
Malignant Histology
n
%
n
%
n
%
151 161 390 702
21.5 22.9 55.6 100.0
82 128 35 245
54.3 79.5 9.0 34.9
69 33 355 457
45.7 20.5 91.0 65.1
Abbreviations: ID, initial diagnosis; AUS/FLUS, “atypia of undetermined significance/follicular lesion of undetermined significance”; SEN, “suspicious for a follicular neoplasm”; FN, “follicular neoplasm”; SEM, “suspicious for malignancy”. a “Indeterminate” diagnostic category includes cases originally classified as “atypia”; AUS/FLUS, SFN, FN, “suspicious,” and SFM.
TABLE 6. SOD Performance for Thyroid FNAs With ID Classified in “Indeterminate” Diagnostic Categorya ID: Atypia/ Parameter AUS
ID: SFN/ FN
ID: Suspicious/ SFM
ID: “Indeterminate”a
Rate of FN Rate of FP Sensitivity Specificity PPV NPV Accuracy
1.2% 59.6% 93.9% 25.0% 24.4% 94.1% 39.1%
0.5% 7.2% 99.4% 20.0% 92.7% 77.8% 92.3%
0.9% 23.5% 98.7% 32.7% 73.2% 93.0% 75.6%
1.3% 27.2% 97.1% 50.0% 62.0% 95.3% 71.5%
Abbreviations: SOD, second-opinion diagnosis; ID, initial diagnosis; AUS/ FLUS, “atypia of undetermined significance/follicular lesion of undetermined significance”; SEN/FN, “suspicious for a follicular neoplasm/ follicular neoplasm”; SEM, “suspicious for malignancy; FN, false-negative results; FP, false-positive results; PPV, positive predictive value; NPV, negative predictive value. a “Indeterminate” diagnostic category includes cases originally classified as “atypia”; AUS/FLUS, SFN/FN), “suspicious,” and SFM.
followed up, 203 (22.7%) would have a repeat FNA, and 182 (20.4%) would be submitted to thyroidectomy for histological diagnosis. In the study of Davidov et al,23 avoidance of surgery after SOD was reported for 25% of the patients in the “indeterminate” diagnostic category: from a total of 129 patients with IDs in this category, 32 were spared from surgical procedures.
DISCUSSION This review found 7154 thyroid FNAs and an overall discordance rate of 28.6% among studies that investigated interinstitutional review or second-opinion diagnosis for thyroid cytological specimens.14,15,21-26 Consultation or 5
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second opinion on pathological material is an important and recognized practice among pathologists and different laboratories. In fact, recommendations regarding personal or interinstitutional consultations were published more than 20 years ago.27 Because diagnostic discrepancies between the original and the reviewed diagnoses have been reported by several studies, SOD is considered a safety practice in the context of interinstitutional consultations and may detect diagnostic errors that could result in potential changes in clinical management for the referred patients.3,5,13 Weir et al,4 for example, analyzed 1000 interinstitutional pathology consultations and found that 70% of the diagnostic discordances with clinical relevance resulted from interpretation differences between the original and the referred institutions. Although not unfailing, studies have shown that SOD is frequently better corroborated by clinicopathological follow-up when compared with ID.2,4,15,25 In the study of Manion et al5 that analyzed surgical pathology material, SOD was supported by clinical or pathological follow-up in 83% of the cases classified as major diagnostic discordances. In the field of cytology, the validation of a cytological diagnosis is usually performed by comparison with the corresponding histological diagnosis (the “gold standard” test).28 In this review, we found that 4 studies reported higher PPV values22,23,26 or higher diagnostic accuracy rates21,23 after SOD, meaning that SOD provided a more correct diagnosis compared with the IDs. For the current study, we have to acknowledge that the better results of SOD may be a potential bias because the selected studies were performed in large medical centers with experience in the field of cytopathology. Despite SOD being better validated by cytohistological correlation, observer variation and diagnostic discrepancies still remain an issue in thyroid pathology,8,9 especially for follicular-pattern lesions in both cytology16-18 and histology.10-12 Among the reviewed studies, few reported the discordance rates for specific diagnostic categories of thyroid FNAs.22,23,25 As expected, the highest discordance rates were found in the “indeterminate,” “follicular neoplasm,” and “suspicious for malignancy” diagnostic categories, as observed in the study of Park et al.25 Well-defined morphological criteria as well as standardized diagnostic terminology such as the BSRTC19 are intended to diminish observer variation between pathologists/laboratories and to provide better communication with clinicians. However, marked vari6
ability has been found in classifying a thyroid FNA specimen using standardized terminology. In fact, the reported incidence of AUS/FLUS ranged from 0.7% to 27%20,29 and for SFN/FN from 2% to 24% in studies that reviewed large series that applied the BSRTC terminology to thyroid FNA aspirates.20,30 We investigated the effect of SOD in the “indeterminate” diagnostic category of thyroid FNAs. Because the terminology classification was not uniform among the reviewed studies—the BSRTC19 was appropriately used in 3 of the selected studies24-26—we classified a thyroid FNA case as “indeterminate” when the ID was reported as satisfactory but not definitively diagnostic, that is, neither benign nor malignant. Using these criteria, we encountered 2292 IDs (32.0% of thyroid FNAs) in the “indeterminate” diagnostic category. In contrast, analyzing data from 25,445 thyroid FNAs, Bongiovanni et al20 found 5692 “indeterminate” cases (22.4%) including 2441 cases (9.6%) diagnosed as AUS/FLUS, 2571 cases (10.1%) diagnosed as FN/SFN, and 680 cases (2.7%) diagnosed as suspicious for malignancy. The higher rate of “indeterminate” thyroid FNAs found in our review may be explained by the selected studies analyzing interinstitutional consultations. Olson et al,26 for example, observed that the diagnostic rate for the indeterminate category was still high (15%) after SOD and exceeded the rate of 7% recommended by the BSRTC.19 The authors explained that a growing number of patients with indeterminate thyroid FNAs were referred for diagnostic review at their institution.26 The cytological features of a thyroid FNA classified as AUS/FLUS include cellular abnormalities that are more pronounced than benign changes but are not completely sufficient for a diagnosis of SFN/FN, suspicious for malignancy, or malignant.19,31 Repeat FNA is the recognized management for patients with a cytological diagnosis of AUS/FLUS and usually results in a definitive diagnosis.19 In a study published by Onder et al,32 56% of the thyroid FNAs initially diagnosed as AUS/FLUS were reclassified as either benign or malignant after repeat FNA. Jing et al33 demonstrated that consensus review may also have a role in the evaluation of thyroid nodules belonging to the “indeterminate” diagnostic category. From 50 cases initially diagnosed as AUS/FLUS, a definitive diagnosis was obtained for 27 cases (54%), including 26 cases (52%) reclassified as nonneoplastic/benign and 1 case (2%) reclassified as malignant. A lower overall Cancer Cytopathology
