3.1 Patient characteristics
In total, 662 patients with ENKTL were included, and the baseline characteristics were listed in Table 1. Primary tumors of 583 patients (88.0%) occurred in the upper aerodigestive tract. The median age was 45 years (range 12–86), and 108 (16.3%) patients were aged over 60; male patients accounted for 437 (66.0%), and the male-to-female ratio was 1.9:1. Most patients (53.4%) had B symptoms. Overall, 526 (79.4%) patients had good ECOG scores (≤1). LDH levels were elevated in 225 (33.9%) patients, and the majority (59.8%) had positive EBV-DNA. Based on PINK-E scoring, 511 (77.1%) patients were assigned to the low-risk group (0 or 1).
Among them, nine cases (1.4%) had CNS involvement at initial diagnosis of ENKTL (Table 1 and Table 2). Of them, the median age was 37 years (range, 20-62 years), and only one patient was older than 60 years. Six patients were male and three were female. Six patients had B symptoms, and only one patient was positive for bone marrow involvement. All nine patients had positive EBV-DNA. Except for three patients who were asymptomatic at the time of diagnosis with CNS involvement, the other six patients presented with various symptoms, including cranial neuropathy, blurred vision, motor aphasia, headache, fatigue and vomiting. Except for two patients who had primary CNS ENTKL, the other seven patients had concurrent CNS involvement. Common extranodal involved sites in this study included bone (n=4), paranasal sinuses (n=3), breast (n=1), kidney (n=1), adrenal gland (n=1) and bone marrow (n=1). CNS involvement was diagnosed by positive histopathology and cytology in four patients and by positive FCM in three patients. Two patients were diagnosed by positive MRI.
Table 1
Clinical characteristics of 662 patients with ENKTL
Characteristics
|
Total(n=662)(%)
|
CNS involvement(n=9)(%)
|
Age(year)
|
|
|
Median(range)
|
45(12-86)
|
37(20-62)
|
<60
|
554(83.6)
|
8(88.9)
|
≥60
|
108(16.3)
|
1(11.1)
|
Sex
|
|
|
Female
|
225(33.9)
|
3(33.3)
|
Male
|
437(66.0)
|
6(66.7)
|
ECOG PS
|
|
|
0 or 1
|
526(79.4)
|
4(44.4)
|
≥2
|
136(20.5)
|
5(55.6)
|
B symptoms
|
|
|
Absent
|
308(46.5)
|
3(33.3)
|
Present
|
354(53.4)
|
6(66.7)
|
AASS
|
|
|
Stage I/II
|
453(68.4)
|
2(22.2)
|
Stage III/IV
|
209(31.5)
|
7(77.8)
|
BM involvement
|
|
|
Absent
|
615(92.9)
|
8(88.9)
|
Present
|
47(7.0)
|
1(11.1)
|
PINK-E score
|
|
|
0 or 1
|
511(77.1)
|
1(11.1)
|
≥2
|
151(22.8)
|
8(88.9)
|
Primary Tumor Location
|
|
|
Upper aerodigestive tract
|
583(88)
|
4(44.4)
|
Nonupper aerodigestive tract
|
79(11.9)
|
5(55.6)
|
Serum LDH
|
|
|
<250
|
437(66.1)
|
5(55.6)
|
≥250
|
225(33.9)
|
4(44.4)
|
Plasma EBV-DNA
|
|
|
Negative
|
95(14.3)
|
9(100)
|
Positive
|
396(59.8)
|
0(0)
|
Unknown
|
171(25.8)
|
0(0)
|
WBC(×10^9 L-1)
|
|
|
≥4
|
469(70.8)
|
6(66.7)
|
<4
|
193(29.2)
|
3(33.3)
|
Platelet(×10^9 L-1)
|
|
|
≥100
|
555(83.8)
|
9(100)
|
<100
|
107(16.2)
|
0(0)
|
Hb (g/L)
|
|
|
≥110
|
508(76.7)
|
7(77.8)
|
<110
|
154(23.3)
|
2(22.2)
|
Abbreviations: AASS, Ann Arbor staging system; BM, bone marrow; EBV, Epstein–Barr virus; ECOG PS, Eastern Cooperative Oncology Group performance status; Hb, hemoglobin; LDH, lactate dehydrogenase; PINK-E, prognostic index of natural killer lymphoma with Epstein–Barr virus; WBC, white blood cell.
