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Abstract

BACKGROUND:

No tumor biomarker (TM) is available for de novo metastatic lung adenocarcinoma.

OBJECTIVE:

To examine the serum levels of carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen (CA) 19-9, CA125, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), and lactate dehydrogenase (LDH) to predict de novo metastatic lung adenocarcinoma.

METHODS:

This was a retrospective study of geriatric ( $\geqslant$ 60 years of age) patients with lung cancer diagnosed at Shanxi Cancer Hospital from 02/2012 to 12/2017. CEA, CYFRA21-1, CA199, NSE, CA125, TPA, and TPS were detected by ELISA and LDH was detected by LDH kit. Their predictive value was assessed using receiver operating characteristic (ROC) curves and multivariable logistic regression.

RESULTS:

The positive rates of LDH and TMs were higher in the metastatic group (all $P<$ 0.05). The best single TMs were CYFRA21-1 (70.5% sensitivity) and CA199 (92.0% specificity). When using any two, the best were CYFRA21-1 $+$ TPA (77.1% sensitivity) and CA199 $+$ TPA or NSE (both 84.1% specificity). High LDH and CA125 statuses were each independently associated with brain, bone, liver, and lung metastases (all $P<$ 0.05).

CONCLUSIONS:

Abnormal level of LDH and TMs, alone or in combination, had predictive value for metastasis in geriatric patients with lung adenocarcinoma; these indicators were also associated with the metastatic site.

Keywords

Lung adenocarcinoma lactate dehydrogenase tumor marker metastasis elderly

1. Introduction

Lung cancer is the leading cause of cancer-related mortality in the world [25]. Non-small cell lung cancer (NSCLC) accounts for $>$ 80% of all lung cancers, and adenocarcinoma is the most common subtype of NSCLC. Most newly diagnosed lung cancers are metastatic at presentation, especially in adenocarcinoma [20]. In addition, the incidence of lung cancer has been increased in the elderly population and at least half of the advanced NSCLC patients are diagnosed at $>$ 65 years of age [23]. The 5-year overall survival of lung cancer after diagnosis is only 15.6% [33]. With the development of detection technologies and the advent of novel targeted and immune therapies [7, 27, 28], the outcomes of the patients who respond to therapies are obviously improved [1, 7, 14, 22]. Nevertheless, due to the comorbidities and frailty of the elderly population, the treatment of lung cancer, particularly metastatic lung cancer, is challenging [1, 26]. In the geriatric population, metastasis is a common reason of cancer-related death [17]. Therefore, cancer management should take the physical condition, tolerance, and metastatic status into account, especially in elderly patients [24, 30].

Imaging examinations like computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI) provide information about local and distant metastases, but pathological examination remains the gold standard for the diagnosis of metastasis. Traditional imaging cannot detect lesions $<$ 0.4 cm and even a pathological examination may miss those small lesions [33]. Tumor markers (TMs) such as the carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA21-1), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) all play important roles in cancer and are recommended by the National Academy of Clinical Biochemistry (NACB) and the European Group on Tumor Markers (EGTM) for cancer diagnosis, therapy monitoring, prognosis, and surveillance of recurrent disease [6, 31]. Lactate dehydrogenase (LDH) levels at presentation of stage IV NSCLC have been shown to be independently associated with the metastatic burden of NSCLC [12]. LDH5, the isoenzyme with the highest activity, correlated with TKTL1, a known prognostic marker for NSCLC [9]. Serum LDH levels are dramatically increased in stage IV NSCLC [13]. Nonetheless, none of these biomarkers are used for the diagnosis of de novo metastatic lung adenocarcinoma.

Therefore, to explore single or combinations of biomarkers for the prediction and diagnosis of metastatic lung adenocarcinoma is an urgent problem to be solved. The aim of the present study was to examine the serum levels of CEA, CYFRA21-1, NSE, carbohydrate antigen (CA) 19-9, CA125, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), and LDH in elderly patients with lung adenocarcinoma and to investigate the sensitivity and specificity of those biomarkers to predict and diagnose de novo distant metastasis.

2. Materials and methods

2.1 Study design and patients

This was a retrospective study of geriatric ( $\geqslant$ 60 years of age) patients with lung cancer diagnosed at Shanxi Cancer Hospital from February 2012 to December 2017. The ethical committee of Shanxi Cancer Hospital approved this study (ethical ID: 201835).

