Journal Article Page
Jump to
European Urology
Volume 48, issue 1, pages 1-178, July 2005Prostate Cancer
Insulin-like Growth Factor 1, Chromogranin A and Prostate Specific Antigen Serum Levels in Prostate Cancer Patients and Controls
Martin Marszalek a b, Johann Wachter a b, Anton Ponholzer a b, Thomas Leitha c, Michael Rauchenwald a b, Stephan Madersbacher a b * 
.
Accepted 14 March 2005, Published online 2 April 2005, pages 34 - 39
Abstract Full-Text PDF (245 KB) Create Platinum Slide Series Place a comment
Abstract
Objective:
Insulin-like growth factor 1 (IGF-1) and chromogranin A (CGA) are currently discussed as supplemental serum markers for prostate cancer (PC) diagnosis. To address this issue we determined serum levels of IGF-1, CGA and PSA in men with newly diagnosed PC and controls.
Methods:
A consecutive series of 156 men (median age: 67 yrs) with newly diagnosed, untreated PC and 271 controls (69 yrs) were recruited. The diagnosis of PC was made by transrectal ultrasound guided biopsies only. In controls, the presence of PC was excluded by digito-rectal examination, serum prostate specific antigen (PSA) levels by using age-specific reference values and–if indicated–by transrectal ultrasound guided 12-core biopsies. Serum levels of IGF-1, CGA and PSA were compared between cases and controls and correlated to histopathological findings and age.
Results:
Serum PSA-levels were significantly higher in men with PC (49.6 ± 13.9 ng/ml, mean ± standard error of the mean; median: 7.0 ng/ml) than in controls (2.6 ± 0.2 ng/ml; median: 1.3 ng/ml) (p < 0.001). In contrast, serum levels of IGF-1 (PC: 166 ± 6.1 ng/ml, median: 155 ng/ml; controls: 159 ± 4.5 ng/ml, 153 ng/ml) and CGA (PC: 92 ± 7.4 U/l, median: 67 U/l; controls: 117 ± 12.0 U/l; median: 74 U/l) were identical in both groups (p > 0.05). Serum levels of IGF-1 and CGA revealed no correlation to serum PSA, Gleason score and number of positive biopsy cores. In the PC-cohort all three serum markers did not correlate with age. In controls, PSA (p = 0.018) and CGA (p < 0.001) correlated positively and IGF-1 (p < 0.001) negatively with age.
Conclusion:
Our data suggest that quantification of IGF-1 and CGA-serum levels provides no useful information in the diagnosis of PC.
Keywords: Insulin-like growth factor, Chromogranin A, Tumour marker, Prostate.
Article Outline
1. Introduction
Insulin-like growth factor 1 (IGF-1) is a growth hormone dependent polypeptide related to cell growth and differentiation [1]. IGF-1 is mainly produced in the liver in response to growth hormone secretion and regulates cell proliferation, differentiation and apoptosis in the prostate [2], and [3]. IGF-1 secretion seems to be modulated by prostate specific antigen (PSA) [4], and [5]. While prospective studies provided evidence for a relationship between circulating levels of both IGF-1 and IGF binding protein (IGFBP-3) and the risk for developing PC, the role of IGF-1 in the diagnosis of PC is controversially discussed [6], [7], and [8].
Chromogranin A (CGA) is increasingly accepted as a serum marker for neuroendocrine differentiation of malignant tumours of various origins. PC-cells can undergo neuroendocrine differentiation resulting in a release of CGA as a paracrine factor [9]. These cells are usually distinct from prostate basal and secretory cells and produce numerous hormonal factors besides CGA including serotonin, histamine, somatostatin and vascular endothelial growth factor. In a recent study, human prostate neuroendocrine cells were found to represent a cell lineage of their own, being of neurogenic origin and therefore distinct from the urogenital sinus-derived prostate secretory and basal cells [10], and [11]. Neuroendocrine cells invade the urogenital sinus around the 10th week of embryonal development [10], and [11]. Malignant differentiated neuroendocrine cell should be distinguished from normal prostatic neuroendocrine cells due to differences of cellular processes and morphologic features resembling adjacent cancer cells [10], and [11]. Studies on the role of CGA as a serum marker for PC are scant [12], [13], and [14].
