World J Surg DOI 10.1007/s00268-015-3032-6
ORIGINAL SCIENTIFIC REPORT
The Implementation of the Bethesda System for Reporting Thyroid Cytopathology Improves Malignancy Detection Despite Lower Rate of Thyroidectomy in Indeterminate Nodules Dania Hirsch1,4 • Eyal Robenshtok1,4 • Gideon Bachar2,4 • Diana Braslavsky3,4 Carlos Benbassat1,4
•
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background The Bethesda system for reporting thyroid cytopathology (TBSRTC) was developed in 2009 to standardize the terminology for interpreting fine-needle aspiration (FNA) specimens. Methods A historical prospective case series design was employed. The study group included patients with a thyroid nodule classified as TBSRTC AUS/FLUS (B3) or FN/SFN (B4) in 2011–2012 in a tertiary university-affiliated medical center. Rates of surgery and malignancy detection were compared to our pre-TBSRTC (1999–2000) study. Results Of 3927 nodules aspirated, 575 (14.6 %) were categorized as B3/B4. Complete data were available for 322. Thyroidectomy was performed in 123 (38.2 %) cases: 66/250 (26.4 %) B3 and 57/72 (79.2 %) B4. Differentiated thyroid cancer was found in 66 (53.7 %) patients: 30/66 (45.5 %) B3 and 36/57 (63.2 %) B4 (p = 0.075). Operated patients were younger than the non-operated (B3: 52.4 ± 16 vs. 59.7 ± 13 years, p = 0.009; B4: 51.7 ± 15 vs. 60.5 ± 14 years, p = 0.042), and operated B3 nodules were larger than the non-operated (27.2 vs. 22.2 mm, p = 0.014). Additional FNA was done in 160 patients (49.7 %): 137/250 (54.8 %) B3 and 23/72 (31.9 %) B4 (p = 0.002). The additional B3 nodules aspirations yielded a diagnosis of B2 in 84 patients (61.3 %), B3 in 48 (35 %), and B4 in 5 (3.6 %). Of the 23 repeated B4 aspirations, B2 was reported in 5 (21.7 %), B3 in 12 (52.2 %), B4 in 4 (17.4 %), and B6 in 2 (8.7 %). The number of aspirated nodules was twice that reported in 1999–2000. The rate of indeterminate nodules increased from 6 to 14.6 %, the surgery rate decreased from 52.3 to 38.2 %, and the accuracy of malignancy diagnosis increased from 25.9 to 53.7 %. Conclusions The application of TBSRTC significantly improves diagnostic accuracy for indeterminate thyroid nodules, leading to higher rates of malignancy detection despite lower rates of thyroidectomies.
Hirsch D. and Robenshtok E. contributed equally to this work. & Dania Hirsch
[email protected] 1
Endocrine Institute, Rabin Medical Center, 49100 Petach Tikva, Israel
Eyal Robenshtok
[email protected] 2
Department of Otorhinolaryngology and Head and Neck Surgery, Rabin Medical Center, 49100 Petach Tikva, Israel
Gideon Bachar
[email protected] 3
Institute of Pathology, Rabin Medical Center, 49100 Petach Tikva, Israel
Diana Braslavsky
[email protected] 4
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Carlos Benbassat
[email protected] 123
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Introduction Thyroid nodules are found in all age groups in the general population, although the risk increases with age and is higher in females. The reported prevalence in adults is 4–8 % by palpation and up to 67 % by ultrasound [1, 2]. According to autopsy studies, less than 5 % of thyroid nodules are cancerous [3, 4]. Therefore, the primary clinical objective is to reliably detect malignant nodules while avoiding unnecessary surgery for benign lesions. Fine-needle aspiration (FNA) is a simple, reliable, and minimally invasive technique to evaluate thyroid nodules. It successfully distinguishes malignant from benign nodules in 70–85 % of cases. The remainder, however, are defined as indeterminate and pose a diagnostic dilemma [5, 6]. To guide clinicians in their management, several international classification systems have been formulated. In 2006, the American Thyroid Association recommended a 4-tiered system wherein thyroid nodules are categorized as nondiagnostic, benign, malignant, and suspicious or indeterminate. This was later adopted in its 2009 guidelines as well [7, 8]. In 2009, the US National Cancer Institute (NCI) published a 6-tiered classification, The Bethesda system for reporting thyroid cytopathology (TBSRTC) [9]. The suspicious category in the earlier classification was subdivided into three categories: atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS, Bethesda III), follicular neoplasm/ suspicious for follicular neoplasm (FN/SFN, Bethesda IV), and suspicious for malignancy (Bethesda V). The Bethesda system is unique in providing not only a detailed description of the cytological diagnostic criteria but also the expected risk of malignancy and recommendations for management for each category. Numerous groups have reported their experience with TBSRTC, but only a limited number of studies compared the management and outcomes of indeterminate thyroid nodules before and after its introduction with inconsistent methodologies and results [10–17]. In 2003, we evaluated the clinical and cytological features of indeterminate follicular thyroid lesions diagnosed at our medical center [18]. In the present study, we analyzed a large cohort of B3B4 nodules to determine whether the implementation of TBSRTC was associated with changes in the malignancy prediction/detection rate for indeterminate nodules.