The inclusion criteria were: 1) diagnosis of NSCLC; and 2) $\geqslant$ 60 years of age. The exclusion criteria were: 1) history of another malignancy or mixed pathological types; 2) 86 incomplete laboratory data; 3) main organ dysfunction; 4) relevant concomitant medical condition (i.e., main organ dysfunction, hepatobiliary disease, diabetes, moderate to severe heart disease, moderate to severe kidney disease, acute pneumonia or pancreatitis, etc.) that could influence or potentially influence LDH and TMs.

2.2 Data collection

All patients underwent percutaneous lung biopsy, lung resection, and biopsy at the metastatic site. Pathological diagnosis was performed by at least two pathologists. Pathological diagnosis is the gold standard for the diagnosis of lung cancer.

The patients were divided into the metastatic ( $n=$ 498) and non-metastatic ( $n=$ 465) groups. Age, gender, smoking history, immunohistochemistry (IHC), TNM stage, site of metastasis, and number of distant metastasis were collected. The definition of metastatic status and TNM stage were based on the IASLC 8 ${}^{\text{th}}$ TNM Lung Cancer Staging System. The diagnosis of metastasis was established on the basis of clinical workup procedures, which included CT, ultrasound, MRI, positron emission tomography (PET) scanning, emission CT, fine-needle aspiration biopsy, pleural fluid cytology, and/or biopsy.

2.3 LDH and tumor markers

Fasting blood samples were taken before the patients had received any cancer treatment. Fasting blood samples were centrifuged (3000 rpm) for 10 min to obtain the serum. CEA, CYFRA21-1, CA199, NSE, CA125, TPA, and TPS were detected by enzyme-linked immunosorbent assay (ELISA) using TECAN and reagent kits (IDL Biltech, Sweden). LDH was detected by LDH kit (diasys, shanghai, China). The normal values of these TMs were previously established by our hospital and according to the literature [8]: CEA $<$ 3 $\mu$ g/L, CA199 $<$ 20 U/ml, CYFRA21-1 $<$ 4 ng/ml, CA125 $<$ 30 U/ml, NSE $<$ 12 $\mu$ g/L, TPA $<$ 2 ng/ml, TPS $<$ 150 U/L, and LDH $<$ 248 U/L.

Figure 1.

Study flowchart.

2.4 Statistical analysis

All data were analyzed using SPSS 22.0 for windows (IBM, Armonk, NY, USA). Continuous data were tested for normal distribution using the Kolmogorov-Smirnov test. Normally distributed continuous data are presented as means $\pm$ standard deviation and were analyzed using the Student $t$ test. Non-normally distributed continuous data are presented as medians (interquartile range (IQR)) and were analyzed using the Wilcoxon test. Continuous data are presented as frequencies and were analyzed using the chi-square test. Statistically significant differences were defined as two-sided $P$ values $<$ 0.05. Receiver operating characteristic (ROC) curves were plotted and the areas under the curve (AUC) were calculated to determine the cutoff value of the TMs for predicting the metastatic status. Logistic regression was used to identify factors independently associated with metastasis. Variables with $P<$ 0.05 in the univariable analyses were analyzed by multivariable regression.

Table 1
Characteristics of the elderly patients with lung adenocarcinoma

Characteristics	Control ( $N=$ 465)	Metastatic ( $N=$ 498)	All	$P$
Age (years), mean $\pm$ SD (range)	67.6 $\pm$ 5.5 (60–88)	67.3 $\pm$ 5.7 (60–86)	67.4 $\pm$ 5.6 (60–88)	0.505
Gender ( $n$ , %)				0.044
Male	293 (63.0)	282 (56.6)	575 (59.7)
Female	172 (37.0)	216 (43.4)	388 (40.3)
Smoking status ( $n$ , %)				0.191
Never	212 (45.6)	248 (49.8)	460 (47.8)
Ever	253 (54.4)	250 (50.2)	503 (52.2)
Drinking status ( $n$ , %)				0.471
Never	390 (83.9)	426 (85.5)	816 (84.7)
Ever	75 (16.1)	72 (15.3)	147 (15.3)
Tumor statement ( $n$ , %)				$<$ 0.001
1	158 (34.0)	54 (10.8)	212 (22.0)
2	161 (34.6)	250 (50.2)	411 (42.7)
3	87 (18.7)	71 (14.3)	158 (16.4)
4	59 (12.7)	123 (24.7)	182 (18.9)
Nodal involvement ( $n$ , %)				$<$ 0.001
0	199 (42.8)	75 (15.1)	274 (28.5)
1	84 (18.1)	44 (8.8)	128 (13.3)
2	112 (24.1)	219 (44.0)	331 (34.4)
3	70 (15.1)	160 (32.1)	230 (23.9)
TTF-1 ( $n$ , %)				0.352
Negative	50 (20.8)	59 (24.4)	109 (22.6)
Positive	190 (79.2)	183 (75.6)	373 (77.4)
NaspinA ( $n$ , %)				0.770
Negative	58 (25.8)	61 (27.0)	119 (26.4)
Positive	167 (74.2)	165 (73.0)	332 (73.6)
CK7 ( $n$ , %)				0.846
Negative	5 (3.4)	6 (4.3)	11 (3.7)
Positive	140 (96.6)	149 (96.1)	295 (96.1)
Ki67 score, mean $\pm$ SD	46.9 $\pm$ 22.0	46.4 $\pm$ 22.5	46.6 $\pm$ 22.1	0.827
Number of metastasis site ( $n$ , %)
Single		231 (46.4)
Multiple		267 (53.6)
Site of metastasis ( $n$ , %)
Brain		157 (31.5)
Liver		49 (9.8)
Bone		101 (20.3)
Adrenal		59 (11.8)
Pleural		245 (51.7)
Lung		133 (26.7)

