Human Epididymis Protein 4 as a Diagnostic Marker of Ovarian Cancer and Its Reference Interval in Korean Population

Hee-Yeon Woo

doi:10.3343/lmo.2016.6.1.12

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Woo: Human Epididymis Protein 4 as a Diagnostic Marker of Ovarian Cancer and Its Reference Interval in Korean Population

Review Article

Diagnostic Immunology

Laboratory Medicine Online 2016; 6(1): 12-18.

Published online: 1 January 2016

DOI: https://doi.org/10.3343/lmo.2016.6.1.12

Human Epididymis Protein 4 as a Diagnostic Marker of Ovarian Cancer and Its Reference Interval in Korean Population

Hee-Yeon Woo, M.D.

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

Corresponding author: Hee-Yeon Woo. Department of Laboratory Medicine, Kangbuk Samsung Hospital, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea. Tel: +82-2-2001-2387, Fax: +82-2-723-0447, heeyeon.woo@samsung.com

Received 16 February 2015 Revised 2 June 2015 Accepted 16 June 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

Human epididymis protein 4 (HE4), which complements cancer antigen 125 (CA125), has emerged as a new diagnostic biomarker that can discriminate between benign and malignant ovarian tumors. The risk of ovarian malignancy algorithm (ROMA) incorporates CA125, HE4, and menopausal status to classify patients with pelvic masses into those at high or low risk of developing ovarian cancer. The reference interval of HE4 among Korean population was different from those recommended by the manufacturer or evaluated in the Chinese.

Keywords: Human epididymis protein 4, Ovarian cancer, Risk of ovarian malignancy algorithm, Reference interval

Figures and Tables

Table 1

Reference intervals of risk of ovarian malignancy algorithm (ROMA) value for different commercially available diagnostic tests

	Elecsys HE4+Elecsys CA125	Architect HE4+Architect CA125	HE4 EIA^*+ARCHITECT CA125	ARCHITECT HE4+CanAg CA125^*
Premenopausal
High-risk	≥ 11.4	≥ 7.4	≥ 13.1	≥ 12.5
Low-risk	< 11.4	< 7.4	< 13.1	< 12.5
Postmenopausal
High-risk	≥ 29.9	≥ 25.3	≥ 27.7	≥ 14.4
Low-risk	< 29.9	< 25.3	< 27.7	< 14.4

^*Fujirebio Diagnostics.

Table 2

Sensitivity and specificity of HE4 and CA125 for distinguishing between malignant and benign ovarian tumors

Group	HE4			CA125			ROMA
Group	Sensitivity (95% CI)	Specificity (95% CI)	Cutoff^*	Sensitivity (95% CI)	Specificity (95% CI)	Cutoff^*	Sensitivity (95% CI)	Specificity (95% CI)	Cutoff^*
Individuals with ovarian cancer (N = 149)	0.57 (0.49-0.66)	0.97 (0.92-0.99)	76	0.74 (0.66-0.81)	0.69 (0.60-0.77)	35	0.61 (0.53-0.69)	0.95 (0.91-0.99)	18.1
Individuals <45 yr (N=44)	0.2 (0.09-0.35)	0.98 (0.92-0.99)	67	0.48 (0.32-0.63)	0.72 (0.61-0.81)	40	0.22 (0.11-0.38)	0.96 (0.90-0.99)	13.7
Individuals ≥ 55 yr (N = 54)	0.78 (0.64-0.88)	0.93 (0.68-1.00)	86	0.89 (0.77-0.96)	0.8 (0.52-0.96)	24	0.94 (0.85-0.99)	0.8 (0.52-0.96)	19.3

^*Upper reference values of 97.5%.

Abbreviation: CI, confidence interval.