Aim of our study was to assess the role of serum levels of CGA and IgF-1 in the diagnosis of PC. We therefore determined IGF-1 and CGA serum levels in men with newly diagnosed PC and controls and correlated these values to serum PSA-levels, histopathological findings and age.
2. Materials and methods
2.1. Patients
Men with newly diagnosed, untreated PC and, as controls, men without PC were included to this study. Diagnosis of PC was made by transrectal ultrasound guided 12-core biopsies in all patients. Tumour grading was determined by the Gleason score and tumours were categorized into well (Gleason score 2 to 5), moderately (Gleason score 6–7) and poorly differentiated (Gleason score 8–10) tumours. In controls, the presence of PC was excluded by a negative digito-rectal examination (DRE) and serum PSA-level using age-specific reference values: 40–49 yrs: 2.5 ng/ml, 50–59: 3.5 ng/ml, 60–69 yrs: 4.5 ng/ml, 70–79 yrs: 6.5 ng/ml [15]. If indicated a 12-core transrectal ultrasound guided biopsy of the prostate was performed. Overall, 13.5% of controls (n = 37) underwent a prostate biopsy prior study inclusion. Institutional review board approval was obtained and patients/controls gave informed consent.
2.2. Methods
All serum samples of PC-patients were obtained before prostate biopsy. Total and free PSA serum levels were assessed using PSA Total EIA II and PSA Free EIA assay (both manufactured by Roche Diagnostics GmbH; D-68298 Mannheim, Germany): Total PSA: intraassay variation: 1.8–2.7%, interassay variation: 2.9–5.7%; free PSA: intrassay variation: 1.2–3.2%; interassay variation: 1.3–2.2%. IGF-1 serum levels were determined using the DSL-5600 assay (Diagnostic Systems Laboratories Inc, TX-77598 Webster, Texas, USA): intraassay variation: 1.5–3.4%; interassay variation: 1.5–8.2%. CGA serum levels were quantified with the CGA-RIA CT assay (CIS bio international, F-91192 Gif/Yvette Cedex, France): intraassay variation: 2.2–6.0%; interassay variation: 5.3–8.5%.
2.3. Statistical analysis
All statistical analyses were conducted using Statistical Package for Social Sciences, version 8.0.0 (SPSS Inc., Chicago, IL). We used Spearman correlation coefficient and Kruskal Wallis H test to assess differences in marker serum levels between groups and correlation of marker serum levels with Gleason scores and age. All statistical tests were two sided and statistical significance was set as p < 0.05.
3. Results
3.1. Patient characteristics
A total of 427 men (66.9 ± 10.3 yrs; median 68 yrs) entered this study, 156 men (66.7 ± 7.7 yrs; median 67 yrs) with newly diagnosed PC and 271 controls (67.1 ± 11.6 yrs; median 69 yrs) (Table 1). Serum PSA levels were significantly higher in the PC-group (49.6 ± 13.9 ng/ml; range: 41325.4 ng/ml; median 7.0 ng/ml) as compared to controls (2.6 ± 0.2 ng/ml; range: 0.1–18.7 ng/ml; median 1.3 ng/ml; p < 0.001) (Table 1, Fig. 1). In the PC-group, serum PSA levels of less than 10 ng/ml were present in 66.0%, 10.1–20 ng/ml in 12.8% and above 20 ng/ml in 21.2% of patients (Table 1). PSA levels above the age-specific ranges were present in 14% of controls and in 76.2% of PC-patients. Free to total PSA ratio was significantly lower in the PC-group (12.6 ± 0.6%; range: 2.8–36.0%; median 11.4%) as compared to controls (20.7 ± 1.1%; range: 2.1–47.9%; median 19.5%; p < 0.001). Initial therapy was radical prostatectomy in 122 (78.2%) patients, brachytherapy with Palladium103 in one (0.6%) and androgen deprivation therapy with LHRH-antagonists in 33 patients (21.2%).
