| Abstract|| |
Background: Prostate carcinoma is the second leading cause of cancer-related deaths in males worldwide. The burden is expected to grow 1.7 million new cases and 499,000 new deaths by 2030. In developing countries such as India, prostate carcinoma will show an increase by 140% in the next few years. Although the diagnosis of prostate carcinoma can usually be made on histological features, now a days many immunohistochemical (IHC) markers are used to distinguish it from benign mimickers as well as in predicting prognosis and treatment. Out of these markers, Ets-related gene (ERG product) is a proto-oncogene which participates in chromosomal translocations and is frequently over expressed in prostate carcinoma which harbors ERG-transmembrane protease, serine 2 fusion. Materials and Methods: Fifty cases of carcinoma prostate diagnosed in needle biopsies and prostatic chips, in the Department of Pathology of a tertiary care teaching hospital in Punjab, India, were included in the present study. The slides were observed under the light microscope, and Gleason scoring was done using the 2005 International Society of Urological Pathology modified Gleason system. IHC study for ERG expression was done on all the cases, for which anti-ERG monoclonal rabbit clone antibody EP111 (Dako, Denmark) was used. Lymphocytes and endothelial cells were taken as in built positive controls for staining. The intensity of ERG positivity was scored as no staining (0), weak staining (+1), moderate staining (+2) and intense staining (+3). The H score was then calculated by multiplying the intensity of the stain with the percentage (0-100) of the cells showing that staining intensity. The H-score has a range of 0-300. The relationship between IHC expression and clinico-pathological parameters was compared and analyzed using Chi-square test. P < 0.05 was considered statistically significant. Results: Majority of patients included in the study were in the age group of 61-80 (84% of the total). When ERG expression was studied with age-specific rates, it was not found to be statistically significant. The most common pattern noted in the present study was 4 + 3, constituting 36% of total, followed by 3 + 4 constituting 32%. Calculating the score, the majority of patients had a Gleason score of 5-8, constituting 76% of total. Out of the total fifty cases of prostate carcinoma, ERG was positive in 29 cases (58%) and negative in 21 cases (42%). Fourteen out of 21 (48%) of the ERG positive cases had an intensity score of 3. When the ERG intensity was correlated with the Gleason score group, it was seen that patients having Gleason score 7-8 showed ERG positivity in 19 out of 38 cases (50%), with 11/19 (57%) cases showing an ERG intensity score of 3. The Gleason score group 9-10 showed ERG positivity in 83% (10/12) cases, 20% (2/10) cases showing intensity score of 3. This correlation was found to be statistically significant. Conclusion: ERG immunostaining was performed in a small Indian cohort of prostate cancer patients, diagnosed in trucut biopsy specimens and prostatic chips. ERG expression was found in 58% patients. An increase in the ERG expression was observed with an increase in Gleason score. The intensity of ERG expression, however, decreased with an increasing Gleason score.
Keywords: Carcinoma prostate, Ets-related gene transcription factor, Expression, Immunohistochemistry, India
|How to cite this article:|
Mannan R, Bhasin TS, Manjari M, Singh G, Bhatia PK, Sharma S. Immunohistochemical expression of Ets-related gene-transcriptional factor in adenocarcinoma prostate and its correlation with Gleason score. Indian J Pathol Microbiol 2016;59:489-95
|How to cite this URL:|
Mannan R, Bhasin TS, Manjari M, Singh G, Bhatia PK, Sharma S. Immunohistochemical expression of Ets-related gene-transcriptional factor in adenocarcinoma prostate and its correlation with Gleason score. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Jul 16];59:489-95. Available from: http://www.ijpmonline.org/text.asp?2016/59/4/489/191794
| Introduction|| |
Carcinoma of the prostate is the second leading cause of cancer-related deaths in males in the world with 905,330 and 1.1 million cases and 258,400 and 307,000 deaths in 2008 and 2011, respectively. Almost 70% cases were from developed countries.  Prostate carcinoma accounts for about 15% of all cancers in the developed countries, compared with 4% in the developing world.  According to the National Cancer Registry Programme conducted by the Indian Council of Medical Research, New Delhi, the prostate is the second leading site of cancer in males in metropolitan cities such as Kolkata, Thiruvananthapuram, Delhi, and Pune. Its incidence is estimated to increase by 140% in the next few years.  The quantum of carcinoma prostate cases worldwide is expected to increase to 1.7 million new cases and 499,000 new deaths because of population explosion and aging. 
