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Distinguishing malignant from benign prostate using content of 17 chemical elements in prostatic tissue

Vladimir Zaichick

Radionuclide Diagnostics Department, Medical Radiological Research Centre, Russia

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Sofia Zaichick

Department of Medicine, University of Illinois College of Medicine, Chicago, USA

DOI: 10.15761/ICST.1000208

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Abstract

Contents of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn in normal (n=37), benign hypertrophic (BPH, n=32) and cancerous human prostate (PCa, n=60) were investigated using a combination of non-destructive and destructive methods: instrumental neutron activation analysis and inductively coupled plasma atomic emission spectrometry, respectively. Mean values ± standard error of mean (M ± SΕΜ) for mass fraction (mg/kg on dry mass basis) of chemical element in the normal prostatic parenchyma were as follows: Al 34.1 ± 3.5, B 1.04 ± 0.18, Ba 1.53 ± 0.21, Br 32.9 ± 3.6, Ca 2428 ± 233, Cu 9.85 ± 0.97, Fe 132 ± 7,  K 11650 ± 434, Li 0.0419 ± 0.0055, Mg 1071 ± 76, Mn 1.32 ± 0.09, Na 10987 ± 393, P 7617 ± 368, S 8657 ± 254, Si 101 ± 11, Sr 2.34 ± 0.38, and Zn 1061 ± 153, respectively. It was observed that the mass fractions of all chemical elements investigated in the study with the exception of P show significant variations in cancerous prostate when compared with normal and BPH prostate. The contents of Ca, K, Mg, Na, S, and Zn were significantly lower and those of Al, B, Ba, Br, Cu, Fe, Li, Mn, Si, and Sr were significantly higher in cancerous prostate than in normal and BPH tissues. Finally, we propose to use the Ca, S, and Zn mass fraction in a needle-biopsy core and also Ca∙S∙Zn test as the most informative indicators for distinguishing malignant from benign prostate. For example, sensitivity, specificity, and accuracy of Ca∙S∙Zn test were 100-9%, 100-2%, and 100-2%, respectively. Further studies on larger number of samples are required to confirm our findings, to study the impact of the chemical element contents on prostate cancer etiology and to examine the long-term pathological outcome.

Key words

chemical elements, prostate, benign prostatic hypertrophy, prostatic carcinoma, neutron activation analysis

Introduction

The prostate gland may be a source of many health problems in men past middle age, the most common being benign prostatic hyperplasia (BPH), and prostatic carcinoma (PCa). BPH is a noncancerous enlargement of the prostate gland leading to obstruction of the urethra and can significantly impair quality of life [1]. The prevalence of histological BPH is found in approximately 50-60% of males age 40-50, in over 70% at 60 years old and in greater than 90% of men over 70 [2,3]. In many Western industrialized countries, including North America, PCa is the most frequently diagnosed form of noncutaneous malignancy in males and, except for lung cancer, is the leading cause of death from cancer [4-9]. Although the etiology of BPH and PCa is unknown, some electrolytes and trace elements have been highlighted in the literature in relation to the development of these prostate diseases [10-29].

Electrolytes and trace elements have essential physiological functions such as maintenance and regulation of cell function and signalling, gene regulation, activation or inhibition of enzymatic reactions, neurotransmission, and regulation of membrane function. Essential or toxic (mutagenic, carcinogenic) properties of chemical elements depend on tissue-specific need or tolerance, respectively [30]. Excessive accumulation, deficiency or an imbalance of the chemical elements may disturb the cell functions and may result in cellular degeneration, death and malignant transformation [31].

In reported studies significant changes of chemical element contents in hyperplastic and cancerous prostate in comparison with those in the normal prostatic tissue were observed [31-64]. Moreover, a significant informative value of Zn content as a tumor marker for PCa diagnostics was shown by us [65,66]. Hence it is possible that besides Zn, some other chemical elements also can be used as tumor markers for distinguish between benign and malignant prostate.

Current methods applied for measurement of chemical element contents in samples of human tissue include a number of methods. Among these methods the instrumental neutron activation analysis with high resolution spectrometry of short-lived radionuclides (INAA-SLR) is a non-destructive and one of the most sensitive techniques. It allows measure the chemical element contents in a few milligrams tissue without any treatment of sample. Analytical studies of the Br, Ca, K, Mg, Mn, and Na contents in normal, BPH and PCa tissue were done by us using INAA-SLR [15,21,28,67,68]. Nondestructive method of analysis avoids the possibility of changing the content of chemical elements in the studied samples [69-72], which allowed for the first time to obtain reliable results. In particular, it was shown that the average mass fraction of Br, Ca, Mg, and Mn, in BPH tissue does not differ from normal level [67], but in PCa tissues the mean values of Br and Mn are higher while those of Ca and Mg are lower than in healthy prostatic tissue [68,73]. Obtained results formed the basis for a new method for differential diagnosis of BPH and PCa, the essence of which was to determine the content of chemical elements in the material of transrectal needle biopsy of prostate indurated site.

It is obvious that the most effective will be non-destructive analytical methods because they involve a minimal treatment of sample since the chances of significant loss or contamination would be decreased. However the INAA-SLR allow only determine the mean mass fractions of 6-7 chemical elements in the tissue samples of normal and cancerous prostate glands [15,21,28,67,68]. The inductively coupled plasma atomic emission spectrometry (ICP-AES) is a more power analytical tool than INAA-SLR [18,22,47] but sample digestion is a critical step in elemental analysis by this method. In the present study both analytical methods were used and the results obtained for some chemical elements by ICP-AES were under the control of INAA-SLR data.

The present study had three aims. The main objective was to obtain reliable results about the Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn contents in intact prostate of healthy men aged over 40 years and in the prostate gland of age-matched patients, who had either BPH or PCa combining in consecutive order non-destructive INAA-SLR with destructive ICP-AES. The second aim was to compare the levels of chemical elements in normal, hyperplastic, and cancerous prostate, and the third aim was to evaluate the chemical element content for diagnosis of prostate cancer.