affiliated hospital, from January 2011 to December 2012 were screened for a diagnosis of Bethesda III (B3) or Bethesda IV (B4) nodules. The cytology and pathology reports of the patients who met these criteria were reviewed, and clinical data were collected from the medical files, as follows: patient age and sex, risk factors for thyroid cancer (radiation exposure and family history), TSH level, lesion size, repeated FNAs, and pathologic diagnosis. Patients with missing histological data were excluded. Incidental carcinomas distinct from the target nodules were not included in the analysis. Participants in a previous study from our medical center diagnosed with follicular lesions by thyroid aspiration from January 1999 to December 2000 served as the comparison group [18]. The earlier study had been designed to investigate the predictive value of indeterminate cytology, not its prevalence. To estimate the prevalence of indeterminate lesions, we counted all thyroid FNAs performed at our medical center during that study period. All aspirations in 1999–2000 and 2011–2012 were performed by one of two experienced cytopathologists using a 23-gage needle attached to a 20-mL plastic syringe. Four to 6 smears were obtained from each aspirate. Some of the slides were fixed in 95 % alcohol and stained with Papanicolaou stain, and some were air dried and stained with May-Grunwald Giemsa stain. On-site assessment for adequacy was routinely performed.
Statistical analysis Statistical calculations for the present study were performed with the SigmaStat 2.03 computerized program (Systat Software Inc., Point Richmond, CA, USA). Results are expressed as mean ± standard deviation (SD) unless otherwise indicated. Independent Student’s t test was used to analyze between-group differences in numerical variables, and v2 test or Fisher’s exact test was used for categorical variables. Observed differences were assumed to be statistically significant if the probability of chance occurrence (p value) was less than 0.05. The study was approved by our local institutional Ethics Review Board.
Results Characteristics of the study group
Methods The study was approved by our local institutional Ethics Review Board. The medical records of all patients who underwent thyroid FNA at Rabin Medical Center, a tertiary university-
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From January 2011 to December 2012, 3945 FNAs were performed in our medical center, of which 18 were excluded because of inadequate reportage. The distribution of the nodules by Bethesda diagnosis is shown in Table 1. Of
World J Surg Table 1 Bethesda classification of thyroid nodules aspirated in 2011–2012 Bethesda category
No. FNAs performed (n = 3927)
p = 0.018), and were operated on more frequently (79.2 vs. 26.4%, p = 0.001).
