A total of 625 patients were included in this study. We excluded 23 patients on chronic hemodialysis from further analysis because serum sIL-2R levels during hemodialysis can be elevated regardless of the presence of lymphoma or other disease [7, 8]. Patient characteristics are shown in Table 1. Of the 602 patients, 337 (56%) were men, and 421 (70%) had fever. The degree of fever was not identified in one febrile patient, but a record of “high grade fever” before hospitalization was mentioned.
Table 1
Patient characteristics and biomarkers used.
| All (n = 602) | Febrile group (n = 421) | Afebrile group (n = 181) |
| Lymphoma (n = 80) | Non-lymphoma (n = 522) | P value | Lymphoma (n = 52) | Non-lymphoma (n = 369) | P value | Lymphoma (n = 28) | Non-lymphoma (n = 153) | P value |
Age, years | 73 (61–79) | 68 (52–76) | 0.011 | 73 (60–81) | 67 (46–76) | 0.004 | 68 (61–78) | 70 (63–76) | 0.992 |
Men, n (%) | 40 (50) | 297 (57) | 0.300 | 29 (56) | 203 (55) | 1.000 | 11 (39) | 94 (61) | 0.048 |
sIL-2R, U/mL | 5,275 (1,943–12,225) | 1,120 (665–2,050) | < 0.001 | 7,590 (4,075–14,625) | 1,230 (718–2,380) | < 0.001 | 1,895 (981–5,560) | 797 (496–1,520) | < 0.001 |
White blood cells, 109/L | 5.8 (3.9–8.8) | 7.5 (5.1–11.4) | 0.001 | 5.2 (3.2–8.0) | 8.0 (4.6–12.0) | < 0.001 | 6.5 (5.0–9.2) | 6.8 (5.6–9.6) | 0.509 |
Monocyte count, 109/L | 0.6 (0.4–0.9) | 0.5 (0.3–0.8) | 0.075 | 0.7 (0.4–1.1) | 0.5 (0.3–0.8) | 0.038 | 0.5 (0.4–0.7) | 0.6 (0.4–0.8) | 0.934 |
Monocyte percentage, % | 11 (7–16) | 7 (5–10) | < 0.001 | 13 (8–17) | 7 (5–10) | < 0.001 | 8 (7–11) | 7 (6–10) | 0.092 |
M/L ratio | 0.8 (0.5–1.1) | 0.5 (0.3–0.9) | < 0.001 | 1.0 (0.6–1.4) | 0.6 (0.3–1.0) | < 0.001 | 0.6 (0.3–0.9) | 0.5 (0.3–0.8) | 0.273 |
Hemoglobin, g/dL | 11.0 (8.7–12.5) | 10.8 (9.1–12.6) | 0.703 | 10.0 (8.2–11.3) | 10.6 (9.1–12.5) | 0.018 | 12.9 (10.9–14.5) | 11.5 (9.6–12.9) | 0.022 |
Platelet count, 109/L | 137 (75–240) | 227 (135–332) | 0.008 | 92 (54–159) | 226 (131–333) | 0.003 | 232 (201–298) | 228 (155–328) | 0.721 |
C-reactive protein, mg/dL | 6.1 (1.7–9.3) | 5.8 (1.7–12.9) | 0.614 | 7.9 (4.4–12.7) | 7.8 (2.7–15.5) | 0.772 | 1.1 (0.4–6.0) | 2.5 (0.3–6.1) | 0.435 |
LDH, IU/L | 473 (286–841) | 260 (193–416) | < 0.001 | 587 (374–942) | 259 (192–416) | < 0.001 | 288 (212–486) | 264 (194–416) | 0.356 |
Ferritin, ng/mL | 583 (221–1,839) | 416 (184–984) | 0.083 | 939 (417–2,413) | 481 (219–1,198) | 0.007 | 176 (70–624) | 279 (116–545) | 0.213 |
ESR, mm/h | 55 (24–87) | 67 (33–100) | 0.063 | 68 (36–90) | 70 (42–102) | 0.436 | 32 (10–51) | 48 (20–81) | 0.100 |
Data are presented as median (interquartile range) unless otherwise indicated. |
sIL-2R, soluble interleukin-2 receptor; M/L ratio, monocyte-to-lymphocyte ratio; LDH, lactate dehydrogenase; ESR, erythrocyte sedimentation rate. |
Of 602 patients, 80 (13%) were diagnosed with lymphoma (52 in the febrile group and 28 in the afebrile group). The median serum sIL-2R level was significantly higher in patients with lymphoma than in those without lymphoma (5,275 U/mL vs. 1,120 U/mL, P < 0.001). In the febrile group, the median sIL-2R levels were significantly higher in patients with lymphoma than in those without lymphoma (7, 590 U/mL [IQR, 4,075–14,625 U/mL] and 1, 230 U/mL [IQR, 718–2,380 U/mL], respectively). In the afebrile group, similar significant trends with relatively low sIL-2R levels were observed; the median sIL-2R levels were 1,895 U/mL (IQR, 981–5,560 U/mL) in afebrile patients with lymphoma and 797 U/mL (IQR, 496–1,520 U/mL) in those without lymphoma. In the febrile group, WBC and PLT counts were significantly lower, and monocyte percentage, monocyte-to-lymphocyte ratio, and LDH levels were significantly higher in patients with lymphoma than in those without lymphoma, although there was no significant difference between patients with and without lymphoma in the afebrile group (Table 1).