This disease exhibits significant diversity in clinical presentation, histopathology, and survival rate, thus necessitating assessment of the neoplasm's aggressive potential in all individual cases.  Diagnosis is usually based on needle biopsies, performed because of complaints of urinary obstruction and/or infection, an elevated prostate-specific antigen (PSA) levels, or suspicion of malignancy on rectal examination or transrectal ultrasound. The histopathology report includes the Gleason score, along with documentation of the number of biopsy strips infiltrated by the tumor, and the percentage of biopsies involved by it. 
It is important to supplement routine histopathological examination with other methods because it has a few limitations. These include presence of morphological mimickers of carcinoma prostate such as adenosis and atypical adenomatous hyperplasia or a limited focus of the tumor, a very low-grade, or very high-grade carcinoma, all of which cause difficulty in interpretation. Besides, there is still significant inter-observer variability in estimation of Gleason score among pathologists. ,,
Therefore, newer markers are now being increasingly used to provide better diagnostic accuracy, therapeutic stratification, and prognostication in prostate cancer patients.
One of the most common genetic alterations seen in prostate cancer involves Ets-related gene-1 (ERG-1). ERG is a transcription factor belonging to the erythroblast transformation-specific (ETS) family. It is involved in many important cellular processes including differentiation, cell proliferation, angiogenesis, cell migration, hematopoiesis, and apoptosis. This proto-oncogene is expressed in the urogenital tract and hematopoietic cells.  Gene fusions involving sequences of transmembrane protease serine 2 (promoter of TMPRSS2) and protein coding sequences of ERG result in over expression of ERG in prostate tumors.  This TMPRSS2-ERG fusion has been shown to occur in 50-70% cases in different studies. Unlike leukemias where translocations are common, genetic rearrangements were not identified in epithelial carcinomas until Tomlins et al. demonstrated ERG gene fusions in carcinoma prostate.  The presence of this fusion is now believed to be a critical event in the development of carcinoma prostate.  Studies have demonstrated strong correlation between ERG expression and progression of disease in surveillance cohorts.  Hence, determination of ERG expression has assumed significance in deciding treatment options and prognostication.
The fusion gene is usually determined by fluorescent insitu hybridization (FISH). The presence of this fusion gene has been found to correlate well with positive ERG staining in cancer epithelial cells using antibodies.  Since ERG demonstration by immunohistochemistry (IHC) is more economical compared to FISH, is faster, and produces results comparable to FISH, it is now being used by laboratories worldwide.
A number of studies using IHC have shown that ERG expression is more in cases having higher Gleason score. The intensity of ERG expression in prostate carcinoma, on the other hand, shows significant inverse correlation with Gleason score. , However, not many of these have been done on Indian population, and not much data are available on the relationship of ERG expression using IHC, with grade and stage of prostate cancer in our population patients.
The present study was conducted on fifty cases of histopathologically proven cases of prostatic carcinoma diagnosed. Gleason scoring was done, along with IHC for ERG expression, to determine a correlation between the two.
| Materials and Methods|| |
Fifty cases of carcinoma prostate diagnosed in needle biopsies and prostatic chips, in the Department of Pathology of a tertiary care teaching hospital from Punjab, India, were included in the present study. Detailed clinical data of the patient were recorded.
Routine histopathological processing was done, followed by staining with hematoxylin and eosin. The slides were observed under the light microscope, and Gleason scoring was done using the 2005 International Society of Urological Pathology modified Gleason system.
IHC was done on formalin-fixed sections, and paraffin embedded 4 μm sections of representative blocks of each tumor were mounted on poly-lysine coated slides. Antigen retrieval was done in a pressure cooker using sodium citrate buffer solution at pH 6.0. Peroxidase inhibition was then done, followed by washing in tris buffer saline and protein block. To evaluate ERG expression, anti-ERG monoclonal rabbit clone antibody EP111 (Dako, Denmark) was used. Secondary detection system used was Envision (Dako, Denmark) where antigen was visible as a brown-colored pigment after incubation with DAB (3,3'- diaminobenzidine).
Only the cases which had more than 10% cells positive for ERG were included for scoring. Lymphocytes and endothelial cells were taken as in built positive controls for staining. The intensity of ERG positivity was scored as no staining (0), weak staining (+1), moderate staining (+2), intense staining (+3). The H score was then calculated by multiplying the intensity of the stain with the percentage (0-100) of the cells showing that staining intensity. The H-score has a range of 0-300.