3. Results

3.1 Patients and tumor characteristics

Figure 1 presents the study flowchart. Among the 963 geriatric patients with lung adenocarcinoma and with available TMs between February 2012 and December 2017, 498 were metastatic and 465 were non-metastatic (Fig. 1). Table 1 presents the characteristics of the patients. The 963 patients were 60 to 88 years old (mean of 67.4 $\pm$ 5.6 years). There were 460 (47.8%) non-smokers and 816 non-drinkers (84.7%). There were 388 women (40.3%) and 575 men (59.7%). The metastatic group contained 230 (46.2%) and 268 (53.8%) with a single and multiple metastasis sites, respectively). The most common metastatic sites were pleural, brain, lung, bone, adrenal, and liver, accounting for 51.7%, 31.5%, 26.7%, 20.3%, 11.8%, and 9.8%, respectively.

Table 2
Comparison of the tumor markers according to lung adenocarcinoma metastasis in elderly patients

Indicators	Control		Metastatic		$P$
	(median, IQR)		(median, IQR)
LDH (U/L)	199.00	(51.00)	221.00	(88.00)	$<$ 0.001
CEA ( $\mu$ g/L)	2.90	(7.72)	6.30	(36.53)	$<$ 0.001
CYFRA21-1 (ng/ml)	1.88	(3.31)	3.45	(7.33)	$<$ 0.001
CA199 (U/ml)	13.09	(19.87)	16.15	(34.22)	$<$ 0.001
NSE ( $\mu$ g/L)	5.14	(3.12)	5.89	(4.78)	$<$ 0.001
CA125 (U/ml)	6.44	(15.09)	28.39	(82.58)	$<$ 0.001
TPA (ng/ml)	1.00	(1.70)	1.55	(3.86)	$<$ 0.001
TPS (U/L)	90.34	(112.34)	119.19	(167.36)	$<$ 0.001

LDH $=$ lactate dehydrogenase; CEA $=$ carcinoembryonic antigen; CYFRA21-1 $=$ cytokeratin-19 fragment; CA199 $=$ carbohydrate antigen 199; NSE $=$ neuron-specific-enolase; CA125 $=$ carbohydrate antigen 125; TPA $=$ tissue polypeptide antigen; TPS $=$ tissue polypeptide specific antigen; IQR $=$ interquartile range.

3.2 LDH and tumor markers

The serum levels and positive rate of LDH and serum TMs such as CEA, CYFRA21-1, CA199, NSE, CA125, TPA, and TPS in the metastatic group were all higher than in the control group ( $P<$ 0.05) (Table 2). The multivariable analysis showed that female gender (OR $=$ 1.592, 95% CI: 1.192–2.126, $P=$ 0.002), high LDH status (OR $=$ 2.407, 95% CI: 1.702–3.404, $P<$ 0.001), high CEA status (OR $=$ 1.450, 95% CI: 1.089–1.930, $P=$ 0.01), high CYFRA21-1 status (OR $=$ 2.046, 95% CI: 1.486–2.816, $P<$ 0.001), and high CA125 status (OR $=$ 3.590, 95% CI: 2.613–4.931, $P<$ 0.001) were independently associated with lung cancer metastasis (Table 3).