%
Thyroidectomy
B1
216
5.5
B2
2977
75.8
B3 B4
457 118
11.6 3.0
B5
57
1.5
B6
102
2.6
Table 2 Comparison between patients with B3 and B4 thyroid nodules p
B3
B4
No. pts
250
72
Female sex (%)
81.2
77.8
0.589
Age, year (mean ± SD)
57.8 ± 14
53.5 ± 15
0.018
Risk factors for DTC (%)
6.8
9.4
0.67
Hypothyroidism (%)
15.3
17.2
0.86 0.912
Lesion size, mm (mean ± SD)
23.4 ± 11
23.4 ± 12
Repeated FNA, n (%)
137 (54.8)
23 (31.9)
0.002
Operated, n (%)
66 (26.4)
57 (79.2)
0.001
DTC, n (%)
30/66 (45.5)
36/57 (63.2)
0.075
DTC differentiated thyroid carcinoma
the 575 patients with B3 or B4 nodules (14.6 %), complete data were available for 322: 250 B3, 72 B4. The patientand tumor-related clinical characteristics are presented in Table 2. Comparing patients with B3/B4 nodules, those with B4 were younger (53.5 ± 15 vs. 57.8 ± 14 years,
Thyroidectomy was performed in 123 of the 322 patients (38.2 %): 66/250 with B3 nodules (26.4 %) and 57/72 with B4 (79.2 %). Differences between the operated and nonoperated patients are shown in Table 3. The operated patients were younger than the non-operated in both B3 and B4 groups (B3: 52.4 ± 16 vs. 59.7 ± 13 years, p = 0.009; B4: 51.7 ± 15 vs. 60.5 ± 14 years, p = 0.042). Within the B3 group, the operated patients had larger nodules than the non-operated (27.2 ± 13.7 vs. 22.2 ± 10 mm, p = 0.014). The percentage of patients with risk factors for thyroid cancer or hypothyroidism was not different between the groups. Repeated FNA Data on repeated FNAs are presented in Table 3. One hundred sixty patients (49.2 %) underwent at least one FNA in addition to the one analyzed in the present study: 137/250 (54.8 %) with B3 nodules and 23/72 (31.9 %) with B4 nodules (p = 0.002). Within the 137 repeated B3 nodules aspirations, the additional FNA yielded a diagnosis of B2 in 84 patients (61.3 %), B3 in 48 (35 %), and B4 in 5 (3.6 %). Of the 23 repeated B4 aspirations, B2 was reported in 5 (21.7 %), B3 in 12 (52.2 %), B4 in 4 (17.4 %), and B6 in 2 (8.7 %). Of the 137 repeated B3 nodules FNAs, 66 were done after the index FNA (prospectively). Of those, 46 nodules (69.7 %) were categorized as B2, none of them was operated. Additional 15 nodules (22.7 %) were classified again as B3, of which 3 patients
Table 3 Comparison between operated and non-operated patients with B3 and B4 thyroid nodules B3 (n = 250)
B4 (n = 72)
Non-operated
Operated
No. pts
184 (73.6)
66 (26.4)
Female (%)
83.6
75
p
0.182
Non-operated
Operated
15 (20.8)
57 (79.2)
93.3
73.7
p
0.281
Patient age, year (mean ± SD)
59.7 ± 13
52.4 ± 16
0.009
60.5 ± 14
51.7 ± 15
0.042
Lesion size, mm (mean ± SD)
22.2 ± 10
27.2 ± 13.7
0.014
25 ± 13
23 ± 12
0.602
Risk factors (%)
5
11.6
0.140
0
11.5
0.580
Hypothyroidism (%)
15.2
15.5
0.878
8.3
19.2
0.673
Repeated FNA, all n (%)
109/184 (59.2)
28/66 (42.4)
0.298
5/15 (33.3)
18/57 (31.5)
0.758
B2
75 (68.8)
9 (32.1)
0.001
2 (40)
3 (16.7)
NS
B3
33 (30.3)
15 (53.6)
0.037
2 (40)
10 (55.6)
0.032
B4
1 (0.9)
4 (14.3)
0.005
1 (20)
3 (16.7)
0.607
B6
0
0
NS
0
2 (11.1)
0.489
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World J Surg Table 4 Comparison between benign and malignant B3 and B4 operated nodules B3, n = 66
B4, n = 57
Benign
Malignant
No. pts, n (%)
36 (54.5)
30 (45.5)
Female sex (%)
79.5
70
0.563
76.2
72.2
0.98
Patient age, year (mean ± SD) Lesion size, mm (mean ± SD)
54 ± 14 28.9 ± 14
50 ± 18 25.1 ± 12
0.613 0.268
57 ± 12.3 22.8 ± 10
48.5 ± 15.4 23.1 ± 13
0.036 0.914
Risk factors (%)
3.1
21.5
0.043
5
15.6
0.387
Hypothyroidism (%)
12.9
18.5
0.720
15
21.8
0.722
were operated (2 with benign pathology, 1 PTC). In 5 patients (7.6 %), the repeated prospective FNA was B4; 4 were operated (2 with PTC and 2 with benign pathology) and 1 was referred for surgery. Of the 23 repeated B4 nodules FNAs, 6 were done prospectively. The diagnosis was B6 in 2 (in both surgery revealed malignant pathology) and B4 in 1 (in whom the pathology was benign). Two additional patients in whom the repeated FNA was categorized as B3 and 1 patient with B2 were not operated. Within the 66 operated patients with B3 nodules, results of an additional FNA were available in 28. Of these, 9 (32.1 %) were classified as B2 nodules in the repeated test, 15 (53.6 %) as B3 and 4 (14.3 %) as B4. Within the 57 patients with B4 nodules that were operated, a repeated FNA was available in 18 and yielded a B2 classification in 3 (16.7 %), B3 in 10 (55.6 %), B4 in 3 (16.7 %), and B6 in 2 (11.1 %).
