Fine Needle Aspiration. Acta Cytologica DOI: /

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1 Fie Needle Aspiratio Received: March 1, 2016 Accepted after revisio: May 12, 2016 Published olie: Jue 25, 2016 Impact of the Afirma Gee Expressio Classifier Result o the Surgical Maagemet of Thyroid Nodules with Category III/IV Cytology ad Its Correlatio with Surgical Outcome Shweta Chaudhary a Yaju Hou a Rulog She a Shveta Hooda b Zaibo Li a a Departmet of Pathology, Wexer Medical Ceter, Ohio State Uiversity, Columbus, Ohio, ad b Departmet of Pathology, Ohio Valley Medical Ceter, Wheelig, W.Va., USA Key Words Thyroid odules Fie-eedle aspiratio Idetermiate cytology Follicular lesio with udetermied sigificace Suspicious for follicular eoplasm Thyroid carcioma Afirma gee expressio classifier but was 50% i cases suspicious for follicular eoplasm (SFN). The surgical excisioal rate was sigificatly decreased i SFN cases after the Afirma test. Coclusios: The Afirma GEC is useful for further risk stratifyig SFN cases S. Karger AG, Basel Abstract Objective: The Afirma gee expressio classifier (GEC) is a molecular test to further classify idetermiate fie-eedle aspiratio (FNA) as beig or suspicious for maligacy. Study Desig: A total of 158 FNAs with Bethesda category III/IV cytology were set for a Afirma GEC test. We correlated the Afirma GEC results with surgical outcome ad also compared the data after Afirma s implemetatio with the data before. Results: Amog the 158 FNAs, the Afirma result was beig i 63 (40%), suspicious i 85 (54%) ad usatisfactory i 10 (6%). I total, 73 (86%) suspicious Afirma cases had surgery ad 28 (38%) showed carcioma. I cotrast, oly 8 (13%) beig Afirma cases had surgery ad all of them were beig. The sesitivity, specificity, egative predictive value ad positive predictive value (PPV) of Afirma were 100, 15, 100 ad 38%, respectively. The PPV was 20% i cases with follicular lesio of udetermied sigificace, karger@karger.com S. Karger AG, Basel /16/ $39.50/0 Itroductio Thyroid odules are very commo, with cliically palpable odules i 5% of adults ad ultrasoud-detected odules i up to 68% of radomly selected idividuals [1 4]. However, oly 5 15% of thyroid odules are maligat [5]. Although cliical assessmet, thyroid-stimulatig hormoe measuremet ad ultrasoud evaluatio are able to erich the yield of maligat odules, fie-eedle aspiratio (FNA) plays a vital role i evaluatig thyroid odules with assessig cellular morphologic features [6, 7]. FNA ca classify most thyroid odules with a defiitive diagosis of either beig or maligat. However, up to 30% show Bethesda category III cytology follicular lesio of udetermied sigificace/atypia of udetermied sigificace (FLUS/AUS) or Bethesda category IV cytology suspicious for follicular eoplasm (SFN) or Correspodece to: Dr. Zaibo Li Departmet of Pathology, Wexer Medical Ceter, Ohio State Uiversity 410 West, 10th Aveue Columbus, OH (USA) osumc.edu Dowloaded by: Uiversity of Chicago Library

2 Hürthle cell eoplasm (HCN) [6, 7]. Curret guidelies recommed a repeat FNA for category III lesios, ad lobectomy for category IV lesios ad repeated category III lesios. However, oly 15 35% prove to be maligat o follow-up surgical specimes, idicatig that uecessary surgeries are beig performed for the majority of patiets, leadig to icreased medical cost ad surgical complicatios [8, 9]. Although molecular tests with specific gee mutatios/rearragemets (icludig BRAF, RAS, RET/ PTC ad PAX8-PPARr, etc.) have a high specificity i detectig maligat cases, they have limited sesitivity ad egative predictive value (NPV) ad fail to detect as may as 30% of maligat cases [10 13]. Therefore, a preoperative test with a high sesitivity ad NPV is eeded to accurately idetify beig odules with idetermiate cytology ad avoid uecessary diagostic surgery. The Afirma gee expressio classifier (GEC) developed by Veracyte Ic. (South Sa Fracisco, Calif., USA) measures the expressio of 142 gees to determie if a FNA sample with idetermiate cytology is beig or suspicious for maligacy. The Afirma GEC test is reported to have a NPV of 94 95% ad a positive predictive value (PPV) of 37 38% i thyroid odules with FLUS/AUS or FN/HCN [14, 15]. Beside the iitial study, oly limited studies with the Afirma GEC have bee reported, with variable NPVs ad PPVs [16, 17]. I this study, we aimed to review the experiece of the Afirma GEC test i our istitutio ad ivestigate the impact of its result o the surgical maagemet of thyroid odules with category III/IV cytology ad its correlatio with surgical outcome ad cytomorphologic features. 