Table 3
Univariable and multivariable analyses of the associations of various tumor markers with lung adenocarcinoma metastasis in elderly patients

Characteristics	Univariable analysis OR (95% CI)	$P$ value	Multivariable analysis OR (95% CI)	$P$
Age	0.992 (0.970–1.015)	0.505
Sex		0.044		0.002
Male	Reference		Reference
Female	1.305 (1.008–1.690)		1.592 (1.192–2.126)
Smoking status		0.192
Never	Reference
Ever	0.845 (0.658–1.088)
Drinking status		0.471
Never	Reference
Ever	0.879 (0.619–1.249)
LDH		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	3.191 (2.326–4.377)		2.407 (1.702–3.404)
CEA		$<$ 0.001		0.011
Negative	Reference		Reference
Positive	2.043 (1.575–2.651)		1.450 (1.089–1.930)
CYFRA21-1		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	3.214 (2.419–4.270)		2.046 (1.486–2.816)
CA199		0.001		0.851
Negative	Reference		–
Positive	1.562 (1.199–2.034)		–
NSE		$<$ 0.001		0.166
Negative	Reference		–
Positive	3.880 (2.079–7.243)		–
CA125		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	4.660 (3.459–6.279)		3.590 (2.613–4.931)
TPA		$<$ 0.001		0.065
Negative	Reference		–
Positive	2.339 (1.763–3.104)		–
TPS		$<$ 0.001		0.510
Negative	Reference		–
Positive	1.655 (1.267–2.161)		–

LDH $=$ lactate dehydrogenase; CEA $=$ carcinoembryonic antigen; CYFRA21-1 $=$ cytokeratin-19 fragment; CA199 $=$ carbohydrate antigen 199; NSE $=$ neuron-specific enolase; CA125 $=$ carbohydrate antigen 125; TPA $=$ tissue polypeptide antigen; TPS $=$ tissue polypeptide specific antigen.

Figure 2.

ROC curve analysis of different markers to predict the metastatic status. (A) Individual tumor markers. (B) Combinations of tumor markers.

3.3 Prediction for metastatic status

The highest AUC of single TM was achieved by CA125 (AUC $=$ 0.734), and the lowest was CA199 (AUC $=$ 0.559) (Table 4) (Fig. 2A). The cutoff value of LDH, CEA, CYFRA211, CA199, NSE, CA125, TPA, and TPS were 226.5 U/L, 5.97 $\mu$ g/L, 2.07 ng/ml, 59.55 U/ml, 8.32 $\mu$ g/L, 15.29 U/ml, 1.53 ng/ml, and 213.67 U/L, respectively. The highest AUC of any two combined indicators was achieved by CYFRA21-1 $+$ CA125 (AUC $=$ 0.756) and the lowest was TPA $+$ TPS (AUC $=$ 0.610) (Table 4). The ROC curves of the combined TMs with AUC $>$ 0.7 are displayed in Fig. 2B.

Table 4
The areas under the ROC curves of the different indicators

Indicators	Area under	$P$	95% CI
	the curve
LDH	0.639	$<$ 0.001	0.604–0.674
CEA	0.624	$<$ 0.001	0.589–0.659
CYFRA21-1	0.680	$<$ 0.001	0.647–0.714
CA199	0.559	0.002	0.523–0.595
NSE	0.593	$<$ 0.001	0.557–0.629
CA125	0.734	$<$ 0.001	0.702–0.765
TPA	0.606	$<$ 0.001	0.570–0.642
TPS	0.598	$<$ 0.001	0.563–0.634
LDH $+$ CEA	0.679	$<$ 0.001	0.645–0.713
LDH $+$ CYFRA21-1	0.658	$<$ 0.001	0.624–0.692
LDH $+$ CA199	0.659	$<$ 0.001	0.625–0.693
LDH $+$ NSE	0.652	$<$ 0.001	0.618–0.686
LDH $+$ CA125	0.721	$<$ 0.001	0.689–0.753
LDH $+$ TPA	0.651	$<$ 0.001	0.617–0.685
LDH $+$ TPS	0.646	$<$ 0.001	0.611–0.681
CEA $+$ CYFRA21-1	0.701	$<$ 0.001	0.669–0.734
CEA $+$ CA199	0.645	$<$ 0.001	0.610–0.679
CEA $+$ NSE	0.656	$<$ 0.001	0.622–0.690
CEA $+$ CA125	0.738	$<$ 0.001	0.706–0.769
CEA $+$ TPA	0.670	$<$ 0.001	0.636–0.704
CEA $+$ TPS	0.652	$<$ 0.001	0.618–0.687
CYFRA21-1 $+$ CA199	0.679	$<$ 0.001	0.645–0.712
CYFRA21-1 $+$ NSE	0.641	$<$ 0.001	0.606–0.676
CYFRA21-1 $+$ CA125	0.756	$<$ 0.001	0.726–0.787
CYFRA21-1 $+$ TPA	0.680	$<$ 0.001	0.647–0.714
CYFRA21-1 $+$ TPS	0.668	$<$ 0.001	0.634–0.702
CA199 $+$ NSE	0.622	$<$ 0.001	0.587–0.657
CA199 $+$ CA125	0.729	$<$ 0.001	0.697–0.760
CA199 $+$ TPA	0.636	$<$ 0.001	0.601–0.671
CA199 $+$ TPS	0.622	$<$ 0.001	0.587–0.657
NSE $+$ CA125	0.709	$<$ 0.001	0.677–0.742
NSE $+$ TPA	0.624	$<$ 0.001	0.589–0.659
NSE $+$ TPS	0.617	$<$ 0.001	0.582–0.652
CA125 $+$ TPA	0.739	$<$ 0.001	0.708–0.771
CA125 $+$ TPS	0.731	$<$ 0.001	0.699–0.762
TPA $+$ TPS	0.610	$<$ 0.001	0.574–0.645
TOTAL	0.734	$<$ 0.001	0.702–0.765