Table 2
Clinical features of nine patients
Case
|
Age/Sex
|
AASS
|
B symptom
|
Symptom(s)
|
LDH
|
EBV DNA
|
Extranodal sites involvement
|
Lesion location
in CNS
|
CNS
diagnosis
|
1
|
36/M
|
IV
|
Yes
|
Cranial neuropathy
|
Normal
|
1.71x 103
|
Paranasal sinuses
|
Unidentified
|
Positive FCM only
|
2
|
37/M
|
IV
|
No
|
Blurred vision
|
Normal
|
1.15x 103
|
Bone
|
Right eye
|
Positve MRI and cytology
|
3
|
62/F
|
IV
|
Yes
|
None
|
Elevated
|
6.56x104
|
Paranasal sinuses, bones, bone marrow, adrenal gland
|
Unidentified
|
Positive FCM only
|
4
|
42/F
|
IV
|
No
|
Blurred vision
|
Normal
|
1.06x102
|
No
|
Left eye
|
Positive MRI only
|
5
|
50/M
|
I
|
No
|
Motor aphasia
|
Normal
|
1.00x102
|
No
|
Left frontal lobe
|
Positive MRI and histopathology
|
6
|
20/M
|
IV
|
Yes
|
Fatigue and vomiting
|
Elevated
|
2.96x105
|
Bones,
|
Pituitary gland
|
Positive MRI and histopathology
|
7
|
37/F
|
IV
|
Yes
|
None
|
Elevated
|
4.74x104
|
Breast
|
Right temporal lobe
|
Positive MRI only
|
8
|
49/M
|
I
|
Yes
|
Headache
|
Normal
|
2.68x102
|
No
|
Left pons, left temporal lobe, right thalamus, right ventricle, corpus callosum
|
Positive MRI and histopathology
|
9
|
20/M
|
IV
|
Yes
|
None
|
Elevated
|
2.22x107
|
Paranasal sinuses, bones, kidney
|
Unidentified
|
Positive FCM only
|
Abbreviations: AASS, Ann Arbor staging system; CNS, central nervous system; CSF, cerebrospinal fluid; EBV, Epstein–Barr virus; FCM, flow cytometry; MRI, magnetic resonance imaging;
The extranodal sites included in this study are the paranasal sinuses, breast, kidney, adrenal gland, uterus, testis, bone and bone marrow.
3.2 Immunohistochemical phenotype
ENKTL was diagnosed by adequate immunohistochemistry that included CD20, cytoplasmic CD3ε, CD5, CD56, cytotoxic granule proteins (granzyme B, GrB; T-cell intracellular antigen 1, TIA-1), and EBV-encoded small RNAs (EBER) in situ hybridization. The immunohistochemical results of nine patients are listed in Table 3. All nine cases were positive for cytoplasmic CD3ε, positive for cytotoxic granule proteins, and negative for CD20. Seven of these nine patients (77.8%) were negative for CD5 and positive for CD56. Three cases were positive for CD30. The median proliferation index Ki-67 was 60% (range, 15–85%). All patients had positive EBER.
Table 3
Immunohistochemical makers and EBER of nine patients
Case
|
CD3ε
|
CD20
|
CD5
|
CD56
|
CD30
|
GrB
|
TIA-1
|
Ki-67
|
EBER
|
1
|
+
|
-
|
-
|
-
|
+
|
+
|
+
|
45%
|
+
|
2
|
+
|
-
|
-
|
+
|
NA
|
+
|
+
|
15%
|
+
|
3
|
+
|
-
|
-
|
+
|
NA
|
+
|
+
|
55%
|
+
|
4
|
+
|
-
|
+
|
+
|
-
|
+
|
+
|
60%
|
+
|
5
|
+
|
-
|
-
|
+
|
NA
|
+
|
+
|
80%
|
+
|
6
|
+
|
-
|
-
|
-
|
+
|
+
|
+
|
85%
|
+
|
7
|
+
|
-
|
-
|
+
|
-
|
+
|
+
|
60%
|
+
|
8
|
+
|
-
|
+
|
+
|
-
|
+
|
+
|
85%
|
+
|
9
|
+
|
-
|
-
|
+
|
+
|
+
|
+
|
70%
|
+
|
Abbreviations: EBER, EBV-encoded small RNAs; GrB, Granzyme B; NA, not available; TIA-1, T-cell intracellular antigen 1.
3.3 Treatment
All nine patients received at least one cycle of systemic chemotherapy. Detailed first-line therapeutic regimens are listed in Table 4. All nine patients received intrathecal chemotherapy with methotrexate or cytarabine. Among them, except for one patient who received a high-dose methotrexate and cytarabine (MA) regimen, eight patients received asparaginase-based systemic chemotherapy, including L-asparaginase, etoposide, dexamethasone and cisplatin (LVDP, n=4), dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE, n=1), gemcitabine, asparaginase, ifosfamide, dexamethasone, and high-dose methotrexate (GLID+HD-MTX, n=1), programmed cell death protein 1 (PD-1) inhibitor, pegaspargase, gemcitabine, oxaliplatin (PP-GEMOX, n=1), methotrexate, etoposide, dexamethasone, pegaspargase, and PD-1 inhibitor (MEDPP, n=1). Two patients received radiotherapy after systemic chemotherapy.
