|Year : 2017 | Volume
| Issue : 4 | Page : 246-252
Serum prostate-specific antigen as a tumor marker for its correlation with histopathological diagnosis of prostatomegaly
Biswadeep Sarkar, Arvind Bhake
Department of Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed University), Wardha, Maharashtra, India
|Date of Web Publication||17-May-2018|
Dr. Biswadeep Sarkar
Department of Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed University), Wardha - 442 004, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Prostatomegaly is common in men past fifth decade of life and has been the most common cause of symptoms associated with lower urinary tract obstruction. The emergence of prostate-specific antigen (PSA) has come to rescue of clinicians at screening the prostate cancer by its raised value in serum. The further research over the PSA brought out few new indices which are sensitive in screening and suggesting prostate cancer such as the ratio between free and bound PSA, PSA density (PSAD), and PSA velocity. Objectives: The objective of this study is (1) to study serum PSA level and PSAD at the differentiation of benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia, and prostatic carcinoma (PCa) established at prostatic tissue diagnoses, (2) evaluation of the significance of total prostate-specific antigen (TPSA) level in the intermediate range of 4–10 ng/ml at assessment of benign versus malignant prostatomegaly at tissue diagnoses, and (3) to draw cutoff values of PSAD (0.15 vs. 0.18 ng/ml/cc) in suggesting benign versus malignant prostatomegaly at tissue diagnoses. Materials and Methods: Digital rectal examination was carried out in suspected clinical cases of prostatomegaly. One hundred and eight cases of prostatomegaly have undergone TPSA estimation prospectively by Vidas TPSA kit. PSAD was calculated as the ratio between TPSA and the volume of the prostate. The sample received for histopathological diagnoses were either sextant biopsy (25 specimens), transurethral resection of prostate (68 specimens), and prostatectomy (15 specimens). Results: TPSA was performed in total 108 patients of prostatomegaly, of which 35 (40.22%) cases had TPSA in the range of ≤4 ng/ml, 37 (34.25%) cases had TPSA in the range of 4.01–10 ng/ml, and 36 (33.33%) cases had TPSA in the range of >10 ng/ml. The mean PSAD cutoff of <0.18 ng/ml/cc had revealed 79 (90.80%) cases of BPH. The mean PSAD cutoff of ≥0.18 ng/ml/cc had revealed 8 (9.1%) cases of BPH, 19 (100%) cases of PCa and 2 (100%) cases of prostatic intraepithelial neoplasia (PIN). Final tissue diagnoses in total 108 cases were as follows: BPH – 87 (80.55%) cases, PIN – 2 (1.85%) cases, and prostatic adenocarcinoma – 19 (17.59%) cases. Conclusion: The TPSA value over 10 ng/ml and mean PSAD value over 0.15 or over 0.18 ng/ml/cc can be used as criteria for prostatic biopsy. The mean PSAD cutoff of over 0.18 ng/ml/cc works superiorly for the diagnoses of malignant prostatomegaly, selection of the cases for the prostatic biopsy and medical or surgical management of prostatomegaly.
Keywords: Prostate-specific antigen level, prostatic tissue diagnoses, prostatomegaly
|How to cite this article:|
Sarkar B, Bhake A. Serum prostate-specific antigen as a tumor marker for its correlation with histopathological diagnosis of prostatomegaly. J Datta Meghe Inst Med Sci Univ 2017;12:246-52
|How to cite this URL:|
Sarkar B, Bhake A. Serum prostate-specific antigen as a tumor marker for its correlation with histopathological diagnosis of prostatomegaly. J Datta Meghe Inst Med Sci Univ [serial online] 2017 [cited 2018 Jun 19];12:246-52. Available from: http://www.journaldmims.com/text.asp?2017/12/4/246/232578
| Introduction|| |
The advancing age in the life of a man ironically is associated with the advancement of prostate for its size. Prostatomegaly is common in men past fifth decade of life and has been the most common cause of symptoms associated with lower urinary tract obstruction.,,,
Fortunately, the common underlying process of prostatomegaly is of benign prostatic hyperplasia (BPH), but a sizable is made up of prostatic carcinoma (PCa).,,,,, In the Western world, the incidence of PCa is on the rise, and it has become the second-most common cause of death in men in Western countries.,
In the year of 1990, some new biomarkers came in the medical field catering to the need of clinicians and pathologists in the diagnostic and prognostic field of oncology and prostate-specific antigen (PSA) was one of them. PSA was studied for its efficiency and efficacy as a tumor marker by several workers in the past two decades.,,,, Several studies were undertaken globally for PSA density (PSAD) and its utility as a screening tool to differentiate between benign versus malignant prostatomegaly.,,,,,,,,,,,,,,,,,,,,,
Aim and objectives
Studying total PSA and PSAD as a marker at the differentiation of benign neoplastic and malignant neoplastic lesions of the prostate supported by statistical methods.