The relationship between IHC expression and clinicopathological parameters was statistically analyzed using SPSS version 12 software (IBM SPSS Statistics, IBM Corporation, Armonk, NY). Chi-square test was used for data analysis. P < 0.05 was considered statistically significant.
| Results|| |
The majority of patients in the study had multiple symptoms, with frequency and urgency together being the most common (40%) with only three cases having a positive family history of prostate carcinoma. Out of the total fifty cases of prostate carcinoma, immunopositivity rate of ERG expression was 58% (29/50). Of these positive cases, 48% (14/29) had an intense staining of +3 [Table 1].
Age group-specific Ets-related gene expression and correlation
Majority of patients included in the study were in the age group of 61-80 (84% of the total). When ERG expression was studied, highest positivity (80%) was seen in patients aged 80 years and above, followed by 54.7% positivity seen in age group of 61-80 years. However, this was not found to be statistically significant (P = 0.531) [Table 2].
|Table 2: Correlation of Ets - related gene expression with age group specificity|
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Correlation of Ets-related gene expression and Gleason score
The most common pattern noted in the present study was 4 + 3, constituting 36% of total, followed by 3 + 4 constituting 32%. Calculating the score, the majority of patients had a Gleason score of 5-8, constituting 76% of total. Patients with a score 9-10 constituted 26% of the total.
Correlating the Gleason score with ERG expression, it was noted that patients with Gleason score 7 and 8 showed 50% ERG positivity, whereas patients with Gleason score 9 and 10 showed ERG positivity in 83.3% cases. An increase in the ERG positivity was observed with increase in Gleason score, and it was found to be statistically significant (P = 0.041) [Table 3].
|Table 3: Correlation of Ets - related gene expression with Gleason score|
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Correlation of ETS-related gene intensity with Gleason score
When the ERG intensity was correlated with the Gleason score group, it was seen that patients having Gleason score 7-8 showed ERG positivity in 19 out of 38 cases (50%), with 11/19 (57%) cases showing an ERG intensity score of 3. The Gleason score group 9-10 showed ERG positivity in 83% (10/12) cases, 2/10 (20%) cases showing intensity score of 3. This correlation was found to be statistically significant (P = 0.024) [Table 4].
| Discussion|| |
Since the 1980's, there has been a drastic rise in the incidence of prostate cancer world wide. It was thought earlier that the prevalence of carcinoma prostate in India is lower compared to the western countries. However, at present, we know that this is not true. More cases are being detected due to increased awareness, migration to urban areas, lifestyle modifications, and availability of better diagnostic modalities. According to the Indian Cancer Registry statistics, cases of carcinoma prostate will double by 2020.  Takiar and Vijay studied the data pooled from five urban population-based cancer registries functioning under the National Cancer Registry Programme during two different periods to study changes in patterns of cancer incidence and found that cancer prostate is the most important among emerging cancers.  Hence, it is important to have easily accessible, reproducible, accurate and economically viable methods of diagnosis, and prognostic markers, so as to be able to determine appropriate therapy and management.
Although there has been an improvement in correlation between Gleason score done on trucut biopsy, and pathological staging done on radical prostatectomy due to the implementation of the modified Gleason score, there is still significant upgrading of the score in radical prostatectomies.  Moreover, considerable inter-observer variation in the Gleason grading is seen among different pathologists. Berg et al. performed histopathological re-evaluation in 350 cases of carcinoma prostate and found that in 23% cases, the results of the re-evaluation were different from the original reports.  This assumes significance in low to intermediate risk cases, where it can alter management. Hence, it is important to increase there producibility of Gleason score by supplementing it with newer markers.
The small percentage of total prostate volume (0.05-0.5%) sampled in a needle biopsy might lead to under sampling of the most relevant area of cancer. In such cases, novel histopathological and molecular markers may predict the presence of higher grade areas which have been missed in sampling, due to occurrence of molecular aberrations before histopathological changes in the tissue.  Additional help is also required in distinguishing benign conditions mimicking prostate cancer, including adenosis, prostatitis, atypical adenomatous hyperplasia, and nephrogenic adenoma. 
Therefore, newer markers using techniques such as IHC, FISH, and polymerase chain reaction (PCR) are now being increasingly used to provide better diagnostic accuracy, therapeutic stratification, and prognostication in prostate cancer patients.