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diagnostic resolution rate (42.5%) after SOD was demonstrated in the present review. However, the diagnostic resolution rate for the “indeterminate” diagnostic category was highly variable among the reviewed studies, ranging from 27.8% to 100%. Furthermore, as defined in this review, the “indeterminate” diagnostic category comprises a broader and more heterogeneous group of lesions compared with the AUS/FLUS category of the BSRTC, including cases originally reported as SFN, FN, and SFM. A potential bias of the present study is the heterogeneous classification of the type of discrepancy and the diagnostic terminology reported among the selected studies. In fact, 2 of the studies that used the BSRTC were more specific regarding the classification of discrepancies. Bajaj et al,24 for example, classified the discordances as minor and major disagreements corresponding to 1- to 2-step deviation of BSRTC terminology. As expected, they verified a higher rate of changes in clinical management in the group of major disagreements compared with those of minor disagreements. Park et al25 also included detailed data comparing ID, SOD, type of change in clinical mangement (medical vs surgery, alteration of the type of surgery, etc.) for each category of the BSRTC terminology. Because of the heterogeneity of the reported results regarding the types of discrepancies in the majority of the studies, we did not try to use stricter criteria to classify the discrepancies such as those used in the study of Bajaj et al.24 The heterogeneity of the diagnostic thyroid FNA terminology may also explain some discrepancies between our review and other studies. When we stratified the “indeterminate” diagnostic category into 3 subcategories (AUS/FLUS [III], SFN/FN [IV], and SFM [V] of the BSRTC terminology), for example, expressive differences in the malignant rates were found compared with those published in the meta-analysis of Bongiovanni et al.20 In their study, the malignant rates for BSRTC diagnostic categories III, IV, and V were 15.9%, 26.1%, and 75.2%, respectively. In contrast, we found higher malignant rates such as 45.7% for category III and 91.0% for category V. A possible explanation for our high rate of malignancy for diagnostic category III may be related to the inclusion of thyroid FNA specimens with primary diagnosis reported as “atypia” in the study of Park et al.25 We cannot exclude that many thyroid specimens originally reported as “atypia” could represent cases with some cytological features of a papillary thyroid carcinoma. We can speculate that a lower rate of malignancy would be Cancer Cytopathology
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expected if the cases reported as “atypia” were excluded from BSRTC category III in the study of Park et al.25 A similar comment is valid for the high rate of malignancy found in BSRTC diagnostic category V. Again, the results were mostly influenced by the study of Park et al.25 First, their study contributed 300 thyroid FNAs originally called “suspicious for malignancy,” which represent, as shown in Table 5, the majority of the cases analyzed in this diagnostic category. Second, they showed that 95% of those cases were malignant on clinicopathological follow-up. It is highly probable that a significative number of those cases may represent an “undercall” bias of the original diagnoses. If so, a lower rate of malignancy would be estimated for BSRTC diagnostic category V in our analysis. The different malignant rates for BSRTC diagnostic category IV observed in our review and in the study of Bongiovanni et al20 were expected. A recent meta-analysis that evaluated the cytological diagnosis SFN before and after the introduction of BSRTC terminology showed highly variable rates of malignancy among 33 studies, ranging from 9.5% to 47.4%. Interestingly, the authors found that after the introduction of BSRCT terminology, there was a statistically significant increase in both the malignancy and surgical follow-up rates for the diagnostic category of SFN, which means that standardized terminology ensures appropriate patient management.30 FNA is considered an essential method for the initial approach to patients with thyroid nodules. This procedure accurately diagnoses the majority of thyroid nodules, distinguishing nonneoplastic lesions from malignant ones. Hence, the initial management of a patient with a thyroid nodule is largely based on the results of the cytological examination of thyroid FNA specimens.34,35 For patients with thyroid nodules who are referred from one institution to another for treatment consideration, review of the cytological material is an important step because of the potential change in clinical management. Although a small rate (6.2%) of overall clinical impact of SOD was found in our review, we have also shown that for the group of patients with discordant cytological diagnoses, almost one-third (30.4%) were considered for changes or potential changes in clinical management. In the study of Park et al,25 the majority of the patients were changed from surgical to medical management, and one-fourth were altered from clinical management to a surgical procedure. Regarding the “indeterminate” diagnostic category, 7
Original Article
we have shown that after SOD the majority of patients (56.9%) would be managed with clinical follow-up, and only one-fifth would be submitted to thyroidectomy. Finally, Davidov et al23 observed that 25% of patients with a thyroid FNA originally classified as “indeterminate” were spared from surgical treatment after revision of their diagnoses. However, it is difficult to accurately evaluate the role of SOD in patient management. Indeed, changes in clinical management take into account several factors such as age, sex, characteristics of the nodule on physical examination, and scintigraphic and ultrasonographic findings. Especially in the context of referred patients, the clinical decision is not only based on cytology. There are important issues regarding second opinion on pathological material, such as consumption of a pathologist’s time reviewing the original specimens and costs related to professional reimbursement. However, a considerable reduction of costs would be achieved if one considers that an accurate diagnosis prevents inappropriate treatment5,15 and if resource consumption of the alternatives (ie, repeat sampling or clinical follow-up) is entered into the analysis. Second opinion and consensus review of thyroid FNA specimens are important tools to achieve accurate diagnoses resulting in correct management of patients by avoiding unnecessary surgeries and, consequently, saving costs. Bajaj et al,24 for example, estimated a cost saving of approximately