The Koren Journl of Pthology 2014; 48: 201-208 ORIGINAL ARTICLE Clssic Ppillry Thyroid Crcinom with Tll Cell Fetures nd Tll Cell Vrint Hve Similr Clinicopthologic Fetures Woo Jin Oh 1 Young Sub Lee 1 Uiju Cho 1 J Seong Be 2 Sohee Lee 2 Min Hee Kim 3 Dong Jun Lim 3 Gyeong Sin Prk 1 Youn Soo Lee 1 Chn Kwon Jung 1 Deprtments of 1 Hospitl Pthology, 2 Surgery, nd 3 Internl Medicine, The Ctholic University of Kore College of Medicine, Seoul, Kore Received: Februry 5, 2014 Revised: April 22, 2014 Accepted: April 24, 2014 Corresponding Author Chn Kwon Jung, M.D. Deprtment of Hospitl Pthology, Seoul St. Mry s Hospitl, The Ctholic University of Kore College of Medicine, 222 Bnpo-dero, Seocho-gu, Seoul 137-701, Kore Tel: +82-2-2258-1622 Fx: +82-2-2258-1627 E-mil: ckjung@ctholic.c.kr Bckground: The tll cell vrint of ppillry thyroid crcinom (TCVPTC) is more ggressive thn clssic ppillry thyroid crcinom (PTC), but the percentge of tll cells needed to dignose TCVPTC remins controversil. In ddition, little is known bout the clinicopthologic fetures of clssic PTC with tll cell fetures (TCF). Methods: We retrospectively selected nd reviewed the clinicopthologic fetures nd presence of the BRAF muttion in 203 cses of clssic PTC, 149 cses of clssic PTC with TCF, nd 95 cses of TCVPTCs, which were defined s PTCs hving < 10%, 10-50%, nd 50% tll cells, respectively. Results: TCVPTCs nd clssic PTCs with TCF did not vry significntly in clinicopthologic chrcteristics such s pthologic (p) T stge, extrthyroidl extension, pn stge, lterl lymph node metstsis, or BRAF muttions; however, these fetures differed significntly in TCVPTCs nd clssic PTCs with TCF in comprison to clssic PTCs. Similr results were obtined in subnlysis of ptients with microcrcinoms ( 1.0 cm in size). Conclusions: Clssic PTCs with TCF showed similr BRAF muttion rte nd clinicopthologic fetures to TCVPTCs, but more ggressive chrcteristics thn clssic PTCs. Key Words: Thyroid neoplsms; Histologic types; Clssifiction; Tll cell fetures Ppillry thyroid crcinom (PTC) is disese with n indolent course, excellent overll prognosis, nd long-term survivl rte close to tht of the generl popultion; 1 however, some vrints of PTC hve been ssocited with n incresed risk of recurrent disese nd ggressive behvior. 2 The tll cell vrint of PTC (TCVPTC) is the most common ggressive vrint of PTC. 2-4 The incidence of TCVPTC rnges from 4% to 17% of ll PTCs, nd its disese-free 10-yer survivl rte is believed to be 10% to 15% lower thn tht of clssic PTC. 5,6 The incidence of this disese in Kore hs been reported to be up to 5%, lthough there re limited existing dt. 7,8 Some studies suggest tht TCV PTC is still under-dignosed worldwide. 3-5,9,10 In fct, 1% to 13% of tumors originlly dignosed s clssic PTC cn be reclssified s TCV by thyroid expertise. 11,12 TCVPTC ws originlly described by Hwk nd Hzrd 9 in 1976 s distinctive subtype of PTC. Tll tumor cells re t lest three times s tll s they re wide nd hve moderte to bundnt eosinophilic cytoplsm, bslly oriented nuclei nd nucler fetures typicl of clssic PTC. 2,10 TCVPTCs present lter in life nd hve more ggressive pthologic fetures such s lrger size nd higher frequency of extrthyroidl extension, lymph node metstsis, vsculr invsion, nd distnt metstsis, when compred to clssic PTC. 5,9,11,13,14 However, some studies hve shown tht the worse prognosis of TCVPTC is relted to prognostic fctors such s old ge, tumor size, nd extrthyroidl extension rther thn the histologic type itself. 