- To study serum total, PSA level in digital rectal examination (DRE) suspected malignant prostatomegaly patients
- To study serum PSA level and PSAD at the differentiation of benign prostatic hyperplasia, PIN, and prostate cancer established at prostatic tissue diagnoses
- Evaluation of the significance of total PSA level in the intermediate range of 4 ng/ml to 10 ng/ml at the assessment of benign versus malignant prostatomegaly at tissue diagnoses and to study relevant values of PSAD in the intermediate range of total PSA
- To draw cutoff values of PSAD (0.15 vs. 0.18 ng/ml/cc) in suggesting benign versus malignant prostatomegaly at tissue diagnoses.
| Materials and Methods|| |
The study was carried out in the Department of Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed University), Wardha, Maharashtra over a period of 2 years from July 2014 to July 2016 in total 108 suspected clinical cases of prostatomegaly.
DRE was carried out in all clinically suspected cases of prostatomegaly in the present study. Transrectal ultrasonography (TRUS) was performed using ALOKA Prosound Alpha-7 scanner using a 10 MHz transverse sector probe. The volume of the prostate was measured using prolate ellipsoid formula., Sextant biopsies were carried out using standard operating procedure per rectally under sonographic guidance.,,
The PSA levels were assessed by enzyme-linked fluorescent assay (ELFA) using Mini Vidas Biomerieux-ELFA strip reader using the kit of Vidas. The morning blood sample was collected from the patients before any manipulative procedure over the prostate, including DRE. PSAD was calculated as the ratio between total prostate-specific antigen (TPSA) and the volume of the prostate.
The sample received for histopathological diagnoses were either sextant biopsy (25 specimens), transurethral resection of prostate (68 specimens), and prostatectomy (15 specimens). Routine Hematoxylin and eosin stain were carried out in 4–5 microns thick sections of the paraffin block by established procedures. The Gleason score was performed on the tissue of the prostate reported as PCa using the standard references.,,
The present study included 108 patients of prostatomegaly. The maximum numbers of patient recruited in the study were in the age range of 60–69 years and 70–79 years, having 49 (45.37%) and 43 (39.81%) cases, respectively. The age of the youngest patient of prostatomegaly in the present study was 45 years, and older one was 83 years. The age of occurrence of prostatomegaly and its tissue diagnoses is described in [Table 1].
The present study observed that the Grade II prostatomegaly and grades over it were clinically most symptomatic. The descending order of symptoms for benign prostatic lesions were poor stream – 70 (80.45%) cases, difficulty in voiding – 45 (51.72%), increased frequency – 42 (48.27%) cases, incomplete voiding – 39 (36.11%) cases, acute retention – 20 (22.98%) cases, urgency – 19 (21.83%) cases, nocturia – 16 (18.39%) cases, and dysuria – 15 (17.24%) cases. The descending order of symptoms for malignant prostatic lesions were difficulty in voiding – 18 (94.73%), increased frequency – 17 (89.47%) cases, incomplete voiding – 14 (73.68%) cases, poor stream – 12 (63.15%) cases, hematuria – 7 (36.84%) cases, nocturia – 7 (36.84%) cases, and acute retention, dysuria, and urgency – 3 (15.78%) cases each. Hematuria was observed with malignant prostatic lesions in 7 (36.84%) cases, but not seen in any benign prostatic lesions.
Digital rectal examination
In the present study, there were 16 (14.81%) patients of Grade I prostatomegaly, 56 (51.85%) patients of Grade II prostatomegaly, 35 (32.40%) patients of Grade III prostatomegaly and 1 (0.92%) patient of Grade IV prostatomegaly on DRE.
The nodular, asymmetrical enlarged, firm, hard, and knobby to palpate the prostate with suspicion of malignant prostatomegaly was seen in 45 (41.66%) patients, out of which 19 (17.59%) cases turned out to be PCa and 26 (24.07%) cases were diagnosed as a BPH on tissue diagnosis.