All studies were approved by the Ethical Committees of the Medical Radiological Research Centre, Obninsk.

Material and methods

Samples

The patients studied (n=92) were hospitalized in the Urological Department of the Medical Radiological Research Centre. All of them were European-Caucasian, citizens of Moscow and Obninsk (a small city in a non-industrial region 105 km south-west of Moscow). Transrectal puncture biopsy of suspicious indurated regions of the prostate was performed for every patient, to permit morphological study of prostatic tissue at these sites and to estimate their chemical element contents. In all cases the diagnosis has been confirmed by clinical and morphological results obtained during studies of biopsy and resected materials. The age of 32 patients with BPH ranged from 56 to 78 years, the mean being 66 ± 6 (M ± SD) years. The 60 patients aged 40-79 suffered from PCa (stage T1-T4). Their mean age was 65 ± 10 (M ± SD) years.

Intact (Norm) prostates were removed at necropsy from 37 men aged 41-87 who had died suddenly. All deceased were European-Caucasian, citizens of Moscow. Their mean age was 55 ± 11 (M ± SD) years. The majority of deaths were due to trauma. Tissue samples were collected from the peripheral zone of dorsal and lateral lobes of their prostates, within 2 days of death and then the samples were divided into two portions. One was used for morphological study while the other was intended for chemical element analysis. A histological examination was used to control the age norm conformity, as well as to confirm the absence of microadenomatosis and latent cancer [15,21,28].

Sample preparation

All tissue samples were divided into two portions. One was used for morphological study while the other was intended for chemical element analysis. After the samples intended for chemical element analysis were weighed, they were freeze-dried and homogenized. The sample weighing about 10 mg (for biopsy materials) and 50-100 mg (for resected materials) was used for chemical element measurement by INAA-SLR. The samples for INAA-SLR were sealed separately in thin polyethylene films washed beforehand with acetone and rectified alcohol. The sealed samples were placed in labeled polyethylene ampoules.

After NAA-SLR investigation the prostate samples were taken out from the polyethylene ampoules and used for ICP-AES. The samples were decomposed in autoclaves; 1.5 mL of concentrated HNO3 (nitric acid at 65 %, maximum (max) of 0.0000005 % Hg; GR, ISO, Merck) and 0.3 mL of H2O2 (pure for analysis) were added to prostate tissue samples, placed in one-chamber autoclaves (Ancon-AT2, Ltd., Russia) and then heated for 3 h at 160–200°C. After autoclaving, they were cooled to room temperature and solutions from the decomposed samples were diluted with deionized water (up to 20 mL) and transferred to plastic measuring bottles. Simultaneously, the same procedure was performed in autoclaves without tissue samples (only HNO3+H2O2+ deionized water), and the resultant solutions were used as control samples.

Instrumentation and methods

Information detailing with the NAA-SLR and ICP-AES methods used and other details of the analysis was presented in our previous publication [15,18,21,22,28,47,67,68].

Certified reference materials

For quality control, ten subsamples of the certified reference materials IAEA H-4 Animal muscle from the International Atomic Energy Agency (IAEA), and also five sub-samples INCT-SBF-4 Soya Bean Flour, INCT-TL-1 Tea Leaves and INCT-MPH-2 Mixed Polish Herbs from the Institute of Nuclear Chemistry and Technology (INCT, Warszawa, Poland) were analyzed simultaneously with the investigated prostate tissue samples. All samples of CRM were treated in the same way as the prostate tissue samples. Detailed results of this quality assurance program were presented in earlier publications [18,22,47].

Computer programs and statistic

A dedicated computer program for INAA mode optimization was used [74]. All prostate samples for INAA-SLR were prepared in duplicate and mean values of chemical element contents were used in final calculation. For elements investigated by INAA-SLR and ICP-AES the mean of all results was used. Using the Microsoft Office Excel software, the summary of statistics, arithmetic mean, standard deviation, standard error of mean, minimum and maximum values, median, percentiles with 0.025 and 0.975 levels was calculated for chemical element mass fraction in normal, benign hyperplastic and cancerous prostate tissue. The difference in the results between BPH and Norm, PCa and Norm, and PCA and BPH was evaluated by Student’s t-test. For the construction of “individual data sets for chemical element mass fraction in normal, benign hypertrophic and cancerous prostate” diagrams the Microsoft Office Excel software was also used.

Results

Table 1 depicts certain statistical parameters (arithmetic mean, standard deviation, standard error of mean, minimal and maximal values, median, percentiles with 0.025 and 0.975 levels) of the Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn contents in normal, benign hypertrophic and cancerous prostate.

The ratios of means and the difference between mean values of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fraction in normal, benign hypertrophic and cancerous prostate are presented in Table 2.

The comparison of our results with published data for Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fraction in normal, benign hypertrophic and cancerous prostate is shown in Table 3.

Table 4 contains parameters of the importance (sensitivity, specificity and accuracy) of Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fraction for the diagnosis of PCa calculated in this work.

Figures 1 and 2 depict individual data sets for Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fraction and  for Ca∙S∙Zn test in all samples of normal, benign hypertrophic and cancerous prostate, respectively.

Discussion

As was shown by us [18,22,47]  the use of CRM IAEA H-4, INCT-SBF-4 Soya Bean Flour, INCT-TL-1 Tea Leaves, and INCT-MPH-2 Mixed Polish Herbs as certified reference materials for the analysis of samples of prostate tissue can be seen as quite acceptable. Good agreement of the Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn contents analyzed by INAA-SLR and ICP-AES with the certified data of reference materials indicates an acceptable accuracy of the results obtained in the study of chemical elements of the prostate samples presented in Tables 1–3.