a million dollars because 33 patients with thyroid nodules were spared from surgery (thyroidectomy) based on SOD. Concerning the 7154 thyroid FNA consultations of this review, the 6.2% overall clinical impact rate of SOD seems small. However, as previously discussed, the clinical impact was significant for the patients with discordant cytological diagnoses, changing clinical management in nearly 30% of the patients belonging to this group. Even if the rates of clinical impact for major diagnostic discrepancies are not high according to the literature data for both surgical pathology2-6 and cytology,15,22,24,25 inappropriate management may result in significant morbidity, expensive health care costs, and potential litigations. In summary, this review showed that second opinions of thyroid FNA specimens improve diagnostic accuracy and potentially change the clinical management of patients with thyroid nodules. SOD also demonstrated a significant rate of diagnostic resolution for thyroid FNAs originally diagnosed as “indeterminate,” establishing 8
definitive diagnoses and enhanced accuracy. We believe that second-opinion review of thyroid FNA specimens is highly beneficial for patients referred from one institution to another and should be recommended as an standardized practice. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
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Gupta D, Layfield LJ. Prevalence of inter-institutional anatomic pathology slide review: a survey of current practice. Am J Surg Pathol. 2000;24:280-284. Abt AB, Abt LG, Olt GJ. The effect of interinstitutional anatomic pathology consultations on patient care. Arch Pathol Lab Med. 1995;119:514-517. Kronz JD, Westra WH, Epstein JI. Mandatory second opinion surgical pathology at a large referral hospital. Cancer 1999;86:24262435. Weir MM, Jan E, Colgan TJ. Interinstitutional pathology consultations: a reassessment. Am J Clin Pathol. 2003;120:405-412. Manion E, Cohen MB, Weydert J. Mandatory second opinion in surgical pathology referral material: clinical consequences of major disagreements. Am J Surg Pathol 2008;32: 732-737. Renshaw AA, Gould EW. Reducing false-negative and falsepositive diagnoses in anatomic pathology consultation material. Arch Pathol Lab Med. 2013;137:1770-1773. Frable WJ. Surgical pathology—second reviews, institutional reviews, audits, and correlations. Arch Pathol Lab Med. 2006;130: 620-625. Kronz JD, Westra WH. The role of second opinion pathology in the management of lesions of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 2005;13:81-84. Hamady ZZR, Mather N, Lansdown MR, Davidson L, Maclennan KA. Surgical pathology second opinion in thyroid malignancy: impact on patient S management and prognosis. EJSO. 2005;31: 74-77. Hirokawa M, Carney JA, Goellner JR, et al. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol. 2002;26:1508-1514. Franc B, de la Salmoniere P, Lange F, et al. Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Hum Pathol. 2003;34:1092-1100. Elsheikh TM, Asa SL, Chan JK, et al. Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol. 2008;130:736-744. Layfield LJ, Jones C, Rowe L, Gopez EV. Institutional review of outside cytology materials: a retrospective analysis of two institutions S experiences. Diagn Cytopathol. 2002;26:45-48. Lueck N, Jensen C, Cohen MB, Weydert JA. Mandatory second opinion in cytopathology. Cancer Cytopathol. 2009;117:82-91. Bomeisl PE, Alam S, Wakely PE. Interinstitutional consultation in fine-needle aspiration cytopathology. Cancer Cytopathol. 2009;117: 237-246. Clary KM, Condel JL, Liu Y, Johnson DR, Grzybicki DM, Raab SS. Interobserver variability in the fine needle aspiration biopsy
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diagnosis of follicular lesions of the thyroid gland. Acta Cytol. 2005;49:378-382. Stelow EB, Bardales RH, Crary GS, et al. Interobserver variability in thyroid fine-needle aspiration interpretation of lesions showing predominantly colloid and follicular groups. Am J Clin Pathol. 2005;124:239-244. Gerhard R, da Cunha Santos G. Inter- and intraobserver reproducibility of thyroid fine needle aspiration cytology: an analysis of discrepant cases. Cytopathology. 2007;18:105-111. Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol. 2009;132:658-665. Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytol. 2012;56:333-339. Baloch ZW, Hendreen S, Gupta PK, et al. Interinstitutional review of thyroid fine-needle aspirations: impact on clinical management of thyroid nodules. Diagn Cytopathol. 2001;25:231-234. Tan YY, Kebebew E, Reiff E, et al. Does routine consultation of thyroid fine-needle aspiration cytology change surgical management? J Am Coll Surg. 2007;05:8-12. Davidov T, Trooskin SZ, Shanker B-A, et al. Routine secondopinion cytopathology review of thyroid fine needle aspiration biopsies reduces diagnostic thyroidectomy. Surgery. 2010;48:12941301. Bajaj J, Morgenstein N, Sugrue C, Wasserman J, Wasserman P. Clinical impact of second opinion in thyroid fine needle aspiration cytology (FNAC): a study of 922 interinstitutional consultations. Diagn Cytopathol. 2012;40:422-429. Park JH, Kim HK, Kang S-W, et al. Second opinion in thyroid fine-needle aspiration biopsy by the Bethesda system. Endocr J. 2012;59:205-212. Olson MT, Boonyaarunnate T, Han PA, Umbricht CB, Ali SZ, Zeiger MA. A tertiary center’s experience with second opinion
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review of 3885 thyroid cytopathology specimens. J Clin Endocrinol Metab. 2013;98:1450-1457. Association of Directors of Anatomic and Surgical Pathology. Consultations in surgical pathology. Am J Surg Pathol. 1993;17:743745. Clary KM, Silverman JF, Liu Y, et al. Cytohistologic discrepancies: a means to improve pathology practice and patient outcome. Am J Clin Pathol. 2002;117:567-573. Ohori NP, Schoedel KE. Variability in the atypia of undetermined significance/follicular lesion of undetermined significance diagnosis in the Bethesda system for reporting cytopathology: sources and recommendations. Acta Cytol. 2011;55:492-498. Boonyaarunnate T, Olson MT, Ali SZ. Suspicious for a follicular neoplasm before and after the Bethesda system for reporting thyroid cytopathology: impact of standardized terminology. Acta Cytol. 2013;57:455-463. Bongiovanni M, Krane JF, Cibas ES, Faquin WC. The atypical thyroid fine-needle aspiration: past, present, and future. Cancer Cytopathol. 2012;120:73-86. Onder S, Firat P, Ates D. The Bethesda system for reporting thyroid cytopathology: an institutional experience of the outcome of indeterminate categories. Cytopathology. 2013 [Epub ahead of print]. Jing X, Knoepp SM, Roh MH, et al. Group consensus review minimizes the diagnosis of follicular lesion of undetermined significance and improves cytohistologic concordance. Diagn Cytopathol. 2012;40:1037-1042. Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA Cancer J Clin. 2009;59:99-110. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19: 1167-1214.