4 There is still controversy with regrd to wht percentge of tll cells defines TCVPTC. 2,9,15 Thresholds rnging from 10 to 75% hve been suggested by vrious studies. 2,5,15-18 PTCs hrboring fewer tll cells thn the required cutoff percentge re dignosed s clssic PTC with tll cell fetures (TCF). Therefore, the incidence nd clinicl results of TCVPTC my vry ccording to different dignostic criteri nd the pthologist s level of experience. 15,19 pissn 1738-1843 eissn 2092-8920 2014 The Koren Society of Pthologists/The Koren Society for Cytopthology This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License (http://cretivecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. 201
202 Oh WJ, et l. The gol of this study ws to investigte the prevlence of TCVPTC in Kore nd possible differences in clinicopthologic fetures between TCVPTCs nd clssic PTCs with TCF ccording to the percentge of tll cells. MATERIALS AND METHODS of 244 consecutive ptients with TCVPTC (n=95) nd clssic PTC with TCF (n=149) nd lso selected 203 consecutive ptients with clssic PTC s control group. The ge of the ptients t the time of dignosis rnged from 22 to 79 yers (men 47.6 yers for clssic PTC, men 51.0 yers for clssic PTC with TCF, nd men 47.1 yers for TCVPTC). Ptients Histopthologic review We performed retrospective review of prospectively mintined dtbse of ptients with PTC under pprovl by the Institutionl Review Bord of The Ctholic University of Kore Seoul St. Mry s Hospitl (KC13RISI0917). A totl of 2,139 ptients underwent surgery for PTC St. Mry s Hospitl between Jnury 2012 nd December 2013. We enrolled totl All clssic PTC, clssic PTC with TCF nd TCVPTC cses were reviewed by three bord-certified surgicl pthologists (C.K.J, G.S.P, nd Y.S.L) with specil interest in thyroid to identify clinicopthologic chrcteristics nd the percentge of tll cells. Tll cells were defined s cells with height t lest three times their width, bundnt eosinophilic cytoplsm nd nucler fetures chrcteristic of clssic PTCs such s enlrged, irregulr, cler nuclei with grooves nd pseudo-inclusions (Fig. 1).2,5,13,19 A tumor ws clssified s clssic PTC if it hd ny well-formed ppillry structure nd contined <10% tll cells. A tumor ws further defined s clssic PTC with TCF if it hrbored between 10% nd 50% tll cells (Fig. 2) nd s TCVPTC if it contined 50% or more tll cells. The 50% criterion for TCVPTC ws bsed on the World Helth Orgniztion clssifiction nd previous studies on TCVPTC.5,12,13,15,18-21 To determine whether smples reched the cutoff vlues of 10% nd 50% of tll cells in the whole sections of tumor tissue, we used digitl trining set which hs the known percentge clculted from digitiztion of whole slide imging. Discrepncies between the observers were found in less thn 10% of the reviewed slides. A consensus ws reched when there ws discrepncy between the observers. We excluded ny cses with tumor necrosis or mrked Fig. 1. Tll cell vrint of ppillry thyroid crcinom exhibits elongted folliculr nd closely pcked ppillry growth ptterns. Tll cells disply prominent cell membrnes, dense eosinophilic cytoplsm, nd nucler fetures typicl of ppillry crcinom. A B A B C Fig. 2. Clssic ppillry thyroid crcinoms with tll cell fetures contin 10% to 50% of cells with tll cell chrcteristics. (C) Dotted lines show the re contining tll cells. Tll cells re rrnged bck-to-bck in prllel pttern. Two smll boxes indicte regions enlrged imges (A, clssic ppillry; B, tll cells).