Table 1 Principal patient characteristics
| PC-patients | Controls | p-Value | |
|---|---|---|---|
| Age [yrs] | 67.0 ± 7.7 | 69.0 ± 11.6 | p = 0.71 |
| PSA [ng/ml] | 7.0 ± 13.9 | 1.3 ± 0.2 | p < 0.001 |
| <10 ng/ml | 66.0% | 95.9% | p < 0.001 |
| 10.1–20 ng/ml | 12.8% | 4.1% | p < 0.001 |
| >20 ng/ml | 21.2% | 0.0% | p < 0.001 |
| CGA [U/l] | 67.4 ± 7.4 | 73.8 ± 12.0 | p = 0.12 |
| IGF-1 [ng/ml] | 154.5 ± 6.0 | 153.0 ± 4.5 | p = 0.33 |
| Gleason score (biopsy results) | |||
| 2–5 | 19 (15.6%) | ||
| 6–7 | 79 (64.8%) | ||
| 8–10 | 24 (19.6%) | ||
Median values and standard errors of the mean are given.
00154-5/assets/gr1.jpg)
Fig. 1 PSA-, IgF1- and CGA-serum levels in PC-patients and controls. In contrast to PSA, there was no difference of IGF-1 and CGA serum levels between cases and controls. Columns indicate the respective mean values and standard errors of the mean.
3.2. IGF-1 and CGA serum levels
Serum IGF-1 levels averaged at 167 ± 6.0 ng/ml (range: 10.0–448.0 ng/ml; median 154.5 ng/ml) in the PC-group and at 159 ± 4.5 ng/ml (range: 5.0–530.0 ng/ml; median 153.0 ng/ml) in controls (p = 0.33) (Fig. 1). CGA serum levels were also comparable between PC-patients (92 ± 7.4 U/l; range: 17.1–423.6 U/l; median 67.4 U/l) and controls (117 ± 12.0 U/l; range: 17.0–1161.8 U/l; median 73.8 U/l; p = 0.12) (Fig. 1).
3.3. Impact of age on PSA, fPSA, IGF-1 and CGA serum levels
The impact of age on PSA, IGF-1 and CGA serum levels was analysed separately for PC-patients and controls (Fig. 2). In PC-patients, there was no correlation (p > 0.05) between patient age and PSA, CGA or IGF-1 (Fig. 2). In controls, however, PSA (p = 0.018) and CGA (p < 0.001) correlated positively and IGF-1 (p < 0.001) negatively with age (Fig. 2). Free PSA serum levels were positively correlated to age in cases (p = 0.002) and controls (p = 0.045).
00154-5/assets/gr2.jpg)
Fig. 2 Impact of age on serum levels of PSA, IgF1 and CGA in PC-patients and controls. In PC-patients, there was no correlation between PSA, IGF1 and CGA and age. In contrast, all three markers were correlated to age in the control group.
3.4. Impact of tumour grading on PSA, IGF-1 and CGA serum levels
To minimize grading errors, only radical prostatectomy specimens (n = 122) were used for subsequent analyses: well defined tumours (Gleason score 2–5) were present in 19 (15.6%), moderately defined tumours (Gleason score 6–7) in 79 (64.8%) and poorly defined tumours (Gleason score 8–10) in 24 (19.6%) (Table 1). Serum-PSA increased from 5.5 ± 2.1 ng/ml (median ± standard error of the mean) in those with highly differentiated tumours to 13.8 ± 10.5 ng/ml in those with poorly differentiated tumours (Gleason score 8–10) (Fig. 3). In contrast, neither IGF-1 nor CGA-serum levels were correlated to the Gleason score on radical prostatectomy specimens (Fig. 3). Because of the discrepancy between highly significant differences in PSA serum levels between cases and controls and non significant differences of IGF-1 and CGA serum levels, we abstained from calculating ratios of these different serum markers.