9
The Value of Second Opinion in Thyroid Cytology A Review Rene Gerhard, MD, PhD1 and Scott L. Boerner, MD, FRCPC2
BACKGROUND: Second-opinion diagnosis (SOD) on pathological material is an accepted practice before definitive therapy is considered for referred patients. The thyroid gland is an anatomical site prone to diagnostic disagreement between pathologists. We performed a review of the literature that addressed the role of interinstitutional SOD on thyroid fineneedle aspirations (FNAs). METHODS: Nine studies comprising second opinions on thyroid FNAs were selected. The parameters analyzed included: discordances between the initial diagnoses (IDs) and SODs; cytohistologic correlation; changes in the clinical management of the patients with thyroid nodules after SOD. The same parameters were applied to the “indeterminate” diagnostic category comprising cases initially reported as “atypia,” “atypia of undetermined significance/follicular lesion of undetermined significance,” “suspicious for a follicular neoplasm,” “follicular neoplasm,” “suspicious,” and “suspicious for malignancy.” RESULTS: A total of 7154 thyroid FNAs were retrieved, showing an overall discordance rate between ID and SOD of 28.6%. In general, SOD was better supported by clinical follow-up and histological diagnosis, showing higher diagnostic accuracy in comparison with ID. Almost one-third (30.4%) of the discordant cases resulted in changes in the clinical management of patients with thyroid nodules. Numerous thyroid FNAs initially categorized as “indeterminate” were definitively classified as benign or malignant by SOD, with an overall diagnostic resolution rate of 42.5%, sensitivity of 97.9%, and diagnostic accuracy of 73.7%. CONCLUSIONS: Second-opinion review of thyroid FNA improves diagnostic accuracy and potentially changes clinical management. SOD also demonstrates a significative rate of diagnostic resolution for thyroid FNAs originally diagnosed as “indeterminate.” Cancer (Cancer CytoC 2014 American Cancer Society. pathol) 2014;000:000-000. V
KEY WORDS: thyroid fine-needle aspiration; second opinion; cytology; clinical management.
INTRODUCTION Second-opinion or interinstitutional review of pathological material is an accepted practice in many institutions before a definitive therapy is initiated for referred patients.1 Several studies addressed the role of a second opinion in surgical pathology material and analyzed the discordances between the initial (outside) and reviewed (inhouse) diagnoses. According to these studies, diagnostic discrepancies that resulted in change of clinical management and/or therapy for the referred patient ranged from 1.2% to 5.8%.2-6 There are some anatomical sites that are more prone to diagnostic disagreements, including the gastrointestinal,5 genitourinary,6 female genital tract,3-5 hematolymphoid system,4,6 serosal surface,3 skin,5 and breast6,7 sites. The thyroid gland is the anatomic site that showed the highest rate of disagreement in a study that analyzed the second-opinion diagnosis of head and neck lesions.8 In another study, a major discrepancy rate of 8% between the original histological diagnosis and the second opinion was found in the examination of a Corresponding author: Scott L. Boerner, Director of Cytopathology, Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, University of Toronto, University Health Network, 200 Elizabeth Street, 11th Floor, Eaton Wing, Toronto, Ontario M5G 2C4, Canada; [email protected] 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Received: February 26, 2014; Revised: April 10, 2014; Accepted: April 11, 2014 Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cncy.21436, wileyonlinelibrary.com
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Original Article
series consisting of 66 cases of thyroid carcinomas.9 Despite well-defined morphological criteria, considerable inter- and intraobserver variability has been described for the histological diagnosis of follicular thyroid carcinoma10,11 and the follicular variant of papillary thyroid carcinoma.10,12 The type of specimen submitted for review is another factor related to discrepant diagnosis, and cytology is claimed to have a higher discordance rate between the original and the reviewed diagnoses compared withsurgical pathology.2,13 However, studies that evaluated large series of second opinions in the field of cytology found discrepancy diagnostic rates similar to those of surgical pathology reviews.14,15 Regarding the thyroid gland, the cytology of thyroid lesions is also subjected to diagnostic variability and disagreement between pathologists, especially for the diagnosis of follicular lesions and follicular neoplasms.16-18 Recently, a meta-analysis of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC)19 demonstrated wide variation in the use of the diagnostic categories “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS), and “follicular neoplasm/suspicious for a follicular neoplasm” (FN/SFN) among the examined publications.20 The purpose of this study was to perform a review of the published studies that addressed the role of second opinion in the field of thyroid cytology. We examined the discordances between the initial and the reviewed (second-opinion) reported diagnoses, as well as the cytohistological correlation and the impact of the reviewed diagnoses on clinical management of patients with thyroid nodules. We also investigated the effect of second opinion in the “indeterminate” thyroid fine-needle aspiration (FNA) results, comprising diagnoses such as AUS/FLUS, FN/SFN, and suspicious for malignancy.