Ppillry Thyroid Crcinom with Tll Cell Fetures 203 mitotic ctivity ( 3 mitoses/10 high power field, 400 ) becuse these pthologic fetures themselves could be relted to tumor ggressiveness. 5,6,19,20 In cses with multiple tumor foci, the lrgest tumors were selected s the primry lesions. TNM stging ws performed ccording to the Americn Joint Committee s Cncer stging mnul 7th edition. BRAF muttion nlysis Of totl of 447 PTC cses, 417 underwent BRAF muttion testing. Genomic DNA ws extrcted from two or three 10-μm thick prffin tissue sections using the QIAmp DNA Mini kit (Qigen, Hilden, Germny). The tissue sections were mnully microdissected to enrich for tumor cells. We screened for muttions in exon 15 of the BRAF gene using polymerse chin rection mplifiction nd direct DNA sequencing, s described previously. 8,22 Sttisticl nlysis We used Student s t-test to compre two different groups of continuous prmetric dt with norml distribution. Person s chi-squre test ws used to ssess the reltionship between ctegoricl vribles. For the multivrite nlysis, we included ll vribles with univrite probbility (p) vlue of <.10 in binry logistic regression test. Two-sided p-vlues <.05 were considered to be sttisticlly significnt. Sttisticl nlysis ws performed with SPSS ver. 16.0 (SPSS Inc., Chicgo, IL, USA). RESULTS Out of totl of 2,139 ptients with PTCs, 149 (7.0%) hd clssic PTC with TCF nd 95 (4.4%) hd TCVPTC. Comprison of clinicopthologic chrcteristics mong histopthologic types When the clinicopthologic fetures of clssic PTCs were compred with those of TCVPTCs nd clssic PTCs with TCF, ptients with clssic PTCs were younger t the time of surgery nd showed lower pt nd pn stges, lower rte of extrthyroidl extension, lower rte of lterl lymph node metstsis, nd lower frequency of BRAF muttions (Tble 1). All BRAF mu- Tble 1. Clinicopthologic chrcteristics of ppillry thyroid crcinom (PTC) ccording to histopthologic types Chrcteristic Clssic PTC (A) (%) Clssic PTC with TCF (B) (%) TCVPTC (C) (%) p-vlue (A vs B+C) p-vlue (A vs B) p-vlue (B vs C) No. of cses 203 149 95 Men ge 47.6 51.0 47.1.000.000.017 Age (yr).002.000.042 < 45 95 (46.8) 41 (27.5) 38 (40.0) 45 108 (53.2) 108 (72.5) 57 (60.0) Gender NS NS NS Femle 164 (80.8) 123 (82.6) 82 (86.3) Mle 39 (19.2) 26 (17.4) 13 (13.7) Multifoclity NS.040 NS Single 111 (54.7) 65 (43.6) 49 (51.6) Multiple 92 (45.3) 84 (56.4) 46 (48.4) pt stge.000.000 NS pt1 126 (62.0) 41 (27.5) 23 (24.2) pt2 3 (1.5) 3 (2.0) 0 (0) pt3 74 (36.5) 104 (69.8) 71 (74.7) pt4 0 (0) 1 (0.7) 1 (1.1) ETE.000.000 NS Absent 129 (63.5) 44 (29.5) 23 (24.2) Present 74 (36.5) 105 (70.5) 72 (75.8) pn stge.000.003 NS pn0 105 (51.7) 51 (35.4) 27 (29.0) pn1 98 (48.3) 93 (64.6) 66 (71.0) Lterl LNM.003.002 NS Absent 191 (94.1) 121 (84.0) 81 (87.1) Present 12 (5.9) 23 (16.0) 12 (12.9) BRAF muttion b.000.000 NS Absent 34 (16.7) 4 (3.1) 3 (3.6) Present 169 (83.3) 127 (96.9) 80 (96.4) TCF, tll cell fetures; TCVPTC, tll cell vrint of ppillry thyroid crcinom; NS, not significnt; ETE, extrthyrodil extension; LNM, lymph node metstsis. Seven tumors of unknown pn stge (pnx) re excluded; b BRAF muttion testing is vilble for 417 cses.
