|Year : 2016 | Volume
| Issue : 1 | Page : 112-116
Role of androgen receptor in prostatic neoplasia versus hyperplasia
Irma Husain1, Saumya Shukla2, Priyanka Soni2, Nuzhat Husain2
1 Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
2 Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||13-Apr-2016|
Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow - 226 010, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Androgens play a fundamental role in the growth, differentiation, and maintenance of prostate tissue. The objective of the study was to evaluate and compare the androgen receptor (AR) expression in benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and prostatic adenocarcinoma. A relationship between the Gleason score and AR expression was also determined in cases of prostatic adenocarcinoma.
Materials and Methods: A total of 25 cases were collected which included 10 cases of prostatic adenocarcinoma, 10 cases of BPH, and five cases of PIN. Histopathological evaluation was done to determine the type of lesion including Gleason scoring. Immunohistochemistry (IHC) was performed for AR using monoclonal anti-AR antibody.
Results: Specific AR immunostaining was present in all 25 cases in varying intensity. The staining was more intense in cases of adenocarcinoma and PIN as compared BPH. There was no significant statistical difference in the intensity of staining of AR. The Gleason score was inversely related to the intensity of AR staining in adenocarcinoma. There was no significant statistical association between the AR expression and tumor, necrosis, metastasis (TNM) stage.
Discussion: AR nuclear expression is present in benign and malignant prostatic epithelium. In this study, cases of prostate cancer demonstrated a higher staining intensity for AR when compared with BPH. The intensity of AR staining in prostate cancer significantly reduces as the Gleason grade of the tumor increases. The staining intensity for AR was heterogeneous specifically in cases of prostate cancer. Our results indicate that AR maybe considered as a prognostic marker in prostate cancer.
Keywords: Androgen, prostate, receptor
|How to cite this article:|
Husain I, Shukla S, Soni P, Husain N. Role of androgen receptor in prostatic neoplasia versus hyperplasia. J Can Res Ther 2016;12:112-6
| > Introduction|| |
The lesions of the prostate gland are responsible for significant morbidity and mortality among adult males worldwide. The prostate is a fibromuscular, retroperitoneal organ encircling the neck of the urinary bladder and the urethra weighing approximately 20 g in adults. Anatomically and biologically, the prostatic parenchyma is divided into four zones: Peripheral, central, transitional, and the anterior fibromuscular stroma. The proliferative lesions in each zone are distinct. Hyperplasia most commonly affects the transitional zone, while carcinomas arise in the peripheral region. The common lesions affecting the prostate that lead to prostatic enlargement or growth include benign prostatic hyperplasia (BPH), prostatitis, prostatic intraepithelial neoplasia (PIN), and prostatic adenocarcinoma.,,
BPH or nodular hyperplasia is nonmalignant overgrowth of the prostatic gland characterized by hyperplasia of the stromal and the epithelial cells, commonly presents with lower urinary tract symptoms and urinary retention.
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. The incidence of prostate cancer is low in the Asian countries; however, the incidence is rising by 1% every year. About 60% of newly diagnosed prostate cancer patients present with metastatic disease. The metastasis is generally hematogenous and is commonly found in lymph nodes, bone, liver, and lung. The incidence of prostatic carcinoma increases significantly after the age of 50 years. The most common histological variant is adenocarcinoma. PIN was first described by McNeal in 1965. PIN is further subdivided in low and high grades depending on the nuclear changes. PIN is detected in about 70% cases above the age of 70 years.,
Androgens, mainly testosterone and 5-alpha-dihydrotesterone (DTH), play a fundamental role in the growth, differentiation, and maintenance of prostate tissue. The effects of the androgen are mediated via the specific androgen receptors (ARs) that belong to the nuclear receptor family. The AR is most closely related to the progesterone receptor and the main function of the AR is as a DNA-binding transcription factor that regulates gene expression.
The objective of the study was to evaluate and compare the AR expression in BPH, PIN, and prostatic adenocarcinoma. A relationship between the Gleason score and AR expression was also determined in cases of prostatic adenocarcinoma.
| > Materials and Methods|| |
Formalin fixed-paraffin embedded (FFPE) archival prostatic tissue specimens were obtained. A total of 25 cases were collected which included 10 cases of prostatic adenocarcinoma, 10 cases of BPH, and five cases of PIN.