Table 4
Treatment methods and outcomes of nine patients
Case
|
Nasal
type
|
First-line treatment
|
IT
|
Treatment response
|
PFS
(months)
|
OS
(months)
|
outcome
|
Cause of death
|
1
|
Yes
|
LVDP x2, radiotherapy
|
Yes
|
CR
|
12
|
56
|
Dead
|
Hemophagocytic
syndrome
|
2
|
No
|
Surgical resection of a right intraorbital tumor, LVDP x2
|
Yes
|
PD
|
4
|
9
|
Dead
|
PD
|
3
|
Yes
|
LVDP x6
|
Yes
|
CR
|
23
|
25
|
Dead
|
PD
|
4
|
No
|
SMILE x6, radiotherapy
|
Yes
|
CR
|
60
|
60
|
Alive
|
-
|
5
|
No
|
Surgical resection of left frontal lobe mass, GLID+HD-MTX x2
|
Yes
|
CR
|
5
|
5
|
Dead
|
Infection
|
6
|
Yes
|
MEDPP x6
|
Yes
|
CR
|
10
|
10
|
Alive
|
-
|
7
|
No
|
PP-GEMOX x3
|
Yes
|
PD
|
3
|
5
|
Dead
|
Hemophagocytic
syndrome
|
8
|
No
|
HD-MA x2
|
Yes
|
PD
|
2
|
3
|
Dead
|
PD
|
9
|
Yes
|
LVDP x2
|
Yes
|
PR
|
3
|
3
|
Dead
|
Kidney failure
|
Abbreviations: CR, complete response; GLID+HD-MTX, gemcitabine, asparaginase, ifosfamide, dexamethasone, and high-dose methotrexate; HD-MA, high-dose methotrexate and cytarabine; IT, intrathecal injection; LVDP, L-asparaginase, etoposide, dexamethasone and cisplatin; MEDPP, methotrexate, etoposide, dexamethasone, pegaspargase, PD-1 inhibitor; PD, progressive disease; PP-GEMOX, PD-1 inhibitor, pegaspargase, gemcitabine, oxaliplatin; PR, partial response; SMILE, dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide.
3.4 Survival outcomes of patients with CNS involvement at initial diagnosis of ENKTL
The median follow-up for the entire cohort was 72 months (95% confidence interval [CI], 67.8-76.2 months), and the median OS for the entire cohort was not reached. Among the 662 patients, 268 died. For all patients, the 5-year OS was 58.9%. The median OS was longer for patients with early-stage ENKTL than for those with advanced-stage ENKTL (not reached vs. 18 months, p<0.001). Moreover, the median OS of patients with low-risk PINK-E was also longer than that of patients with high-intermediate-risk PINK-E (not reached vs. 24 months, p<0.001). The median OS of patients with nonupper aerodigestive tract involvement was 24 (95% CI, 2.5-45.5) months, while the median OS of patients with upper aerodigestive tract involvement was not reached.
In nine patients with CNS involvement at initial diagnosis of ENKTL, seven patients died. Three of them died of systemic progression, two died of ENKTL-associated hemophagocytic syndrome, one died of treatment-related infections, and one died of acute kidney failure. Five patients achieved CR after first-line treatment. Of them, two patients had disease relapses after 12 months, and two sustained CR by the last follow-up. Three patients had disease progression during the initial treatment. One patient with kidney involvement achieved PR after the initial treatment but died of acute kidney failure. The median OS of patients with CNS involvement at initial diagnosis of ENKTL was 9 (95% CI, 0-20.7) months, and the 1-year OS was 44.4%. Notably, the median OS of four patients who received LVDP chemotherapy was 9 (95% CI, 0-30.6) months, while the median OS of other regimens was 5 (95% CI, 2.9-7.1) months (p=0. 696). Additionally, the median OS of patients who achieved CR after first-line chemotherapy was evidently longer than that of patients who did not achieve CR (56 months vs. 3 months, p=0.015).
3.5 Review of reported cases with CNS involvement at initial diagnosis of ENKTL
We identified 18 patients with CNS involvement at initial diagnosis of ENKTL from literature reviews [10-12, 15]. A total of 27 cases were collected, and the baseline features of those cases are listed in Table 5. For all patients, the median age was 48 (range, 13-83) years, and most patients were male. In most cases (18, 66.7%), tumor lesions were located in the nonupper aerodigestive tract and initially presented with an advanced stage. Of the 22 patients with survival data, 63.6% died of progressive disease, and the median survival time was 7.5 (range, 0.5-139) months.
Table 5
The reported cases of patients with CNS involvement at initial diagnosis of ENKTL
Characteristics
|
Miyata-Takata et al. 201715
|
Nevel et al. 201911
|
Li et al. 202112
|
Cai et al. 202110
|
Present study
|
Number of cases
|
4
|
4
|
5
|
5
|
9
|
Median age(range)
(year)
|
46(21-77)
|
57(44-83)
|
49(18-53)
|
46(13-57)
|
37(20-62)
|
Sex(F/M)
|
1/3
|
NA
|
1/4
|
1/4
|
3/6
|
Nasal-type(yes/no)
|
0/4
|
2/2
|
0/5
|
NA
|
4/5
|
Ann Arbor Stage(I/II / III/IV)
|
4/0
|
1/3
|
2/3
|
0/5
|
2/7
|
Outcome(dead/alive)
|
3/1
|
3/1
|
1/4
|
NA
|
7/2
|
Median survival(range)
(months)
|
24(4-139)
|
4.3(0.5-27)
|
6(3-75)
|
NA
|
9(3-60)
|
Abbreviation: NA, not available.