204 Oh WJ, et l. Tble 2. Multivrite nlysis of clinicopthologic chrcteristics of ppillry thyroid crcinom ccording to histopthologic type Chrcteristic Odds rtio (95% confidence intervl) A vs B+C A vs B B vs C Age (<45 yr vs 45 yr) 1.92 (1.22-3.01) 2.39 (1.42-4.04) 0.66 (0.36-1.23) Gender (femle vs mle) 0.88 (0.50-1.56) 1.03 (0.54-1.95) 0.63 (0.28-1.42) Multifoclity (unifocl vs multifocl) 1.28 (0.83-1.97) 1.50 (0.92-2.44) 0.68 (0.38-1.21) ETE (bsent vs present) 3.30 (2.13-5.10) 2.81 (1.70-4.64) 1.57 (0.82-2.98) LN metstsis (bsent vs present) 1.84 (1.17-2.90) 1.71 (1.01-2.90) 1.10 (0.58-2.07) BRAF muttion (bsent vs present) 5.14 (2.15-12.65) 5.26 (1.75-15.76) 0.82 (0.17-3.91) A, clssic ppillry thyroid crcinom; B, clssic ppillry thyroid crcinom with tll cell fetures; C, tll cell vrint of ppillry thyroid crcinom; ETE, extrthyrodil extension; LN, lymph node. p<.05. Tble 3. Clinicopthologic chrcteristics of ppillry thyroid microcrcinom (PTC) ( 1.0 cm) ccording to histopthologic type Chrcteristic Clssic PTC (A) (%) Clssic PTC with TCF (B) (%) TCVPTC (C) (%) p-vlue (A vs B+C) p-vlue (A vs B) p-vlue (B vs C) No. of cses 164 67 43 Men ge (yr) 45.6 51.3 48.7.001.000 NS Age (yr).003.006 NS < 45 76 (46.3) 18 (26.9) 13 (30.2) 45 88 (53.7) 49 (73.1) 30 (69.8) Gender.034 NS NS Femle 132 (80.5) 60 (89.6) 39 (90.7) Mle 32 (19.5) 7 (10.4) 4 (9.3) Multifoclity.033.035 NS Single 96 (58.5) 29 (43.3) 21 (48.8) Multiple 68 (41.5) 38 (56.7) 22 (51.2) pt stge.000.000 NS pt1 120 (73.2) 28 (41.8) 17 (39.5) pt3 44 (26.8) 39 (58.2) 26 (60.5) pn stge.014 NS NS pn0 94 (57.3) 29 (45.3) 15 (36.6) pn1 70 (42.7) 35 (54.7) 26 (63.4) Lterl LNM.045.007 NS Absent 160 (97.6) 57 (89.1) 40 (97.6) Present 4 (2.4) 7 (10.9) 1 (2.4) BRAF muttion b.001.005 NS Absent 29 (17.7) 2 (3.3) 2 (5.1) Present 135 (82.3) 59 (96.7) 37 (94.9) TCF, tll cell fetures; TCVPTC, tll cell vrint of ppillry thyroid crcinom; NS, not significnt; LNM, lymph node metstsis. Five tumors of unknown pn stge (pnx) re excluded; b BRAF muttion testing is vilble for 264 cses. ttions were V600E muttions. There were no sttisticlly significnt differences between TCVPTCs nd clssic PTCs with TCF with regrd to men ge nd clinicopthologic fetures such s pt, extrthyroidl extension, pn, lterl lymph node metstsis, or rte of BRAF muttion (Tble 1). In multivrite nlysis (Tble 2), ge group, extrthyroidl extension, lymph node metstsis, nd BRAF muttions of clssic PTC were significntly different from those of TCVPTCs nd clssic PTCs with TCF. The clinicopthologic fetures of TCVPTCs were not significntly different from those of clssic PTCs with TCF. Subnlysis of microcrcinoms ( 1.0 cm in size) ccording to histologic subtype Ptients with clssic PTCs were younger t surgery nd showed higher frequency of single lesions, lower pt nd pn stges, lower rte of extrthyroidl extension, nd lower frequency of BRAF muttions, compred to ptients with clssic PTCs with TCF or TCVPTCs (Tble 3). There were no sttisticlly significnt differences in clinicopthologic chrcteristics between TCVPTCs nd clssic PTCs with TCF (Tble 3). Subnlysis of unifocl tumors ccording to histologic subtype We only included unifocl cncers to eliminte ny possible bis from tumor multifoclity. We further nlyzed the clinicopthologic differences between clssic PTCs, clssic PTCs with TCF or TCVPTCs. The results for unifocl cncers were in the sme rnge: clinicopthologic fetures of clssic PTCs were sig-