Table 1. Some statistical parameters of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fractions (mg/kg, dry mass basis) in normal, benign hyperplastic (BPH), and cancerous (PCa) prostate

Tissue

Element

Mean

SD

SEM

Min

Max

Median

Per.0.025

Per.0.975

Normal

Al

34.1

17.7

3.5

9.60

73.3

28.9

11.9

70.8

n=37

B

1.04

0.86

0.18

0.30

3.0

0.70

0.30

2.89

 

Ba

1.53

1.00

0.21

0.38

4.33

1.18

0.42

3.75

 

Br

32.9

17.7

3.6

12.5

80.7

28.2

12.6

70.9

 

Ca

2428

1232

233

1180

6893

2195

1197

5553

 

Cu

9.85

4.65

0.97

4.10

22.2

8.30

4.98

19.8

 

Fe

132

40

7.0

62.0

218

133

67.6

212

 

K

11650

2340

434

6325

18198

11403

7352

15489

 

Li

0.0419

0.0264

0.0055

0.0150

0.101

0.0300

0.0161

0.100

 

Mg

1071

409

76

447

2060

1017

520

1955

 

Mn

1.32

0.42

0.09

0.750

2.80

1.30

0.836

2.23

 

Na

10987

2158

393

6415

15300

10911

6718

15151

 

P

7617

1839

368

5969

14838

7225

6017

11741

 

S

8657

1271

254

5662

12567

8569

6680

11366

 

Si

101

55

11

32.3

235

94.1

37.0

205

 

Sr

2.34

1.86

0.38

0.87

8.10

1.47

0.916

6.43

 

Zn

1061

933

153

223

5868

983

251

2342

BPH

Al

24.4

10.2

3.2

8.40

38.2

25.6

10.0

38.2

n=32

B

1.51

0.79

0.26

0.700

3.20

1.20

0.760

3.02

 

Ba

1.22

0.68

0.20

0.420

2.32

0.970

0.468

2.24

 

Br

30.7

17.2

3.4

5.50

77.0

26.2

5.75

63.8

 

Ca

2032

547

165

1168

2762

1898

1173

2757

 

Cu

9.86

3.96

1.25

6.00

18.9

8.30

6.25

17.9

 

Fe

131

66

12

56.5

376

116

60.6

279

 

K

14471

2454

740

11683

20519

13552

12025

19744

 

Li

0.039

0.024

0.007

0.013

0.088

0.030

0.014

0.086

 

Mg

1201

276

83

687

1585

1263

749

1552

 

Mn

1.19

0.31

0.09

0.800

1.80

1.20

0.800

1.73

 

Na

11612

2882

869

7762

15503

10564

7893

15400

 

P

7907

1385

418

6279

11780

7547

6512

10888

 

S

8787

1616

487

7671

13507

8289

7726

12401

 

Si

141

79

24

72.1

333

102

73.1

307

 

Sr

3.69

1.84

0.45

1.60

8.30

3.40

1.76

7.66

 

Zn

1297

725

119

312

4432

1173

325

2642

PCa

Al

328

243

73

43.5

765

310

47.9

736

n=60

B

12.6

11.7

3.7

1.50

43.2

8.40

2.15

37.4

 

Ba

26.7

25.1

7.6

1.83

72.3

20.1

1.95

69.4

 

Br

99.9

42.5

8.9

16.0

177

102

17.2

174

 

Ca

674

193

58

382

952

751

411

931

 

Cu

17.1

8.6

2.0

4.50

30.6

12.8

6.21

30.5

 

Fe

171

105

15

35.0

472

137

45.0

424

 

K

8542

1672

504

6047

11833

8784

6270

11402

 

Li

0.251

0.181

0.054

0.040

0.550

0.240

0.0433

0.545

 

Mg

346

193

61

136

632

313

138

624

 

Mn

6.99

4.49

1.35

1.00

16.2

5.80

1.33

15.0

 

Na

7511

2133

643

3913

12239

7228

4420

11539

 

P

6675

1542

465

2845

8546

6900

3553

8489

 

S

5343

1290

389

3394

7241

5022

3541

7238

 

Si

284

128

39

83.0

535

342

94.0

490

 

Sr

5.75

2.00

0.60

2.10

9.20

5.50

2.63

8.98

 

Zn

136

73

9.9

27.0

327

119

39.0

309

M: arithmetic mean, SD: standard deviation; SEM: standard error of mean, Min: minimum value, Max: maximum value, Per. 0.025: percentile with 0.025 level, Per. 0.975: percentile with 0.975 level.

Table 2. Ratio of means and the reliability of difference between mean values of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fractions in normal (N), benign hypertrophic (BPH) and cancerous prostate (PCa)

Mass fraction ratio

BPH  and Normal

PCa and Normal

PCa and BPH

Student’s

t-test, p=

Ratio

BPH/N 

Student’s

t-test, p=

Ratio

PCa/N

Student’s

t-test, p=

Ratio

PCa/BPH

Al

0.052

0.716

0.0025

9.62

0.0020

13.4

B

0.160

1.45

0.012

12.1

0.015

8.34

Ba

0.39

0.797

0.0076

17.5

0.0071

21.9

Br

0.65

0.933

0.0000001

3.04

0.00000006

3.25

Ca

0.17

0.837

0.00000004

0.278

0.000004

0.332

Cu

0.99

1.00

0.0027

1.74

0.0044

1.73

Fe

0.95

0.992

0.025

1.30

0.046

1.31

K

0.0042

1.24

0.00008

0.733

0.000004

0.590

Li

0.71

0.931

0.0032

5.99

0.0029

6.44

Mg

0.26

1.12

0.00000002

0.323

0.0000002

0.288

Mn

0.32

0.902

0.0019

5.30

0.0016

5.87

Na

0.52

1.06

0.00022

0.684

0.0013

0.647

P

0.61

1.04

0.13

0.876

0.063

0.844

S

0.82

1.02

0.0000009

0.617

0.00002

0.608

Si

0.16

1.40

0.00075

2.81

0.0060

2.01

Sr

0.027

1.58

0.00015

2.46

0.013

1.56

Zn

0.23

1.22

0.0000006

0.128

0.00000000001

0.105

Statistically significant values (p ≤ 0.05) are in bold.

