Americn Joint Committee on Cncer Stging nd Clinicopthologicl High-Risk Predictors of Oculr Surfce Squmous Neoplsi A Study From Tertiry Eye Center in Indi Sheetl Chuhn, MSc; Seem Sen, MD; Anjn Shrm, PhD; Rdhik Tndon, MD; Seem Kshyp, MD; Neelm Pushker, MD; Murugesn Vnthi, MD; Nmrt Shrm, MD Context. Oculr surfce squmous neoplsi (OSSN) is the most common tumor of conjunctivl epithelium ssocited with risk of permnent visul impirment. It includes conjunctivl intrepithelil neoplsi nd squmous cell crcinom. Although Americn Joint Committee on Cncer TNM (AJCC-TNM) stging is commonly used in vrious tumors, it hs only recently been described for OSSN. Objectives. To evlute the prognostic relevnce of AJCC-TNM stging nd the clinicopthologicl fetures in OSSN. Design. Sixty-four histopthologiclly proven cses of OSSN (20 conjunctivl intrepithelil neoplsi nd 44 squmous cell crcinom) were included in the study. The AJCC-TNM stging nd clinicopthologicl fetures of OSSN cses were recorded. Ptients were followed up for 17 to 40 months (medin, 32 months). Univrite nd multivrite nlyses were performed to determine the prognostic vlue of vrious clinicopthologicl fetures. Results. Longer sunlight exposure (P ¼.01), diffuse growth pttern (P ¼.02), lrger tumor size (2 cm) (P ¼.03), histopthologicl dignosis of squmous cell crcinom (P ¼.02), nd orbitl invsion or invsion of djcent structures (T3 or T4) (P,.001) emerged s significnt predictors of reduced recurrence-free survivl. Using multivrite nlysis, higher T ctegory (T3 or T4) ws the most importnt prognostic indictor of poor outcome. Conclusions. A higher T ctegory (T3 or T4) is n importnt predictor of clinicl outcome, nd the use of the AJCC-TNM stging system is recommended in the mngement of ll ptients with OSSN. Longer sunlight exposure, lrger tumor size (2 cm), orbitl invsion or invsion of djcent structures (T3 or T4), nd histopthologicl dignosis of squmous cell crcinom re other clinicopthologicl fetures of prognostic relevnce in ptients with OSSN. (Arch Pthol Lb Med. 2014;138:1488 1494; doi: 10.5858/rp.2013-0353-OA) Oculr surfce squmous neoplsi (OSSN) is the most common tumor of the oculr surfce, with n estimted incidence of 0.02 to 3.5 cses per 100 000 worldwide. 1 It represents spectrum of lesions tht rnges from conjunctivl intrepithelil neoplsi (CIN) to invsive squmous cell crcinom (SCC), involving the conjunctiv nd cornel epithelium. 2 Oculr surfce squmous neoplsi Accepted for publiction Jnury 8, 2014. From the Deprtment of Oculr Pthology (Ms Chuhn nd Drs Sen nd Kshyp), Deprtment of Oculr Microbiology (Dr A. Shrm), Corne nd Refrctive Surgery Service (Drs Tndon nd N. Shrm), Ophthlmoplsty Service (Dr Pushker), nd Corne nd Oculr Surfce Service (Dr Vnthi), Dr Rjendr Prsd Centre for Ophthlmic Sciences, All Indi Institute of Medicl Sciences, New Delhi. The uthors hve no relevnt finncil interest in the products or compnies described in this rticle. Reprints: Seem Sen, MD, Deprtment of Oculr Pthology, Dr Rjendr Prsd Centre for Ophthlmic Sciences, All Indi Institute of Medicl Sciences, A-132, Defence Colony, New Delhi 110024, Indi (e-mil: ssenop@rediffmil.com). occurs predominntly in older men, lthough n incresed incidence hs recently been observed in individuls younger thn 50 yers. 3 While the lesions re usully confined to the oculr surfce, they hve the cpbility to metstsize (0% 16%) 4 6 nd recur (17% 24% for CIN 7 nd 30% 41% for SCC 1 ). Avilble dt regrding prognostic fetures ffecting survivl in ptients with OSSN re limited nd