Neutrophil lymphocyte ratio predicts survival in pancreatic neuroendocrine tumors

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1 2454 Neutrophil lymphocyte rtio predicts survivl in pncretic neuroendocrine tumors GUOPEI LUO 1 3*, CHEN LIU 1 3*, HE CHENG 1 3*, KAIZHOU JIN 1 3, MENG GUO 1 3, YU LU 1 3, JIANG LONG 1 3, JIN XU 1 3, QUANXING NI 1 3, JIE CHEN 4 nd XIANJUN YU Deprtment of Pncretic Surgery, Fudn University Shnghi Cncer Center; 2 Deprtment of Oncology, Shnghi Medicl College of Fudn University; 3 Pncretic Cncer Institute, Fudn University, Shnghi ; 4 Deprtment of Gstroenterology, The First Affilited Hospitl, Sun Yt-Sen University, Gungzhou, Gungdong , P.R. Chin Received December 20, 2016; Accepted Jnury 31, 2017 DOI: /ol Abstrct. Although the prognostic role of neutrophil lymphocyte rtio (NLR) hs been confirmed in vriety of tumors, the prognostic role of NLR in pncretic neuroendocrine tumors (PNETs) hs not been exmined. The present study ws performed to ssess the role of NLR s prognostic fctor in ptients with PNETs. Clinicl dt were retrospectively retrieved from single institution. The best cut off vlue for bseline NLR levels ws determined by the receiver operting chrcteristic (ROC) curve nd re under the ROC curve. The primry event ws overll survivl nd event times were ssessed by the Kpln Meier method. Potentil fctors ssocited with the elevtion of NLR in PNETs were exmined. A totl of 165 consecutive ptients with pthologiclly confirmed PNETs were included in this study. The cutoff vlue of NLR ws 2.4 by ROC curve (re under ROC curve, 0.70). NLR >2.4 ws found to be poor prognostic fctor in the univrite nd multivrite nlyses. Ptients with NLR vlue >2.4 hd higher proportion of tumor size t >3 cm (P=0.001), TNM stge III or IV (P=0.019), nd G2/G3 (P=0.003). We concluded tht NLR is n independent predictor of overll survivl for ptients with PNETs. Aberrnt elevtion of NLR identifies high risk ptients with ggressive chrcteristics. Introduction Pncretic neuroendocrine tumors (PNETs) re rre but clinicl importnt tumors with n incidence of pproximtely Correspondence to: Dr Xinjun Yu or Dr Guopei Luo, Deprtment of Pncretic Surgery, Fudn University Shnghi Cncer Center, 270 Dong'An Rod, Shnghi , P.R. Chin E mil: yuxinjun@fudnpci.org E mil: luoguopei@hotmil.com * Contributed eqully Key words: pncretic neuroendocrine tumor, prognosis, pncretic neuroendocrine tumors, neutrophil lymphocyte rtio 1 in 100,000 of the popultion, ccounting for 1 2% of ll pncretic tumors in incidence nd 10% in prevlence (1 4). They re brodly ctegorized s functioning or non functioning tumors bsed on their clinicl mnifesttion (5). Unlike functioning neoplsms, non functioning PNETs re often detected t n dvnced stge due to the lck of specific symptoms (6). PNETs re highly heterogeneous neoplsms presenting spectrum of biologic behvior (7,8). Aggressive progression cn even be observed in incidentlly detected nd smll tumors (9). Potentil prognostic fctors, including mitoses, vsculr invsion, metstsis, necrosis, Ki 67 expression, nd nucler grde, re mostly bsed on pthologicl exmintion (2,3,10,11). Therefore, circulting biomrkers re needed to predict their mlignnt behvior nd prognosis. Neutrophil lymphocyte rtio (NLR) is derived from the bsolute neutrophil count divided by the bsolute lymphocyte count nd is routinely used, relible, nd convenient mrker (12). It is n index of systemic inflmmtion, which is common phenomenon nd prognostic determinnt of cncer (12). In recent yers, incresing evidence hs demonstrted the role of NLR in evluting tretment response nd predicting prognosis in vrious types of cncer (13 17). For exmple, in pncretic denocrcinom, NLR