ERG is most often referred to not only as"Ets-related gene,"but also as"v-ets erythroblastosis virus E26 oncogene-related" gene, located on chromosome 21. It is an important transformation factor belonging to ETS transcription factor family. TMPRSS2 gene is also located on chromosome 21. Northern analysis has demonstrated that TMPRSS2 is expressed at a higher level in prostate epithelium compared to other normal human tissues.  ERG and TMPRSS2 are separated by a 3 megabase segment containing a number of other genes.  The TMPRSS2-ERG fusion is the most common genomic alteration seen in prostate cancer and leads to the over expression of the ERG oncoprotein.  ERG activation has been found to occur in the early stages of tumor development.  This has a profound effect on cancer initiation and progression. ERG oncoprotein over expression inhibits differentiation of prostatic epithelial cells and causes dysregulation of DNA repair genes. 
Percentage and intensity of ERG expression have been shown to correlate with stage of disease. Teng et al. have demonstrated that ERG expression is associated with a higher Gleason score, a higher pathological stage, a higher risk of extension of the tumor beyond the prostate and into the seminal vesicles.  A study done by Suryavanshi et al. on a subset of the Indian population has also shown that increased stage of cancer in prostate tumors is associated with increased percentage of ERG positivity but decreased intensity of ERG expression. 
Studies on the prognostic significance of ERG expression have yielded mixed results. Berg et al. have demonstrated that ERG protein expression in prostate biopsies is associated with increased risk of disease progression in patients on active surveillance, which is now being widely used as an alternative to therapy in low-grade cancers of the prostate.  Bismar et al. have also documented a significant association between ERG expression, patient survival and progression to castration - resistant carcinoma. These studies suggest that the evaluation of ERG expression in prostatic cancers may prove to helpful in prognosis and in deciding the line of treatment in these cases. ,
Some studies, however, have found no association between ERG expression and prognosis in men treated with radical prostatectomy  and in men with localized prostate cancer.  Hence, the role of IHC expression of ERG as a prognostic marker is still under the anvil. The same applies to its utility as a predictive marker of response to therapy.
ERG expression has been detected using FISH and PCR, which are time-consuming, expensive, and not readily available. Studies suggest that IHC detection of ERG protein expression may be used as a surrogate marker for demonstration of ERG rearrangements on FISH due to concordance between results obtained by both methods. ,, Specific monoclonal ERG antibodies are now commercially available, for example, rabbit antibodies, and studies by Chaux et al.  and Falzarano et al.  have determined that these antibodies are very accurate in determining ERG expression, with sensitivities of 86% and 96%, and specificities of 89% and 99%, respectively. Because of the specificity of ERG staining for prostate cancer, it would constitute evidence to expedite a repeat biopsy in cases where only ERG-positive atypical glands are seen. 
Furusato et al. have determined that a strong concordance exists between ERG-positive high-grade prostatic intraepithelial neoplasia (HGPIN) and ERG-positive carcinoma. This implies that ERG may be used as a marker for risk stratification in those with a diagnosis of HGPIN.  Gao et al. concluded that follow-up biopsies in patients with HGPIN with ERG rearrangements showed an increased incidence of prostate cancer.  Because of all these factors, IHC detection of ERG is gradually assuming importance in the diagnosis of prostate cancer and therapeutic stratification of the patients.
The technique however has its own limitations. It cannot reveal whether the genetic aberration causing over expression of ERG is a deletion, translocation, or duplication. It cannot determine the nature of the fusion partner. This assumes importance because both of these factors may have an effect on outcome. 
The purpose of the present study was to determine the percentage of prostate tumors showing ERG positivity and to determine a relationship between ERG positivity, ERG intensity and Gleason score. Our study included fifty cases of carcinoma prostate, diagnosed in both needle biopsies and prostatic chips. The Gleason score was first assigned to these specimens, and then percentage of ERG positivity and intensity of staining was evaluated using IHC.
Most of the patients (84%) in the present study were in the age group of 61-80 years, showing that prostate carcinoma usually affects the elderly age group. Similar results were demonstrated in studies conducted. 
The majority of patients complained of multiple lower urinary tract symptoms. Seventy percent of the patients complained of both frequency and urgency while the remaining complained of dysuria, along with frequency. Although lower urinary tract symptoms do not have any direct correlation with prostate cancer, Martin et al. have shown that there is 2.26-fold increased incidence of prostate cancer in these cases compared with men having no symptoms. 