Table 3

Sensitivity and specificity of HE4 and CA125 for distinguishing between malignant and benign ovarian tumors

Group	HE4			CA125			ROMA
Group	Sensitivity (95% CI)	Specificity (95% CI)	Cutoff^*	Sensitivity (95% CI)	Specificity (95% CI)	Cutoff^*	Sensitivity (95% CI)	Specificity (95% CI)	Cutoff^*
Individuals with ovarian cancer (N = 149)	0.7 (0.64-0.73)	0.89 (0.84-0.94)	55	0.68 (0.62-0.72)	0.77 (0.71-0.83)	45	0.67 (0.63-0.70)	0.93 (0.87-0.96)	11.6
Individuals <45 yr (N=44)	0.45 (0.27-0.66)	0.91 (0.84-0.95)	55	0.8 (0.67-0.89)	0.52 (0.44-0.56)	19	0.63 (0.51-0.75)	0.72 (0.64-0.77)	5.9
Individuals ≥ 55 yr (N = 54)	0.83 (0.64-0.88)	0.93 (0.68-1.00)	63	0.96 (0.87-1.00)	0.8 (0.52-0.96)	21	0.98 (0.59-1.00)	0.8 (0.53-0.93)	11.3

^*from ROC analysis.

Abbreviation: CI, confidence interval.

Table 4

Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ROMA for stratification of patients with pelvic masses, as reported in the literature

Author	ROMA cut-off point (%)	Study population N	Diagnostic methods	Sensitivity (%)			Specificity (%)			PPV (%)			NPV (%)
Author	ROMA cut-off point (%)	Study population N	Diagnostic methods	All	PM	M	All	PM	M	All	PM	M	All	PM	M
Moore RG et al. [6]	M-27.7	M-283	CA 125-CMIA	88.7	76.5	92.3	74.7	74.8	74.7	60.1	33.8	74.0	93.9	9.5	92.6
Moore RG et al. [6]	PM-13.1	PM-248	HE4-EIA	88.7	76.5	92.3	74.7	74.8	74.7	60.1	33.8	74.0	93.9	9.5	92.6
Molina R et al. [114]	M-27.7	AII-495	CA 125-CMIA	90.1	74.1	95.2	87.7	88.9	83.1	74	44.4	88.9	95.8	96.6	92.5
Molina R et al. [114]	PM-13.1		HE4-CMIA	90.1	74.1	95.2	87.7	88.9	83.1	74	44.4	88.9	95.8	96.6	92.5
Moore RG et al. [7]	M-27.7	M-217	CA 125-CMIA	88.1	81.3	90.2	74.9	74.2	76	38.1	17.8	56.1	97.3	98.3	95.8
Moore RG et al. [7]	PM-13.1	PM-255	HE4-EIA	88.1	81.3	90.2	74.9	74.2	76	38.1	17.8	56.1	97.3	98.3	95.8
Anton C et al. [17]	M-39.7	M-73	CA 125-ECLIA	75.9	77.8	63.9	81.8	79.3	97.3	-	-	-	-	-	-
Anton C et al. [17]	PM-13.9	PM-47	HE4-EIA	75.9	77.8	63.9	81.8	79.3	97.3	-	-	-	-	-	-
Anton C et al. [17]	M-27.7	M-73	CA 125-ECLIA	74.1	77.8	72.2	75.8	69	81.1	-	-	-	-	-	-
Anton C et al. [17]	PM-13.1	PM-47	HE4-EIA	74.1	77.8	72.2	75.8	69	81.1	-	-	-	-	-	-
Partheen K et al. [114]	M-26	M-276	CA 125-CMIA	-	75	75	-	81	87.1	-	60.7	62.8	-	90.7	90.7
Partheen K et al. [114]	PM-17	PM-98	HE4-EIA	-	75	75	-	81	87.1	-	60.7	62.8	-	90.7	90.7
Van Gorp T et al. [19]	M-12.5	AII-374	CA 125-EIA	84.7	66.7	91.0	76.8	87.8	58.8	71	60.5	74.3	88.2	90.4	83.3
Van Gorp T et al. [19]	PM-14.4		HE4-EIA	84.7	66.7	91.0	76.8	87.8	58.8	71	60.5	74.3	88.2	90.4	83.3
Novotny Z et al. [119]	M-37.7	M-256	CA 125-CMIA	-	-	85.7	-	-	95	-	-	62.06	-	-	98.65
Novotny Z et al. [119]			HE4-CMIA	-	-	85.7	-	-	95	-	-	62.06	-	-	98.65
Karlsen et al. [116]	M-25.3	M-597	CA 125-CMIA	94.8	91.8	92.6	76.5	40.2	75.5	-	-	-	-	-	-
Karlsen et al. [116]	PM-7.4	PM-621	HE4-CMIA	94.8	91.8	92.6	76.5	40.2	75.5	-	-	-	-	-	-
Ortiz-Munoz et al. [103]	M-29.9	M-118	CA 125-ECLIA	93.1	90	94.7	90.7	82.4	94.1	71.1	60	78.3	98.2	96.6	98.8
Ortiz-Munoz et al. [103]	PM-11.4	PM-61	HE4-ECLIA	93.1	90	94.7	90.7	82.4	94.1	71.1	60	78.3	98.2	96.6	98.8
Lenhardt et al. [104]	M-25.3	M-256	CA 125-CMIA	76.6	66.6	72.1	-	-	-	-	-	-	-	-	-
Lenhardt et al. [104]	PM-7.4	PM-271	HE4-CMIA	76.6	66.6	72.1	-	-	-	-	-	-	-	-	-
Kalapotharacos et al. [105]	M-10.4	M-154	CA 125-ECLIA	-	82	99	-	-	-	-	-	-	-	-	-
Kalapotharacos et al. [105]	PM-4.6	PM-123	HE4-EIA	-	82	99	-	-	-	-	-	-	-	-	-
Sandri et al. [116]	M-25.3	M-191	CA 125-CMIA	91.2	85.2	91.5	-	-	-	-	-	-	-	-	-
Sandri et al. [116]	PM-7.4	PM-158	HE4-CMIA	91.2	85.2	91.5	-	-	-	-	-	-	-	-	-
Montagnana et al. [65]	M-14.4	M-53	CA 125-EIA	-	53.5	82.5	-	80.6	84.6
Montagnana et al. [65]	PM-12.5	PM-51	HE4-EIA	-	53.5	82.5	-	80.6	84.6