The best sensitivity and specificity of single TM were achieved with CYFRA21-1 (70.5%) and CA199 (92.0%), respectively. The highest and lowest Youden’s index of single TM were 38.4% and 12.3% respectively. Furthermore, when using any combination of LDH and another TM to predict the metastatic status, the highest sensitivity and specificity were achieved for CYFRA21-1 $+$ TPA (77.1%) and CA199 $+$ TPA or NSE (both were 84.1%), respectively. The highest and lowest Youden’s index were 41.1% and 19.8% respectively. Finally, the combined use of all indicators in predicting metastatic status resulted in sensitivity, specificity, and Youden’s index of 65.7%, 72.7%, and 38.4%, respectively (Table 5).

Table 5

Diagnostic value of different indicators for metastatic lung adenocarcinoma

Indicators	Sensitivity	Specificity	Youden’s
	(%)	(%)	index (%)
LDH	48.0	76.1	24.1
CEA	52.0	69.9	21.9
CYFRA21-1	70.5	57.4	27.9
CA199	20.3	92.0	12.3
NSE	29.7	86.7	16.4
CA125	65.5	72.9	38.4
TPA	50.6	70.3	20.9
TPS	28.3	86.9	15.2
LDH $+$ CEA	62.7	68.8	31.5
LDH $+$ CYFRA21-1	53.4	73.8	27.2
LDH $+$ CA199	57.8	68.8	26.6
LDH $+$ NSE	55.6	68.6	24.2
LDH $+$ CA125	69.7	66.0	35.7
LDH $+$ TPA	50.8	74.2	25.0
LDH $+$ TPS	51.2	73.1	24.3
CEA $+$ CYFRA21-1	62.7	67.7	30.4
CEA $+$ CA199	54.4	74.8	25.2
CEA $+$ NSE	54.4	72.0	26.5
CEA $+$ CA125	66.3	72.0	38.3
CEA $+$ TPA	46.4	81.1	27.5
CEA $+$ TPS	61.9	63.2	25.1
CYFRA21-1 $+$ CA199	58.0	70.9	29.0
CYFRA21-1 $+$ NSE	52.6	71.2	23.8
CYFRA21-1 $+$ CA125	75.1	66.0	41.1
CYFRA21-1 $+$ TPA	77.1	49.9	27.0
CYFRA21-1 $+$ TPS	50.8	73.8	24.6
CA199 $+$ NSE	38.3	84.1	22.4
CA199 $+$ CA125	72.5	65.1	37.7
CA199 $+$ TPA	39.2	84.1	23.2
CA199 $+$ TPS	45.8	74.0	19.8
NSE $+$ CA125	58.8	76.8	35.6
NSE $+$ TPA	41.4	81.3	22.7
NSE $+$ TPS	45.4	75.5	20.9
CA125 $+$ TPA	70.5	67.3	37.8
CA125 $+$ TPS	59.6	76.0	35.6
TPA $+$ TPS	56.4	64.7	21.1
TOTAL	65.7	72.7	38.4