Table 2 shows the final diagnoses of patients who participated in the analysis. A total of 80 patients (13.3%) were diagnosed with lymphoma; 31 had diffuse large B-cell lymphoma (17 belonged to the afebrile group), eight had intravascular lymphoma (all belonged to the febrile group), seven had follicular lymphoma (six belonged to the afebrile group), four had extranodal NK/T-cell lymphoma (all belonged to the febrile group), four had Hodgkin’s lymphoma (three belonged to the febrile group), three had angioimmunoblastic T-cell lymphoma, three had adult T-cell leukemia/lymphoma, and 16 had lymphoma of other or uncertain subtype. Four patients were strongly considered to have lymphoma clinically, but were histologically unproven. Seven patients presented with lymphoma-associated hemophagocytic lymphohistiocytosis. In total, 22 patients, all of whom belonged to the febrile group, were diagnosed with hemophagocytic lymphohistiocytosis (seven lymphoma-associated, four infection-associated, six autoimmune disease-associated, and five other or unknown etiology). Hematologic disorders other than lymphoma and hemophagocytic lymphohistiocytosis included 14 lymphoproliferative disorders and seven hypereosinophilic syndromes.
Table 2
Final diagnosis of the study participants.
| All (n = 602) | Febrile group (n = 421) | Afebrile group (n = 181) |
Lymphoma | 80 | 52 | 28 |
Diffuse large B-cell lymphoma | 31 | 14 | 17 |
Intravascular lymphoma | 8 | 8 | 0 |
Follicular lymphoma | 7 | 1 | 6 |
Extranodal NK/T-cell lymphoma | 4 | 4 | 0 |
Hodgkin’s lymphoma | 4 | 3 | 1 |
Angioimmunoblastic T-cell lymphoma | 3 | 2 | 1 |
Adult T-cell leukemia/lymphoma | 3 | 2 | 1 |
Other and uncertain subtype | 16 | 14 | 2 |
Histologically unproven | 4 | 4 | 0 |
Hemophagocytic lymphohistiocytosis* | 22* | 22* | 0 |
Lymphoma-associated* | 7* | 7* | 0 |
Infection-associated | 4 | 4 | 0 |
Autoimmune disease-associated | 6 | 6 | 0 |
Other or unknown etiology | 5 | 5 | 0 |
Lymphoproliferative disorder | 14 | 10 | 5 |
Hypereosinophilic syndrome | 7 | 3 | 4 |
Multiple myeloma | 5 | 0 | 5 |
Other hematologic disorder | 13 | 6 | 7 |
Non-hematologic neoplasm | 82 | 30 | 52 |
Infectious diseases | 127 | 111 | 16 |
Autoimmune diseases | 122 | 98 | 24 |
Drug | 18 | 14 | 4 |
Miscellaneous | 70 | 44 | 26 |
Not identified | 49 | 38 | 11 |
*Seven patients with lymphoma-associated hemophagocytic lymphohistiocytosis are listed (redisplayed). |
The ROC curves for the prediction of lymphoma by analyzing sIL-2R levels as well as other variables (age, WBC count, monocyte-to-lymphocyte ratio, PLT count, and LDH level) are shown in Fig. 1 and Supplementary Fig. 1, respectively. In all the patients, the AUROC of sIL-2R for the diagnosis of lymphoma was 0.82 (95% confidence interval [CI], 0.76–0.87). The sensitivity and specificity were 66.2% and 85.8%, respectively, with an optimal cut-off level of 3,250 U/mL. The AUROC of sIL-2R was significantly higher in the febrile group than in the afebrile group (AUROC value [95%CI]: 0.88 [0.83–0.94] in the febrile group and 0.75 [0.65–0.85] in the afebrile group, P = 0.028). The sensitivity and specificity were 82.7% and 83.5%, respectively, with an optimal sIL-2R cutoff value of 3,250 U/mL in the febrile patients, and 89.3% and 55.6%, respectively, with an optimal cutoff value of 868 U/mL in afebrile patients. The diagnostic performance (sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio) with different cut-off values is shown in Table 3.