Ppillry Thyroid Crcinom with Tll Cell Fetures 205 Tble 4. Multivrite nlysis of clinicopthologic chrcteristics of ppillry thyroid crcinom subtypes ccording to ge group (<45 yers nd 45 yers) Chrcteristic Odds rtio (95% confidence intervl) A vs B+C A vs B B vs C Age<45 yr Gender (femle vs mle) 0.68 (0.29-1.60) 0.96 (0.35-2.58) 0.44 (0.11-1.72) Multifoclity (unifocl vs multifocl) 0.93 (0.45-1.89) 1.44 (0.59-3.47) 0.37 (0.13-1.04) ETE (bsent vs present) 2.91 (1.45-5.85) 2.99 (1.25-7.10) 0.82 (0.28-2.38) LN metstsis (bsent vs present) 2.95 (1.33-6.56) 3.76 (1.25-11.30) 0.53 (0.15-1.92) BRAF muttion (bsent vs present) 16.58 (2.04-135.07) 7.75E8 0.00 Age 45 yr Gender (femle vs mle) 1.04 (0.48-2.28) 1.06 (0.45-2.48) 0.83 (0.30-2.29) Multifoclity (unifocl vs multifocl) 1.48 (0.86-2.57) 1.43 (0.79-2.61) 0.96 (0.47-1.97) ETE (bsent vs present) 3.62 (2.05-6.38) 2.80 (1.50-5.21) 2.18 (0.92-5.15) LN metstsis (bsent vs present) 1.49 (0.84-2.63) 1.31 (0.70-2.46) 1.34 (0.64-2.84) BRAF muttion (bsent vs present) 3.55 (1.27-9.97) 3.33 (1.04-10.71) 1.03 (0.17-6.15) A, clssic ppillry thyroid crcinom; B, clssic ppillry thyroid crcinom with tll cell fetures; C, tll cell vrint of ppillry thyroid crcinom; OR, odds rtio; CI, confidence intervl; ETE, extrthyrodil extension; LN, lymph node. p<.05. nificntly different from those of clssic PTCs with TCF or TCVPTCs, but no significnt differences were observed in clinicopthologic chrcteristics between TCVPTCs nd clssic PTCs with TCF (Appendices 1, 2). Subnlysis of histologic subtypes ccording to ptient ge groups (<45 yers vs 45 yers) In multivrite subnlysis by ptient ge group (Tble 4), there were no significnt differences in clinicopthologic vribles between ptients under or over the ge of 45 in the clssic PTC with TCF nd TCVPTC groups. The clinicopthologic fetures of clssic PTCs were significntly different from those of clssic PTCs with TCF or TCVPTCs cross ge groups. DISCUSSION We demonstrted tht clssic PTC with TCF (PTC with 10% to 50% tll cells) hd the sme demogrphic nd clinicopthologic chrcteristics s TCVPTC, nd these tumors showed more ggressive fetures thn clssic PTC. TCVPTC typiclly ffects older ptients nd hs lrger size, higher stge t presenttion, higher rte of extrthyroidl extension, greter risk of recurrence, nd poorer disese-specific survivl compred to clssic PTC. 3,4,9,16,18,19,23 Bernstein et l. 24 indicted tht despite controlling for size, TCVs of ppillry thyroid microcrcinoms were still ssocited with higher pt nd, pn stge nd ggressive pthologic fetures such s extrthyroidl extension. In our study, we lso demonstrted tht microcrcinoms with tll cell component were more ggressive thn those with clssic PTC morphology. There is controversy regrding the high incidence of lymph node metstsis in TCVPTC. Some uthors hve demonstrted tht ptients with TCVPTC hve higher rte of nodl metstses thn ptients with clssic PTC. 4,16 Bernstein et l. 24 showed tht microcrcinoms with TCVPTC hve higher rte of centrl lymph node metstsis thn microcrcinoms with clssic PTC (39% vs 13%). However, other uthors did not find significnt differences in the lymph node positivity rte between clssic PTCs nd TCVPTCs. 3,17,19 For exmple, Gnly et l. 19 demonstrted no differences in nodl metstses mong TCVPTCs, clssic PTCs with TCF nd clssic PTCs. Such discrepncies might be cused by different ptient ges or different criteri regrding the percentge of tll cells necessry for dignosis of TCVPTC. In our multivrite nlysis ccording to the ge groups, there were significnt differences in the rtes of lymph node metstsis between clssic PTC nd clssic PTC with TCF in ptients under the ge of 45 yers. However, the differences in lymph node metstsis rte disppered in ptients over the ge of 45 yers. Johnson et l. 16 nd Bernstein et l. 24 used 30% threshold of tll cells nd showed higher rte of nodl positivity in TCVPTCs. Investigtors who used 50% to 75% threshold of tll cells for TCVPTC dignosis did not find significnt differences in nodl positivity between TCVPTCs nd clssic PTCs. 17,19 Vrious investigtors hve used different thresholds of 10%, 15 30%, 11,15,24 50%, 5,12,13,15,18-21 70%, 3 or 75% 2,14,17 tll cells to define TCVPTC. Ghossein nd LiVolsi 5 nd Reglbuto et l. 18 suggested cut-off of t lest 50% tll cells to clssify TCVPTC.