re mostly inconclusive. In OSSN, most recurrences re confined to the oculr surfce, which cn usully be controlled by excision or locl tretment. Although less frequent, distnt metstsis cn prove to be ftl. 8,9 The Americn Joint Committee on Cncer TNM (AJCC-TNM) stging system hs been recently used for stging OSSN, but few studies 10,11 hve vlidted its clinicl relevnce. The im of the present study ws to evlute the prognostic relevnce of AJCC-TNM stging in ptients with OSSN treted t tertiry eye center in Indi. The impct of other clinicopthologicl fetures ws lso ssessed. 1488 Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l
Tble 1. AJCC-TNM Clssifiction of 64 Ptients With Oculr Surfce Squmous Neoplsi AJCC-TNM Clssifiction No. (%) T1N0M0 4 (6) T2N0M0 38 (59) T2N1M0 1 (2) T3N0M0 4 (6) T4N0M0 12 (19) T4N0M1 1 (2) T4N1M0 3 (5) T4N1M1 1 (2) Abbrevition: AJCC, Americn Joint Committee on Cncer. Most of the ptients belonged to T2N0M0 or T4N0M0 ctegory. MATERIALS AND METHODS Ptients Sixty-four ptients with OSSN (20 CIN nd 44 SCC) were enrolled in the present study from 2009 to 2010. Informed consent ws obtined from the ptients. The study ws pproved by the Institute Ethics Committee, All Indi Institute of Medicl Sciences, New Delhi (IESC/T-95/01.04.10&RT-24/04.06.2010). Clinicl Fetures Clinicl dt on the ptients were recorded, including ge, sex, lterlity, history of oculr trum, durtion of sunlight exposure, geneticlly predisposed stte, tumor loction, nd type of lesion. All of the ptients were clssified on the bsis of their socioeconomic sttus using the Socioeconomic Sttus Scle by Kuppuswmy. 12 A history of prolonged sun exposure ws determined by self-reported history nd by the occuption of the ptient. The AJCC-TNM clssifiction of conjunctivl crcinom ws used to stge ll cses of OSSN. 13 Ptients with orbitl invsion or invsion of djcent structures were ssigned to higher T ctegory (T3 or T4). Histopthologicl Fetures Gross exmintion of the excised tumor ws performed, including mesurement of the lrgest tumor dimeter. Hemtoxylin-eosin stined sections were exmined to confirm the dignosis of OSSN (CIN or SCC). Sebceous crcinom cses were excluded bsed on light microscopic fetures. The CIN cses were further clssified s mild, moderte, severe dysplsi, or crcinom in situ bsed on the extent of epithelil involvement. Invsion ws ruled out by obtining 3 to 5 seril sections (depending on the size of lesion). The SCC cses were ctegorized s well differentited or s poorly differentited depending on the extent of kertiniztion. 14 The presence of orbitl invsion or invsion of djcent structures ws determined, s well s the extent of srcomtoid differentition. Sttisticl Anlysis All sttisticl nlyses were performed using the SPSS 18.0 sttisticl pckge (SPSS, Inc, Chicgo, Illinois). The ssocitions of clinicopthologicl fetures with T ctegory nd metstsis were exmined using contingency tbles, which were further nlyzed using the v 2 test. Survivl probbility (recurrence-free survivl for OSSN nd disese-free survivl for SCC) ws clculted using the Kpln-Meier method. Univrite nlysis with the Cox proportionl hzrds model ws performed to determine every identified prognostic fctor; multivrite nlysis with the Cox proportionl hzrds model ws used to explore combined effects. A difference of P,.05 ws considered sttisticlly significnt. RESULTS Clinicl Fetures The TNM clssifiction ws T2N0M0 in 38 ptients nd T4N0M0 in 12 ptients (Tble 1). The men ge of the ptients ws 64 yers (SD, 16; rnge, 6 84 yers), nd there