MATERIAL AND METHODS Selection Criteria
The reviewed studies were selected from the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) using the following key words: “interinstitutional consultation” or “second opinion” combined with “cytology” or “thyroid cytology.” We chose studies containing information related to consultation/second opinions from one 2
institution to a referred institution, so that intradepartmental consultations were excluded. Nine publications written in English were selected; 3 of them analyzed thyroid cytological specimens among other types of cytological material and were cited in the Introduction section of the present article.13-15 The other 6 publications specifically evaluated second opinions from thyroid FNA specimens.21-26 General Parameters Analyzed
Selected data were extracted from the publications for further analysis. The parameters that were reported by the studies and that were examined in the present study include: 1) characteristics of the reviewed study (duration of the study, number of cases for each study); 2) the diagnostic discordances between the initial diagnosis (ID) and the second opinion (number of discordant cases, overall discordance rate, discordance rates for specific diagnostic category); 3) correlation with histological diagnosis and clinical follow-up; 4) second-opinion diagnostic performance; 5) changes or potential changes in the clinical management of the patients with thyroid nodules after the second-opinion diagnoses (SODs); and 6) the clinical impact of SOD. “Indeterminate” Diagnostic Category
In the present study, we examined the results of SOD for nondefinitive ID of thyroid FNA specimens. For the purpose of this study, the nondefinitive diagnosis was defined as “indeterminate.” Excluding the nondiagnostic/unsatisfactory results, the following reported IDs were pooled from the reviewed studies to establish the “indeterminate” category: “atypia,” “atypia of undetermined significance/ follicular lesion of undetermined significance” (AUS/ FLUS), “suspicious for a follicular neoplasm” (SFN), “follicular neoplasm” (FN), “suspicious,” and “suspicious for malignancy” (SFM). We further investigated several parameters for the “indeterminate” cytological category: 1) overall discordance rates between ID and SOD; 2) diagnostic resolution rate (number of cases definitively reclassified as benign or malignant on SOD); 3) SOD performance; and 4) potential changes in the clinical management after SOD. Statistical Analysis
Statistical analysis was performed on the data extracted from the reviewed studies. True positives (TPs) were Cancer Cytopathology
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TABLE 1. Summary of the Literature Review Authors
Focus of the Study
Baloch et al Layfield et al Tan et al Lueck et al Bomeisl et al Davidov et al Bajaj et al Park et al Olson et al Total
Thyroid FNAs Cytology specimens Thyroid FNAs Cytology specimens FNAs Thyroid FNAs Thyroid FNAs Thyroid FNAs Thyroid FNAs
No. of Thyroid FNAs
Duration of Study (Years)
Number of Discordant Cases
Rate of Discordance
183 14 147 N/A 173 331 922 1499 3885 7154
1.5 2.0 3.8 1.6 4.3 5.0 2.0 1.0 2.8
110 4 27 9 28 113 122 394 1238 2045
60% 29% 18% N/A 16% 34% 13% 26% 32% 28.6%
Abbreviation: FNAs, fine-needle aspiration biopsies.
defined as SODs of abnormal cytology (“indeterminate” or malignant) and a corresponding histological diagnosis of malignancy. The “indeterminate” category was considered a positive result because this diagnostic category, as defined in the present study, most probably leads to surgical management of the thyroid nodule. On the other hand, true negatives (TNs) were defined as a SODs reported as negative with corresponding benign histology. False-positive (FP) results corresponded to SODs of abnormal cytology in a histologically benign lesion and false-negative (FN) results as SODs reported as negative in a proven malignant lesion by histology. For SODs of “indeterminate” ID, diagnostic performance was calculated according to the following parameters: sensitivity 5 (TP/[TP1FN]); specificity 5 (TN/[TN1FP]); positive predictive value (PPV) 5 (TP/[TP1FP]); negative predictive value (NPV) 5 (TN/[TN1FP]); and accuracy 5 ([TP1TN]/[TP1TN1FP1FN]). These calculations were only performed for the 3 large series that applied the BSRCT terminology to report the SODs.24-26
RESULTS A total of 7154 thyroid FNAs were retrieved from all but 1 of the reviewed studies, ranging from a minimum of 1413 to a maximum of 388526 specimens. In the study of Lueck et al,14 SOD was performed for 499 cytological specimens, including thyroid FNAs, but an actual number of thyroid specimens was not reported. The mean duration of the studies was 2.7 years (range, 15-5.0 years); see Table 1). There were a total of 2045 cases with discordant diagnosis between ID and SOD. The discordance rates were highly variable among the examined studies, ranging Cancer Cytopathology
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from 13%24 to 60%,21 with an overall discordance rate of 28.6% (Table 1). The discordance rates between ID and SOD for specific cytological diagnostic categories were reported by few studies22,23,25 as follows: nondiagnostic, ranging from 12%25 to 33%22; benign, ranging from 9%22 to 23%25; indeterminate, ranging from 21%22 to 87%25; suspicious for malignancy, ranging from 38%22 to 76%25; and malignant, ranging from 5%22 to 14%.23 The discordance rate for the diagnostic category of follicular neoplasm was 70% and was reported only in the study of Park et al.25 Statistically significant changes in the cytological diagnostic categories after SOD were found in the study of Olson et al,26 with an increased number of nondiagnostic, benign, and malignant diagnoses and a decreased number of indeterminate and suspicious categories. Correlation of the cytological findings with the histological diagnosis was reported for 2011 cases, corresponding to 28.1% of the total number of thyroid FNA specimens. The studies of Tan et al22 and Davidov et al23 showed increased numbers of TNs and lower FP results with subsequent improvement in specificity and PPV after SOD. Increased numbers of TPs and higher PPV (with a value of 99.2%) after SOD were found in the study of Olson et al.26 The accuracy of thyroid FNA was improved with SOD: increment rates of 12% (from 73% to 85%) and 14% (from 60% to 74%) in diagnostic accuracy were detected in the studies of Baloch et al21 and Davidov et al,23 respectively. In general, for the discordant diagnosis, SOD was better supported by histological diagnosis and/or clinical follow-up in comparison with ID. In the studies of Bomeisl et al15 and Park et al25 SOD was better supported by surgical or clinical follow-up in 62% and 68.8% of the discordant cases, respectively. 3
Original Article TABLE 2. Clinical Impact and Changes in Clinical Management of Patients With Thyroid Nodules After SOD Parameters Number of thyroid FNA cases Number of discordant cases Number of cases that changed management % Changed patient management Clinical impact of SOD
Tan et al
Lueck et al
Bomeisl et al
Bajaj et al
Park et al
Total
147 27 4 14.8% 2.7%
N/Aa 9 3 33.3% N/Aa
173 21 13 61.9% 7.5%
922 122 75 61.5% 8.1%
1499 394 79 20.1% 5.3%
2741 573 174 30.4% 6.2%
Abbreviations: SOD, second-opinion diagnosis; FNA, fine-needle aspiration biopsy. a Because it was not possible to calculate the clinical impact of the 3 discordant cases reported in the study of Lueck et al, they were excluded from the analysis of the overall clinical impact: 171 discordant cases were included, resulting in an overall clinical impact rate of 6.2%.