The FFPE tissue blocks were sectioned at 3–4 μm, using a microtome (Leica, Germany), mounted on tissue bond-coated slides (Biocare, USA) and stained with hematoxylin and eosin (H and E) for histopathological evaluation to determine the type of lesion including Gleason scoring in cases of prostatic adenocarcinoma. Immunohistochemistry (IHC) was done by the standard protocol. The tissue section on coated slides was fixed overnight at 60°C in a dry oven, deparaffinized in xylene, and rehydrated through graded ethanol series. Sections were blocked with 3% hydrogen peroxide in methanol for 30 min to quench any endogenous peroxidase activity, if present, and were then processed for antigen retrieval in Pascal (DAKO Cytomation, California) by placing in sodium citrate buffer (pH-6.0). Sections were incubated for an hour with anti-AR-pan, rabbit monoclonal (Biogenex, Hyderabad F39.4.1), followed by treatment with polymer-based secondary antibody kit (Dakopatts, Envision kit, Denmark). Bound antibody was visualized using diaminobenzidine, according to the manufacturer's instructions. Sections were counterstained with hematoxylin and mounted. Positive and negative (by omitting primary antibody) controls were run with all batches.
The number and intensity of immunoreactive nuclei were assessed. Owing to the heterogeneous content of positive staining cells, especially in cases of carcinoma, each slide was scanned at × 50 to identify the area with the highest staining. The intensity of staining was evaluated on a scale of 0–3, where 0 = no staining, 1 = weak staining (+), 2 = moderate staining (++), and 3 = strong staining (+++). The intensity grades were reported independently by two pathologists and in cases of non-concordance a third opinion was taken.
Statistical analysis was performed using the IBM-Statistical Package for Social Sciences (SPSS, International Business Machines Corporation, New York, USA) analysis software, version 16. Chi-square test was used for the categorical variables. All P were calculated with two-sided tests and P ≤ 0.05 was considered significant and highly significant when P ≤ 0.01.
| > Results|| |
A total of 25 cases were collected which included 10 cases of prostatic adenocarcinoma, 10 cases of BPH, and five cases of PIN. The mean age was 65.5 years, while the age range varied from 45 to 83 years. All the 25 (100%) patients presented with urinary symptoms and difficulty in micturition. Hematuria, loss of appetite, loss of weight, and backache were symptoms that were present in patients with either adenocarcinoma or PIN [Table 1]. The presence of loss of weight/appetite was statistically significant (P < 0.001) when documented in cases of either adenocarcinoma or PIN.
|Table 1: Association between the general characteristics of the patients with BPH, PIN, and adenocarcinoma (n=25)|
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On digital rectal examination, the consistency of the prostate was soft in nine cases (36%), firm in eight cases (32%), and hard in eight cases (32%). All cases of prostatic adenocarcinoma had a firm to hard prostate on digital rectal examination.
The serum prostate-specific antigen (PSA) levels were between the range of 3.83 ng/ml and143 ng/ml. In eight out of the 10 cases of prostatic adenocarcinoma, the PSA levels were <10 ng/ml. Among the 10 cases of BPH, eight patients had serum PSA levels below 10 ng/ml [Table 1].
Specific AR immunostaining was exclusively nuclear and was present in all 25 cases in varying intensity. The staining was observed in the nuclei of the malignant epithelial cells, hyperplastic glandular epithelial cells, and a proportion of the interglandular stromal cells. The staining was more intense in cases of adenocarcinoma and PIN as compared to BPH [Figure 1][Figure 2][Figure 3]. However, there was no significant statistical difference in the intensity of staining of AR in neoplasia versus hyperplasia (P = 0.143) [Table 1].
|Figure 1: (a) Benign prostatic hyperplasia (BPH) with cystically dilated glands and luminal corpora amylacea (H and E, x100). (b) The benign glands lined by bilayered epithelial with luminal glandular and abluminal myoepithelial cells (H and E, x200). H and E = Hematoxylin and eosin|
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|Figure 2: (a and b) AR staining of moderate intensity in the benign glands and periglandular stromal cells (red arrow) in BPH (DAB, ×200)|
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|Figure 3: (a and b) Prostatic intraepithelial neoplasia (PIN) with nuclear stratification and nuclear enlargement (H and E, x200). (c) AR staining of strong intensity in cases of PIN (DAB, x200)|
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In cases of BPH, the cells facing the lumen stained more intensively as compared to the basal cells. A heterogeneous staining was observed in cases of prostatic adenocarcinoma. Both AR positive and AR negative nuclei were present in the same field demonstrating the variability of AR staining [Figure 4] and [Figure 5]. The intensity of AR staining in cases of adenocarcinoma was moderate in four cases (40%) and strong in six cases (60%). The cases which demonstrated moderate AR staining had the Gleason score of <8. This implies that the Gleason score was inversely related to the intensity of AR staining in adenocarcinoma (P = 0.032). There was no significant statistical association between the AR expression and tumor, necrosis, metastasis (TNM) stage [Table 2].