Table 3. Median, minimum and maximum value of means of chemical element contents (mg/kg, dry mass basis) in normal, benign hyperplastic (BPH), and cancerous (PCa) prostate according to data from the literature in comparison with our results

Prostate

 tissue

Element

 

Published data [Reference]

This work

Median of means

(n)a

Minimum of means

M or M ± SD, (n)b

Maximum of means

M or M ± SD, (n)b

 

M ± SD

Normal

Al

34.2 (6)

13 ± 66  (50) [31]

59 (9) [32]

34.1 ± 17.7

 

B

1.0 (10)

<0.47  (50) [31]

1.2  (1) [33]

1.04 ± 0.86

 

Ba

1.75 (10)

0.12 (50) [31]

102 ± 82 (10) [34]

1.53 ± 1.00

 

Br

30.0 (18)

14 ± 9 (4) [35]

50 ± 32 (10) [36]

32.9 ± 17.7

 

Ca

1990 (22)

427 ± 117  (21) [37]

7500 ± 12300 (57) [38]

2428 ± 1232

 

Cu

9.6 (28)

1.37  (-) [39]

1488 ± 47 (10) [40]

9.85 ± 4.65

 

Fe

118 (34)

5.7 ± 0.1 (5)  [41]

1224 ± 76 (10) [40]

132 ± 40

 

K

11800(20)

4360 ± 364 (27) [42]

13000 ± 660  (16) [43]

11650 ± 2340

 

Li

-

-

-

0.042 ± 0.026

 

Mg

1020 (21)

498 ± 172 (13) [38]

2056 ± 476 (21) [37]

1071 ± 409

 

Mn

1.48 (24)

<0.47 (12) [44]

106 ± 18 (5) [45]

1.32 ± 0.42

 

Na

10500(16)

23 ± 26 (13[38]

13700 ± 3500 (4) [46]

10987 ± 2158

 

P

7120 (15)

2060 ± 690 (13) [38]

14500 (12) [44]

7617 ± 1839

 

S

7370 (6)

5300 ± 750 (57) [38]

8810 ± 730 (16) [47]

8657 ± 1271

 

Si

100 (6)

51 (1) [48] 

111 ± 64 (64) [18]

101 ± 55

 

Sr

1.46 (13)

0.75 ± 0.09 (48) [31]

2.61 ± 3.07 (27) [17]

2.34 ± 1.86

 

Zn

525 (75)

101 (1) [49]

3218 ± 41  (10) [40]

1061 ± 933

BPH

Al

-

-

-

24.4 ± 10.2

 

B

-

-

-

1.51 ± 0.79

 

Ba

-

-

-

1.22 ± 0.68

 

Br

23.3 (2)

18 ± 9 (27) [42]

21.5 ± 13 (9) [50]

30.7 ± 17.2

 

Ca

3100 (6)

1000 (34) [51]

5100 ± 3200 (9) [52]

2032 ± 547

 

Cu

15 (12)

3 ± 1 (7) [53]

885 ± 80 (10) [40]

9.86 ± 3.96

 

Fe

197 (10)

5.9 ± 0.4 (8) [41]

1345 ± 95 (27) [42]

131 ± 66

 

K

7400 (5)

1010 ± 100 (27) [42]

12800 ± 1900 (43) [54]

14471 ± 2454

 

Li

-

-

-

0.039 ± 0.024

 

Mg

820 (7)

566 ± 130 (25) [55]

1560 ± 50 (10) [56]

1201 ± 276

 

Mn

9 (4)

6.5 (-) [57]

23 ± 13 (27) [42]

1.19 ± 0.31

 

Na

7800 (1)

7800 (34) [51]

7800 (34) [51]

11612 ± 2882

 

P

7600 (3)

7590 ± 1120 (43) [54]

19300 ± 14300 (9) [52]

7907 ± 1385

 

S

37400 (1)

37400 ± 2100 (9) [52]

37400 ± 2100 (9) [52]

8787 ± 1616

 

Si

-

-

141 ± 79

 

Sr

4.4 (2)

3.8 ± 0.6 (43) [50]

5.0 ± 3.0  (10) [36]

3.69 ± 1.84

 

Zn

725 (39)

55 ± 25 (23) [58]

3800 ± 65 (10) [56]

1297 ± 725

PCa

Al

-

-

-

328 ± 243

 

B

1.78 (1)

1.78 ± 0.65 (23) [59]

1.78 ± 0.65 (23) [59]

12.6 ± 11.7

 

Ba

-

-

-

26.7 ± 25.1

 

Br

1.5 (1)

1.5 ± 0.6 (27) [42]

1.5 ± 0.6 (27) [42]

99.9 ± 42.5

 

Ca

1830 (10)

658 ± 109 (12) [52]

11200 (1) [60]

674 ± 193

 

Cu

13 (14)

4.0 ± 3.0 (11) [53]

1930 ± 65 (10) [40]

17.1 ± 8.6

 

Fe

195 (15)

12.5 ± 5.0 (20) [58]

6850 (1) [60]

171 ± 105

 

K

5600 (5)

740 ± 90 (27) [42]

18100 ± 400 (4) [61]

8542 ± 1672

 

Li

-

-

-

0.251 ± 0.181

 

Mg

935 (5)

361 ± 174 (25) [55]

1050 ± 720 (11) [53]

346 ± 193

 

Mn

17.3 (6)

8.0 ± 2.0 (3) [62]

160 ± 22 (5) [45]

6.99 ± 4.49

 

Na

5100 (1)

5100 (4) [63]

5100 (4) [63]

7511 ± 2133

 

P

5400 (3)

3620 ± 680 (12) [52]

7700 ± 3900 (12) [54]

6675 ± 1542

 

S

6900 (1)

6900 ± 1100(12)[ 52]

6900 ± 1100 (12) [52]

5343 ± 1290

 

Si

-

-

-

284 ± 128

 

Sr

-

-

-

5.75 ± 2.00

 

Zn

200 (44)

16.7 ± 3.5 (3) [62]

840 ± 85 (13) [64]

136 ± 73

M: arithmetic mean, SD: standard deviation, (n)a: number of all references, (n)b: number of samples.