Table 3
The diagnostic performance of sIL-2R for lymphoma, stratified by the presence of fever.
| Total (n = 625) | Febrile group (n = 437) | Afebrile group (n = 188) |
Cutoff | Se | Sp | LR+ | LR- | Se | Sp | LR+ | LR- | Se | Sp | LR+ | LR- |
500 | 96.2 | 16.1 | 1.1 | 0.2 | 98.1 | 11.9 | 1.1 | 0.2 | 92.9 | 25.5 | 1.2 | 0.3 |
1000 | 86.2 | 45.6 | 1.6 | 0.3 | 94.2 | 38.2 | 1.5 | 0.2 | 71.4 | 63.4 | 2.0 | 0.5 |
2000 | 73.8 | 73.9 | 2.8 | 0.4 | 88.5 | 69.9 | 2.9 | 0.2 | 46.4 | 83.7 | 2.8 | 0.6 |
3000 | 66.2 | 83.9 | 4.1 | 0.4 | 82.7 | 81.6 | 4.5 | 0.2 | 35.7 | 89.5 | 3.4 | 0.7 |
4000 | 58.8 | 89.7 | 5.7 | 0.5 | 75.0 | 88.3 | 6.4 | 0.3 | 28.6 | 92.8 | 4.0 | 0.8 |
5000 | 51.2 | 92.0 | 6.4 | 0.5 | 65.4 | 91.3 | 7.5 | 0.4 | 25.0 | 93.5 | 3.8 | 0.8 |
sIL-2R, soluble interleukin-2 receptor; Se, sensitivity; Sp, specificity; LR+, positive likelihood ratio; LR-, negative likelihood ratio. |
AUROC values (95% CI) of the other variables in all patient cohorts were as follows: age, 0.59 (0.52–0.65); WBC count, 0.62 (0.55–0.68); monocyte-to-lymphocyte ratio, 0.63 (0.56–0.69); PLT count, 0.65 (0.59–0.72); and LDH level, 0.70 (0.63–0.76). The AUROC values of the PLT count and LDH level in the febrile group were significantly greater than those in the afebrile group (Supplementary Fig. 1).
The distribution of serum sIL-2R levels according to the disease category is shown in Table 4. Among patients diagnosed with diseases other than lymphoma, 14% (74/522) had serum sIL-2R levels above 3,275 U/mL. In addition to lymphoma, a certain number of patients with hematologic disorders, such as hemophagocytic lymphohistiocytosis, lymphoproliferative disorder, and hypereosinophilic syndrome, tuberculosis, rickettsiosis, and adverse drug reactions showed markedly elevated sIL-2R levels above 5,000 U/mL.
Table 4
Distribution of serum sIL-2R levels by disease category.
| sIL-2R ≤ 2,000 (n = 407) | 2,000 < sIL-2R ≤ 5,000 (n = 112) | 5,000 < sIL-2R (n = 83) |
Lymphoma | 21 | 18 | 41 |
Hemophagocytic lymphohistiocytosis* | 7 | 4 | 4 |
Hypereosinophilic syndrome | 3 | 1 | 3 |
Lymphoproliferative disorder | 3 | 8 | 3 |
Multiple myeloma | 5 | 0 | 0 |
Other hematologic disorder | 11 | 1 | 1 |
Non-hematologic neoplasm | 71 | 9 | 2 |
Infectious diseases | 80 | 33 | 14 |
Tuberculosis | 5 | 5 | 4 |
Rickettsiosis | 0 | 1 | 3 |
Autoimmune disease | 100 | 18 | 4 |
Drug | 6 | 9 | 3 |
Miscellaneous | 64 | 3 | 3 |
Not identified | 36 | 8 | 5 |
*Non-lymphoma-associated hemophagocytic lymphohistiocytosis only. |
sIL-2R, soluble interleukin-2 receptor. |