00154-5/assets/gr3.jpg)
Fig. 3 Correlation of PSA, IGF-1 and CGA with Gleason-score. Columns indicate median values.
4. Discussion
The interest in the insulin-like growth factor axis, in particular of IGF-1 and IGF binding protein 3 (IGFBP-3), for PC was primarily triggered by prospective studies providing evidence for a relationship between IGF-1 and IGFBP-3 serum levels and the risk of developing PC [7], [16], and [17]. Wolk et al. reported on an association between serum levels of IGF-1 and the risk of PC [18]. In a nested case-control study, Chan et al. concluded that circulating levels of IGF-1 and IGFBP-3 may predict the risk of developing advanced-stage PC, but their utility for screening patients with early stage disease may be limited [7]. Oliver et al. investigated 176 cases and 324 matched controls selected out of a cohort of 7.383 men and observed that the risk of PC increased across quartiles of IGF-1 and IGF-2 [19]. Associations between IGFs and cancer risk were stronger for advanced cases [19]. Woodson et al. challenged these encouraging reports in a prospective Finnish study that observed no evidence to support a causal association between serum IGF-1 or IGFBP-3 and the risk of PC [20]. Nevertheless, the majority of studies support the role of IGF-1 as a predictor for PC-development. Recently, Janssen et al. have shown that measurement of serum levels of IGF-1 and/or IGFBP-3 in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer [21]. The authors concluded that the endocrine IGF-1 system is not directly involved in the growth of early stages of prostate cancer [21].
The role of IGF-1 in the diagnosis of PC is more controversially discussed. The negative findings of our study are in line with the majority of series suggesting that IGF-1 serum levels provide no relevant information for the diagnosis of PC. Cutting et al. analysed 94 consecutive patients undergoing TRUS-guided 6-core prostate biopsies [22]. The authors observed no statistical significant difference of serum IGF-1 levels between PC-patients and controls [22]. Finne et al. quantified IGF-I and IGFBP-3 serum levels in 665 consecutive men undergoing prostate biopsies [23]. After adjustment for prostate volume, the negative association between serum IGF-1 and PC-risk was no longer significant [23]. The authors concluded that serum IGF-1 is not a useful diagnostic test for PC [23]. Ismail et al. investigated 652 men undergoing prostate biopsies and concluded that serum IGF-1 and IGFBP-3 do not predict the results of prostate biopsy [8]. In a subsequent study, serum IGF-1 and IGFBP-3 did not correlate with tumour volume or Gleason score [24]. Again these data are in line with our study as we also observed–in contrast to PSA–no correlation between IGF-1 serum levels and Gleason score (Fig. 3). Djavan et al. investigated 245 consecutive men with PSA-levels between 2.5–15 ng/ml undergoing octant biopsies [17]. Although IGF-1 and IGF-1 density were unable to enhance the performance of PSA, the IGF-1/PSA ratio significantly improved PC-detection over the use of PSA alone [17]. Nam et al. studied 1.031 consecutive men undergoing prostate biopsy because of elevated serum PSA-levels [25]. In their study IGF-1 levels were lower in cases than in controls (p = 0.05) yet not predictive for the presence of PC [25]. Similar findings were reported by Baffa et al. [26]. In summary, the majority of studies failed to demonstrate a role of IGF-1 for diagnosis of PC.
One potential limitation of our approach is the exclusion of PC in our control group. Although all individuals with PSA-values above the age-specific ranges underwent a 12-core ultrasound guided biopsy, we can not fully exclude PC in these controls (such as in those with normal PSA and DRE. It is worth to note that the median PSA-value in our control group was 1.3 ng/ml.