TABLE 3. Discordances Between ID and SOD and Diagnostic Resolution Rate Regarding “Indeterminate” Diagnostic Categorya
Authors Baloch et al Layfield et al Tan et al Lueck et al Bomeisl et al Davidov et al Bajaj et al Park et al Olson et al Total
ID 5 “Indeterminate”a
SOD 6¼ “Indeterminate”a
Discordance Rate
Definitively Classified by SOD
Diagnostic Resolution Rate
97 3 81 6 17 129 82 393 1484 2292
74 3 N/Ab 6 N/Ab 81 N/Ab 300 867 1331
76.3% 100.0% N/Ab 100.0% N/Ab 62.8% N/Ab 76.3% 58.4% 63.0%
27 2 N/Ab 6 13 59 39 248 546 940
27.8% 66.7% N/Ab 100.0% 76.5% 45.7% 47.6% 63.1% 36.8% 42.5%
Abbreviations: ID, nitial diagnosis; bSOD, second-opinion diagnosis. a “Indeterminate” diagnostic category includes cases originally classified as “atypia”; “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS); “suspicious for a follicular neoplasm” (SFN); “follicular neoplasm” (FN); “suspicious”; “and suspicious for malignancy” (SFM). b N/A, data not available for the studies of Tan et al, Bomeisl et al, and Bajaj et al.
Data extracted from 5 studies demonstrated that from a total of 573 discordant cases, 30.4% (174 cases) resulted in changes or potential changes in the clinical management of patients with thyroid nodules after SOD.14,15,22,24,25 However, the rates of changes (or potential changes) in the clinical management for the discordant cases were variable among the examined studies: the minimum rate, 14.8%, was found in the study of Tan et al,22 and rates above 60% were encountered in the studies of both Bomeisl et al15 and Bajaj et al24 (Table 2). In their series, Park et al25 carefully analyzed the type of changes in clinical management after SOD: 44% of the patients were changed from surgical to medical management; 25% from medical to surgical management; 22% had changes in the type of medical management (clinical follow-up or repeat FNA); and 9% had changes in the type of surgical procedure (lobectomy vs total thyroidectomy). In another study, an alteration from medical to surgical procedure was observed in 54% of the patients who underwent a change in clinical management after SOD.15 The clinical impact of SOD was calculated as the ratio between the number of discordant cases that resulted 4
in changes or potential changes in clinical management and the total number of concordant and discordant cases. Regarding the studies of Tan et al,22 Bomeisl et al,15 Bajaj et al,24 and Park et al,25 the overall clinical impact of SOD was 6.2%, corresponding to 171 discordant cases that resulted in modifications of clinical management in a total series of 2741 thyroid FNAs. The highest clinical impact rate was 8.1%,and was found in the series of Bajaj et al,24 in which from a total of 922 patients with thyroid FNAs, 75 had discordances between ID and SOD that resulted in some kind of change of medical or surgical management (Table 2). As defined in the present study, there were 2292 IDs that fitted in the “indeterminate” diagnostic category, corresponding to 32% of the total number of thyroid FNA specimens. With the exception of 3 studies,15,22,24 it was possible to calculate the discordance rate for the “indeterminate” diagnostic category: from a total of 2112 IDs in this diagnostic category, 1331 cases were discordant according to SOD, resulting in an overall discordance rate of 63% (Table 3). We also verified that for all but 122 of the examined studies, comprising 2211 IDs categorized Cancer Cytopathology
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TABLE 4. Distribution of Reclassified Diagnoses (SODs) according to BSRTC Terminology BSRTC Diagnostic Category Nondiagnostic Benign AUS/FLUS FN/SFN SFM Malignant Total
TABLE 5. Cytohistological Correlation for Thyroid FNAs with ID Classified in the “Indeterminate” Diagnostic Categorya
n
%
106 579 530 332 303 361 2211
4.8 26.2 24.0 15.0 13.7 16.3 100.0
Abbreviations: SOD, second-opinion diagnosis; BSRTC, Bethesda System for Reporting Thyroid Cytopathology; AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; FN/SFN, follicular neoplasm/suspicious for a follicular neoplasm; SFM, suspicious for malignancy.
as “indeterminate,” 940 cases were definitively classified as benign (579 cases, 26.2%) or malignant (361 cases, 16.3%) by SOD, with an overall diagnostic resolution rate of 42.5% (Table 3). SOD was not definitively diagnostic for the remaining cases that were reclassified as nondiagnostic (106 cases, 4.8%) or persisted as “indeterminate” (1165 cases, 52.7%). The detailed distribution of the reclassified diagnoses according to BSRTC terminology is shown in Table 4. However, as shown in Table 3, both the discordance and diagnostic resolution rates for the “indeterminate” diagnostic category were highly variable among the examined studies. It was possible to outline SOD performance for the “indeterminate” diagnostic category according to data pooled from the 3 studies with the largest series of thyroid FNAs.24-26 The cytohistological correlation of 702 cases with IDs classified in the “indeterminate” diagnostic category showed a malignant rate of 65.1% (Table 5). From these 702 cases, SOD showed a sensitivity of 98.7% and a specificity of 32.7%, with a FN rate of 0.9% and a FP rate of 23.5%. The PPV, NPV and overall accuracy for SOD were 73.2%, 93.0%, and 75.6%, respectively (Table 6). We also stratified the “indeterminate” diagnostic category into 3 subcategories: atypia/AUS/FLUS (151 cases, 21.5%), SFN/FN (161 cases, 22.9%), and suspicious/ SFM (390 cases, 55.6%), as shown in Table 5. Next, we calculated the SOD performance for each of the 3 diagnostic subcategories (Table 6). Potential changes in the clinical management of patients with thyroid FNA results classified as “indeterminate” were also investigated. Data from 6 studies,14,15,22,24-26 comprising 893 patients with IDs fitted in the “indeterminate” diagnostic category, showed that after SOD 508 patients (56.9%) would be clinically Cancer Cytopathology
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Total ID Atypia/AUS/FLUS SFN/FN Suspicious/SFM Total
Benign Histology
Malignant Histology
n
%
n
%
n
%
151 161 390 702
21.5 22.9 55.6 100.0
82 128 35 245
54.3 79.5 9.0 34.9
69 33 355 457
45.7 20.5 91.0 65.1
Abbreviations: ID, initial diagnosis; AUS/FLUS, “atypia of undetermined significance/follicular lesion of undetermined significance”; SEN, “suspicious for a follicular neoplasm”; FN, “follicular neoplasm”; SEM, “suspicious for malignancy”. a “Indeterminate” diagnostic category includes cases originally classified as “atypia”; AUS/FLUS, SFN, FN, “suspicious,” and SFM.
