REVIEW. Prognostic Scores for Predicting Recurrence in Patients with Differentiated Thyroid Cancer. Charoonsak Somboonporn. Abstract.

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1 DOI: Prgnstic Scres fr Predicting Recurrence in Differentiated Thyrid Cancer Cases REVIEW Prgnstic Scres fr Predicting Recurrence in Patients with Differentiated Thyrid Cancer Charnsak Smbnprn Abstract Backgrund: Differentiated thyrid cancer (DTC) is a cancer grup that shares mlecular and cellular rigin but shws different clinical curses and prgnses. Several prgnstic factrs have been reprted fr predicting recurrence fr individual patients. This literature review aimed t evaluate prgnstic scres fr predicting recurrence f DTC. Materials and Methds: A search f the MEDLINE database fr articles published until December 2015 was carried ut using the terms thyrid neplasms AND (recurrent OR persistent) AND (scre OR mdel OR nmgram). Studies were eligible fr review if they indicated the develpment f prgnstic scring mdels, derived frm a grup f independent prgnstic factrs, in predicting disease recurrence in DTC patients. Results: Of the 308 articles btained, five were eligible fr evaluatin. Tw scring mdels were develped fr DTC including bth papillary and fllicular carcinma, ne fr papillary carcinma, and the ther tw fr papillary micrcarcinma. The number f patients included in the scre develpment chrt ranged frm 59 t 1,669. The number f evaluated ptential prgnstic factrs ranged frm 4 t 25. Tumr-related factrs were the mst cmmn factrs included in the final scres, with cervical lymph nde metastases being the mst cmmn. Only tw studies shwed internal validatin f the derived scre. Cnclusins: There is a paucity f prgnstic scres fr predicting disease recurrence in patients with DTC, in particular fr fllicular thyrid carcinma. Several limitatins f the created scres were fund. Perfrmance f the scres has nt been adequately studied. Cmprehensive validatin in multiple chrts is recmmended befre widespread use. Keywrds: Thyrid neplasms - recurrence - prgnsis - prgnstic scres Asian Pac J Cancer Prev, 17 (5), Intrductin Thyrid cancer cmprises a grup f tumrs with different characteristics. Differentiated thyrid cancer (DTC) cmprises papillary carcinma and fllicular carcinma, including their variants. Mstly, DTC has an indlent clinical curse with lw mrtality. The 10-year survival rates fr papillary and fllicular thyrid cancer have been reprted t be 93-94% and 84-85%, respectively (Hundahl et al., 1998; Mazzaferri and Kls, 2001). Hwever, a mre aggressive disease with lw survival and high recurrence ccurs in sme patients. Althugh disease-specific mrtality is f great cncern, recurrence is anther imprtant utcme as a result f a lng-term clinical curse f the disease. Identifying patients f ptentially having high risk f recurrence helps individual management plan. A wide variety f individual prgnstic factrs fr DTC recurrence have been reprted in the literature (Haugen et al., 2016); hwever, using all f them is nt practical. Hence, prgnstic scring mdels have been develped t ease risk stratificatin in rutine clinical practice. The aim f this review was t identify and evaluate available prgnstic scres in predicting disease recurrence in patients with DTC. Materials and Methds Eligibility criteria fr selecting studies A review f previusly published articles explring prgnstic scres fr DTC recurrence was carried ut. A search f the MEDLINE database until December 2015 was dne using the terms thyrid neplasms AND (recurren* OR persisten*) AND (scr* OR mdel OR nmgram*) with language limitatin t articles published in English. After screening the titles and abstracts, as well as full text articles when needed, the eligible articles were identified fr data extractin. The eligibility criteria included studies identifying independent prgnstic factrs fr DTC recurrence using multivariate analysis and creating scring mdel frm these significant prgnstic factrs. Data extractin and presentatin Department f Radilgy, Faculty f Medicine, Khn Kaen University, Khn Kaen, Thailand *Fr crrespndence: charnsak. sm@gmail.cm Asian Pacific Jurnal f Cancer Preventin, Vl 17,