3.4 Prediction for the site of metastasis

The 498 metastatic patients were further analyzed for the associations of the TMs with various metastatic sites (Table S1). High LDH status (OR $=$ 1.592, 95% CI: 1.079–2.349, $P=$ 0.02), high CEA status (OR $=$ 2.321, 95% CI: 1.535–3.511, $P<$ 0.001), high CYFRA21-1 status (OR $=$ 1.899, 95% CI: 1.293–2.787, $P=$ 0.001), and high CA125 status (OR $=$ 1.549, 95% CI: 1.066–2.253, $P=$ 0.02) were independently associated with brain metastasis. High LDH status (OR $=$ 1.704, 95% CI: 1.086–2.674, $P=$ 0.02), high CYFRA21-1 status (OR $=$ 2.329, 95% CI: 1.502–3.610, $P<$ 0.001), and high CA125 status (OR $=$ 3.590, 95% CI: 2.613–4.931, $P<$ 0.001) were independently associated with bone metastasis. High LDH status (OR $=$ 3.795, 95% CI: 2.093–6.879, $P<$ 0.001) and high CA125 status (OR $=$ 2.280, 95% CI: 1.256–4.136, $P=$ 0.007) were independently associated with liver metastasis. High NSE status (OR $=$ 4.151, 95% CI: 2.086–8.258, $P<$ 0.001) and high TPA status (OR $=$ 2.715, 95% CI: 1.541–4.785, $P=$ 0.001) were independently associated with adrenal gland metastasis. High CA125 status (OR $=$ 4.223, 95% CI: 3.107–5.739, $P<$ 0.001) was independently associated with pleural metastasis. Finally, high LDH status (OR $=$ 2.616, 95% CI: 1.750–3.911, $P<$ 0.001), high CYFRA21-1 status (OR $=$ 2.057, 95% CI: 1.357–3.117, $P=$ 0.001), and high CA125 status (OR $=$ 1.721, 95% CI: 1.155–2.565, $P=$ 0.008) were independently associated with lung metastasis.

4. Discussion

No TM has been examined for the diagnosis of de novo metastatic lung adenocarcinoma. Therefore, this study aimed to examine the serum levels of CEA, CYFRA21-1, NSE, CA19-9, CA125, TPA, TPS, and LDH in elderly patients with lung adenocarcinoma to predict de novo metastatic disease. The results suggest that abnormal level of LDH and TMs, alone or in combination, had predictive value for metastasis in geriatric patients with lung adenocarcinoma; these indicators were also associated with the metastatic site.

LDH is a key enzyme in glycolysis and is related to the survival and proliferation of cancer-initiating cells [29]. Abnormally high levels of LDH are associated with distant metastasis and indicate a poor prognosis in lung cancer [5, 9, 12, 13]. LDH levels at presentation of stage IV NSCLC have been shown to be independently associated with the metastatic burden of NSCLC [12]. Increased levels of TMs like CEA, CYFRA21-1, NSE, and CA125 are commonly used in the diagnosis, treatment decisions, response evaluation, and prognosis [3, 4, 10, 15, 16, 19, 21]. In the present study, the results were consistent with the above studies. Beside these indicators, CA199, TPA, and TPS were included in this study to clarify their predictive value for metastasis. Primarily, the levels and the abnormal rates of LDH and TMs in the metastatic group were obviously higher than in the control group. In the present study, when using only one TM to diagnose metastasis, CA125 was the best one with 65.5% sensitivity and 72.9% specificity. The sensitivity of CA125 was the highest, while the best specificity was CA199 (92.0%). Furthermore, a combination of any two TMs was also used. The combination of CYFRA21-1 and TPA had the highest sensitivity, with 77.1%, and the best specificity was CA199 and NSE or TPA, with 84.1%. The CYFRA21-1 and CA125 combination had the highest Youden’s index with 41.1%. Molina et al. [16] found that the sensitivity and specificity of a panel of TMs (CA153, SCC, CEA, CYFRA21-1, pro-GRP, and NSE) reached 88.5% and 82% to diagnosed lung cancer. Maybe due to the selection of participants, the sensitivity was not so high in the present study.