The average prostate volume and its final histopathological diagnosis observed in the study are stated in [Table 2].
|Table 2: Distribution of prostate volume with histopathological diagnosis|
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In the present study, the association between the different prostate volume ranges with benign, malignant and premalignant lesion of prostate, derived value χ2 = 7.61 and P = 0.05, which is statistically not significant.
Sextant biopsies under the guidance of TRUS were carried out in 25 (23.14%) numbers of cases. In 68 (62.96%) cases, the histopathological diagnosis was done from TURP specimen and in 15 (13.88%) cases the histopathological diagnosis was done by prostatectomy specimen.
In the present study, there were 87 (80.55%) cases of benign prostatic hyperplasia [Figure 1], 2 (1.85%) cases of prostatic intraepithelial neoplasm [Figure 2] and 19 (17.59%) cases of adenocarcinoma prostate [Figure 3]. All the prostate cancer diagnosed in 19 (17.59%) cases was adenocarcinoma of the prostate, and its variant was not encountered on histopathological examination in the subsequent tissue of prostate in the present study.
|Figure 1: Benign prostatic hyperplasia shows bilayered ducts lined by benign cuboidal cells surrounded by fibromuscular stroma (H and E, ×10)|
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|Figure 2: High-grade prostatic intraepithelial neoplasm shows lumen of the prostatic duct filled by proliferating atypical and malignant cells, limited within the basement membrane of the duct along with focal small collection of lymphocytes. HE: High power|
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|Figure 3: Adenocarcinoma prostate shows tubular structure made up of malignant cells, seen at places and lost in the part of the field. Invasion of stroma too is noticed. Gleason Score-7 (H and E, ×10)|
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Total prostate-specific antigen
The total PSA in accordance with the normal established division in the ranges of ≤4, 4.01–10, and >10 ng/ml and the lesions within the prostate are depicted in [Table 3].
|Table 3: Distribution of total prostate-specific antigen with various prostatic lesions|
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The lowest value of TPSA was 0.39 ng/ml and was associated with BPH and lowest TPSA value observed with PCa was 9.7 ng/ml.
The statistical values for TPSA at 4 ng/ml as a cutoff for predicting benignancy or malignancy of the prostate had a sensitivity of 100%, specificity of 62.59%, positive predictive value (PPV) of 28.77%, and negative predictive value (NPV) of 100%.
Total prostate-specific antigen and digital rectal examination
DRE was suspicious for malignancy in 45 (41.66%) out of total 108 cases, of which 26 (24.07%) cases had TPSA value of ≤4 ng/ml and 19 (17.59%) cases had TPSA value of >4 ng/ml. The DRE could diagnose the malignant cases correctly in 42.22%, i.e., 19 cases when compared with that of the raising value of TPSA and supported by tissue diagnosis. However, there were 26 (57.77%) cases which were erroneously suspicious of malignancy on DRE.
Prostate-specific antigen density
The observation regarding cutoff for PSAD at 0.15 ng/ml/cc and are depicted in [Table 4].
|Table 4: Distribution of prostate-specific antigen density at cutoff of 0.15 ng/ml/cc|
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The observation regarding cutoff for PSAD at 0.18 ng/ml/cc and are depicted in [Table 5].
|Table 5: Distribution of prostate-specific antigen density at cutoff of 0.18 ng/ml/cc|
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The statistical values for PSAD at 0.15 ng/ml/cc as a cutoff for predicting benignancy or malignancy of the prostate had a sensitivity of 100%, specificity of 78.38%, PPV of 46.67% and NPV of 100%.
The statistical values for PSAD at 0.18 ng/ml/cc as a cutoff for predicting benignancy or malignancy of the prostate had a sensitivity of 100%, specificity of 91.58%, PPV of 72.41%, and NPV of 100%.
Total prostate-specific antigen and prostate-specific antigen density
The present study had observed a single (5.26%) case of PCa and 36 (41.37%) of BPH in the intermediate TPSA range of 4.01–10 ng/ml. However, there exist no overlaps of PCa and BPH at PSAD cutoff of 0.15 as well as 0.18 ng/ml/cc in the intermediate TPSA range of 4.01–10 ng/ml.
Gleason score and its relation with total prostate-specific antigen
The present study observed the Gleason score of 5–7 in 18 (94.73%) and Gleason score of 2–4 in 1 (5.26%) case.