The role of CGA in PC is not well documented [11], [12], and [13]. Though CGA appears to follow serum levels of the dominant tumour marker our data suggest that this is not the case in PC as we observed no correlation between CGA and PSA. Furthermore, CGA-serum levels did not correlate to the Gleason score (Fig. 3). These data are in contrast to a recent series of Sciarra et al. who observed an association between CGA and pathological stage in 83 patients undergoing radical prostatectomy [27]. There is accumulating evidence, however, that CGA might play a role as a marker for advanced PC, particularly under androgen deprivation and during the hormone refractory phase of the disease [12], [13], [28], and [29]. The pathomechanism leading to the age-related increase of CGA in our control population are unclear (Fig. 2). One can hypothesize that neuroendocrine differentiated cells increase in number with benign prostatic enlargement and lead–in parallel to PSA–to an age-related increase in those without PC.
In conclusion our data indicate that quantification of IGF-1 and CGA-serum levels provides no useful information in the diagnosis of PC.
References
- [1] G. Fuerstenberger, H.J. Senn. Insulin-like growth factors and cancer. Lancet Oncol 3 (2002) (298 - 302)
- [2] P.J. Kaplan, S. Mohan, P. Cohen, B.A. Foster, N.M. Greenberg. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res 59 (1999) (2203 - 2209)
- [3] L. Jerome, L. Shiry, B. Leyland-Jones. Deregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions. Endocr Relat Cancer 10 (2003) (561 - 578) Crossref.
- [4] A. Grimberg. Mechanisms by which IGF-I may promote cancer. Cancer Biol Ther 2 (2003) (630 - 635)
- [5] K.W. Watt, P.J. Lee, T. M’Timkulu, W.P. Chan, R. Loor. Human prostate-specific antigen: structural and functional similarity with serine proteases. Proc Natl Acad Sci USA 83 (1986) (3166 - 3170) Crossref.
- [6] P. Stattin, S. Rinaldi, C. Biessy, U.H. Stenman, G. Hallmans, R. Kaaks. High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort. J Clin Oncol 22 (2004) (3104 - 3112) Crossref.
- [7] J.M. Chan, M.J. Stampfer, J. Ma, P. Gann, J.M. Gaziano, M. Pollak, et al.. Insulin-like growth factor I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 94 (2002) (1099 - 1106) Crossref.
- [8] H.A. Ismail, M. Pollak, H. Behlouli, S. Tanguay, L.R. Bégin, A.G. Aprikian. Insulin like growth factor 1 and Insulin like growth factor binding protein 3 for prostate cancer detection in patients undergoing prostate biopsy. J Urol 168 (2002) (2426 - 2430)
- [9] M.P. Roudier, L.D. True, R.L. Vessella, C.S. Higano. Metastatic conventional prostatic adenocarcinoma with diffuse chromogranin A and androgen receptor positivity. J Clin Pathol 57 (2004) (321 - 323) Crossref.
- [10] G. Aumueller, M. Leonhardt, M. Jannsen, L. Konrad, A. Bjartell, P.A. Abrahamsson. Neurogenic origin of human prostate endocrine cells. Urology 53 (1999) (1041 - 1048)
- [11] N. Vashchenko, P.A. Abrahamsson. Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol 47 (2005) (147 - 155) Abstract, Full-text, PDF, Crossref.
- [12] J.T. Wu, A.J. Erickson, K.C. Tsao, C.F. Sun. Elevated serum chromogranin A is detectable in patients with carcinomas at advanced disease stages. Ann Clin Lab Sci 30 (2000) (175 - 178)
- [13] M. Ferrero-Pous, A.M. Hersant, A. Pecking, M. Bresard-Leroy, M.F. Pichon. Serum chromogranin A in advanced prostate cancer. BJU Int 88 (2001) (790 - 796) Crossref.
- [14] C.K. Chuang, T.L. Wu, K.C. Tsao, S.K. Liao. Elevated serum chromogranin A precedes prostate-specific antigen elevation and predicts failure of androgen deprivation therapy in patients with advanced prostate cancer. J Formos Med Assoc 102 (2003) (480 - 485)
- [15] J.E. Oesterling, W.H. Corner, S.J. Jacobsen, H.A. Guess, M.M. Lieber. Influence of patient age on the serum PSA concentration. An important clinical observation. Urol Clin North Am 20 (1993) (671 - 680)
- [16] C.S. Mantzoros, A. Tzonou, L.B. Signorello, M. Stampfer, D. Trichopoulos, H.O. Adami. Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 76 (1997) (1115 - 1118)
- [17] B. Djavan, B. Bursa, C. Seitz, G. Soeregi, M. Remzi, A. Basharkhah, et al.. Insulin-like growth factor 1 (IGF-1), IGF-1 density, and IGF-1/PSA ratio for prostate cancer detection. Urology 54 (1999) (603 - 606) Crossref.