2 Materials ad Methods Patiet Selectio After istitutioal review board approval at Ohio State Uiversity, a pathology archive database search was performed for two periods of 3 years (the post-afirma period, July 2012 to Jue 2015, ad the pre-afirma period, July 2009 to Jue 2012) to retrieve thyroid FNA cases. The Afirma GEC test was implemeted durig July 2012 for thyroid odules with FLUS/AUS, SFN or HCN i our istitutio. The surgical pathology diagosis was matched to the origial FNA odule by locatio ad size. Icidetal papillary thyroid microcarciomas that did ot match the origial FNA odule were excluded. All iitial FNA cases with a iterpretatio of FLUS/AUS, but with repeat FNAs which were iterpreted as beig, FLUS/AUS, SFN, suspicious for maligacy or maligacy, were also excluded from the curret study cohort. However, the fial repeat FNAs with a iterpretatio of FLUS/AUS were icluded. The majority of FLUS/AUS cases set for Afirma test i our cohort were repeat FNAs (81%, 72/89), with a small portio beig iitial FNAs (19%, 17/89). Table 1. Afirma GEC results i 158 thyroid odules with category III/IV cytology Afirma results FLUS/AUS SFN HCN Total Beig 41 (46) 22 (39) 0 (0) 63 (40) Suspicious 41 (46) 31 (55) 13 (100) 85 (54) Usatisfactory 7 (8) 3 (5) 0 (0) 10 (6) Total Values i paretheses are percetages. Thyroid FNA Procedure FNA biopsies were performed by radiologists uder ultrasoud guidace. The specimes were submitted for Romaowsky staiig ad/or Papaicolaou staiig ad additioal material was submitted for cytospi preparatios with Papaicolaou staiig. The FNA cytology diagoses were redered by 6 cytopathologists usig the Bethesda System for Reportig Thyroid Cytopathology (TBSRTC) criteria. All cases with Afirma GEC testig were further reviewed by Z.L. or R.S. to evaluate the cytomorphologic features. Surgical Follow-Up Results ad Histologic Pathology The Afirma GEC results ad surgical follow-up results were collected. Surgical specimes were received i 10% formali, embedded i paraffi ad staied with stadard hematoxyli ad eosi. Histologic diagoses were redered by subspecialized head/ eck surgical pathologists. Afirma GEC Testig Besides passes for cytology aalysis durig the FNA procedure, oe extra eedle pass was also collected separately for the Afirma GEC test i our istitutio. Thyroid odules with a cytology iterpretatio of FLUS/AUS, SFN or HCN were set to Veracyte Ic. for the Afirma GEC test at the request of the submittig cliicia ad the results were reported back to our istitutio ad recorded i the patiet s electroic medical record. Veracyte Ic. did ot perform the cytology evaluatio. Statistical Aalysis Data were recorded usig Microsoft Excel spreadsheet software (Microsoft, Redmod, Wash., USA). Fisher s exact test was used to compare the differece with a two-sided aalysis. All the aalyses were doe usig the SAS 9.3 system (SAS Istitute, Cary, N.C., USA), ad a p value <0.05 was cosidered statistically sigificat. Results Afirma GEC Results ad Correlatio with Surgical Outcomes ad Cytomorphologic Features Durig a 3-year period after Afirma s implemetatio, 376 (15%) FNAs were idetified from a total of 2,560 as havig a Bethesda System iterpretatio of category III/ IV cytology (FLUS/AUS, SFN or HCN). I total, 158 out Chaudhary/Hou/She/Hooda/Li Dowloaded by: Uiversity of Chicago Library