Imported from Clinica Chimica Acta 2015;440:143-151.

All-PM+M; PM, premenopausal; M, postmenopausal; ECLIA, electro-chemilumines cence immunoassay; ELA, enzyme immunometric assay; CMIA, chemiluminescent micropartide immunoassay.

Table 5

Characteristics of reference individuals

Characteristic	Number of individuals
Premenopausal	912
Postmenopausal	851
Body mass index (BMI)
<18.5 (lean)	114
18.5-22.9 (normal)	923
23.0-24.9 (overweight)	386
≥25.0 (obese)	351
Smoking
Non-smoker	1,198
Former smoker	26
Current Smoker	49
Hormone therapy
Yes	59
No	1,704

Table 6

Reference intervals of HE4 and ROMA value according to age groups

	Age group (n)	Upper reference limit (95% CI)
HE4 (pmol/L)	< 30 (126)	59.93 (53.59-66.27)
	30-49 (751)	64.02 (61.99-66.05)
	50-59 (575)	72.06 (65.51-78.61)
	≥ 60 (357)	93.84 (66.68-121.00)
	Total (1,809)	75.59 (70.90-80.28)
ROMA (%)	< 30 (126)	11.4 (8.75- 14.05)
	30-49 (726)	12.8 (11.62-13.98)
	50-59 (575)	18.5 (15.61- 21.39)
	≥ 60 (357)	22.8 (17.70- 27.90)
	All (1,809)	17.1 (15.43- 18.77)

Abbreviation: CI, confidence interval.

Notes

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

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