my be used to ssess survivl in unselected cohorts, ptients with dvnced diseses treted with chemotherpy, nd ptients undergoing curtive surgery (13 16). In ddition, NLR ws sttisticlly significntly ssocited with tumor stge, differentition, performnce sttus, CA19 9, C rective protein, nd lbumin levels in pncretic denocrcinom (16). However, the prognostic role of NLR in PNETs hs not been evluted. The present study ws performed to exmine the role of blood NLR s prognostic fctor in lrge cohort of ptients with PNETs. Potentil clinicopthologicl fctors ssocited with the bnorml elevtion of NLR in PNETs were lso evluted. Mterils nd methods Ptients. The dtbses of Shnghi Cncer Center, Fudn University (Shnghi, Chin) were collected to identify potentil ptients with pthologicl confirmed PNETs between

2 LUO et l: NLR AND PANCREATIC NEUROENDOCRINE TUMOR PROGNOSIS nd Dt were retrieved regrding ptient demogrphics, symptoms, tumor size, loction, functioning sttus, histologic grde, lymph node involvement, vessel invsion, nerve invsion, nd TNM stges. Positive symptoms included bdominl nd bck pin, weight loss, nuse, vomiting, ftigue nd jundice. Ptients with functioning PNETs or ptients with non functioning PNETs nd without the bove mentioned symptoms were viewed s incidentl PNETs (18). The ptients were stged bsed on the 7th edition of Americn Joint Committee on Cncer (AJCC) TNM stging system. Tumors were ctegorized s G1, G2, G3 ccording to the 2010 World Helth Orgniztion (WHO) clssifiction (bsed on the Ki 67 index nd the mitotic index) (19). Ptients were followed up >18 months or until deth. The lbortory dt including neutrophil nd lymphocyte were obtined before mjor tretments within 2 weeks. The NLR ws clculted by the bsolute neutrophil count divided by the bsolute lymphocyte count. The receiver operting chrcteristic (ROC) curve nd re under the ROC curve were pplied to select the best cut off vlues for bseline NLR. The current study ws pproved by the ethics committee of Shnghi Cncer Center, Fudn University. Sttisticl nlysis. Univrite nd multivrite nlyses bsed on Cox proportionl hzrds model were used to nlyze potentil prognostic fctors. Fctors with P<0.05 in the univrite nlysis were further included in the multivrite nlysis. The effect of the NLR nd other fctors on survivl ws estimted using the Kpln Meier method. Person's χ² test or Fisher's exct test ws used to nlyze ctegoricl dt s pproprite. The nlysis ws performed using the STATA 12.0 sttisticl softwre pckge (SttCorp LP, College Sttion, TX, USA). A two sided P<0.05 ws considered to indicte sttisticlly significnt difference. Tble I. Demogrphics nd clinicl chrcteristics. Demogrphic or clinicl chrcteristic Prmeter No. (%) Age (41.8) >50 96 (58.2) Gender Mle 76 (46.1) Femle 89 (53.9) Loction Hed 68 (41.2) Others 97 (58.8) Size (cm) 3 57 (34.5) >3 108 (65.5) TNM stge I, II 107 (64.8) III, IV 58 (35.2) Grde G1 63 (46.3) G2 58 (42.6) G3 15 (11.0) Functioning Positive 18 (10.9) Negtive 147 (89.1) Symptom Positive 78 (47.3) Negtive 87 (52.7) Only 136 cses hd informtion for grde. TNM, tumor node metstsis. Results Ptients dt nd survivl nlysis. A totl of 165 consecutive ptients with pthologiclly confirmed PNETs were included in the present study (Tble I). The medin ge ws 52, with 58.2% of ptients hving n ge >50. More thn 50% of ptients were femle, with femle to mle rtio of 1.2:1. A totl of 68 ptients (41.2%) hd tumors locted t the hed of the pncres nd 97 ptients (58.8%) t the body, or til of the pncres, or whole pncres. The medin size ws 4 cm, with >60% of cses hving tumors >3 cm in dimeter. More thn 60% of ptients hd stge I or II tumors. Nerly 50% of the ptients hd G1 tumors (G1 46.3%, G2 42.6%, G3 11.0%) nd 18 ptients (10.9%) hd functioning diseses. Nerly hlf of the ptients (47.3%) hd PNETs with symptoms. The cut off vlue of NLR s prognostic predictor of ptients with PNETs ws 2.4 by ROC curve (re under ROC curve, 0.70, sensitivity 71.4%, specificity 76.5%, Fig. 1), with 28.5% of ptients hving NLR levels higher thn the selected cut off vlue. Sixty five ptients were followed up <18 months nd 1 ptient hd periopertive deth nd 10 ptients were lost to follow up (10/165, 6.1%), leving 89 ptients for the survivl nlysis. The univrite nlysis, TNM stge III or IV (HR=14.33, P<0.01), NLR >2.4 (HR=7.15, P=0.003), G3 diseses (HR=17.82, P<0.01), nd incidentl Figure 1. The receiver operting chrcteristic (ROC) curve nd re under the ROC curve for the neutrophil lymphocyte rtio s prognostic fctor. PNETs (HR=0.27, P=0.006) were prognostic fctors for ptients' overll survivl, wheres gender, ge, tumor size, nd loction were not sttisticlly significntly ssocited with overll survivl (Tble II; Fig. 2). In the multivrite nlysis, TNM stge III or IV (HR=6.70, P=0.001), NLR >2.4 (HR=3.60, P=0.011), nd G3 diseses (HR=6.31, P=0.004) were poor prognostic fctors for overll survivl (Tble II). Prmeters correlted with bseline NLR levels. The χ 2 test ws employed to nlyze clinicl nd pthologic fctors correlted with bseline NLR levels (NLR 2.4 nd NLR >2.4,

3 2456 Tble II. Univrite nd multivrite nlysis for overll survivl of ll ptients using the Cox proportionl hzrds model. Univrite nlysis Multivrite nlysis Chrcteristic Prmeter No. HR 95% CI P vlue HR 95% CI P vlue Age > Gender Mle 38 1 Femle Size (cm) > Loction Hed 33 1 Others TNM stge I, II III, IV NLR > Grde G1, G G Unknown Symptom Positive Negtive Only 65 ptients followed up <18 months nd 1 ptient hd periopertive deth nd 10 ptients were lost to follow up, leving 89 ptients for the survivl nlysis. HR, hzrd rtio; CI, confidence intervl; NLR, neutrophil lymphocyte rtio; TNM, tumor node metstsis. Figure 2. Kpln Meier survivl curves ccording to neutrophil lymphocyte rtio (NLR) 2.4 or NLR >2.4. Tble III). A NLR >2.4 ws sttisticlly significntly ssocited with tumor size (P=0.001), TNM stge III or IV (P=0.019), nd tumor grde (P=0.003), but not with ge, gender, loction, symptoms, vessel invsion, nd nerve invsion. Of note, NLR >2.4 ws ssocited with positive lymph sttus (P=0.067) nd functioning sttus (P=0.084). Discussion To the best of our knowledge, this study is the first to investigte the prognostic role of NLR in PNETs. Using ROC curve, the cut-off vlue of NLR s prognostic predictor of ptients with PNETs ws 2.4. NLR >2.4 ws found to be poor prognostic fctor in both univrite nd multivrite nlyses for ptients with PNETs. We lso showed tht n NLR >2.4 ws sttisticlly significntly ssocited with tumor size >3 cm, TNM stge III or IV, nd tumor grde. We demonstrted tht NLR is prognostic mrker of ptients with PNETs which my predict their clinicl outcome nd ggressive fetures. NLR is more widely vilble nd convenient compred with other biomrkers. Therefore, considering its prognostic role in PNETs, NLR my be used to strtify ptients with high risk of therpeutic resistnce, erly recurrence, or metstsis. In ddition, NLR hs the potentil to determine therpeutic strtegy, monitor disese progression, nd evlute tretment response. Mounting evidence hs shown tht cncer ssocited inflmmtion is key fctor of prognosis in ptients with cncer (12). In study by Hochwld et l, tumor necrosis ws correlted strongly with prognosis in ptients with PNETs (10). Previous findings demonstrted tht higher NLR level ws significntly correlted with lrger tumor size, histologic tumor necrosis, nd tumor differentition (20). In this study, we lso showed tht NLR ws significntly correlted with tumor size, TNM stge, nd tumor grde, which re ll strongly ssocited with tumor necrosis. A vriety of mrkers of systemic inflmmtion hve been evluted over the pst decde for therpeutic response nd predicting survivl, including NLR, Glsgow prognostic score nd its modified version, prognostic index, pltelet