3 Table 2. Correlatio betwee surgical follow-up ad Afirma GEC results i 86 cases Afirma results FLUS/AUS with surgical follow-up SFN with surgical follow-up HCN with surgical follow-up Total with surgical follow-up beig maligat beig maligat beig maligatbeig maligat Beig 6 (100) 0 (0) 2 (100) 0 (0) 0 (0) 0 (0) 8 (100) 0 (0) Suspicious 28 (80) 7 (20) 13 (50) 13 (50) 4 (33) 8 (67) 45 (62) 28 (38) Usatisfactory 3 (75) 1 (25) 1 (100) 0 (0) 0 (0) 0 (0) 4 (80) 1 (20) Total 37 (82) 8 (18) 16 (55) 13 (45) 4 (33) 8 (67) 57 (66) 29 (34) Values i paretheses are percetages. of 376 (42%) cases were set for Afirma GEC aalysis; these icluded a beig result i 63 (40%), suspicious result i 85 (54%) ad usatisfactory result i 10 (6%). Whe stratified by differet categories, Afirma GEC was able to reclassify 46% of the FLUS/AUS cases ad 39% of SFN cases as beig, but all 13 HCN FNAs showed suspicious results by Afirma GEC test ( table 1 ). Sevety-three (86%) out of 85 suspicious Afirma cases had surgery; 45 (62%; icludig 28 FLUS/AUS, 13 SFN ad 4 HCN cases) were histologically beig ad 28 (38%; icludig 7 FLUS/AUS, 13 SFN ad 8 HCN cases) showed carcioma [icludig 11 classic papillary thyroid carciomas, 11 follicular variat papillary thyroid carciomas (FVPTC; 3 ivasive types ad 8 oivasive types) ad 6 follicular carciomas]. I cotrast, oly 8 (13%) out of 63 beig Afirma cases had surgery ad all of them were histologically beig ( table 2 ). Also, 5 (50%) out of 10 cases with a usatisfactory Afirma result had surgery, with 4 cases as beig ad 1 case as maligat histologically. Twelve HCN cases with suspicious Afirma results had surgical follow-up, with 4 cases as histologically beig ad 8 cases as histologically maligat. Afirma s overall sesitivity, specificity, NPV ad PPV i Bethesda category III/IV thyroid odules was 100, 15, 100 ad 38%, respectively. Amog the differet FNA categories, PPV was lowest (20%) i the FLUS/AUS group, 50% i the SFN group ad highest (67%) i the HCN group ( table 3 ). Compariso betwee Pre-Afirma Data ad Post-Afirma Data: The Distributio of FNA Iterpretatio Categories ad Surgical Excisio Rates of Thyroid Nodules with Bethesda Category III/IV Cytology We also examied whether the implemetatio of the Afirma GEC test had ay effect o the iterpretatio of Afirma Test o Thyroid Nodules Table 3. Sesitivity, specificity, NPV ad PPV of the GEC i FLUS, SFN ad HCN categories Sesitivity, % thyroid FNA by cytopathologists. The distributio of each FNA category except suspicious for maligacy did ot show a sigificat chage after the implemetatio of the Afirma GEC test (data ot show). The decrease of FNAs with a iterpretatio of suspicious for maligacy i post-afirma data was offset by the slight icrease of maligat FNAs, idicatig icreased cofidece amog the cytopathologists. Each category s percetage was also withi the reported rages. Similarly, o sigificat differece i patiet age ad female:male ratio was idetified betwee the pre-afirma data ad post-afirma data (data ot show). Next, we examied whether the implemetatio of the Afirma GEC test had ay effect o the surgical excisio rates of thyroid odules with category III/IV cytology. Sice more tha half of the category III/IV cases were ot set for a Afirma test, the compariso was aalyzed betwee 158 cases with a Afirma test ad pre-afirma cases. The compariso data showed that the surgical excisio rate was sigificatly decreased i the SFN group (76 vs. 52%, p = 0.001) after Afirma test, but ot i the FLUS/ AUS group (51 vs. 51%) or HCN group (69 vs. 92%; ta- Specificity, % NPV, % PPV, % FLUS/AUS SFN HCN a. 67 Total a. = Not statistically sigificat. 3 Dowloaded by: Uiversity of Chicago Library

4 Table 4. Surgical follow-up rates for patiets with category III/IV cytology betwee the pre- ad post-afirma periods FNA categories Pre-Afirma Post-Afirma cases with Afirma test with surgery, total cases, % with surgery, total cases, % p with surgery, Post-Afirma cases with suspi cious Afirma results total cases, % 1 p FLUS/AUS s s. SFN HCN s s. Total s s. = Not statistically sigificat. 