2 Charnsak Smbnprn These data were extracted and presented fr each study: first authr s name, publicatin year, cuntry f rigin, characters f study patients, recurrence rate, fllw-up perid, the number f patients in the scre develpment and validatin chrt (if presented), Table 1. Prgnstic Scres fr Differentiated Thyrid Cancer Recurrence 2370 Asian Pacific Jurnal f Cancer Preventin, Vl 17, 2016 the number f factrs included in the scring mdel, explred ptential prgnstic factrs, independent prgnstic factrs btained frm multivariate analysis, and perfrmance f the scre (if presented). Individual prgnstic factrs were categrized accrding t the First authr Welsch M Onitil AA Buffet C Niemeier LA Kim KM Publicatin year Cuntry Germany USA France USA Krea Study patients DTC DTC PMCA PMCA PTC Recurrence rate (%) Fllw-up perid, year (Mean + SD r mean) 9 ± ± * and 4.8** 8.3 Number f patients in the scre develpment chrt , Number f patients in the scre validatin chrt NA 595 NA 40 NA Number f prgnstic factrs included in the scring mdel Tumr factrs Tumr histlgy Tumr histpathlgic grading Tumr size Tumr fibrsis Psammma bdies Anatmic lcatin f primary tumr Superficial lcatin f primary tumr Multifcality Distance t resected margin f primary tumr Histlgic lymph nde metastases Preperative imaging lymph nde metastases Vascular invasin Infiltratin f surrunding tissue r ETE Tumr capsule invlvement Thyrid capsule invasin Infiltrative brder Psitive resectin margin Lymph nde status mrphlgy Lymph nde in PET scan Lymph nde in RAI scan Pulmnary metastases mrphlgy Pulmnary metastases in PET scan Pulmnary metastases in RAI scan Bne scan Bne metastases mrphlgy Bne metastases in PET scan Bne metastases in RAI scan Other rgan metastases mrphlgy Other rgan metastases in PET scan Other rgan metastases in RAI scan Distant metastases Patient factrs Age Gender Serum Tg level befre RAI treatment Serum Tg level 6 weeks after RAI treatment Current serum Tg level (at any time) Hashimt s thyriditis Treatment factrs BRAF V600E mutatin Type f thyrid surgery Pst-thyridectmy RAI treatment Initial cervical lymph nde surgery Initial diagnsis year DTC, differentiated thyrid cancer; PTC, papillary thyrid carcinma; PMCA, papillary micrcarcinma; PET, psitrn emissin tmgraphy; RAI, radiactive idine; Tg, thyrglbulin ; ETE, extrathyrid extensin; NA, nt applicable due t scre validatin nt perfrmed; *in aggressive grup, **in nn-aggressive grup; indicates prgnstic factrs that did nt shw statistically significant assciatin with recurrence; indicates prgnstic factrs that shwed statistically significant assciatin with recurrence; indicates prgnstic factrs selected int the prgnstic scre

3 DOI: Prgnstic Scres fr Predicting Recurrence in Differentiated Thyrid Cancer Cases Table 2. Prgnstic Factrs and Crrespnding Scre Pints in the Multiparameter Scring System (Welsch et al., 2007) Prgnstic factrs Characteristics Scre pints Gender Male 1 Female -1 Age Fr every year < Fr every year > Histlgy Papillary -1 Fllicular 1 Primary histpathlgic grading G1-2 G2 1 G3 2 G4 5 Primary lymph nde status (accrding t histlgic reprt) N metastases -1 Ipsilateral metastases 2 Cntralateral metastases 3 Tumr diameter Fr every mm < Fr every mm > Infiltratin f surrunding tissue N 0 Yes 5 Tumr capsule invlvement Yes -2 N 1 Thyrid capsule N cntact t capsule -2 Cntact t capsule 2 Extensin beynd capsule 4 Lymph nde status mrphlgy N metastases -1 Ipsilateral metastases 2 Cntralateral metastases 4 Lymph nde in PET scan N FDG uptake -2 Psitive FDG uptake 2 Lymph nde in RAI scan Psitive RAI uptake -1 N RAI uptake 2 Pulmnary metastases mrphlgy N metastases -1 One metastasis 3 2 metastases 5 Pulmnary metastases in PET scan N FDG uptake -2 Psitive FDG uptake 4 Pulmnary metastases in RAI scan Psitive RAI uptake -1 N RAI uptake 4 Bne scan Negative -1 Psitive 3 Bne metastases mrphlgy N metastases 0 One metastasis 5 2 metastases 7 Bne metastases in PET scan N FDG uptake -2 Psitive FDG uptake 4 Bne metastases in RAI scan Psitive RAI uptake -1 N RAI uptake 4 Other rgan metastases mrphlgy N metastases -1 One metastasis 2 2 metastases 3 Other rgan metastases in PET scan N FDG uptake -1 Psitive FDG uptake 1 Other rgan metastases in RAI scan Psitive RAI uptake -1 N RAI uptake 2 Serum Tg level befre RAI treatment (ng/ml) < >100 4 Serum Tg level 6 weeks after RAI treatment (ng/ml) < >100 6 Serum Tg level at any time f presentatin (ng/ml) < >100 7 PET, psitrn emissin tmgraphy; RAI, radiactive idine; Tg, thyrglbulin Asian Pacific Jurnal f Cancer Preventin, Vl 17,