4 LUO et l: NLR AND PANCREATIC NEUROENDOCRINE TUMOR PROGNOSIS 2457 Tble III. NLR, ptient demogrphics nd clinicl chrcteristics. Demogrphic or clinicl chrcteristic Prmeter NLR 2.4 NLR >2.4 P vlue Age > Gender Mle Femle Loction Hed Others Size (cm) > TNM stge I, II III, IV Grde G G2/G Lymph sttus Positive Negtive Vessel invsion Positive Negtive Nerve invsion Positive Negtive Functioning Positive Negtive Symptom Positive Negtive For cses tht underwent curtive resection only. NLR, neutrophil lymphocyte rtio, TNM, tumor-node-metstsis. lymphocyte rtio, nd prognostic nutrition index (21,22). Of these mrkers, NLR is routinely vilble nd promising mrker tht cn be used to ssess systemic inflmmtion nd therpeutic responses (13,21,22). For exmple, Wng et l found tht NLR ws the only mrker of inflmmtion for prognosis on multivrite nlysis nd elevted NLR ws better thn the modified Glsgow prognostic score, prognostic index, pltelet lymphocyte rtio, nd prognostic nutrition index for prognostiction in ptients with pncretic cncer (22). Another study demonstrted tht bseline NLR nd NLR, which were used s potentil prognostic mrkers in ptients with dvnced pncretic cncer, were ltered following tretment with chemotherpy (13). In the current study, we confirm the prognostic role of NLR in ptients with PNETs by both univrite nd multivrite nlyses. In ddition to specific mrkers in functioning PNETs, there re generl biomrkers used to dignose nd monitor functioning nd non functioning PNETs (23). Chromogrnin A (CgA) is the most widely used biomrker nd hs been reported to be elevted in 50 80% of ptients with PNETs. It is n idel biomrker used to monitor disese progression for cses with CgA elevtion (23). However, in study conducted by Shermn et l, no correltion between CgA nd survivl ws found in ptients with PNETs in multivrite nlysis (24). Pncretic polypeptide is 36 mino cid protein secreted by endocrine cells locted primrily in the pncretic hed nd uncinte process, with low sensitivity of 31% in PNETs (25). Neuron specific enolse is biomrker with sensitivity of 33% nd specificity of 100% in ptients with gstroenteropncretic neuroendocrine tumors (26). It is lso n independent predictor of survivl for ptients with dvnced G1/2 PNETs undergoing peptide receptor rdionuclide therpy (27). Pncresttin is post trnsltionl frgment of CgA peptide nd hs gret sensitivity nd specificity for detecting PNETs nd correltes with survivl (24). However, lthough not vrying with proton pump inhibitor s CgA, pncresttin my be ffected by insulin nd glucose homeostsis (23). Therefore, NLR hs the potentil to serve s supplementl prognostic predictor to these biomrkers. The current study hs severl shortcomings. Firstly, despite reltively lrge smple size, the retrospective feture of this study my limit its clinicl ppliction. Further prospective evidence with lrge smple size is needed. In ddition, NLR is non specific mrker tht could be ffected by severl confounders, minly including bcteril inflmmtion, immunologic response, nd nticncer tretments (13). In ddition, the predicting role of NLR in combintion with other biomrkers including CgA, pncretic polypeptide, nd neuron specific enolse ws not demonstrted. Furthermore, the dynmics of NLR during tretment nd follow up were not presented in the current study.