The metastasis of different sites may accompanied by the elevation of different indicators. The most frequently metastatic site of adenocarcinoma are lung, bone, and brain when not including pleural metastasis [18]. In the present study, pleural metastasis had a high incidence (51.7%). The occurrences of brain, liver, bone, adrenal, and lung were 31.5%, 9.8%, 20.3%, 11.8%, and 26.7%, respectively. High serum levels of CEA are considered to be an independent risk factor for brain metastasis development in lung adenocarcinoma [2]. In addition, Lee et al. [11] reported that CEA levels were related to brain, bone, and lung metastasis, but not pleura in advanced NSCLC. The present study showed that serum CEA levels were associated with brain metastasis in geriatric patients with lung adenocarcinoma, but not pleura, bone, liver, adrenal and lung metastasis. In advanced NSCLC, the levels of CYFRA21-1 were reported to have a relationship with metastatic occurrence in brain, bone, liver, lung, and pleura. The NSE levels only correlate with brain and bone metastasis [32]. Nevertheless, CYFRA21-1 was relevant to brain, bone, and lung metastasis in lung adenocarcinoma, but not liver, adrenal, and pleura in the present study. The discrepancies may due to the different subtypes of lung cancer.

The serum levels of LDH and TMs investigated here were inclined and prone to abnormality in the metastatic group. The assessment of these indicators could be clinically helpful for determining whether lung adenocarcinoma has a high likelihood of being metastatic at presentation. In previous studies, more attention had been paid to differentiate between malignant and benign lung lesions [31]. Nevertheless, identifying the presence of distant metastasis is equally important for the proper management of the patients [22]. The present study strongly suggests that the proper use of LDH and TMs can indicate metastasis and the site of metastasis. Taken together, negative CA199 singly has higher specificity and the combination of CYFRA21-1 and CA125 has higher value to predict metastasis in elderly patients with lung adenocarcinoma.

The present study has limitations. The patients were from a single center and were selected. Only adenocarcinoma was studied and the other types of lung cancer should also be explored. In addition, the retrospective nature of the study limits the analysis to the available data, Further studies are needed to validate the results in multiple centers and the predictive value of TMs should be determined in non-elderly patients.

In conclusion, abnormal level of LDH and TMs, alone or in combination, had predictive value for metastasis in geriatric patients with lung adenocarcinoma; these indicators were also associated with the metastatic site.

Footnotes

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary Table

Table S1

Univariable and multivariable analyses of the predictive indicators for the site of metastasis in elderly lung adenocarcinoma

Characteristics	Univariable analysis OR (95% CI)	$P$	Multivariable analysis OR (95% CI)	$P$
Brain
LDH		$<$ 0.001		0.019
Negative	Reference		Reference
Positive	2.238 (1.561–3.207)		1.592 (1.079–2.349)
CEA		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	2.899 (1.942–4.328)		2.321 (1.535–3.511)
CYFRA21-1		$<$ 0.001		0.001
Negative	Reference		Reference
Positive	2.735 (1.931–3.874)		1.899 (1.293–2.787)
CA199		0.023		0.921
Negative	Reference		–
Positive	1.493 (1.057–2.110)		–
NSE		0.001		0.346
Negative	Reference		–
Positive	2.590 (1.478–4.539)		–
CA125		$<$ 0.001		0.022
Negative	Reference		Reference
Positive	2.306 (1.630–3.262)		1.549 (1.066–2.253)
TPA		$<$ 0.001		0.100
Negative	Reference		–
Positive	2.260 (1.595–3.204)		–
TPS		$<$ 0.001		0.406
Negative	Reference		–
Positive	1.932 (1.368–2.730)		–
Bone
LDH		$<$ 0.001		0.021
Negative	Reference		Reference
Positive	2.218 (1.447–3.400)		1.704 (1.086–2.674)
CEA		0.387
Negative	Reference
Positive	1.206 (0.789–1.844)
CYFRA21-1		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	2.699 (1.777–4.099)		2.329 (1.502–3.610)
CA199		0.067
Negative	Reference
Positive	1.474 (0.973–2.234)
NSE		0.066
Negative	Reference
Positive	1.904 (0.959–3.780)
CA125		0.028		$<$ 0.001
Negative	Reference		Reference
Positive	1.596 (1.050–2.425)		3.590 (2.613–4.931)
TPA		$<$ 0.001		0.064
Negative	Reference
Positive	2.373 (1.564–3.600)
TPS		0.088
Negative	Reference
Positive	1.439 (0.948–2.184)
Liver
LDH		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	4.309 (2.398–7.742)		3.795 (2.093–6.879)