206 Oh WJ, et l. In our study, we used 10% threshold for clssic PTCs with TCF nd 50% threshold for TCVPTCs. Using this definition, lymph node metstses were significntly more frequent in clssic PTCs with TCF nd TCVPTCs thn in clssic PTCs. We lso demonstrted sttisticlly significnt difference between clssic PTCs nd clssic PTCs with TCF (10% to 50% tll cells) with regrd to lymph node sttus such s pn nd lterl lymph node metstsis (Tble 1). Beninto et l. 15 reported tht ptients with clssic PTC with TCF (tumors with 10% tll cells) hve more ggressive tumor fetures such s older ge t onset, higher stge, more extrthyroidl extension (3% to 14%), more lymph node metstses (40% to 68%), incresed lymphovsculr invsion (2% to 17%), nd higher frequency of positive surgicl mrgins, compred with clssic PTC. These ggressive fetures hve been shown to be ssocited with greter risk of recurrence nd were mintined with incresing tll cell percentge ( 10%, 30%, 50%) within PTCs with tll cells. 15 Other uthors hve suggested tht clssic PTCs with TCF my be significntly ssocited with older ge t presenttion, lrger tumor size, higher frequency of extrthyroidl extension, nd BRAF muttions regrdless of the percentge of tll cells. 13 We lso demonstrted sttisticlly significnt difference in clinicopthologic fetures nd BRAF muttions between clssic PTCs nd clssic PTCs with TCF (10% to 50% tll cells) (Tble 1). The more ggressive clinicopthologic fetures of clssic PTCs with TCF nd TCVPTCs t presenttion trnslte into worse outcomes. 19 Recent clinicl guidelines lso suggest tht TCVPTCs require more ggressive surgicl resection. 25 The ggressive nture of TCVPTC my be relted to higher prevlence of BRAF muttions. 26 BRAF muttions in PTC hve been correlted with ggressive tumor behvior, including extrthyroidl extension, tumor recurrence, dvnced tumor stge t presenttion nd lymph node metstsis, 27 even in microcrcinoms. 28 The BRAF oncogene is strong ctivtor of the mitogen-ctivted protein kinse signling pthwy, which leds to uncontrolled cell prolifertion nd trnsformtion into mlignncy. 29 BRAF muttion lso plys role in extrcellulr mtrix remodeling nd is ssocited with n increse in mtrix metlloproteinses, desmoplstic stroml rection, nd invsiveness. 30 Finkelstein et l. 21 demonstrted significnt ssocition between the presence of the BRAF muttion nd fibrosis, desmoplstic stroml rection, nd infiltrting tumor borders. The BRAF muttion occurs commonly in Koren ptients with PTC, rnging in frequency from 52% to 87% of ll cses. 8 The prevlence of the BRAF muttion worldwide is reported to be s high s 80% to 100% in TCVPTCs. 29 For exmple, Bernstein et l. 24 demonstrted tht the BRAF muttion ws detected in 93% of ll microcrcinoms with TCVPTC. In our study, the prevlence of the BRAF muttion ws 96.9% nd 96.4% in clssic PTCs with TCF nd TCVPTCs, respectively. Age t presenttion is the single most importnt prognostic fctor in thyroid cncer. 1 In our study, we found tht clssic PTCs with TCF nd TCVPTCs were more frequent in ptients over the ge of 45. Interestingly, PTCs with 10% tll cells were pthologiclly more ggressive thn clssic PTCs regrdless of ge groups (<45 yers nd 45 yers). Our study hs some limittions, such s retrospective design, reltively smll smple size, nd the fct tht the dt were collected by one institution. Furthermore, we did not nlyze the outcomes nd prognosis of ptients becuse the followup period ws too short. In conclusion, PTCs with more thn 10% tll cells show more ggressive