p
Benign
Malignant
21 (37)
36 (63)
p
70
Bachar ar et al
Hirsch et al
60 50 40 30 20 10 0
Indeterminated Thyroidectomy rate nodules (%) (%)
Malignancy detecon (%)
Fig.1 Comparison between pre- and post-Bethesda classification
malignancy increased from 25.9 % (15/58) to 53.7 % (66/ 123). Data are presented in Fig. 1.
Pathology report A final pathologic diagnosis of differentiated thyroid cancer (DTC) was made in 66 of the 123 operated patients (53.7 %): 30/66 (45.5 %) with B3 nodules and 36/57 (63.2 %) with B4. This difference reached trend level statistical significance (p = 0.075). Differences between patients with surgically proven benign and malignant nodules are shown in Table 4. The incidence of DTC among all nodules classified as B3 and B4, whether triaged to surgery or not was 12 % (30/ 250) and 50 % (36/72), respectively. FNA before and after the Bethesda system In our previous study [10], from January 1999 to December 2000, 1854 thyroid FNAs were performed. Of them, 111 (6 %) were categorized as indeterminate follicular lesions compared to 14.6 % (575/3927) in the present study. The overall operative rate for indeterminate cytology decreased after adoption of TBSRTC from 52.3 % (58/111) to 38.2 % (123/322), and the accuracy of cytology to diagnose
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Discussion The introduction of TBSRTC was a valuable step toward uniformity and consensus in reporting FNA results in thyroid disease [7]. The present study reports the experience of a tertiary university-affiliated medical center with the Bethesda classification and management recommendations. We found that use of TBSRTC refined the cytopathologic interpretation of indeterminate FNA specimens and doubled the rate of malignancy detection compared to our pre-Bethesda published results (53.7 vs. 25.9%) despite the lower rate of thyroidectomies performed (38.2 vs. 52.3 %) [18]. The impact of TBSRTC application on the management strategies and outcomes of indeterminate nodules was evaluated by several authors comparing their pre- and postBethesda results. However, these analyses were done in significantly smaller cohorts compared to ours [10–12], some examined only B3 [13, 14] or B4 [15] nodules, and others included only operated cases without data concerning
World J Surg
non-operated nodules [16]. Over all, these studies yielded conflicting results. Harvey et al [17] compared reporting rates and outcomes in a large group of thyroid nodules FNA’s from 2002–2005 and 2009–2011 and found that TBSRTC implementation didn’t affect institution reporting rates and management. However, the reported number of B3 nodules in 2009–2011 was small (72/2432, 2.1 %), and the analysis included B5 nodules and the equivalent cytological diagnosis in the pre-Bethesda classification [17]. In the present study, we excluded B5 nodules and focused in both B3 and B4 nodules since these lesions pose the main diagnostic and therapeutic dilemma. Furthermore, comparison of B5 nodules to the pre-Bethesda indeterminate follicular lesions is invalid. Thus, our work includes the largest cohort of preand post-TBSRTC indeterminate nodules. It is noteworthy that during the study period, 3945 thyroid nodules were aspirated at our center, which is more than twice the number in 1999–2000. This is in accordance with previous reports of a rapid rise in FNA utilization in recent years [19]. We found that 11.6 and 3 % of all thyroid aspirates yielded a diagnosis of B3 (AUS/FLUS) and B4 (FN/SFN) nodule, respectively. The rate of indeterminate nodules increased from 6 % in our pre-Bethesda study [18] to the current 14.6 %, most likely due to different classification criteria. However, it also may reflect the cytologists’ reassurance that nodules with mildly suspicious features can be now included in the AUS/FLUS category without compromising a conservative approach. According to the NCI, AUS/FLUS category should be minimized to less than 7 % of cases [7] but this