5 2458 In conclusion, bseline NLR is strong independent predictor of overll survivl for ptients with PNETs. A high level of NLR hs significnt correltion with lrge tumor size, dvnced stge, nd high grde. Aberrnt elevtion of NLR identifies high risk ptients who my require specil tretment nd close follow up. Acknowledgements The present study ws jointly funded by the Ntionl Science Foundtion for Distinguished Young Scholrs of Chin (no ), the Ntionl Nturl Science Foundtion of Chin (nos , , nd ), Shnghi Municipl Commission of Helth nd Fmily Plnning scientific reserch (no Y0170), nd bsic reserch projects of the Science nd Technology Commission of Shnghi Municiplity (no. 15JC ). References 1. Oberg K nd Eriksson B: Endocrine tumours of the pncres. Best Prct Res Clin Gstroenterol 19: , Luo G, Liu Z, Guo M, Jin K, Xio Z, Liu L, Xu J, Zhng B, Liu C, Hung D, et l: 18 F FDG PET/CT cn be used to detect non functioning pncretic neuroendocrine tumors. Int J Oncol 45: , O'Grdy HL nd Conlon KC: Pncretic neuroendocrine tumours. Eur J Surg Oncol 34: , Ricci C, Csdei R, Tffurelli G, D'Ambr M, Monri F, Cmpn D, Tomssetti P, Sntini D nd Minni F: WHO 2010 clssifiction of pncretic endocrine tumors. Is the new lwys better thn the old? Pncretology 14: , Li J, Luo G, Fu D, Jin C, Ho S, Yng F, Wng X, Yo L nd Ni Q: Preopertive dignosis of nonfunctioning pncretic neuroendocrine tumors. Med Oncol 28: , Yo JC, Hssn M, Phn A, Dgohoy C, Lery C, Mres JE, Abdll EK, Fleming JB, Vuthey JN, Rshid A, et l: One hundred yers fter crcinoid : Epidemiology of nd prognostic fctors for neuroendocrine tumors in 35,825 cses in the United Sttes. J Clin Oncol 26: , Singh S, Dey C, Kennecke H, Koch W, Mroun J, Metrkos P, Mukhtr T, Psiek J, Ryson D, Rowsell C, et l: Consensus recommendtions for the dignosis nd mngement of pncretic neuroendocrine tumors: Guidelines from Cndin ntionl expert group. Ann Surg Oncol 22: , Wiedenmnn B, Pvel M nd Kos Kudl B: From trgets to tretments: A review of moleculr trgets in pncretic neuroendocrine tumors. Neuroendocrinology 94: , Hynes AB, Deshpnde V, Ingkkul T, Vgefi PA, Szymonifk J, Thyer SP, Ferrone CR, Wrgo JA, Wrshw AL nd Fernández del Cstillo C: Implictions of incidentlly discovered, nonfunctioning pncretic endocrine tumors: Short term nd long term ptient outcomes. Arch Surg 146: , Hochwld SN, Zee S, Conlon KC, Colleoni R, Louie O, Brennn MF nd Klimstr DS: Prognostic fctors in pncretic endocrine neoplsms: An nlysis of 136 cses with proposl for low grde nd intermedite grde groups. J Clin Oncol 20: , Cherenfnt J, Tlmonti MS, Hll CR, Thurow TA, Gge MK, Stocker SJ, Lpin B, Wng E, Silverstein JC, Mngold K, et l: Comprison of tumor mrkers for predicting outcomes fter resection of nonfunctioning pncretic neuroendocrine tumors. Surgery 156: , discussion , Guthrie GJ, Chrles KA, Roxburgh CS, Horgn PG, McMilln DC nd Clrke SJ: The systemic inflmmtion bsed neutrophil lymphocyte rtio: Experience in ptients with cncer. Crit Rev Oncol Hemtol 88: , Luo G, Guo M, Liu Z, Xio Z, Jin K, Long J, Liu L, Liu C, Xu J, Ni Q, et l: Blood neutrophil lymphocyte rtio