It was observed that TPSA of a single (5.26%) case in the range of >10 ng/ml with a Gleason score of 2–4. The Gleason score in the range of 5–7 showed 17 (89.47%) cases of PCa with TPSA level >10 ng/ml and 1 case of PCa with TPSA level in the intermediate range of 4.01–10 ng/ml.
| Discussion|| |
The studies of Emokpae et al., Anushree and Venkatesh, Fang et al., Xess et al., Wadgaonkar et al., Ramos et al., Sasaki et al. and Zivkovic et al. had maximum patients in the age range of 60–69 and 70–79 years. The present study also had a similar observation for the number of patients with symptoms of prostatomegaly for the age range.
The present study had 15 out of 19 PCa cases within the age range of 60–79 years. The similar observation for the age of occurrence of PCa cases had been observed in the study of Anushree and Venkatesh  (13/14) and Wadgaonkar et al. (10/11).
The common symptoms associated as quoted by Emokpae et al., Anushree and Venkatesh  and Fang et al. for BPH were difficulty in voiding, poor stream, increased frequency, dribbling, and feeling of incomplete voiding of urine. The present study also made a similar observation for the symptom of benign prostatomegaly. The present study concurs with the observation of Emokpae et al. and Anushree and Venkatesh  that the malignant prostatomegaly is associated with hematuria.
Digital rectal examination
Cooner et al. had noticed that the malignant prostatomegaly on DRE had findings of induration, nodularity, asymmetrical irregular enlargement, and knobby prostate. They had diagnosed 565 out of total 1807 cases suspicious of malignancy. However, they had also observed that the DRE may misguide, as there were sufficient number of cases which were benign on tissue diagnoses. The present study is in agreement with the findings of Cooner et al. that there were overlaps, even benign prostatomegaly may mimic malignant prostatomegaly on DRE as the present study had 45 (41.66%) cases suspicious of PCa on DRE, of which 26 (57.77%) turned out to be benign on tissue diagnoses.
The study of Udeh et al. and Stephan et al. observed no relationship between increases volume of prostate with that of increased occurrence of malignant prostatomegaly. The present study also had a similar observation.
Sextant biopsy complications
The present study has not observed clinical attentive complication while doing 25 (23.14%) sextant biopsy procedures. However, the study of Cooner et al. reported septicemia in two cases who did not take any prophylactic antibiotics and in three cases who had taken prophylactic antibiotics before the biopsy procedure in a total of 835 patients. One patient had developed intrapelvic hematoma and hematuria after the biopsy procedure.
Total prostate-specific antigen versus histopathological diagnoses
The PSA ≤4 ng/ml as a cutoff that would differentiate benign prostatic lesion and malignant one had been observed as a conclusive observation in the studies of Emokpae et al., Wadgaonkar et al., Sasaki et al. and Tauro et al. The findings of aforesaid study were congruent with the concluding observation that the TPSA value ≤4 ng/ml associated with benign prostatomegaly only. However, the TPSA value >4 ng/ml did not indicate the malignant lesions of prostate as had been observed in the study of Emokpae et al., Wadgaonkar et al., Sasaki et al. and Tauro et al.
The study of Anushree and Venkatesh  had found 36 (26.4%) cases and 1 (7.14%) case of BPH and PCa, respectively, in the intermediate range of TPSA, i.e., 4.01–10 ng/ml. Udeh et al. in the study had observed that 57 out of 157 BPH cases and 15 out of 97 PCa cases in the intermediate TPSA range of 4.01–10 ng/ml. The present study had observed 36 (41.37%) out of 87 BPH cases and 1 (5.26%) out of 19 PCa cases in the intermediate TPSA range of 4.01–10 ng/ml. This observation is in agreement with the observation of Anushree and Venkatesh  and Udeh et al.
The TPSA cutoff of 10 ng/ml suggesting the value below for its benignancy and value above for it for its malignancy had also undergone the scrutiny by a few studies. Stephan et al. in their study could find 117 out of 666 BPH cases having TPSA value >10 ng/ml. Anushree and Venkatesh  in their study could find 25 (18.3%) BPH cases having TPSA value >10 ng/ml while Wadgaonkar et al. had observed 6 out of 67 BPH cases in the TPSA range of >10 ng/ml. The present study had made the concurrent observation to that of Anushree and Venkatesh  Wadgaonkar et al. and Stephan et al. Wherein there were 16 (18.39%) cases of BPH, 2 (100%) cases of PIN, and 18 (94.73%) cases of PCa who had the TPSA value of >10 ng/ml in the present study.