suggestion lacks a robust evidentiary basis. It has proved to be unrealistic for many laboratories in studies of their initial experiences with TBSRTC [20, 21]. The Bethesda classification provides no estimation on the expected frequency of B4 category. In previous reports, rates varied widely from 1.2 to 25.3 % [22–29]. Moreover, in some studies [22, 24, 25], the rate of B4 nodules was significantly lower than the rate of B3 nodules, similar to our findings, whereas in others [23, 26–28], the opposite relationship was observed. The Bethesda system offers management guidelines for each diagnostic category relative to the associated malignancy risk. Accordingly, for the AUS/AFLUS category, the recommendation is clinical correlation and a repeat FNA at an appropriate interval. By contrast, the FN/SFN category identifies patients who need at least a surgical lobectomy because the definitive diagnosis relies on histologic examination of the nodule architecture [7]. In the present study, most of the patients with AUS/FLUS cytology (54.8 %) underwent repeated FNAs, whereas most of the patients with FN/SFN cytology (79.2 %) were operated. The rate of repeated FNAs on B3 nodules was higher than reported in
several studies [22, 24, 25, 30], yet, similar to the 56.1 % rate described by VanderLaan et al [31]. The authors found that the majority of cases with a repeat FNA following an indeterminate B3 diagnosis can be more definitively classified as benign or malignant, thereby resolving the uncertain nature of the nodule [31]. Accordingly, in the present study, on repeated aspiration of AUS/FLUS nodules, most (61.3 %) were found to be benign, obviating the need for surgery in the majority of them. However, also in the remaining (38.7 %) B3 nodules with a repeated indeterminate cytological report, most patients (67.9 %) were not operated, probably due to factors related to patients/nodules clinical features. A key strength of our study is that the FNA analyses were made uniformly by two cytopathologists with over 25 years of experience, each. These same cythopathologists also screened FNAs in our previous study [18], making comparison of the results more reliable. A wide variation has been found in diagnostic thresholds and terminologies among pathologists, particularly in use of the term AUS/FLUS [20, 32, 33]. This is mostly relevant for studies in which FNAs were analyzed by multiple cytopathologists of various levels of experience using different pathological practices [27, 28, 34, 35]. Furthermore, we applied TBSRTC prospectively, as it was adopted by our medical center soon after its introduction, whereas in some of the studies, data on malignancy risk according to TBSRTC were generated by retrospective slide review [22, 23, 27, 29] and thereby could have carried an inherent bias [15]. In addition, some authors used institutional reporting systems that are equivalent but not identical to TBSRTC [24] or grouped B3 ? B4 ? B5 nodules into a single cytological indeterminate category [35]. We observed an overall malignancy rate of 53.7 % of the operated B3/B4 nodules (Table 4). Comparing B3 and B4 nodules, there was a borderline statistically significant difference in histologic outcome, with malignancy rates of 45.5 and 63.2 %, respectively. These rates are higher than reported by Wang et al. [34], in their meta-analysis of malignancy risk, wherein rates varied from 0 to 48 % of AUS/FLUS nodules and 14 to 49 % of FN/SFN nodules. Furthermore, the frequency of cancer in the present study is higher than reported in our pre-Bethesda study of indeterminate follicular lesions [18]. The most likely explanation is that the indeterminate nodules that underwent surgery in the current study were a selected group with higher cytological and/or clinical risk of malignancy. Accordingly, it seems we were able to pick most malignant nodules as in others series, despite a lower rate of surgical intervention. Nevertheless, in a recent study by Ho et al [30], in which 65 % of patients presenting with B3 nodules underwent surgery, cancer rate was 37.8 %. This constitutes a frequency of 26.6 % malignancy of the entire B3 cohort, notably higher than the 5–15 % approximation according