4 Charnsak Smbnprn cncept f subject-based classificatin as tumr-related factrs, patient-related factrs, and treatment-related factrs (Gspdarwicz et al., 2006). Results Of the 308 articles screened, five studies were identified and included fr review (Welsch et al., 2007; Onitil et al., 2009; Buffet et al., 2012; Niemeier et al., 2012; Kim et al., 2013). All are retrspective chrt study. The studies were published during 2007 t Tw studies were frm the United States (Onitil et al., 2009; Niemeier et al., 2012), tw frm Eurpe (Welsch et al., 2007; Buffet et al., 2012), and ne frm Asia (Kim et al., 2013). The study size f the scre develpment chrt ranged frm 59 t 1,669 patients, and in ttal cnsisted f 3,106 participants. The study patients were DTC (including bth papillary and fllicular carcinma) in tw studies (Welsch et al., 2007; Onitil et al., 2009), while the remaining three studies included exclusively patients with papillary carcinma (Buffet et al., 2012; Niemeier et al., 2012; Kim et al., 2013); tw f them (Buffet et al., 2012; Niemeier et al., 2012) fcused nly patients with primary tumr size f 1 cm, the s-called papillary micrcarcinma (PMCA). Table 1 represents a summary f the studies included in this review. Prgnstic factrs that were fund withut and with statistically significant assciatin with disease recurrence were indicated as pen circle and clsed circle, respectively. In additin, factrs that were selected int the prgnstic scring mdels were indicated as square. Finally, the number f prgnstic factrs included in the scring mdels ranged frm 4 t 25. Mst f the independent prgnstic factrs were tumr pathlgic factrs, such as cervical lymph nde metastases, tumr size, multifcality, and extrathyrid extensin (ETE). Age and gender were patient factrs that were fund significantly assciated with recurrence in tw f the fur studies examining these factrs. In ne study, BRAF mutatin was fund t be a prgnstic factr fr recurrence in PMCA patients. N treatment factrs were fund t be significantly assciated with recurrence utcme. In three studies, prgnstic scres were develped frm evaluated prgnstic factrs that shwed statistically significant assciatin with recurrence utcme (Buffet et al., 2012; Niemeier et al., 2012; Kim et al., 2013). Hwever, the ther tw studies had variatin in selecting factrs int the final scring scheme. The prpsed scre by Welsch et al. in 2007 adpted all ptential prgnstic factrs int the scring scheme, even thugh sme f them were nt statistically significant. In the study by Onitil et al. in 2009, althugh shwing n significant assciatin with recurrence, tumr histlgy was frced int the mdel, while distant metastasis, an independent factr, was excluded frm the mdel. Applicatin f these five prgnstic scring systems was described as fllws 1. Multiparameter scring system (Welsch et al., 2007): This scre was calculated by additin r subtractin 2372 Asian Pacific Jurnal f Cancer Preventin, Vl 17, 2016 f the scre pints crrespnding t each prgnstic factr (Table 2). Factrs that were nt available were scred with the value zer. Five categries f prbability f disease recurrence were estimated accrding t the crrespnding cut-ff pints: 3.9% fr scres 10; 14.1% fr scres -10 t 0; 46.2% fr scres 0 t 10; 66.7% fr scres 10 t 20; and 100% fr scres > Alternative quantitative t the TNM scring system (Onitil et al., 2009): Prgnstic scre = sum f the fllwings: Histpathlgy = 1 if nt papillary thyrid carcinma, therwise 0; Age = 4 if 45 years, therwise 0; Reginal lymph nde metastases = 4, therwise 0; Primary tumr size = 6 if > 4 cm limited t thyrid gland r any tumr with ETE, therwise 0. Three categries f prbability f 10-year disease-free survival (DFS) were estimated