|Table 2: Association of Gleason score with percentage androgen expression|
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|Figure 4: (a) Prostatic adenocarcinoma with small sized neoplastic glands (H and E,x100) (b) The neoplastic glands are lined by a single layer of cuboidal cells with pale cytoplasm, pleomorphic nuclei with prominent nucleoli (H and E, x200)|
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|Figure 5: (a) Heterogeneous staining for AR in prostate cancer with admixed positive (red arrow) and negative (yellow arrow) cells (DAB, x200). (b and c) Nuclear AR staining of varying intensities in prostate cancer (DAB, x200)|
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| > Discussion|| |
BPH and prostate cancer are the major cause of urinary symptoms and elevated PSA levels in males above the age of 50 years. In our study, the mean age of the patients was 65.5 years. There was no significant age difference detected between the benign and malignant cases. This was in concordance with the study conducted by Men et al., who found a mean age distribution of 64.67 years. Urinary obstruction and lower urinary tract symptoms are present in both malignant as well as nonmalignant lesions; however, presence of hematuria is generally an indicator of malignancy. The clinical findings in our study were also similar as hematuria, loss of appetite, loss of weight, and backache were generally documented in patients with malignant or premalignant lesions.,
Aboseif et al., and Naskar et al., demonstrated that the mean PSA was significantly higher in cases of prostate cancer when compared with BPH and PIN. This finding was similar to our results, as in this study eight out of the 10 cases of prostatic adenocarcinoma had PSA levels <10 ng/ml. While among the 10 cases of BPH, eight patients had serum PSA levels below 10 ng/ml.,
AR is a transcription factor that has a pivotal role in the development of both benign and malignant prostatic lesions. It plays a critical part in the occurrence and progression of prostate cancer. The AR is activated by androgens that bind to its ligand-binding domain (LBD), causing the transcription factor to enter the nucleus and interact with genes via its conserved DNA-binding domain (DBD).
The treatment for prostate cancer involves reducing androgen production or using anti-androgen drugs to block the interaction of hormones with the AR-LBD. Eventually the disease changes into a castration resistant form (CRPC) where LBD mutations render anti-androgens ineffective or where constitutively active AR splice variants, lacking the LBD, become over expressed. This is responsible for recurrence and metastasis of prostate cancers which initially responded well to androgen deprivation therapy.,
The activation of the PI3K/Akt pathway is frequently observed as prostate cancer progresses toward a resistant, metastatic disease. Signaling from this pathway activates numerous survival, growth, metabolic, and metastatic functions characteristic of aggressive cancer. Biomarkers of this pathway have correlated activation of this pathway to high grade disease and higher risk of disease progression.
In this study, all the prostatic lesions demonstrated variable intensity of AR immunostaining. Strong nuclear staining was observed in 60% cases of adenocarcinoma, 60% cases of PIN, and only 20% cases of BPH. So, the highest content of AR was present in cases of prostatic adenocarcinoma. Similar findings were documented in the studies conducted by Qui et al., Brolin et al., and Naskar et al.,,
In our study, the cases of prostate cancer with moderate AR immunostaining had a Gleason score of > 8. Hence, the intensity of AR staining is high in well-differentiated tumors and low in moderately- to poorly-differentiated tumors. This finding was in concordance with the studies conducted by Theodoropoulos et al., Miyamoto et al., and Takeda et al.,,,,,,
In our study, the staining pattern for AR in prostate cancer was heterogeneous and variable. This finding was also documented in the study conducted by Sadi et al., who stated that androgen-dependent and androgen-independent cells are generally admixed. The larger the percentage of androgen dependent cells, the greater will be the extent of involution after androgen withdrawal, and the longer it would take for the androgen independent cells to repopulate the tumor leading to relapse. Hence, high AR content is a good prognostic marker because these tumors respond well to androgen withdrawal therapy and have a longer disease-free survival.
In conclusion, AR nuclear expression is consistently present in benign and malignant prostatic epithelium. AR plays an important role in the growth and proliferation of prostate tissue. In this study, cases of prostate cancer demonstrated a higher staining intensity for AR when compared with BPH. However, this was not statistically significant as the sample size of this study was small. The intensity of AR staining in prostate cancer significantly reduces as the Gleason grade of the tumor increases. The staining intensity for AR was heterogeneous, specifically in cases of prostate cancer. Our results indicate that AR maybe considered as a prognostic marker in prostate cancer.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]