The mean values and all selected statistical parameters were calculated for seventeen (Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn chemical element mass fractions (Table 1). The mass fraction of these chemical elements were measured in all, or a major portion of normal prostate samples. The masses of BPH and PCa samples varied very strong from a few milligrams (sample from needle biopsy material) to 100 mg (sample from resected material). Therefore, in BPH and PCa prostates mass fractions of Zn, Fe and Br were measured in all, or a major portion of samples, mass fractions of Cu - in 29 samples (19 and 10 samples, respectively), mass fractions of Sr  - in 28 samples (17 and 11 samples, respectively), while mass fractions of other chemical elements were determined in 22 samples (11 BPH and 11 PCa samples, respectively).

From Table 2, it is observed that in benign hypertrophic tissues the mass fractions of Al, B, Ba, Br, Ca, Cu, Fe, Li, Mg, Mn, Na, P, S, Si, and Zn not differ from normal levels while the mass fraction of K and Sr are significantly higher. In cancerous tissue the mass fractions of Ca, K, Mg, Na, S, and Zn are significantly lower, and mass fractions of Al, B, Ba, Br, Cu, Fe, Li, Mn, Si, and Sr are significantly higher than in normal tissues of the prostate. All these elements show similar variations in cancerous tissues when compared with benign hypertrophic tissues of the prostate.

The results for all chemical element contents in the prostates of the control group (mean age 55 ± 11 years, range 41-87) are in accordance with our earlier findings in prostates of apparently healthy men aged 41-60 [18]. Mean values obtained for Al, B, Ba, Br, Ca, Cu, Fe, K, Mg, Mn, Na, P, S, Si, Sr, and Zn contents (Table 3) agree well with median of mean values cited by other researches for the normal human prostate [31-49]. Data of the literature also includes samples obtained from patients who died from different diseases.  A number of values for chemical element mass fractions were not expressed on a dry mass basis in the cited literature. Therefore, we calculated these values using published data for water - 80% [56] and ash - 1% on wet mass basis [75] contents in the prostate of adult men. Our results for Br, Ca, Cu, Fe, Mg, P, Sr, and Zn are in accordance with the medians of earlier findings in benign hypertrophic prostate, some higher for  K and Na and some lower for Mn and S (Table 3). In cancerous prostate our results were comparable with published data for Ca, Cu, Fe, K, Na, P, S, and Zn contents, some lover for Mg and Mn, and almost one and two orders of magnitude higher for B and Br, respectively (Table 3). No published data referring to Li mass fractions in normal prostate, Al, B, Ba, Li, and Si in BPH prostate, and Al, Ba, Li, Si, and Sr in cancerous prostate were found.

Analysis of chemical element mass fraction in prostate tissue could become a powerful diagnostic tool. To a large extent, the resumption of the search for new methods for early diagnosis of PCa was due to experience gained in a critical assessment of the limited capacity of the prostate specific antigen (PSA) serum test [76]. In addition to the PSA serum test and morphological study of needle-biopsy cores of the prostate, the development of other highly precise testing methods seems to be very useful. Experimental conditions of the present study were approximated to the hospital conditions as closely as possible. In BPH and PCa cases we analyzed a part of the material obtained from a puncture transrectal biopsy of the indurated site in the prostate. Therefore, our data allow us to evaluate adequately the importance of chemical element mass fraction for the diagnosis of PCa. As is evident from Table 2 and, particularly, from individual data sets (Figure 1), the Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fraction are potentially the most informative test for a differential diagnosis. For example, if 1060 mg/kg (M ± 2SD) is the value of Ca mass fraction assumed to be the upper limit for PCa (Figure 1) and an estimation is made for “PCa or intact and BPH tissue”, the following values are obtained:

Sensitivity = {True Positives (TP)/[TP + False Negatives (FN)]} ·100% = 100-9%;

Specificity = {True Negatives (TN)/[TN + False Positives (FP)]} ·100% = 100-2%;

Accuracy = [(TP+TN)/(TP+FP+TN+FN)] ·100% = 100-2%.

Figure 1. Individual data sets for Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fractions in samples of normal (1), benign hypertrophic (2) and cancerous (3) prostate.

The number of people (samples) examined was taken into account for calculation of confidence intervals [77].  In other words, if Ca mass fraction in a prostate biopsy sample does not exceed 1060 mg/kg, one could diagnose a malignant tumor with accuracy 100-2%. Thus, using the Ca mass fraction-test makes it possible to diagnose cancer in 100-2%; cases (sensitivity). The same way parameters of the importance (sensitivity, specificity and accuracy) of Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fraction for the diagnosis of PCa were calculated (Table 5).

It should be noted, that the Ca, S, and Zn mass fraction are the most informative for the diagnosis of PCa and these tests have very good levels of sensitivity, specificity and accuracy (Table 4). However, it is possible to increase a separation distance between the value of “Upper limit” for PCa and the lowest values among normal and BPH results if use a combination of the Ca, S, and Zn mass fraction. For example, for this purpose a multiplication of Ca, S, and Zn mass fraction normalized to the appropriate mean values for normal prostate can be used:

 Ca∙S∙Zn=(Cai/2428)∙(Si/8657)∙(Zni/1061),                                     (1)

were Cai, Si, and Zni are individual mass fraction of Ca, S, and Zn (mg/kg on dry mass basis) in normal, BPH and cancerous prostate. If the level 0.095 was accepted as the “Upper limit” of Ca∙S∙Zn test for the diagnosis of PCa (Figure 2), the sensitivity, specificity and accuracy of this test are 100-9%, 100-2%, and 100-2%, respectively and the lowest value in normal and BPH prostate (0.136) is 1.43 time higher the highest value in cancerous prostate.