accrding t the crrespnding cut-ff pints: 95% fr scres 0 t 5; 70% fr scres 6 t 10; and 45% fr scres 11 t Scring system fr PMCA (Buffet et al., 2009): Prgnstic scre = sum f the fllwings: Gender: female = 0, male = 1; Multifcality: absent = 0, present = 1; Lymph nde metastases: absent = 0, present = 3. Three categries f 10-year recurrence prbability (with 95% CI) were estimated accrding t the crrespnding cut-ff pints: 2.7% (1.3 t 4.1%) fr scres 0 t 2; 24% (13.7 t 34.3%) fr scres 3 t 4; and 42.6% (12.7 t 72.5%) fr scre Cmbined mlecular-pathlgical scre fr PMCA (Niemeier et al., 2012): Prgnstic scre = 1 if tumr in superficial lcatin f thyrid gland + 1 if BRAF psitive + 1 if multifcality present + 1 if extensive fibrsis in primary tumr present. Three categries f recurrence risk were estimated accrding t the crrespnding cutff pints: 0% fr scres 0 t 2; 20% fr scre 3; and 60% fr scre Clinical prgnstic index f University f Ynsei (Kim et al., 2013): Prgnstic scre = (0.03 x age in years) if male gender if ETE present if preperative lymph nde metastases present. Fur categries f 10-year DFS were estimated accrding t the crrespnding cut-ff pints: 95.6% fr scres <1.50; 94.5% fr scres 1.50 t 2.29; 85.0% fr scres 2.30 t 3.29; and 27.3% fr scres Discussin Since cmbined multiple prgnstic factrs perfrm better in predicting the utcme than individual variable des, all ptential factrs can be evaluated and the factrs that have the mst degree f assciatin with the utcme are identified. Weight f assciatin f these factrs can be used t create a summed prgnstic scre fr predicting the utcme. This review identified five studies attempting t cnstruct the risk predictin mdel fr disease recurrence in patients with DTC. The review fund diversity amng patient characteristics, variability in definitin f utcme and event rate, and variability in the evaluated prgnstic factrs and their definitins in each study. Of all five prgnstic scres, tw were develped in DTC patients, but three scres were studied in purely papillary thyrid

5 carcinma; tw f these fcused nly n PMCA patients. Nne was carried ut in patients with purely fllicular thyrid carcinma. In fact, the ttal number f patients diagnsed with fllicular carcinma included in the tw studies (Welsch et al., 2007; Onitil et al., 2009) was nly 225. Cautin is needed in applying these scres fr predicting utcme in affected patients. Definitin f recurrence utcme varied acrss the studies. The prgnstic scre f Welsch et al. reprted utcme as recurrence rate, while the scre f Kim et al. reprted it as disease-free survival. Hwever, the definitin f recurrence in bth studies was nt clearly defined. Onitil et al. reprted utcme as disease-free survival defined as the time t first recurrence; hwever, the definitin f recurrence was nt clearly defined. Buffet et al. reprted utcme as time t recurrence and clearly defined the definitin f recurrence, based n cytlgical r histlgical analysis, 131 I uptake in the lesin, and predetermined serum thyrglbulin (Tg) level. Niemeier et al. (2012) reprted utcme as recurrence rate and defined recurrence based n serum Tg measurements, neck ultrasngraphy, and clinical examinatin. The candidate prgnstic factrs included fr scre develpment varied widely amng studies. The majrity f them were tumr factrs, such as tumr histlgy, grading, tumr size, ETE, r cervical lymph nde metastases. Patient factrs were als evaluated, including age, gender, serum Tg level at varius time pints, and BRAF mutatin. Only a few treatment factrs were studied, such as type f thyridectmy and 131 I treatment. Amng all studies, mst f the independent prgnstic factrs were tumr pathlgic factrs and they were in accrdance with thse previusly identified in the literature, such as cervical lymph nde metastases (Schneider, et al., 2013; Lee et al., 2014), tumr size (It et al., 2012), multifcality (Qu et al., 2014), and extrathyrid extensin (Kim et al., 2014). This was als the case fr patient factrs, such as age and gender (Kim et al., 2014), and pstperative serum Tg level (Hasbek et al., 2014). BRAF mutatin included in the cmbined mlecular-pathlgical scre fr PMCA (Niemeier