Table S1, continued
Characteristics	Univariable analysis OR (95% CI)	$P$	Multivariable analysis OR (95% CI)	$P$
CEA		0.313
Negative	Reference
Positive	1.364 (0.746–2.492)
CYFRA21-1		$<$ 0.001		0.099
Negative	Reference		–
Positive	2.982 (1.660–5.360)		–
CA199		0.042		0.317
Negative	Reference		–
Positive	1.817 (1.022–3.233)		–
NSE		$<$ 0.001		0.056
Negative	Reference		–
Positive	4.165 (1.971–8.801)		–
CA125		0.001		0.007
Negative	Reference		Reference
Positive	2.770 (1.547–4.959)		2.280 (1.256–4.136)
TPA		0.003		0.175
Negative	Reference		–
Positive	2.395 (1.344–4.268)		–
TPS		0.025		0.513
Negative	Reference		–
Positive	1.934 (1.087–3.441)		–
Adrenal
LDH		$<$ 0.001		0.099
Negative	Reference		–
Positive	2.877 (1.688–4.904)		–
CEA		0.332
Negative	Reference
Positive	1.312 (0.758–2.272)
CYFRA21-1		0.003		0.984
Negative	Reference		–
Positive	2.263 (1.333–3.842)		–
CA199		0.260
Negative	Reference
Positive	1.357 (0.798–2.310)
NSE		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	6.080 (3.161–11.694)		4.151 (2.086–8.258)
CA125		0.002		0.050
Negative	Reference		–
Positive	2.297 (1.353–3.901)		–
TPA		$<$ 0.001		0.001
Negative	Reference		Reference
Positive	3.479 (2.030–5.963)		2.715 (1.541–4.785)
TPS		$<$ 0.001		0.472
Negative	Reference		–
Positive	2.794 (1.633–4.782)		–
Pleural
LDH		0.007		0.148
Negative	Reference		–
Positive	1.553 (1.128–2.139)		–
CEA		0.001		0.146
Negative	Reference		–
Positive	1.709 (1.259–2.319)		–
CYFRA21-1		0.001		0.348
Negative	Reference		–
Positive	1.665 (1.235–2.244)		–
CA199		0.023		0.696
Negative	Reference		–
Positive	1.410 (1.049–1.895)		–

Table S1, continued
Characteristics	Univariable analysis OR (95% CI)	$P$	Multivariable analysis OR (95% CI)	$P$
NSE		0.556
Negative	Reference
Positive	1.186 (0.673–2.091)
CA125		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	4.129 (3.045–5.599)		4.223 (3.107–5.739)
TPA		0.075
Negative	Reference
Positive	1.320 (0.972–1.793)
TPS		0.265
Negative	Reference
Positive	1.186 (0.879–1.599)
Lung
LDH		$<$ 0.001		$<$ 0.001
Negative	Reference		Reference
Positive	3.191 (2.326–4.377)		2.616 (1.750–3.911)
CEA		$<$ 0.001		0.090
Negative	Reference		–
Positive	2.043 (1.575–2.651)		–
CYFRA21-1		$<$ 0.001		0.001
Negative	Reference		Reference
Positive	3.214 (2.419–4.270)		2.057 (1.357–3.117)
CA199		0.001		0.881
Negative	Reference		–
Positive	1.562 (1.199–2.034)		–
NSE		$<$ 0.001		0.316
Negative	Reference		–
Positive	3.880 (2.079–7.243)		–
CA125		$<$ 0.001		0.008
Negative	Reference		Reference
Positive	4.660 (3.459–6.279)		1.721 (1.155–2.565)
TPA		$<$ 0.001		0.638
Negative	Reference		–
Positive	2.339 (1.763–3.104)		–
TPS		$<$ 0.001		0.192
Negative	Reference
Positive	1.655 (1.267–2.161)		–

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Lactate dehydrogenase and serum tumor markers for predicting metastatic status in geriatric patients with lung adenocarcinoma

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Study design and patients

2.2 Data collection

2.3 LDH and tumor markers

Table 1 Characteristics of the elderly patients with lung adenocarcinoma

3.1 Patients and tumor characteristics

Table 2 Comparison of the tumor markers according to lung adenocarcinoma metastasis in elderly patients

Table 3 Univariable and multivariable analyses of the associations of various tumor markers with lung adenocarcinoma metastasis in elderly patients

Table 4 The areas under the ROC curves of the different indicators

4. Discussion

Footnotes

Conflict of interest

Supplementary Table

References

Table 1
Characteristics of the elderly patients with lung adenocarcinoma

Table 2
Comparison of the tumor markers according to lung adenocarcinoma metastasis in elderly patients

Table 3
Univariable and multivariable analyses of the associations of various tumor markers with lung adenocarcinoma metastasis in elderly patients

Table 4
The areas under the ROC curves of the different indicators