Table 4. Parameters of the importance (sensitivity, specificity and accuracy) of Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fractions for the diagnosis of PCa (an estimation is made for “PCa or normal and BPH tissue”)

Element

Limit for PCa

mg/kg, dry mass basis

Sensitivity

%

Specificity

%

Accuracy 

%

Al

85 mg/kg - Lower limit

73 ± 14

100-3

94 ± 4

B

3.9 mg/kg - Lower limit

90 ± 10

100-3

98 ± 2

Ba

4.5 mg/kg - Lower limit

82 ± 12

100-3

96 ± 3

Ca

1060 mg/kg - Upper limit

100-9

100-2

100-2

Mg

600 mg/kg - Upper limit

90 ± 10

95 ± 4

94 ± 3

Mn

2.0 mg/kg - Lower limit

91 ± 9

97 ± 3

96 ± 3

S

7250 mg/kg - Upper limit

100-9

97 ± 3

98 ± 2

Zn

330 mg/kg - Upper limit

100-2

92 ± 3

96 ± 2

M: arithmetic mean, SD: standard deviation.

Figure 2. Individual data sets for Ca∙S∙Zn test in samples of normal (1), benign hypertrophic (2) and cancerous (3) prostate: Ca∙S∙Zn=(Cai/2428)∙(Si/8657)∙(Zni/1061), were Cai, Si, and Zni are individual mass fraction of Ca, S, and Zn (mg/kg on dry mass basis).

Conclusion

The combination of nondestructive INAA-SLR and destructive ICP-AES methods is satisfactory analytical tool for the precise determination of 17 chemical element mass fractions in the tissue samples of normal, BPH and  carcinomatous prostate glands. The sequential application of two methods allowed precise quantitative determinations of mean mass fraction of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn. It was observed that the mass fractions of all chemical elements investigated in the study with the exception of P show significant variations in cancerous tissues when compared with normal and BPH prostate. The contents of Ca, K, Mg, Na, S, and Zn were significantly lower and those of Al, B, Ba, Br, Cu, Fe, Li, Mn, Si, and Sr were significantly higher in cancerous tissues than in normal and BPH tissues. Finally, we propose to use the Ca, S, and Zn mass fraction in a needle-biopsy core as well as Ca∙S∙Zn test as an accurate tool to diagnose prostate cancer. Further studies on larger number of samples are required to confirm our findings, to study the impact of the chemical element contents on prostate cancer etiology and to examine the long-term pathological outcome.

Acknowledgements

We are grateful to Dr. Tatyana Sviridova, Medical Radiological Research Center, Obninsk, and to the late Prof. A.A. Zhavoronkov, Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, for supplying prostate samples. We are also grateful to Dr. Karandaschev V., Dr. Nosenko S., and Moskvina I., Institute of Microelectronics Technology and High Purity Materials, Chernogolovka, Russia, for their help in ICP-AES analysis.

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Editorial Information

Editor-in-Chief

Vicente Notario
Georgetown University Medical Center

Article Type

Research Article

Publication history

Received date: October 04, 2016
Accepted date: October 19, 2016
Published date: October 22, 2016

Copyright

© 2016 Zaichick V. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Zaichick V, Zaichick S (2016) Distinguishing malignant from benign prostate using content of 17 chemical elements in prostatic tissue. Integr Cancer Sci Therap. 3: DOI: 10.15761/ICST.1000208.

Corresponding author

V. Zaichick

Radionuclide Diagnostics Department, Medical Radiological Research Centre, 4, Koroleyva St., MRRC, Obninsk 249036, Russia, Tel: +7 (48439) 60289, Fax: +7 (495) 956 1440.

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1. . Individual data sets for Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fractions in samples of normal (1), benign hypertrophic (2) and cancerous (3) prostate.

Figure 2. Individual data sets for Ca∙S∙Zn test in samples of normal (1), benign hypertrophic (2) and cancerous (3) prostate: Ca∙S∙Zn=(Cai/2428)∙(Si/8657)∙(Zni/1061), were Cai, Si, and Zni are individual mass fraction of Ca, S, and Zn (mg/kg on dry mass basis).

Table 1. Some statistical parameters of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fractions (mg/kg, dry mass basis) in normal, benign hyperplastic (BPH), and cancerous (PCa) prostate

Tissue

Element

Mean

SD

SEM

Min

Max

Median

Per.0.025

Per.0.975

Normal

Al

34.1

17.7

3.5

9.60

73.3

28.9

11.9

70.8

n=37

B

1.04

0.86

0.18

0.30

3.0

0.70

0.30

2.89

 

Ba

1.53

1.00

0.21

0.38

4.33

1.18

0.42

3.75

 

Br

32.9

17.7

3.6

12.5

80.7

28.2

12.6

70.9

 

Ca

2428

1232

233

1180

6893

2195

1197

5553

 

Cu

9.85

4.65

0.97

4.10

22.2

8.30

4.98

19.8

 

Fe

132

40

7.0

62.0

218

133

67.6

212

 

K

11650

2340

434

6325

18198

11403

7352

15489

 

Li

0.0419

0.0264

0.0055

0.0150

0.101

0.0300

0.0161

0.100

 

Mg

1071

409

76

447

2060

1017

520

1955

 

Mn

1.32

0.42

0.09

0.750

2.80

1.30

0.836

2.23

 

Na

10987

2158

393

6415

15300

10911

6718

15151

 

P

7617

1839

368

5969

14838

7225

6017

11741

 

S

8657

1271

254

5662

12567

8569

6680

11366

 

Si

101

55

11

32.3

235

94.1

37.0

205

 

Sr

2.34

1.86

0.38

0.87

8.10

1.47

0.916

6.43

 