1 These percetages are ratios of the suspicious Afirma odules that had udergoe surgery to all Afirmatested odules. Table 5. Maligat surgical follow-up rates for category III/IV cases with surgery betwee the pre- ad post- Afirma periods FNA categories Maligat/category III/IV cases with surgery pre-afirma cases post-afirma cases with Afirma test Maligat/category III/IV cases with surgery p value pr e-afirma case post-afirma cases with suspicious Afirma results p value FLUS/AUS 23/84 (27) 8/45 (18).s. 23/84 (27) 7/35 (20).s. SFN 27/78 (35) 13/29 (45).s. 27/78 (35) 13/26 (50).s. HCN 5/9 (56) 8/12 (67).s. 5/9 (56) 8/12 (67).s. Total 55/171 (32) 29/86 (34).s. 55/171 (32) 28/73 (38).s. Values i paretheses are percetages..s. = Not statistically sigificat. ble 4 ). Sice cases with a beig Afirma result should ot have had surgery, we excluded the cases with a beig Afirma test ad surgery from the post-afirma data ad the recompared the surgical excisio rates. As show i table 4, the surgical excisio rate was sigificatly decreased i the total cases (61 vs. 49%, p = 0.009) ad SFN cases (76 vs. 48%, p = ) after Afirma test, but still ot i the FLUS/AUS cases (51 vs. 44%) ad HCN group (69 vs. 92%). The overall maligacy rates i all category III/IV cases did ot sigificatly chage after Afirma GEC implemetatio ( table 5 ). There was a icreased tedecy i maligacy rates i SFN cases with surgical excisio, but this was ot statistically sigificat due to the small sample size. 4 Discussio Cosistet with the fidigs from Afirma s iitial studies, our data demostrated that the Afirma GEC test was able to reclassify 40% of thyroid odules with category III/IV cytology as beig, theoretically prevetig them from udergoig uecessary surgical excisio [15, 18]. I our study, although the surgical excisio rate i all cases with category III/IV cytology seemed to decrease from 61 to 54% after the implemetatio of Afirma GEC, the statistical aalysis did ot show a sigificat differece, which may have bee caused by the small sample size. However, the surgical excisio rate was sigificatly decreased i the SFN group (76 vs. 52%, p = 0.001) after the Afirma test. Although Afirma s overall sesitivity ad NPV i thyroid odules with category III/IV cytology Chaudhary/Hou/She/Hooda/Li Dowloaded by: Uiversity of Chicago Library

5 Afirma Test o Thyroid Nodules were both 100% due to the absece of false egative cases, its specificity ad PPV were oly 15 ad 38%, respectively. These aalytical performace characteristics are cosistet with the observatios of aother study [19]. However, the fact that oly 8 cases with a beig Afirma result were surgically cofirmed limited the accuracy of the sesitivity, specificity ad NPV of the Afirma GEC test obtaied i the curret study, the results of which should therefore be iterpreted with cautio. Oe recet study ivestigated 90 thyroid odules with idetermiate cytology ad beig Afirma durig a media follow-up period of 13 moths ad foud that these odules demostrated a similar growth o soogram to odules with beig cytology, suggestig that the assessmet of thyroid odules with idetermiate cytology ad beig Afirma may be performed similarly to those with beig cytology [20]. Two other recet studies evaluated the log-term maagemet patters ad thyroid surgery rates of Afirmabeig patiets compared to cytopathology-beig patiets ad foud that patiets with beig Afirma ad cytopathology diagoses were maaged similarly ad a ooperative approach to follow-up was cosidered to be a safe alterative to diagostic surgery by the majority of physicias [21, 22]. Whe stratified by differet categories, the PPV was sigificatly improved to 50% i the SFN group, while both sesitivity ad NPV remaied at 100%, idicatig a better performace of Afirma GEC i SFN cases i predictig the surgical outcome. Ideed, whe stratified by differet cytology categories, a decreased surgical excisio rate was oly observed i the SFN group, but ot i the FLUS/AUS ad HCN groups. The similarity i surgical excisioal rate i the FLUS/AUS group durig the pre-afirma verses post- Afirma period may be due to the low surgical excisio rate durig the pre-afirma period (51%) ad the low PPV of the Afirma GEC test (20%). I other words, Afirma GEC oly reclassified about half of the FLUS/AUS or SFN cases as beig, ad almost all of the other cases with suspicious Afirma GEC results uderwet surgical excisio. With a surgical excisio rate of 51% before