TABLE 6. SOD Performance for Thyroid FNAs With ID Classified in “Indeterminate” Diagnostic Categorya ID: Atypia/ Parameter AUS
ID: SFN/ FN
ID: Suspicious/ SFM
ID: “Indeterminate”a
Rate of FN Rate of FP Sensitivity Specificity PPV NPV Accuracy
1.2% 59.6% 93.9% 25.0% 24.4% 94.1% 39.1%
0.5% 7.2% 99.4% 20.0% 92.7% 77.8% 92.3%
0.9% 23.5% 98.7% 32.7% 73.2% 93.0% 75.6%
1.3% 27.2% 97.1% 50.0% 62.0% 95.3% 71.5%
Abbreviations: SOD, second-opinion diagnosis; ID, initial diagnosis; AUS/ FLUS, “atypia of undetermined significance/follicular lesion of undetermined significance”; SEN/FN, “suspicious for a follicular neoplasm/ follicular neoplasm”; SEM, “suspicious for malignancy; FN, false-negative results; FP, false-positive results; PPV, positive predictive value; NPV, negative predictive value. a “Indeterminate” diagnostic category includes cases originally classified as “atypia”; AUS/FLUS, SFN/FN), “suspicious,” and SFM.
followed up, 203 (22.7%) would have a repeat FNA, and 182 (20.4%) would be submitted to thyroidectomy for histological diagnosis. In the study of Davidov et al,23 avoidance of surgery after SOD was reported for 25% of the patients in the “indeterminate” diagnostic category: from a total of 129 patients with IDs in this category, 32 were spared from surgical procedures.
DISCUSSION This review found 7154 thyroid FNAs and an overall discordance rate of 28.6% among studies that investigated interinstitutional review or second-opinion diagnosis for thyroid cytological specimens.14,15,21-26 Consultation or 5
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second opinion on pathological material is an important and recognized practice among pathologists and different laboratories. In fact, recommendations regarding personal or interinstitutional consultations were published more than 20 years ago.27 Because diagnostic discrepancies between the original and the reviewed diagnoses have been reported by several studies, SOD is considered a safety practice in the context of interinstitutional consultations and may detect diagnostic errors that could result in potential changes in clinical management for the referred patients.3,5,13 Weir et al,4 for example, analyzed 1000 interinstitutional pathology consultations and found that 70% of the diagnostic discordances with clinical relevance resulted from interpretation differences between the original and the referred institutions. Although not unfailing, studies have shown that SOD is frequently better corroborated by clinicopathological follow-up when compared with ID.2,4,15,25 In the study of Manion et al5 that analyzed surgical pathology material, SOD was supported by clinical or pathological follow-up in 83% of the cases classified as major diagnostic discordances. In the field of cytology, the validation of a cytological diagnosis is usually performed by comparison with the corresponding histological diagnosis (the “gold standard” test).28 In this review, we found that 4 studies reported higher PPV values22,23,26 or higher diagnostic accuracy rates21,23 after SOD, meaning that SOD provided a more correct diagnosis compared with the IDs. For the current study, we have to acknowledge that the better results of SOD may be a potential bias because the selected studies were performed in large medical centers with experience in the field of cytopathology. Despite SOD being better validated by cytohistological correlation, observer variation and diagnostic discrepancies still remain an issue in thyroid pathology,8,9 especially for follicular-pattern lesions in both cytology16-18 and histology.10-12 Among the reviewed studies, few reported the discordance rates for specific diagnostic categories of thyroid FNAs.22,23,25 As expected, the highest discordance rates were found in the “indeterminate,” “follicular neoplasm,” and “suspicious for malignancy” diagnostic categories, as observed in the study of Park et al.25 Well-defined morphological criteria as well as standardized diagnostic terminology such as the BSRTC19 are intended to diminish observer variation between pathologists/laboratories and to provide better communication with clinicians. However, marked vari6
ability has been found in classifying a thyroid FNA specimen using standardized terminology. In fact, the reported incidence of AUS/FLUS ranged from 0.7% to 27%20,29 and for SFN/FN from 2% to 24% in studies that reviewed large series that applied the BSRTC terminology to thyroid FNA aspirates.20,30 We investigated the effect of SOD in the “indeterminate” diagnostic category of thyroid FNAs. Because the terminology classification was not uniform among the reviewed studies—the BSRTC19 was appropriately used in 3 of the selected studies24-26—we classified a thyroid FNA case as “indeterminate” when the ID was reported as satisfactory but not definitively diagnostic, that is, neither benign nor malignant. Using these criteria, we encountered 2292 IDs (32.0% of thyroid FNAs) in the “indeterminate” diagnostic category. In contrast, analyzing data from 25,445 thyroid FNAs, Bongiovanni et al20 found 5692 “indeterminate” cases (22.4%) including 2441 cases (9.6%) diagnosed as AUS/FLUS, 2571 cases (10.1%) diagnosed as FN/SFN, and 680 cases (2.7%) diagnosed as suspicious for malignancy. The higher rate of “indeterminate” thyroid FNAs found in our review may be explained by the selected studies analyzing interinstitutional consultations. Olson et al,26 for example, observed that the diagnostic rate for the indeterminate category was still high (15%) after SOD and exceeded the rate of 7% recommended by the BSRTC.19 The authors explained that a growing number of patients with indeterminate thyroid FNAs were referred for diagnostic review at their institution.26 The cytological features of a thyroid FNA classified as AUS/FLUS include cellular abnormalities that are more pronounced than benign changes but are not completely sufficient for a diagnosis of SFN/FN, suspicious for malignancy, or malignant.19,31 Repeat FNA is the recognized management for patients with a cytological diagnosis of AUS/FLUS and usually results in a definitive diagnosis.19 In a study published by Onder et al,32 56% of the thyroid FNAs initially diagnosed as AUS/FLUS were reclassified as either benign or malignant after repeat FNA. Jing et al33 demonstrated that consensus review may also have a role in the evaluation of thyroid nodules belonging to the “indeterminate” diagnostic category. From 50 cases initially diagnosed as AUS/FLUS, a definitive diagnosis was obtained for 27 cases (54%), including 26 cases (52%) reclassified as nonneoplastic/benign and 1 case (2%) reclassified as malignant. A lower overall Cancer Cytopathology