Therefore, the conclusive evidence for TPSA cutoff suggesting the benignancy and malignancy of the prostate for the TPSA value of ≤4 ng/ml and 4.01–10 ng/ml in the studies reviewed for present work were non endorsing in nature, but the TPSA value of >10 ng/ml may be utilized to aggregate prostatomegaly for its benign or malignant process to some extent.
Abnormal digital rectal examination and total prostate-specific antigen
Abnormal DRE suspected of malignant prostatomegaly were observed in 26 cases of 87 histopathological diagnosis of BPH, and all these cases had TPSA values of ≤4 ng/ml. This parallax of abnormal DRE suspected of PCa with a normal TPSA cutoff of ≤4 ng/ml had also been cited in the study of Lavallée et al. and Agnihotri et al. which was similar to the finding of the present study.
Abnormal DRE suspected of malignant prostatomegaly though appeared to be more sensitive in diagnosing the malignant cases, but it is confounding as many of the abnormal DRE turn out to be benign by TPSA estimation and tissue diagnosis thus suggesting discordance of abnormal DRE and the TPSA level.
Prostate-specific antigen density
The studies of Tauro et al., Lujan et al. and Udeh et al. advocated mean PSAD cutoff of 0.15 ng/ml/cc that would enable to differentiate between benign prostatomegaly with that of malignant prostatomegaly. However, using the mean PSAD cutoff of 0.15 ng/ml/cc, Sasaki et al. missed 8 cases of cancer and could have saved 43% patient who had undergone a tissue biopsy. Lujan et al. had observed a mean PSAD cutoff of 0.15 ng/ml/cc and 11 cases of PCa got missed in their study. However, the study of Lujan et al. had not revealed the number of patients saved from the biopsy procedure using a mean PSAD cutoff of 0.15 ng/ml/cc.
However, unlike the study of Sasaki et al. and Lujan et al., the present study did not miss a single case of PCa and PIN out of total 19 cases (PCa) and 2 cases (PIN) respectively using a mean PSAD cutoff of 0.15 ng/ml/cc. Therefore, it is a satisfactory test for detection of prostate cancer, but it is unsatisfactory at secluding the BPH cases for which further tissue assessment is required.
Both the studies of Sasaki et al. and Lujan et al. had advocated to shift mean PSAD cutoff from 0.15 to 0.18 ng/ml/cc minimizing false-positive results requiring unnecessary prostate biopsy. The present study offers the similar observation in this regard.
Mean PSAD cutoffs of 0.15 and 0.18 ng/ml/cc for their findings in their study reviewed in the literature were tabulated in the [Table 6] and [Table 7], respectively.
|Table 6: The sensitivity, specificity, positive predictive value and negative predictive value with mean prostate-specific antigen density: prostate-specific antigen density cutoffs of 0.15 ng/ml/cc|
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|Table 7: The sensitivity, specificity, positive predictive value and negative predictive value with mean prostate-specific antigen density cutoffs of 0.18 ng/ml/cc|
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The study of Sasaki et al. and Lujan et al. had concluded that the mean PSAD cutoff of 0.15 ng/ml/cc was unacceptable at differentiating BPH from that of PCa and therefore mean PSAD cutoff should be raised to 0.18 or 0.20 ng/ml/cc or above as suggested in their study. The present study is in agreement with the suggestion of the above studies but has not done the calculation beyond 0.18 ng/ml/cc, which is the mean PSAD cutoff for most of the studies and utilizes the purpose for the suggestion of biopsy.
Gleason score and total prostate-specific antigen
The studies of Wadgaonkar et al., Zivkovic  and Narayan et al. had observed that there was an overlap of TPSA values with the Gleason score. These studies had observed that the Gleason score and TPSA value were unrelated and the P value was statistically insignificant. The present study also had a similar observation.
| Conclusion|| |
Per rectal DRE of the prostate is a conventional practice for the surgeons but its sensitivity is low. DRE alone is not the examination that would sufficiently select cases for the subsequent biopsies or medical and surgical management of prostatomegaly.
The total PSA value over 10 ng/ml and mean PSAD value over 0.15 or over 0.18 ng/ml/cc can be used as criteria for prostatic biopsy.
The PSAD appeared to be superior than total PSA at the screening of PCa and in avoidance of unnecessary biopsy.
The mean PSAD cutoff of over 0.18 ng/ml/cc works superiorly for the diagnoses of malignant prostatomegaly, selection of the cases for the prostatic biopsy and medical or surgical management of prostatomegaly.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]