- [18] A. Wolk, C.S. Mantzoros, S.O. Andersson, R. Bergstrom, L.B. Signorello, P. Lagiou, et al.. Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. J Natl Cancer Inst 90 (1998) (911 - 915) Crossref.
- [19] S.E. Oliver, D. Gunnell, J. Donovan, T.J. Peters, R. Persad, D. Gillatt, et al.. Screen-detected prostate cancer and the insulin-like growth factor axis: results of a population-based case-control study. Int J Cancer 108 (2004) (887 - 892) Crossref.
- [20] K. Woodson, J.A. Tangrea, M. Pollak, T.D. Copeland, P.R. Taylor, J. Virtamo, et al.. Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Cancer Res 63 (2003) (3991 - 3994)
- [21] J.A. Janssen, M.F. Wildhagen, K. Ito, B.G. Blijenberg, R.H. Van Schaik, M.J. Roobol, et al.. Circulating free insulin-like growth factor (IGF)-I, total IGF-1, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval. J Clin Endocrinol Metab 89 (2004) (4391 - 4396) Crossref.
- [22] C.W. Cutting, C. Hunt, J.M. Bland, A.G. Dalgleish, R.S. Kirby. Serum insulin-like growth factor-1 is not a useful marker of prostate cancer. BJU Int 83 (1999) (996 - 999) Crossref.
- [23] P. Finne, A. Auvinen, H. Koistinen, W.M. Zhang, L. Maattanen, S. Rannikko, et al.. Insulin-like growth factor I is not a useful marker of prostate cancer in men with elevated levels of prostate-specific antigen. J Clin Endocrinol Metab 85 (2000) (2744 - 2747) Crossref.
- [24] H.A. Ismail, M. Pollak, H. Behlouli, S. Tanguay, L.R. Begin, A.G. Aprikian. Serum insulin-like growth factor (IGF)-1 and IGF-binding protein-3 do not correlate with Gleason score or quantity of prostate cancer in biopsy samples. BJU Int 92 (2003) (699 - 702) Crossref.
- [25] R.K. Nam, W.W. Zhang, J. Trachtenberg, M.A. Jewett, M. Emami, D. Vesprini, et al.. Comprehensive assessment of candidate genes and serological markers for the detection of prostate cancer. Cancer Epidemiol Biomarkers Prev 12 (2003) (1429 - 1437)
- [26] R. Baffa, K. Reiss, E.A. El-Gabry, J. Sedor, M.L. Moy, D. Shupp-Byrne, et al.. Low serum insulin-like growth factor 1 (IGF-1): a significant association with prostate cancer. Tech Urol 6 (2000) (236 - 239)
- [27] A. Sciarra, G. Voria, S. Monti, L. Mazzone, G. Mariotti, M. Pozza, et al.. Clinical understaging in patients with prostate adenocarcinoma submitted to radical prostatectomy: predictive value of serum chromogranin A. Prostate 58 (2004) (421 - 428) Crossref.
- [28] A. Sciarra, S. Monti, V. Gentile, G. Mariotti, A. Cardi, G. Voria, et al.. Variation in chromogranin A serum levels during intermittent versus continuous androgen deprivation therapy for prostate adenocarcinoma. Prostate 55 (2003) (168 - 179) Crossref.
- [29] M. Tarle, M.Z. Ahel, K. Kovacic. Acquired neuroendocrine-positivity during maximal androgen blockade in prostate cancer patients. Anticancer Res 22 (2002) (2525 - 2529)
EAU Guidelines on Chronic Pelvic Pain
Copyright © 