The most common Gleason score in our study cohort was 7, seen in 68% of our cases, with the most common pattern being 4 + 3. Mean Gleason score was 6.9 in a study by Darnel et al. in a Canadian cohort of patients.  All these studies are in concordance with the fact that majority of patients present with moderately differentiated tumors, having a Gleason score 6-7, in this post-PSA era.
In the current study, ERG positivity was observed in 29 cases (58%) while ERG was negative in 21 cases (42%). A similar result was obtained in studies by Hoogland et al.  and van Leenders et al.,  in which ERG expression was seen in 55% cases and 61% cases of prostate cancer, respectively.
Lower rates of ERG expression have been found in studies done by Bismar et al., Chaux et al., Park et al., Kelly et al., and Verdu et al. In these, ERG expression was seen in 34.4%, 45%, 48.5%, 39.2%, and 49% cases, respectively. ,,,, This discrepancy could be because of smaller size of our cohort, or due to the fact that these studies were done on patients from different regions and ethnicities, compared to ours.
As far as the Indian population is concerned, studies by Ateeq et al. found IHC ERG positivity in 49% patients, and Suryavanshi et al. in 51% cases, which is lesser than ours; however, again, their studies had more number of cases (116 and 100), compared with ours. , The high ERG positivity score in our study could also be attributable to the fact that we mainly cater to a rural population and because of lack of awareness, by the time these patients seek help, they already have advance stage disease. The antibody used by Ateeq et al. was clone EPR 3864 from Epitomics, Burlingame, California, and Suryavanshi et al. used the similar rabbit clone EP 111, ready to use antibody from Dako, as employed in the present study.
In the present study, a correlation was observed between ERG expression and increasing Gleason score. 83.3% (10/12) cases having a Gleason score of 9 showed ERG positivity, compared with 50% (18/34) cases having a Gleason score of 7. An increase in the ERG positivity was observed with an increase in Gleason score, and it was found to be statistically significant (P = 0.041) [Figure 1]. Only four cases had a Gleason score of 8, out of which only one case (25%) showed ERG expression.
|Figure 1: (a) Prostatic adenocarcinoma Gleason pattern 4 + 5; score 9 (H and E, ×400). (b) Same case as in Figure 1a, Ets-related gene transcription factor expression +3 intensity in tumor cells (IHC, ×200). (c) Prostatic adenocarcinoma Gleason pattern 5 + 4; score 9 (H and E, ×100). (d) Same case as in Figure 1c, Ets-related gene transcription factor expression +2 intensity in tumor cells (IHC, ×200)|
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When the ERG intensity was correlated with Gleason score, it was seen that the patients having Gleason score of 7-8 showed 50% (19/38) positivity for ERG, with 57% (11/19) cases having an intensity score of 3. The Gleason score group 9-10 showed 83% (10/12) cases to be positive cases for ERG, with only 20% (2/10) showing an intensity score of 3. This correlation was found to be statistically significant with a P value of 0.024. Thus, majority of ERG-positive cases having Gleason score 7 exhibited +3 intensity while +2 intensities were observed in most ERG-positive cases having a higher Gleason score of 9 [Figure 2]. This implied that the intensity of ERG expression decreased with an increasing Gleason score. Similar results have been obtained in studies by Bismar et al.  Suryavanshi et al. also found a significant decline in ERG intensity in patients with stage 4 disease.  Furusato et al. studied ERG expression in radical prostatectomy specimens, and they also concluded that ERG immunostaining correlated with high Gleason Scores. 
|Figure 2: (a) Prostatic adenocarcinoma Gleason pattern 4 + 3; score 7 (H and E, ×200). (b) Same case as in Figure 3a , Ets-related gene transcription factor expression 2+ intensity in tumor cells (IHC, ×200). (c) Prostatic adenocarcinoma Gleason Pattern 3+4; score 7 (H and E, ×100). (d) Same case as in Figure 2c, Ets-related gene transcription factor expression 3+ intensity in tumor cells (IHC, ×200)|
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| Conclusion|| |
ERG immunostaining was performed in a small Indian cohort of prostate cancer patients, diagnosed in trucut biopsy specimens and prostatic chips. ERG expression was found in 58% patients. An increase in the ERG expression was observed with an increase in Gleason score. The intensity of ERG expression however decreased with an increasing Gleason score.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]