Figure 1. A, Ptient with conjunctivl squmous cell crcinom presenting s diffuse growth. B, Gross ppernce shows lrge tumor (.2 cm). C, Introculr invsion in ptient hving squmous cell crcinom with ciliry body involvement (hemtoxylin-eosin, originl mgnifiction 3100). ws mrked mle prepondernce (mle to femle rtio, 3.6:1). The left eye ws involved in 41 ptients nd the right eye in 23 ptients (Tble 2). The growth pttern ws nodulr in 42 ptients nd diffuse in 22 ptients; diffuse growth Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l 1489
Tble 2. Correltion of Clinicopthologicl Fetures With Histopthologicl Dignosis of CIN or SCC in 64 Ptients With Oculr Surfce Squmous Neoplsi Vrible Totl Ptients, No. (%) Ptients With CIN, No. (%) Ptients With SCC, No. (%) P Vlue Age, y 50 18 (28) 7 (39) 11 (61).55 (NS).50 46 (72) 13 (28) 33 (72) Sex Mle 50 (78) 20 (40) 30 (60).003 Femle 14 (22) 0 14 (100) Lterlity Left eye 41 (64) 15 (37) 26 (63).26 (NS) Right eye 23 (36) 5 (22) 18 (78) Durtion of sunlight exposure Less 30 (47) 6 (20) 24 (80).10 (NS) More 34 (53) 14 (41) 20 (59) Socioeconomic sttus Poor 54 (84) 13 (24) 41 (76).007 Other 10 (16) 7 (70) 3 (30) History of oculr trum Yes 6 (9) 1 (17) 5 (83).65 (NS) No 58 (91) 19 (33) 39 (67) Associted oculr pthology Yes 13 (20) 1 (8) 12 (92).04 No 51 (80) 19 (36) 32 (64) Clinicl ppernce Geltinous 19 (30) 14 (73.6) 5 (26),.001 Leucoplkic 9 (14) 4 (44) 5 (56) Ppillomtous 4 (6) 2 (50) 2 (50) Ulcertive 20 (31) 0 20 (100) Fungting mss 12 (19) 0 12 (100) Tumor loction Limbus 35 (55) 18 (51) 17 (49),.001 Bulbr conjunctiv 6 (9) 0 6 (100) Plpebrl conjunctiv 23 (36) 2 (9) 21 (91) Growth pttern Nodulr 42 (66) 20 (48) 22 (52),.001 Diffuse 22 (34) 0 22 (100) Orbitl invsion or invsion of djcent structures Present 24 (38) 0 24 (100),.001 Absent 40 (63) 20 (50) 20 (50) Mngement Wide surgicl excision 46 (72) 20 (44) 26 (57) Exentertion 18 (28) 0 18 (100),.001 T ctegory T1 or T2 44 (68) 20 (46) 24 (55) T3 or T4 20 (20) 0 20 (100),.001 Lrgest tumor dimeter, cm,2 27 (42) 13 (48) 14 (52) 2 37 (58) 7 (19) 30 (81),.001 Abbrevitions: CIN, conjunctivl intrepithelil neoplsi; NS, not significnt; SCC, squmous cell crcinom. v 2 Test. pttern is shown in Figure 1, A. Twelve cses presented s fungting mss, nd 19 cses were geltinous. Limbus ws most commonly involved (55%), followed by plpebrl conjunctiv (36%). The durtion of disese t presenttion vried from 4 months to 10 yers (men, 2.3 yers; SD, 2.3 yers). A history of prolonged sunlight exposure ws obtined in 34 of 64 ptients (53%). Three ptients hd xeroderm pigmentosum, 6 ptients reported history of oculr trum to the ffected eye, nd 1 ptient wore contct lenses. Thirteen ssocited oculr pthologies in the ffected eye were documented (pterygium in 6 ptients, ctrct in 3 ptients, ptosis in 2 ptients, nd cyst nd nevus in 1 ptient). According to the Socioeconomic Sttus Scle by Kuppuswmy, the socioeconomic bckground in 84% (54 ptients) of the ptients ws poor. Humn immunodeficiency virus serotyping ws negtive in ll ptients, nd no ptient reported history of orgn trnsplnttion. Tumors were surgiclly excised in 46 ptients (72%), nd exenter- 1490 Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l