clinicopthologic fetures thn clssic PTCs regrdless of tumor size nd ge. Clssic PTCs with TCF hve similr BRAF muttion rte nd clinicopthologic chrcteristics to those of TCVPTCs. Therefore, we suggest tht the presence of ny tll cells should be noted in pthologic reports becuse of their clinicl significnce. Conflicts of Interest No potentil conflict of interest relevnt to this rticle ws reported. Acknowledgments This reserch ws supported by the Bsic Science Reserch Progrm through the Ntionl Reserch Foundtion of Kore (NRF) funded by the Ministry of Science, ICT nd future plnning (2013R1A2A2A01068570). REFERENCES 1. LiVolsi VA. Ppillry thyroid crcinom: n updte. Mod Pthol 2011; 24 Suppl 2: S1-9. 2. LiVolsi VA. Ppillry crcinom tll cell vrint (TCV): review. Endocr Pthol 2010; 21: 12-5. 3. Ostrowski ML, Merino MJ. Tll cell vrint of ppillry thyroid crcinom: ressessment nd immunohistochemicl study with comprison to the usul type of ppillry crcinom of the thyroid. Am J Surg Pthol 1996; 20: 964-74. 4. Michels JJ, Jcques M, Henry-Amr M, Brdet S. Prevlence nd prognostic significnce of tll cell vrint of ppillry thyroid crci-
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208 Oh WJ, et l. Appendix 1. Clinicopthologic chrcteristics of unifocl ppillry thyroid crcinom ccording to histopthologic type Chrcteristic Clssic PTC (A) (%) Clssic PTC with TCF (B) (%) TCVPTC (C) (%) p-vlue (A vs B+C) p-vlue (A vs B) p-vlue (B vs C) No. of cses 111 65 49 Men ge (yr) 44.8 51.2 43.9 NS.011.46 Age (yr) NS.012.02 < 45 52 (46.8) 18 (27.7) 24 (49.0) 45 59 (53.2) 47 (72.3) 25 (51.0) Gender NS NS NS Femle 89 (80.2) 51 (78.5) 41 (83.7) Mle 22 (19.8) 14 (21.5) 8 (16.3) pt stge.000.000 NS pt1 70 (63.1) 20 (30.8) 12 (24.5) pt2 2 (1.8) 1 (1.5) 0 (0) pt3 39 (35.1) 44 (67.7) 37 (75.5) pt4 0 (0) 0 (0) 0 (0) ETE.000.000 NS Absent 72 (64.9) 21 (32.3) 12 (24.5) Present 39 (35.1) 44 (67.7) 37 (75.5) pn stge.000.007 NS pn0 66 (59.5) 24 (38.1) 13 (26.5) pn1 45 (40.5) 39 (61.9) 36 (73.5) Lterl LNM.005.005 NS Absent 107 (96.4) 53 (84.1) 43 (87.8) Present 4 (3.6) 10 (15.9) 6 (12.2) BRAF muttion b.002.018 NS Absent 18 (16.2) 2 (3.6) 1 (2.4) Present 93 (83.8) 54 (96.4) 41 (97.6) TCF, tll cell fetures; TCVPTC, tll cell vrint of ppillry thyroid crcinom; NS, not significnt; ETE, extrthyrodil extension; LNM, lymph node metstsis. Two tumors of unknown pn stge (pnx) re excluded; b BRAF muttion testing is vilble for 209 ptients. Appendix 2. Clinicopthologic chrcteristics of unifocl ppillry thyroid microcrcinom ( 1.0 cm) ccording to histopthologic type Chrcteristic Clssic PTC (A) (%) Clssic PTC with TCF (B) (%) TCVPTC (C) (%) p-vlue (A vs B+C) p-vlue (A vs B) p-vlue (B vs C) No. of cses 96 29 21 Men ge (yr) 45.3 52.8 46.5 Age (yr).037.023 NS < 45 46 (47.9) 7 (24.1) 8 (38.1) 45 50 (52.1) 22 (75.9) 13 (61.9) Gender NS NS NS Femle 75 (78.1) 24 (82.8) 19 (90.5) Mle 21 (21.9) 5 (17.2) 2 (9.5) pt stge.019 NS NS pt1 67 (69.8) 15 (51.7) 10 (47.6) pt3 29 (30.2) 14 (48.3) 11 (52.4) pn stge.032 NS NS pn0 61 (63.5) 14 (50.0) 8 (38.1) pn1 35 (36.5) 14 (50.0) 13 (61.9) Lterl LNM NS.041 NS Absent 94 (97.9) 25 (89.3) 20 (95.2) Present 2 (2.1) 3 (10.7) 1 (4.8) BRAF muttion b.047 NS NS Absent 16 (16.7) 1 (4.0) 1 (5.3) Present 80 (83.3) 24 (96.0) 18 (94.7) PTC, ppillry thyroid crcinom; TCF, tll cell fetures; TCVPTC, tll cell vrint of ppillry thyroid crcinom; NS, not significnt; LNM, lymph node metstsis. One tumors of unknown pn stge (pnx) re excluded; b BRAF muttion testing is vilble for 140 ptients.