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diagnostic resolution rate (42.5%) after SOD was demonstrated in the present review. However, the diagnostic resolution rate for the “indeterminate” diagnostic category was highly variable among the reviewed studies, ranging from 27.8% to 100%. Furthermore, as defined in this review, the “indeterminate” diagnostic category comprises a broader and more heterogeneous group of lesions compared with the AUS/FLUS category of the BSRTC, including cases originally reported as SFN, FN, and SFM. A potential bias of the present study is the heterogeneous classification of the type of discrepancy and the diagnostic terminology reported among the selected studies. In fact, 2 of the studies that used the BSRTC were more specific regarding the classification of discrepancies. Bajaj et al,24 for example, classified the discordances as minor and major disagreements corresponding to 1- to 2-step deviation of BSRTC terminology. As expected, they verified a higher rate of changes in clinical management in the group of major disagreements compared with those of minor disagreements. Park et al25 also included detailed data comparing ID, SOD, type of change in clinical mangement (medical vs surgery, alteration of the type of surgery, etc.) for each category of the BSRTC terminology. Because of the heterogeneity of the reported results regarding the types of discrepancies in the majority of the studies, we did not try to use stricter criteria to classify the discrepancies such as those used in the study of Bajaj et al.24 The heterogeneity of the diagnostic thyroid FNA terminology may also explain some discrepancies between our review and other studies. When we stratified the “indeterminate” diagnostic category into 3 subcategories (AUS/FLUS [III], SFN/FN [IV], and SFM [V] of the BSRTC terminology), for example, expressive differences in the malignant rates were found compared with those published in the meta-analysis of Bongiovanni et al.20 In their study, the malignant rates for BSRTC diagnostic categories III, IV, and V were 15.9%, 26.1%, and 75.2%, respectively. In contrast, we found higher malignant rates such as 45.7% for category III and 91.0% for category V. A possible explanation for our high rate of malignancy for diagnostic category III may be related to the inclusion of thyroid FNA specimens with primary diagnosis reported as “atypia” in the study of Park et al.25 We cannot exclude that many thyroid specimens originally reported as “atypia” could represent cases with some cytological features of a papillary thyroid carcinoma. We can speculate that a lower rate of malignancy would be Cancer Cytopathology
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expected if the cases reported as “atypia” were excluded from BSRTC category III in the study of Park et al.25 A similar comment is valid for the high rate of malignancy found in BSRTC diagnostic category V. Again, the results were mostly influenced by the study of Park et al.25 First, their study contributed 300 thyroid FNAs originally called “suspicious for malignancy,” which represent, as shown in Table 5, the majority of the cases analyzed in this diagnostic category. Second, they showed that 95% of those cases were malignant on clinicopathological follow-up. It is highly probable that a significative number of those cases may represent an “undercall” bias of the original diagnoses. If so, a lower rate of malignancy would be estimated for BSRTC diagnostic category V in our analysis. The different malignant rates for BSRTC diagnostic category IV observed in our review and in the study of Bongiovanni et al20 were expected. A recent meta-analysis that evaluated the cytological diagnosis SFN before and after the introduction of BSRTC terminology showed highly variable rates of malignancy among 33 studies, ranging from 9.5% to 47.4%. Interestingly, the authors found that after the introduction of BSRCT terminology, there was a statistically significant increase in both the malignancy and surgical follow-up rates for the diagnostic category of SFN, which means that standardized terminology ensures appropriate patient management.30 FNA is considered an essential method for the initial approach to patients with thyroid nodules. This procedure accurately diagnoses the majority of thyroid nodules, distinguishing nonneoplastic lesions from malignant ones. Hence, the initial management of a patient with a thyroid nodule is largely based on the results of the cytological examination of thyroid FNA specimens.34,35 For patients with thyroid nodules who are referred from one institution to another for treatment consideration, review of the cytological material is an important step because of the potential change in clinical management. Although a small rate (6.2%) of overall clinical impact of SOD was found in our review, we have also shown that for the group of patients with discordant cytological diagnoses, almost one-third (30.4%) were considered for changes or potential changes in clinical management. In the study of Park et al,25 the majority of the patients were changed from surgical to medical management, and one-fourth were altered from clinical management to a surgical procedure. Regarding the “indeterminate” diagnostic category, 7
Original Article
we have shown that after SOD the majority of patients (56.9%) would be managed with clinical follow-up, and only one-fifth would be submitted to thyroidectomy. Finally, Davidov et al23 observed that 25% of patients with a thyroid FNA originally classified as “indeterminate” were spared from surgical treatment after revision of their diagnoses. However, it is difficult to accurately evaluate the role of SOD in patient management. Indeed, changes in clinical management take into account several factors such as age, sex, characteristics of the nodule on physical examination, and scintigraphic and ultrasonographic findings. Especially in the context of referred patients, the clinical decision is not only based on cytology. There are important issues regarding second opinion on pathological material, such as consumption of a pathologist’s time reviewing the original specimens and costs related to professional reimbursement. However, a considerable reduction of costs would be achieved if one considers that an accurate diagnosis prevents inappropriate treatment5,15 and if resource consumption of the alternatives (ie, repeat sampling or clinical follow-up) is entered into the analysis. Second opinion and consensus review of thyroid FNA specimens are important tools to achieve accurate diagnoses resulting in correct management of patients by avoiding unnecessary surgeries and, consequently, saving costs. Bajaj et al,24 for example, estimated a cost saving of approximately a million dollars because 33 patients with thyroid nodules were spared from surgery (thyroidectomy) based on SOD. Concerning the 7154 thyroid FNA consultations of this review, the 6.2% overall clinical impact rate of SOD seems small. However, as previously discussed, the clinical impact was significant for the patients with discordant cytological diagnoses, changing clinical management in nearly 30% of the patients belonging to this group. Even if the rates of clinical impact for major diagnostic discrepancies are not high according to the literature data for both surgical pathology2-6 and cytology,15,22,24,25 inappropriate management may result in significant morbidity, expensive health care costs, and potential litigations. In summary, this review showed that second opinions of thyroid FNA specimens improve diagnostic accuracy and potentially change the clinical management of patients with thyroid nodules. SOD also demonstrated a significant rate of diagnostic resolution for thyroid FNAs originally diagnosed as “indeterminate,” establishing 8
definitive diagnoses and enhanced accuracy. We believe that second-opinion review of thyroid FNA specimens is highly beneficial for patients referred from one institution to another and should be recommended as an standardized practice. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
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