et al., 2012) has recently been reprted as a new and prmising prgnstic factrs related t tumr aggressiveness and high recurrent utcme (Kim et al., 2012; Fernandez et al., 2013; Xing et al., 2015). It shuld be nted that althugh nne f treatment factrs were fund t be significantly assciated with recurrence, nly tw studies included factrs f this dmain in their scre develpment chrts (Onitil et al., 2009; Buffet et al., 2012). Mst f the prgnstic scres attributed t nly 3 r 4 high-impact predictrs, which are easy t use, and are therefre practical in rutine clinical use (Onitil et al., 2009; Buffet et al., 2012; Niemeier et al., 2012; Kim et al., 2013). The prgnstic scre which accunted fr several predictrs as the multiparameter scring system seems nt easy t use, althugh the authrs claimed that nly the available predictrs culd be used t calculate the summed scre fr individual patient (Welsch et al., 2007). In additin, the scring mdels, in which the ttal scre was calculated frm the pint scres that were integers, wuld likely ease the use f the scres in the real-wrld DOI: Prgnstic Scres fr Predicting Recurrence in Differentiated Thyrid Cancer Cases clinical practice (Onitil et al., 2009; Buffet et al., 2012; Niemeier et al., 2012). The sample size and the number f utcme events are crucial issues fr prgnstic studies because they affect the regressin mdel assumptin. Nrmally, the mdels require an adequate number f utcme events fr each predictr. The rule f thumb dictates that at least 10 utcme events shuld be btained fr ne independent prgnstic factr (Guyatt, 2006). All studies in this review cnsisted f relatively lw recurrent rates, ranging frm % (r 6-68 events), likely due t shrt fllw-up perid, with the mean f nly years. This raised the cncern as t whether r nt these studies had adequate statistical pwer (Guuatt, 2006), particularly in the study explring a large number f prgnstic factrs (Welsch et al., 2007). Gd mdel perfrmance is imprtant fr widespread clinical applicatin f the scre. Variety in reprting scre perfrmance was bserved, such as percent f true r false classificatin f the utcme (Welsch et al., 2007), % sensitivity and % specificity (Niemeier et al., 2012), r prprtin f variant explained (Kim et al., 2013). The remaining tw studies reprted n infrmatin abut mdel perfrmance (Onitil et al., 2009; Buffet et al., 2012). N studies reprted scre perfrmance in terms f discriminatin ability f the scre, as measured by cncrdance C-index, and the scre calibratin (Pencina and D Agstin, 2004). Internal and external validatin f the derived scre is anther aspect in assessing prgnstic scre utilizatin. Tw studies reprted results f internal validatin f their prgnstic scres, in 595 patients in the study f Onitil et al. and 40 patients in the study f Niemeier et al., respectively. Nne f the evaluated scres perfrmed external validatin. Therefre, further studies shuld be carried ut by perfrming external validatin f these available scres in a different patient setting with an adequate number f sample size, such as a least 100 participants (Verguwe et al., 2005). There are sme limitatins f the review. Rbust cnclusin cannt be made regarding the prgnstic scre fr predicting DTC recurrence due t varying definitins f utcmes and incnsistent use f prgnstic factrs. Since searching f articles was nly dne in MEDLINE database, there is a pssibility that sme eligible studies indexed nly in ther databases may be missed. Language bias may be present because the search strategy was limited t article published in English. In cnclusin, there is a paucity f data n prgnstic scres fr predicting disease recurrence in patients with DTC. Several limitatins f the prpsed scres were fund. Perfrmance was nt adequately studied. Further studies with cmprehensive internal and external validatin in multiple chrts are recmmended befre widespread use. Acknwledgements This review was supprted by research fund frm the Ryal Glden Jubilee Ph.D. schlarship frm the Thailand Research Fund and the Faculty f Medicine, Khn Kaen Asian Pacific Jurnal f Cancer Preventin, Vl 17,

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