Zn

1061

933

153

223

5868

983

251

2342

BPH

Al

24.4

10.2

3.2

8.40

38.2

25.6

10.0

38.2

n=32

B

1.51

0.79

0.26

0.700

3.20

1.20

0.760

3.02

 

Ba

1.22

0.68

0.20

0.420

2.32

0.970

0.468

2.24

 

Br

30.7

17.2

3.4

5.50

77.0

26.2

5.75

63.8

 

Ca

2032

547

165

1168

2762

1898

1173

2757

 

Cu

9.86

3.96

1.25

6.00

18.9

8.30

6.25

17.9

 

Fe

131

66

12

56.5

376

116

60.6

279

 

K

14471

2454

740

11683

20519

13552

12025

19744

 

Li

0.039

0.024

0.007

0.013

0.088

0.030

0.014

0.086

 

Mg

1201

276

83

687

1585

1263

749

1552

 

Mn

1.19

0.31

0.09

0.800

1.80

1.20

0.800

1.73

 

Na

11612

2882

869

7762

15503

10564

7893

15400

 

P

7907

1385

418

6279

11780

7547

6512

10888

 

S

8787

1616

487

7671

13507

8289

7726

12401

 

Si

141

79

24

72.1

333

102

73.1

307

 

Sr

3.69

1.84

0.45

1.60

8.30

3.40

1.76

7.66

 

Zn

1297

725

119

312

4432

1173

325

2642

PCa

Al

328

243

73

43.5

765

310

47.9

736

n=60

B

12.6

11.7

3.7

1.50

43.2

8.40

2.15

37.4

 

Ba

26.7

25.1

7.6

1.83

72.3

20.1

1.95

69.4

 

Br

99.9

42.5

8.9

16.0

177

102

17.2

174

 

Ca

674

193

58

382

952

751

411

931

 

Cu

17.1

8.6

2.0

4.50

30.6

12.8

6.21

30.5

 

Fe

171

105

15

35.0

472

137

45.0

424

 

K

8542

1672

504

6047

11833

8784

6270

11402

 

Li

0.251

0.181

0.054

0.040

0.550

0.240

0.0433

0.545

 

Mg

346

193

61

136

632

313

138

624

 

Mn

6.99

4.49

1.35

1.00

16.2

5.80

1.33

15.0

 

Na

7511

2133

643

3913

12239

7228

4420

11539

 

P

6675

1542

465

2845

8546

6900

3553

8489

 

S

5343

1290

389

3394

7241

5022

3541

7238

 

Si

284

128

39

83.0

535

342

94.0

490

 

Sr

5.75

2.00

0.60

2.10

9.20

5.50

2.63

8.98

 

Zn

136

73

9.9

27.0

327

119

39.0

309

M: arithmetic mean, SD: standard deviation; SEM: standard error of mean, Min: minimum value, Max: maximum value, Per. 0.025: percentile with 0.025 level, Per. 0.975: percentile with 0.975 level.

Table 2. Ratio of means and the reliability of difference between mean values of Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fractions in normal (N), benign hypertrophic (BPH) and cancerous prostate (PCa)

Mass fraction ratio

BPH  and Normal

PCa and Normal

PCa and BPH

Student’s

t-test, p=

Ratio

BPH/N 

Student’s

t-test, p=

Ratio

PCa/N

Student’s

t-test, p=

Ratio

PCa/BPH

Al

0.052

0.716

0.0025

9.62

0.0020

13.4

B

0.160

1.45

0.012

12.1

0.015

8.34

Ba

0.39

0.797

0.0076

17.5

0.0071

21.9

Br

0.65

0.933

0.0000001

3.04

0.00000006

3.25

Ca

0.17

0.837

0.00000004

0.278

0.000004

0.332

Cu

0.99

1.00

0.0027

1.74

0.0044

1.73

Fe

0.95

0.992

0.025

1.30

0.046

1.31

K

0.0042

1.24

0.00008

0.733

0.000004

0.590

Li

0.71

0.931

0.0032

5.99

0.0029

6.44

Mg

0.26

1.12

0.00000002

0.323

0.0000002

0.288

Mn

0.32

0.902

0.0019

5.30

0.0016

5.87

Na

0.52

1.06

0.00022

0.684

0.0013

0.647

P

0.61

1.04

0.13

0.876

0.063

0.844

S

0.82

1.02

0.0000009

0.617

0.00002

0.608

Si

0.16

1.40

0.00075

2.81

0.0060

2.01

Sr

0.027

1.58

0.00015

2.46

0.013

1.56

Zn

0.23

1.22

0.0000006

0.128

0.00000000001

0.105

Statistically significant values (p ≤ 0.05) are in bold.

Table 3. Median, minimum and maximum value of means of chemical element contents (mg/kg, dry mass basis) in normal, benign hyperplastic (BPH), and cancerous (PCa) prostate according to data from the literature in comparison with our results

Prostate

 tissue

Element

 

Published data [Reference]

This work

Median of means

(n)a

Minimum of means

M or M ± SD, (n)b

Maximum of means

M or M ± SD, (n)b

 

M ± SD

Normal

Al

34.2 (6)

13 ± 66  (50) [31]

59 (9) [32]

34.1 ± 17.7

 

B

1.0 (10)

<0.47  (50) [31]

1.2  (1) [33]

1.04 ± 0.86

 

Ba

1.75 (10)

0.12 (50) [31]

102 ± 82 (10) [34]

1.53 ± 1.00

 

Br

30.0 (18)

14 ± 9 (4) [35]

50 ± 32 (10) [36]

32.9 ± 17.7

 

Ca

1990 (22)

427 ± 117  (21) [37]

7500 ± 12300 (57) [38]

2428 ± 1232

 

Cu

9.6 (28)

1.37  (-) [39]

1488 ± 47 (10) [40]

9.85 ± 4.65

 

Fe

118 (34)

5.7 ± 0.1 (5)  [41]

1224 ± 76 (10) [40]

132 ± 40

 