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to TBSRTC, and the 12 % found in the present cohort. In fact, it is approximately twice higher than that found by other authors favoring rather similar surgical strategies of resecting the majority of both B3 and B4 nodules [22, 23]. Thus, it probably reflects specific institutional cytopathology and population characteristics and should not imply revision in TBSRTC definitions or management recommendations of indeterminate nodules. Our results support that sub-classification of indeterminate follicular nodules, as done in TBSRTC, is important in triaging patients for surgery or clinical follow-up. By applying two separate cytological categories to denote diagnostic uncertainty, cytopathologists can express their level of concern of the possibility of an underlying malignancy which will guide subsequent patient management. Indeed, in accordance with TBSRTC recommendations, 79.2 % of nodules with B4 cytology were surgically resected in our study, and malignancy was detected in most of them (63.2 %). As our institution considers surgical intervention appropriate for B4 nodules, it is not surprising that in most of these cases, FNA was not repeated. At the same time, on the basis of clinical judgment and repeated FNA, only 26.4 % of B3 nodules were operated, of which 45.5 % were found to be malignant. In recent years, genetic markers of malignancy have been incorporated in the diagnostic strategy for indeterminate thyroid nodules. However, the positive and negative predictive values of both the oncogene panel of Nikiforov et al. [35] and the Afirma ‘‘gene expression classifier’’ (GEC) system [36] vary dramatically, depending on the pre-test probability of malignancy [37]. The present study suggests that judicious use of the cytological and clinical data may significantly reduce the number of unnecessary thyroidectomies and increase the rate of malignancy detection, implying an improved pre-test probability of DTC. Consequently, in such circumstances, molecular testing is not expected to significantly impact the clinical management of B3/B4 nodules. This is in accordance with the recently published AACE/ACE Disease State Commentary asserting that at present, molecular testing is meant to complement and not replace clinical judgment, sonographic assessment, and visual cytopathology interpretation [38] The present study has limitations. First, it includes complete clinical data on 322/575 (56 %) of patients with B3/B4 nodules. Our hospital serves as tertiary referral center for thyroid FNAs for both community and other hospitals’ endocrinologists. Thus, a substantial proportion of patients referred for thyroid FNA are subsequently managed by their primary endocrinologist with no further follow-up on hospital records. Second, our results reflect the cytological and clinical performance of our institution when applying TBSRTC recommendations and may not be generalizable to other medical centers or community clinics. Moreover, the
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two experienced cytopathologists who performed all aspirations in the study may have acquired additional expertise from 1999–2000 to 2011–2012, contributing to the improved accuracy demonstrated in our study. Nevertheless, the comparison with our own pre-Bethesda results highlights the contribution of TBSRTC to the management of patients with thyroid nodules. In such circumstances and since this paper aimed to evaluate the impact of changes in classification and management with time, the length of the interval between the two series should not be seen as a disadvantage. In conclusion, the current findings demonstrate the benefits of TBSRTC in the preoperative cancer risk assessment of thyroid nodules. Implementation of the more precise characterization and classification of indeterminate cytological findings, together with adherence to the related management guidelines may increase the surgical yield for detection of thyroid cancer.
Conflicting interests
No conflicting interests exist.
Financial disclosure
No competing financial interests exist.
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