LAUSR

With great interest, we read the article published in Leukemia by Dr. Hong et al. [1]. We highly appreciated that they constructed a novel staging system, CA staging system (CASS), for extranodal NK/T-cell lymphoma (ENKTL). Among early-stage patients of the Ann Arbor staging system (AASS), the authors identified patients with nasal lesions without local invasiveness have better overall survival (OS) than the rest. For late-stage patients, the authors combined those with similar survival rates. Those modifications make CASS better in discriminating patients’ survival than AASS, which is confirmed in a large external cohort. However, since most of the patients in their study were nasal type, whether CASS could be used in extranasal patients needs further investigations. Moreover, juvenile ENKTL is recently identified as a rare subtype that is more aggressive than the adult counterpart [2, 3]. Whether CASS could be applied to juveniles remains unclear since most cases were adults in their study. Staging extranasal and juvenile ENKTL is essential clinically but challenging due to the heterogeneity and rareness. Therefore, whether physicians could transfer staging systems from general ENKTL to those subtypes is an important question. In this paper, we investigate the ability of AASS and CASS in depicting and discriminating survival by two large datasets extracted from literature specifically for extranasal and juvenile ENKTL [4] (Supplementary Methods and Table S1); we also summarize the clinical challenges and propose some suggestions aiming to improve the staging system better. We included 164 eligible cases from 22 studies of extranasal ENKTL (Fig. S1a and Supplementary Materials—individual data). According to AASS, from stage I to IV, the number of patients were 81, 36, 4, and 43, after reassigned by CASS, they were 0, 81, 32, and 51, respectively (Fig. 1a). Although CASS showed similar discrimination abilities in predicting 5-year OS compared with AASS (CASS: AUC= 0.652, 95% CI= 0.543-0.745; AASS: AUC= 0.653, 95% CI= 0.546-0.746, p= 0.89, Fig. 1d), the log-rank test for trends showed significant ordered differences in survival curves of CASS (p= 0.025, Fig. 1c), but not in those of AASS (p= 0.11, Fig. 1b). Comparing with AASS, CASS in extranasal ENKTL showed similar survival discrimination but significant trends, hinting at the advantages of combining advancedstage patients. Nevertheless, such modification limited the performance of CASS because most extranasal cases were allocated one later of the corresponding stage (AASS stage I–III to CASS stage II–IV). As ENKTL involving different regions cause various impacts, we conducted exploratory subgroup analysis. Overall, no statistically significant difference was found in discrimination abilities between AASS and CASS. The regions with the highest discrimination abilities were laryngeal and orbit, followed by skin, gastrointestinal (GI) tract, testis, and lung. For ENKTL originate from orbit, lung, and testis, most of the patients were classified into stage II/IV in CASS (stage I/IV in AASS), which limits precise risk-identification [5]. Particularly, patients with ENKTL of central nerve system (CNS) in early-stage (AASS stage I) had a 5-year OS rate of 13% [6]; the staging did not reflect the prognosis accurately. Those phenomena These authors contributed equally: Pujun Guan, Tian Dong