K

11800(20)

4360 ± 364 (27) [42]

13000 ± 660  (16) [43]

11650 ± 2340

 

Li

-

-

-

0.042 ± 0.026

 

Mg

1020 (21)

498 ± 172 (13) [38]

2056 ± 476 (21) [37]

1071 ± 409

 

Mn

1.48 (24)

<0.47 (12) [44]

106 ± 18 (5) [45]

1.32 ± 0.42

 

Na

10500(16)

23 ± 26 (13[38]

13700 ± 3500 (4) [46]

10987 ± 2158

 

P

7120 (15)

2060 ± 690 (13) [38]

14500 (12) [44]

7617 ± 1839

 

S

7370 (6)

5300 ± 750 (57) [38]

8810 ± 730 (16) [47]

8657 ± 1271

 

Si

100 (6)

51 (1) [48] 

111 ± 64 (64) [18]

101 ± 55

 

Sr

1.46 (13)

0.75 ± 0.09 (48) [31]

2.61 ± 3.07 (27) [17]

2.34 ± 1.86

 

Zn

525 (75)

101 (1) [49]

3218 ± 41  (10) [40]

1061 ± 933

BPH

Al

-

-

-

24.4 ± 10.2

 

B

-

-

-

1.51 ± 0.79

 

Ba

-

-

-

1.22 ± 0.68

 

Br

23.3 (2)

18 ± 9 (27) [42]

21.5 ± 13 (9) [50]

30.7 ± 17.2

 

Ca

3100 (6)

1000 (34) [51]

5100 ± 3200 (9) [52]

2032 ± 547

 

Cu

15 (12)

3 ± 1 (7) [53]

885 ± 80 (10) [40]

9.86 ± 3.96

 

Fe

197 (10)

5.9 ± 0.4 (8) [41]

1345 ± 95 (27) [42]

131 ± 66

 

K

7400 (5)

1010 ± 100 (27) [42]

12800 ± 1900 (43) [54]

14471 ± 2454

 

Li

-

-

-

0.039 ± 0.024

 

Mg

820 (7)

566 ± 130 (25) [55]

1560 ± 50 (10) [56]

1201 ± 276

 

Mn

9 (4)

6.5 (-) [57]

23 ± 13 (27) [42]

1.19 ± 0.31

 

Na

7800 (1)

7800 (34) [51]

7800 (34) [51]

11612 ± 2882

 

P

7600 (3)

7590 ± 1120 (43) [54]

19300 ± 14300 (9) [52]

7907 ± 1385

 

S

37400 (1)

37400 ± 2100 (9) [52]

37400 ± 2100 (9) [52]

8787 ± 1616

 

Si

-

-

141 ± 79

 

Sr

4.4 (2)

3.8 ± 0.6 (43) [50]

5.0 ± 3.0  (10) [36]

3.69 ± 1.84

 

Zn

725 (39)

55 ± 25 (23) [58]

3800 ± 65 (10) [56]

1297 ± 725

PCa

Al

-

-

-

328 ± 243

 

B

1.78 (1)

1.78 ± 0.65 (23) [59]

1.78 ± 0.65 (23) [59]

12.6 ± 11.7

 

Ba

-

-

-

26.7 ± 25.1

 

Br

1.5 (1)

1.5 ± 0.6 (27) [42]

1.5 ± 0.6 (27) [42]

99.9 ± 42.5

 

Ca

1830 (10)

658 ± 109 (12) [52]

11200 (1) [60]

674 ± 193

 

Cu

13 (14)

4.0 ± 3.0 (11) [53]

1930 ± 65 (10) [40]

17.1 ± 8.6

 

Fe

195 (15)

12.5 ± 5.0 (20) [58]

6850 (1) [60]

171 ± 105

 

K

5600 (5)

740 ± 90 (27) [42]

18100 ± 400 (4) [61]

8542 ± 1672

 

Li

-

-

-

0.251 ± 0.181

 

Mg

935 (5)

361 ± 174 (25) [55]

1050 ± 720 (11) [53]

346 ± 193

 

Mn

17.3 (6)

8.0 ± 2.0 (3) [62]

160 ± 22 (5) [45]

6.99 ± 4.49

 

Na

5100 (1)

5100 (4) [63]

5100 (4) [63]

7511 ± 2133

 

P

5400 (3)

3620 ± 680 (12) [52]

7700 ± 3900 (12) [54]

6675 ± 1542

 

S

6900 (1)

6900 ± 1100(12)[ 52]

6900 ± 1100 (12) [52]

5343 ± 1290

 

Si

-

-

-

284 ± 128

 

Sr

-

-

-

5.75 ± 2.00

 

Zn

200 (44)

16.7 ± 3.5 (3) [62]

840 ± 85 (13) [64]

136 ± 73

M: arithmetic mean, SD: standard deviation, (n)a: number of all references, (n)b: number of samples.

Table 4. Parameters of the importance (sensitivity, specificity and accuracy) of Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fractions for the diagnosis of PCa (an estimation is made for “PCa or normal and BPH tissue”)

Element

Limit for PCa

mg/kg, dry mass basis

Sensitivity

%

Specificity

%

Accuracy 

%

Al

85 mg/kg - Lower limit

73 ± 14

100-3

94 ± 4

B

3.9 mg/kg - Lower limit

90 ± 10

100-3

98 ± 2

Ba

4.5 mg/kg - Lower limit

82 ± 12

100-3

96 ± 3

Ca

1060 mg/kg - Upper limit

100-9

100-2

100-2

Mg

600 mg/kg - Upper limit

90 ± 10

95 ± 4

94 ± 3

Mn

2.0 mg/kg - Lower limit

91 ± 9

97 ± 3

96 ± 3

S

7250 mg/kg - Upper limit

100-9

97 ± 3

98 ± 2

Zn

330 mg/kg - Upper limit

100-2

92 ± 3

96 ± 2

M: arithmetic mean, SD: standard deviation.