Tble 3. Correltion of Clinicopthologicl Fetures With Higher T Ctegory in 64 Ptients With Oculr Surfce Squmous Neoplsi Vrible Totl Ptients, No. (%) Ptients With T Ctegory of T3 or T4, No. (%) P Vlue Sex Mle 50 (78) 6 (12),.001 Femle 14 (22) 14 (100) Clinicl ppernce Geltinous 19 (30) 0,.001 Leucoplkic 9 (14) 0 Ppillomtous 4 (6) 0 Ulcertive 20 (31) 9 (45) Fungting mss 12 (19) 11 (92) Growth pttern Nodulr 42 (66) 0,.001 Diffuse 22 (34) 20 (91) Orbitl invsion or invsion of djcent structures Present 24 (38) 18 (75),.001 Absent 40 (63) 2 (5) Mngement Wide surgicl excision 46 (72) 3 (7),.001 Exentertion 18 (28) 17 (94) Lrgest tumor dimeter, cm,2 27 (42) 0.03 2 37 (58) 20 (100) Metstsis Present 6 (9) 5 (83).009 Absent 58 (91) 15 (26) Deth Yes 4 (6) 3 (75).04 No 60 (94) 17 (28) Histopthologicl dignosis SCC 44 (69) 20 (100) CIN 20 (31) 0,.001 Abbrevitions: CIN, conjunctivl intrepithelil neoplsi; SCC, squmous cell crcinom. v 2 Test. tion for extensive disese ws performed in 18 ptients (28%). Histopthology Gross exmintion of the excised tumors reveled dimeters rnging from 0.4 to 6.0 cm (men, 2.4 cm; SD, 1.9 cm). Tumor size of t lest 2 cm ws recorded in 58% of ptients (Tble 3); the gross ppernce of lrge tumor is shown in Figure 1, B. Of 20 ptients with CIN (31%), dysplsi ws mild in 7, moderte in 6, nd severe in 7. None of the severe dysplsi cses hd fetures of crcinom in situ. All 44 ptients with SCC (69%) demonstrted invsion into the surrounding tissues. Of the SCCs, 22 were well differentited nd 22 poorly differentited on light microcopy. Srcomtoid differentition ws observed in 3 cses. Orbitl invsion or invsion of djcent structures ws present in 24 of 44 SCC cses (54%). The orbit ws involved in 11 cses, nd introculr invsion ws seen in 10 cses; both orbitl invsion nd invsion of djcent structures ws present in 3 cses. Of 13 ptients with introculr invsion, involvement included the scler in 5, the corne in 3, nd the choroid in 1. Invsion of both the corne nd the scler ws detected in 2 ptients, nd invsion of the scler with ciliry body ws observed in 1 ptient. Ciliry body involvement is shown in Figure 1, C. Clinicl Outcome Follow-up dt were vilble for 48 OSSN cses (14 CIN nd 34 SCC) during 17 to 40 months (medin, 32 months). Recurrence developed in 8 of 48 ptients (17%); of these, 6 were ptients with SCC. Of the 18% of 34 SCC cses tht developed metstsis, regionl lymph node metstsis (preuriculr in 3 ptients nd submndibulr in 1 ptient) ws present in 4 (12%), nd systemic metstsis (lung nd brin in 1 ptient ech) ws present in 2 (6%). All 4 ptients with SCC who died (12%) hd tumor size of t lest 2 cm nd hd high T ctegory (T3 or T4). Assocition of T Ctegory With Clinicopthologicl Fetures of OSSN All the tumors with high T ctegory (T3 or T4) occurred in women, hd lrger tumor dimeter (2 cm), nd were SCC cses. A high T ctegory ws lso significntly ssocited with diffuse growth pttern (20 of 22 cses), fungting mss (11 of 12 cses), exentertion (17 of 18 Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l 1491
Tble 4. Correltion of Clinicopthologicl Fetures With Metstsis nd Deth in 44 Ptients With SCC Vrible Totl Ptients, No. (%) Ptients With Metstsis or Deth, No. (%) Ptients Without Metstsis or Deth, No. (%) P Vlue Age, y 50 11 (25) 7 (64) 4 (36),.001.50 33 (75) 1 (3) 32 (97) Tumor loction Limbus 17 (39) 0 17 (100).001 Bulbr conjunctiv 6 (14) 0 6 (100) Plpebrl conjunctiv 21 (48) 8 (100) 13 (62) Growth pttern Nodulr 22 (50) 1 (5) 21 (95).04 Diffuse 22 (50) 7 (32) 15 (68) Durtion of sunlight exposure Less 24 (55) 1 (4) 23 (96).01 More 20 (45) 7 (35) 13 (65) History of oculr trum Yes 5 (11) 3 (60) 2 (40).03 No 39 (89) 5 (13) 34 (87) Orbitl invsion or invsion of djcent structures Present 24 (55) 7 (29) 17 (71).05 Absent 20 (45) 1 (5) 19 (95) T ctegory T1 or T2 24 (55) 1 (4) 23 (96).01 T3 or T4 20 (45) 7 (35) 13 (65) Lrgest tumor dimeter, cm,2 14 (32) 0 14 (100).04 2 30 (68) 8 (27) 22 (73) SCC Well differentited 22 (50) 1 (5) 21 (96).04 Poorly differentited 22 (50) 7 (32) 15 (68) Abbrevition: SCC, squmous cell crcinom. v 2 Test. cses), metstsis (5 of 6 cses), nd deth (3 of 4 cses) (Tble 3). Assocition of Metstsis nd Deth With Clinicopthologicl Fetures of SCC Metstsis nd deth were significntly ssocited with younger ge (7 of 11 cses), plpebrl tumor loction (8 of 21 cses), diffuse growth pttern (7 of 22 cses), lrger tumor dimeter (8 of 30 cses), longer sunlight exposure (7 of 20 cses), history of trum (3 of 5 cses), nd poorly differentited SCC (7 of 22 cses). These results re summrized in Tble 4. Correltion of Clinicopthologicl Fetures With Recurrence-Free Survivl nd Prognosis Risk of recurrent disese ws greter in ptients with diffuse growth pttern (hzrd rtio [HR], 0.34; P ¼.02), longer sunlight exposure (HR, 3.4; P ¼.01), lrger tumor size of t lest 2 cm (HR, 2.4; P ¼.03), nd higher T ctegory of T3 or T4 (HR, 2.9; P,.001) (Figure 2). In n nlysis compring the 2 histopthologicl groups (CIN nd SCC), dignosis of SCC ws predictor of shorter survivl (HR, 0.22; P ¼.01). On univrite nlysis (Cox proportionl hzrds model), dignosis of SCC nd higher T ctegory (T3 or T4) were significntly ssocited with poor prognosis (Tble 5). On multivrite nlysis, higher T ctegory (T3 or T4) hd n independent prognostic effect on the survivl of ptients with OSSN (Tble 6). COMMENT Oculr surfce squmous neoplsi is common lesion in Indi, s in other prts of the world. The pthogenesis of OSSN is multifctoril. Ultrviolet rdition is known mjor risk fctor for the development of dysplstic nd neoplstic chnges in cornel nd conjunctivl epithelium. Cse-control studies 15 17 hve demonstrted tht the incidence of the tumor increses with higher levels of mbient solr rdition. Our results hve shown direct reltionship between excessive sunlight exposure nd reduced recurrence-free survivl in ptients with OSSN. Humn ppillomvirus nd humn immunodeficiency virus hve lso been cited s possible cofctors in OSSN tht my influence the prognosis. 3,18 20 Recurrence developed in 17% of 48 ptients herein with follow-up dt, which is similr to tht in other studies (17% 41%). 1,7 Lrger tumors (2 cm) nd those with diffuse growth pttern hd higher risk of recurrence. Erlier studies 6,11 hve lso indicted n incresed risk of recurrence in ptients with lrger tumor dimeter nd diffuse growth pttern. A histopthologicl dignosis of SCC nd n AJCC-TNM ctegory of T3 or T4 (infiltrtion of the orbit nd introculr structures) were ssocited with significntly incresed risk of recurrence. Yousef nd 1492 Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l
Figure 2. Kpln-Meier survivl curves show recurrence-free survivl in ptients with oculr surfce squmous neoplsi. Recurrence-free survivl ws worse in ptients with diffuse growth pttern (P ¼.02) (A), longer sunlight exposure (P ¼.01) (B), lrger tumor dimeter (2 cm) (P ¼.03) (C), higher T ctegory (T3 or T4) (P,.001) (D), nd histopthologicl dignosis of squmous cell crcinom (SCC) compred with conjunctivl intrepithelil neoplsi (P ¼.02) (E). Finger 10 hve lso reported tht tumors with n dvnced AJCC-TNM T ctegory, loclly invsive tumors, nd more pthologiclly ggressive tumors hve higher risk of recurrence. The incidence of orbitl invsion nd invsion of djcent structures hs been reported to rnge from 2% to 15% in OSSN cses. However, we found very high incidence of orbitl invsion or invsion of djcent