Establishment of Reference Intervals of Tumor Markers in Korean Adults

Hee-Yeon Woo; Young Jae Kim; Hyosoon Park

doi:10.3343/kjlm.2008.28.3.179

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Woo, Kim, and Park: Establishment of Reference Intervals of Tumor Markers in Korean Adults

Original Article

Korean J Leg Med 2008;28(3):179-184.

Published online: 14 February 2008

DOI: https://doi.org/10.3343/kjlm.2008.28.3.179

Establishment of Reference Intervals of Tumor Markers in Korean Adults

Hee-Yeon Woo, M.D.¹, Young Jae Kim, M.D.², Hyosoon Park, M.D.¹

¹Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

²Masan Samsung Hospital, Sungkyunkwan University School of Medicine, Masan, Korea

Received 8 November 200720 March 2008 Accepted 21 March 2008

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 sensitivity and specificity of tumor markers for detecting cancer could be significantly changed by the reference intervals of tumor markers. We established reference intervals of tumor markers in Korean adults and evaluated its importance, since the reference intervals recommended by the manufacturers were determined in the Caucasian population and have sometimes been adopted without verification.

Methods

We established the reference intervals of alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA)125, carbohydrate antigen (CA)19-9, total prostate specific antigen (TPSA), cytokeratin fragment (Cyfra)21-1, and neuron specific enolase (NSE) according to the CLSI guideline in a maximum number of 1,364 healthy adults aged 20-60 yrs who visited a health promotion center from January to February 2007.

Results

Reference intervals of all tumor markers except for AFP were not in agreement with those recommended by the manufacturers. Reference intervals of CEA, TPSA, CA19-9, CA125, and Cyfra21-1 were age dependent. The mean reference values of NSE, CA125, and CEA were statistically different according to gender (11.72 vs 10.78 ng/mL), menopause status (18.89 vs 12.62 U/mL), and smoking status (2.60 vs 2.12 vs 1.80 ng/mL for smokers, past smokers, and non-smokers, respectively), respectively.

Conclusions

With the verification and establishment of reference intervals of tumor markers in a Korean local population, we found the reference intervals significantly different by either age, gender, smoking or menopause status.

Keywords: Tumor marker, Reference interval, AFP, CEA, CA19-9, CA125, TPSA, Cyfra21-1, NSE

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Table 1.

Reference intervals of tumor markers established in this study

Tumor markers	Reference intervals^∗
AFP (ng/mL)	0.76-6.98
CEA^†,‡ (ng/mL)	0.00-4.51
	Non-smoking: 0.00-3.92
	Smoking: 0.00-5.66
	Past-smoking: 0.00-4.34
CA19-9^‡ (U/mL)	0.60-30.61
CA125^†,‡ (U/mL)	6.39-43.20
	Pre-menopause: 7.67-64.47
	Post-menopause: 5.32-23.94
Cyfra21-1^‡ (ng/mL)	0.07-3.59
TPSA^‡ (ng/mL)	0.30-3.96
NSE^† (ng/mL)	7.56-15.81
	M: 8.09-16.05
	F: 7.24-15.77

^∗ Reference intervals of CEA and Cyfra21-1 were determined by the range of mean±1.96SD, while those of AFP, CA19-9, CA125, NSE, and TPSA were determined by the 2.5th and 97.5th percentiles of the underlying distribution of reference values.

^† Means of reference values of CEA, CA125, NSE were significantly different according to smoking state, menopausal state, and gender, respectively.

^‡ Reference intervals of CEA, CA19-9, CA125, Cyfra21-1, and TPSA were significantly different according to age and reference intervals by age groups, which are described in Table 2.

Abbreviations: AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; Cyfra, cytokeratin fragment; CA19-9, carbohydrate antigen 19-9; CA125, cancer antigen 125; NSE, neuron specific enolase.

Table 2.

Reference intervals showing significant differences by age groups

Age (yr)	Reference intervals^∗
Age (yr)	TPSA, ng/mL	CA125, U/mL	CEA, ng/mL	CA19-9, U/mL	Cyfra21-1, ng/mL
20-30	0.37-2.06^a (79)	6.70-63.96^a (66)	0.00-3.16^a (123)	0.60-31.42^a,b (123)	0.25-3.13^a (119)
31-40	0.33-2.98^a (509)	6.94-50.21^a (153)	0.00-3.73^b (452)	0.60-24.67^a (452)	0.13-3.33^a (416)
41-50	0.34-2.59^a (946)	6.85-75.49^a (178)	0.00-4.78^c (331)	0.60-28.02^a (331)	0.17-3.47^a (202)
51-60	0.27-4.15^b (369)	5.25-25.16^b (273)	0.00-5.13^c (455)	0.60-34.92^b (455)	0.04-4.56^b (128)

Numbers in the parentheses denote the numbers of subjects in each age group.

^∗ The same letters indicate non-significant difference among age groups based on one-way ANOVA test.

Abbreviations: TPSA, total prostate specific antigen; CEA, carcinoembryonic antigen; Cyfra, cytokeratin fragment; CA9-9, carbohydrate antigen 19-9; CA 125, cancer antigen 125.

Table 3.

Proportions of subjects showing tumor marker values above upper reference limits established in this study and those recommended by manufacturers

Tumor markers	Proportions (%) above upper reference limit^∗		P value^†
Tumor markers	Established in this study	Recommended by manufacturers	P value^†
AFP	2.3 (6.98 ng/mL)	2.3 (7.0 ng/mL)	0.80
CEA	2.1 (4.51 ng/mL)	1.8 (4.7 ng/mL)	0.49
CA19-9	2.5 (30.61 U/mL)	1.6 (34 U/mL)	0.11
CA125	2.4 (43.20 U/mL)	3.9 (35 U/mL)	0.12
Cyfra21-1	4.0 (3.59 ng/mL)	6.2 (3.3 ng/mL)	0.038
Total PSA	2.5 (3.96 ng/mL)	2.2 (4.1 ng/mL)	0.72
NSE	2.5 (15.81 ng/mL)	1.2 (16.3 ng/mL)	0.046

^∗ Each upper reference limit is shown in the parenthesis.

^† P<0.05 is statistically significant.

Abbreviations: AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; Cyfra, cytokeratin fragment; CA19-9, carbohydrate antigen 19-9; CA125, cancer antigen 125; NSE, neuron specific enolase.

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