Afirma GEC i the FLUS/AUS group, the implemetatio of Afirma did ot sigificatly decrease the surgical excisio rate i the FLUS/AUS group. However, with a higher surgical excisioal rate of 76% for the SFN group durig the pre- Afirma period, the implemetatio of Afirma did sigificatly decrease the surgical excisio rate. The fidigs are cosistet with the study by Alexader et al. [15], which demostrated that the most sigificat impact of the Afirma GEC test was oted amog SFN thyroid odules. However, i cotrast to that study, we did ot observe ay impact of the Afirma GEC test o FLUS/AUS thyroid odules. Repeat FNA was demostrated to be able to redefie 75 80% of category III/IV cases as either beig or maligat, thus leavig oly 20 25% of odules as repeatedly idetermiate [23, 24]. I light of the results from the curret study, it may be better to repeat FNA rather tha to perform the Afirma GEC test for FLUS/AUS cases, eve for repeated FLUS/AUS cases. However, further prospective studies are warrated to perform a poit to poit aalysis betwee repeat FNA ad the Afirma test for FLUS/AUS cases ad a edpoit eeds to be set for repeatig FNA, at which stage the Afirma GEC test should be performed. I our study, all HCN cases showed suspicious Afirma GEC results ad the surgical excisio rate was very high. Previous studies have demostrated that the presece of Hürthle cells causes false positive Afirma GEC results [17, 25, 26]. Two recet studies have demostrated that a suspicious Afirma GEC result does ot icrease the probability of maligacy i a HCN lesio [27, 28]. However, oe of these studies [27] showed 63% (45/72) of patiets had suspicious Afirma GEC results, which is much lower tha the suspicious rate (100%) i our results. The discrepacy may be caused by the small sample i our study (13 cases). Therefore, the Afirma GEC test for HCNs should be cosidered with cautio ad the Afirma GEC result i such cases should be iterpreted accordigly. There was a icreased tedecy of maligacy rates i SFN cases with surgical excisio after the Afirma test, but this was ot statistically sigificat due to the small sample size. A sigificat portio of maligat cases from both pre- ad post-afirma were FVPTC (40% i pre- Afirma ad 42% i post-afirma), idicatig the difficulty i makig a diagosis of FVPTC o cytology because the characteristic uclear features are less frequetly appreciated. Similarly, a diagosis of follicular carcioma requires capsular ivasio or agioivasio; therefore, it is almost impossible to make that diagosis o cytology. With the presece of both FVPTC ad follicular carcioma cases i our cohort, the Afirma GEC test seems to be able to depict all thyroid carciomas. Oe of the limitatios of the curret study is that o cliical presetatio/follow-up or imagig iformatio was available for the study cohort, makig it difficult to aalyze why half of the FLUS/AUS cases were ot set for Afirma GEC test ad aalyze why some of the cases without Afirma GEC test did ot udergo surgical excisio. The other aspect our curret study did ot ivestigate is the cost aalysis of Afirma GEC implemetatio i our istitutio. Eve though a previous study has suggested 5 Dowloaded by: Uiversity of Chicago Library

6 that the use of Afirma GEC testig i category III/IV thyroid odules may be cost effective because it prevets uecessary surgeries [29], whether the savig from reduced surgeries i SFN thyroid odules is able to justify the cost of implemetatio of the Afirma GEC test i all category III/IV FNA cases i our istitutio warrats future studies with a detailed cost aalysis. I coclusio, our data have demostrated that the use of the Afirma GEC test is able to reduce the umber of uecessary surgical excisios i thyroid odules with SFN, but ot i thyroid odules with FLUS/AUS or HCN. Therefore, it may be better to repeat FNA rather tha perform the Afirma GEC test for FLUS/AUS, ad orderig a Afirma GEC test o HCN cases eeds to be cautioed ad the results should be iterpreted accordigly. Disclosure Statemet The authors have o fiacial coflicts of iterest to disclose. 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