structures (50%) Tble 5. Univrite Anlysis of Clinicopthologicl Fetures in Ptients With Oculr Surfce Squmous Neoplsi Vrible Hzrd Rtio (95% CI) P Vlue Age 0.985 (0.957 1.041).32 Sex 2.544 (0.707 9.154).15 Lterlity 0.705 (0.246 2.021).51 Durtion of sunlight exposure 1.431 (0.493 4.153).51 Socioeconomic sttus 2.544 (0.707 9.154).13 Associted oculr pthology 1.090 (0.299 3.979).89 History of oculr trum 1.763 (0.228 13.603).58 Clinicl ppernce 0.867 (0.584 1.288).48 Tumor loction 1.186 (0.728 1.931).49 Growth pttern 0.163 (0.211 1.262).08 Mngement 7.000 (0.996 49.201).06 Lrgest tumor dimeter 0.265 (0.058 1.204).08 Histopthologicl dignosis of SCC 0.380 (0.127 1.138).05 Orbitl invsion or invsion of djcent structures 0.187 (0.039 0.890).03 Higher T ctegory 0.102 (0.012 0.841).03 Abbrevitions: CI, confidence intervl; SCC, squmous cell crcinom. Sttisticlly significnt. Tble 6. Multivrite Anlysis of Clinicopthologicl Fetures in Ptients With Oculr Surfce Squmous Neoplsi Vrible Hzrd Rtio (95% CI) P Vlue Histopthologicl dignosis of SCC 0.1233 (0.6641 32.9100).12 Orbitl invsion or invsion of djcent structures 0.1020 (0.0124 0.8406).04 Higher T ctegory 0.0429 (0.0050 0.9063).03 Abbrevitions: CI, confidence intervl; SCC, squmous cell crcinom. Sttisticlly significnt. Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l 1493
mong 44 SCC cses. 4,5,6 Cornel nd sclerl invsion ws observed in 25% of ptients in the present study, which is similr to the 30% incidence reported in other studies. 2,9 Although OSSN is considered low-grde mlignncy, 18% of 34 ptients with SCC in our study developed metstsis, nd 12% died of their disese. This is higher thn erlier reports of metstsis (0% 16%) nd deth (0% 8%). 4 6,21 While older men (72%) nd ptients with limbl tumor loction (55%) represented the most common clinicl presenttions of OSSN in the present study, younger ptients nd those with trsl tumor loction hd higher rtes of metstsis nd deth. These ptients with younger ge group nd trsl tumor loction hd lrger tumors (61%) nd poor histopthologicl differentition of their lesions (58%). Histories of prolonged sunlight exposure nd oculr trum hve been suggested s possible risk fctors for OSSN. 22 Ptients with such histories in our study hd n incresed risk of metstsis nd deth. Other high-risk fetures included diffuse growth pttern cliniclly, higher T ctegory (T3 or T4), lrge tumor size (2 cm), nd poorly differentited SCC. To our knowledge, this is the first study tht hs correlted the risk of metstsis or deth with clinicopthologicl fetures in ptients with OSSN. Our study hs shown tht longer sunlight exposure, diffuse growth pttern, lrger tumor size (2 cm), orbitl invsion or invsion of djcent structures (T3 or T4), nd histopthologicl dignosis of SCC re importnt predictors of recurrence in ptients with OSSN or metstsis nd of deth in ptients with SCC. In ddition, younger ptients nd those with trsl tumor loction hve higher risk of metstsis nd deth. Bsed on multivrite nlysis of ll the bove fetures, higher AJCC-TNM T ctegory is the most importnt prognostic indictor of poor outcome. Therefore, the AJCC-TNM stging system is useful nd relible djunct in the mngement of ptients with OSSN. 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Ophthlmology. 1988;95(3):318 321. 22. Wddell K, Kwehngn J, Johnston W, et l. A cse-control study of oculr surfce squmous neoplsi (OSSN) in Ugnd. Int J Cncer. 2010;127(2): 427 432. 1494 Arch Pthol Lb Med Vol 138, November 2014 Clinicopthologicl Predictors of OSSN Chuhn et l