predicts survivl in ptients with dvnced pncretic cncer treted with chemotherpy. Ann Surg Oncol 22: , Bhtti I, Pecock O, Lloyd G, Lrvin M nd Hll RI: Preopertive hemtologic mrkers s independent predictors of prognosis in resected pncretic ductl denocrcinom: Neutrophil lymphocyte versus pltelet lymphocyte rtio. Am J Surg 200: , Stotz M, Gerger A, Eisner F, Szknder J, Loibner H, Ress AL, Kornprt P, AlZoughbi W, Seggewies FS, Lckner C, et l: Incresed neutrophil lymphocyte rtio is poor prognostic fctor in ptients with primry operble nd inoperble pncretic cncer. Br J Cncer 109: , Yng JJ, Hu ZG, Shi WX, Deng T, He SQ nd Yun SG: Prognostic significnce of neutrophil to lymphocyte rtio in pncretic cncer: A met nlysis. World J Gstroenterol 21: , Prmnthn A, Sxen A nd Morris DL: A systemtic review nd met nlysis on the impct of pre opertive neutrophil lymphocyte rtio on long term outcomes fter curtive intent resection of solid tumours. Surg Oncol 23: 31 39, Luo G, Liu Z, Guo M, Jin K, Xio Z, Liu L, Liu C, Xu J, Ni Q, Long J, et l: A comprehensive comprison of clinicopthologic nd imging fetures of incidentl/symptomtic non functioning pncretic neuroendocrine tumors: A retrospective study of single center. Pncretology 15: , Mocci E, Milne RL, Méndez Villmil EY, Hopper JL, John EM, Andrulis IL, Chung WK, Dly M, Buys SS, Mlts N, et l: Risk of pncretic cncer in brest cncer fmilies from the brest cncer fmily registry. Cncer Epidemiol Biomrkers Prev 22: , Viers BR, Houston Thompson R, Boorjin SA, Lohse CM, Leibovich BC nd Tollefson MK: Preopertive neutrophillymphocyte rtio predicts deth mong ptients with loclized cler cell renl crcinom undergoing nephrectomy. Urol Oncol 32: , Ahmd J, Grimes N, Frid S nd Morris Stiff G: Inflmmtory response relted scoring systems in ssessing the prognosis of ptients with pncretic ductl denocrcinom: A systemtic review. Heptobiliry Pncret Dis Int 13: , Wng DS, Luo HY, Qiu MZ, Wng ZQ, Zhng DS, Wng FH, Li YH nd Xu RH: Comprison of the prognostic vlues of vrious inflmmtion bsed fctors in ptients with pncretic cncer. Med Oncol 29: , Lndry CS, Cvness K, Celinski S nd Preskitt J: Biochemicl prognostic indictors for pncretic neuroendocrine tumors nd smll bowel neuroendocrine tumors. Glnd Surg 3: , Shermn SK, Mxwell JE, O'Dorisio MS, O'Dorisio TM nd Howe JR: Pncresttin predicts survivl in neuroendocrine tumors. Ann Surg Oncol 21: , Wlter T, Chrdon L, Chopin lly X, Rverot V, Cffin AG, Chyville JA, Scozec JY nd Lombrd Bohs C: Is the combintion of chromogrnin A nd pncretic polypeptide serum determintions of interest in the dignosis nd follow up of gstro entero pncretic neuroendocrine tumours? Eur J Cncer 48: , Seregni E, Ferrri L, Bjett E, Mrtinetti A nd Bombrdieri E: Clinicl significnce of blood chromogrnin A mesurement in neuroendocrine tumours. Ann Oncol 12 (Suppl 2): S69 S72, Ezziddin S, Khlf F, Vnezi M, Hslerud T, Myer K, Al Zreiqt A, Willinek W, Biersck HJ nd Sbet A: Outcome of peptide receptor rdionuclide therpy with 177Lu octreotte in dvnced grde 1/2 pncretic neuroendocrine tumours. Eur J Nucl Med Mol Imging 41: , 2014.