Usefulness of Serum Thymidine Kinase 1 as a Biomarker for Aggressive Clinical Behavior in B-cell Lymphoma

Heyjin Kim; Hye Jin Kang; Jin Kyung Lee; Young Jun Hong; Seok-Il Hong; Yoon Hwan Chang

doi:10.3343/lmo.2016.6.1.25

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Kim, Kang, Lee, Hong, Hong, and Chang: Usefulness of Serum Thymidine Kinase 1 as a Biomarker for Aggressive Clinical Behavior in B-cell Lymphoma

Original Article

Diagnostic Immunology

Laboratory Medicine Online 2016; 6(1): 25-30.

Published online: 1 January 2016

DOI: https://doi.org/10.3343/lmo.2016.6.1.25

Usefulness of Serum Thymidine Kinase 1 as a Biomarker for Aggressive Clinical Behavior in B-cell Lymphoma

Heyjin Kim, M.D.¹, Hye Jin Kang, M.D.², Jin Kyung Lee, M.D.^1,³, Young Jun Hong, M.D.^1,³, Seok-Il Hong, M.D.^1,³, Yoon Hwan Chang, M.D.^1,³

¹Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.

²Division of Hematology/Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.

³Radiological & Medico-Oncological Sciences, University of Science and Technology, Daejeon, Korea.

Corresponding author: Yoon Hwan Chang. Department of Laboratory Medicine, Korea Cancer Center Hospital, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea. Tel: +82-2-970-1283, Fax: +82-2-973-7143, cyhlabo@kcch.re.kr

Received 5 November 2014 Revised 17 June 2015 Accepted 28 July 2015

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The cell cycle-dependent enzyme thymidine kinase 1 (TK1) is known to increase during cancer cell proliferation and has been reported as a prognostic marker for various hematologic malignancies and solid tumors. This study aimed to determine the reference interval in Korean healthy controls and to evaluate the usefulness of TK1 as a biomarker for aggressive clinical behavior in B-cell lymphoma patients.

Methods

We enrolled 72 previously untreated patients with B-cell lymphoma and 143 healthy controls. Serum TK1 levels were measured by chemiluminescence immunoassay (Liaison®, DiaSorin, USA). We established the reference intervals in healthy controls. The diagnostic performance of serum TK1 was studied using receiver operating characteristic (ROC) analysis, and the correlation between the cutoff level for serum TK1 and clinical characteristics of B-cell lymphoma was evaluated.

Results

The reference range (95th percentile) of serum TK1 in healthy controls was 5.4-21.8 U/L. There was a clear difference in TK1 levels between patients with B-cell lymphoma and healthy controls (40.6±68.5 vs. 11.8±4.4 U/L, P<0.001). The area under the curve of serum TK1 for the diagnosis of B-cell lymphoma was 0.73 (cutoff, 15.2 U/L; sensitivity, 59.7%; specificity, 83.2%). An increased TK1 level (≥15.2 U/L) correlated with the advanced clinical stage (P<0.001), bone marrow involvement (P=0.013), international prognostic index score (P=0.001), lactate dehydrogenase level (P=0.001), low Hb level (<12 g/dL) (P=0.028), and lymphocyte count (P=0.023).

Conclusions

The serum TK1 level could serve as a useful biomarker for aggressive clinical behavior in B-cell lymphoma patients.

Keywords: Thymidine kinase 1, B-cell lymphoma, Serum biomarker

Figures and Tables

Fig. 1

Comparison of serum thymidine kinase 1 (TK1) levels between healthy controls and patients with B-cell lymphoma. The upper and lower ends of the boxes and the box inner lines correspond to the 3rd and 1st quartiles and median values, respectively. Error bars denote minimum and maximum values, and circles and stars indicate outlier values.

Fig. 2

Receiver operating characteristic (ROC) curve of serum thymidine kinase 1 (TK1) levels in patients with B-cell lymphoma. The area under the curve (AUC) of serum TK1 for the diagnosis of B-cell lymphoma was 0.73 (cutoff, 15.2 U/L) with its 95% confidence interval.

Table 1

Baseline characteristics of healthy controls (N=143) and patients with B-cell lymphoma (N=72)

Variables	B-cell lymphoma patients (%)	Healthy controls (%)
Age (yr)
Median	63	45
Range	14-86	28-79
Sex
Male	36 (50)	85 (59)
Female	36 (50)	58 (41)
Ann Arbor stage
I	27 (38)
II	18 (25)
III	5 (7)
IV	22 (31)
Bone marrow involvement
With involvement	11 (15)
Without involvement	61 (85)
Histology
DLBCL	54 (75)
MALT lymphoma	11 (15)
Follicular lymphoma	3 (4)
Others^*	4 (6)

^*Include small lymphocytic lymphoma, splenic B cell lymphoma, DLBCL associated with low-grade MALT lymphoma, and pediatric nodal marginal zone lymphoma.

Abbreviations: DLBCL, diffuse large B-cell lymphoma; MALT lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.

Table 2

Correlation between serum thymidine kinase 1 (TK1) levels and clinical characteristics of 72 patients with B-cell lymphoma

Characteristics	TK1 ≥ 15.2 U/L (N = 49)	TK1 <15.2 U/L (N = 23)	P value
Age	59.4 ± 16.6	57.2 ± 14.4	0.360
Sex			0.800
Male	25	11
Female	24	12
Clinical stage			0.004
I	13	14
II	11	7
III	5	0
IV	20	2
Limited (I+II)	23	21	< 0.001
Advanced (III+IV)	26	2
BM involvement
With involvement	11	0	0.013
Without involvement	38	23
Histologic type			0.348
DLBCL	39	15
MALT	5	6
Follicular	2	1
Others^*	3	1
IPI score			0.001
0	13	12
1	11	10
2	12	0
3	9	0
4	4	1
Low (0+1+2)	36	22	0.029
High (3+4)	13	1
Systemic symptoms			0.422
Absent	42	22
Present	7	1
Survival duration (day)	829.3 ± 451.4	1,014.0 ± 385.0	0.095
Survival state			0.200
Death	12	2
Survival	37	21
LD (U/L) (N = 69)	630.7 ± 573.6	361.9 ± 177.7	0.001
Chromosomal aberration (N = 64)			0.309
Normal karyotype	41	19
Abnormal karyotype	4	0
β₂-Microglobulin (g/L)	2.2 ± 0.9 (N = 14)	1.1 ± 0.5 (N = 6)	0.170
CRP (mg/dL)	3.0 ± 2.5 (N = 22)	2.8 ± 1.8 (N = 3)	0.889
Hb level (g/dL)			0.028
Low Hb ( < 12 g/dL)	24	5
Normal Hb ( ≥ 12 g/dL)	25	18
WBCs (×10⁹/L)	7.00 ± 3.40	6.65 ± 2.10	0.767
Lymphocytes (×10⁹/L)	1.54 ± 6.84	1.84 ± 6.47	0.023
Platelets (×10⁹/L)	261 ± 105	247 ± 48	0.437

^*Include small lymphocytic lymphoma, splenic B cell lymphoma, DLBCL associated with low-grade MALT lymphoma, and pediatric nodal marginal zone lymphoma.

Abbreviations: CRP, c-reactive protein; DLBCL, diffuse large B-cell lymphoma; Hb, hemoglobin; IPI, international prognosis index; LD, lactate dehydrogenase; MALT lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; WBCs, white blood cells.

Notes

This article is available from http://www.labmedonline.org

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