|Year : 2014 | Volume
| Issue : 1 | Page : 8-11
A study of biological determinants of serum prostate specific antigen level in prostatic adenocarcinoma with normal, borderline, and high serum PSA levels
Anu Sumi Issac, Mah-e-Jabeen, K. Pushpalatha Pai
Department of Pathology, Yenepoya Medical College, Yenepoya University, Deralakatte, Mangalore, Karnataka, India
|Date of Web Publication||4-Jun-2014|
Anu Sumi Issac
Department of Pathology, Yenepoya Medical College, Yenepoya University, Deralakatte, Mangalore - 575 018, Karnataka
Source of Support: None, Conflict of Interest: None
Objectives: To find out the reasons for discrepancy in the serum prostate-specific antigen (PSA) values (normal, borderline, and high) in prostatic adenocarcinoma. Materials and Methods: It is a retrospective correlation study of serum PSA levels with the histomorphological variables and age of the patients in adenocarcinoma prostate with normal, borderline, and high serum PSA values. Age of the patients was noted down and hematoxylin and eosin-stained, paraffin-blocked sections were studied. Results: Serum PSA values were found to be directly related to histomorphological variables like Gleason grade and score, tumor cell mass to stroma ratio, necrosis, and cell size; but not with the age of the patients with prostatic adenocarcinoma. Discussion: Publications on relationship between serum PSA levels and Gleason grade and score in adenocarcinoma prostate are rarely found in the literature. Infarction (coagulation necrosis) increases serum value of PSA in benign prostatic tissue which can be true with carcinomas also, as in the present study. Various histomorphologic variables also may affect the serum PSA levels. The age of the patient and serum PSA levels in carcinoma prostate is not found directly proportional, in this study, unlike in normal individuals who show age-specific PSA ranges.
Keywords: Prostate, Adenocarcinoma, Gleason, PSA
|How to cite this article:|
Issac AS, Me, Pai KP. A study of biological determinants of serum prostate specific antigen level in prostatic adenocarcinoma with normal, borderline, and high serum PSA levels. Arch Med Health Sci 2014;2:8-11
|How to cite this URL:|
Issac AS, Me, Pai KP. A study of biological determinants of serum prostate specific antigen level in prostatic adenocarcinoma with normal, borderline, and high serum PSA levels. Arch Med Health Sci [serial online] 2014 [cited 2020 Jan 25];2:8-11. Available from: http://www.amhsjournal.org/text.asp?2014/2/1/8/133778
| Introduction|| |
Prostate cancer contributes significantly to the overall cancer burden, being the most frequent malignant neoplasm and the second leading cause of death from cancer next to lung cancer in men. PSA is the key factor for screening and detection of prostate cancer.  PSA is a kallikrein-like serine protease that is produced exclusively by the epithelial cells of all types of prostatic tissue benign and malignant. , PSA is more sensitive than prostatic acid phosphatase (PAP) in the detection of prostatic carcinoma and is more useful in monitoring responses and recurrences after therapy.  In the present study, a total of 16 cases of adenocarcinoma prostate, three with normal, one with borderline, and 12 with high (more than 100 ng/mL) were studied for serum PSA values with age and four histomorphological variables like Gleason grade and score, tumor cell mass to stroma ratio, necrosis, and cell size to find out the reasons for this variations in serum PSA levels in adenocarcinoma prostate. Normal and borderline PSA in a prostatic adenocarcinoma create a problem in diagnosis which needs to be researched and reasons for this discrepancies has to be explained and answered.
| Materials and Methods|| |
A total of 16 cases with adenocarcinoma prostate with normal (three cases) and borderline serum PSA levels (one case) and PSA more than 100 ng/mL (12 cases) were selected for the study. Five biopsies were transurethral resection of prostate (TURP) and 11 were biopsies obtained by digital rectal examination and ultrasound-guided biopsy. Formalin (10%)-fixed paraffin-blocked tissue sections stained with hematoxylin and eosin were studied for histomorphological pattern, Gleason grade and score, amount of necrosis, ratio of cell mass to stroma, and cell size. The findings were correlated with serum PSA value in each case along with the age of the patient.
| Results|| |
The relation between Gleason grade and score of tumor and normal, borderline, and high PSA is shown in the [Table 1]. [Table 2] shows relationship between serum PSA levels with Gleason score, necrosis, cell to stromal ratio and cell size. Out of four cases of well-differentiated tumors [Figure 1], three cases had normal serum PSA levels and one case had borderline serum PSA value of 8.8 ng/mL. Necrosis was found to be nil in three cases of well-differentiated adenocarcinomas with normal serum PSA value and Gleason score not more than 4. One case of well-differentiated adenocarcinoma with serum PSA level 8.8 ng/mL (borderline) showed minimal necrosis. Cell mass to stromal ratio was found to be not exceeding 1:1 to 3:2 in all four cases of well differentiated adenocarcinomas including the case with borderline serum PSA levels. In all four cases, the tumor cell size was found to be small.
|Figure 1: Well-differentiated adenocarcinoma neoplastic cells lining the glands are small and the serum prostate-specific antigen (PSA) level within normal limit|
Click here to view
|Table 2: Relationship between PSA levels with Gleason score, necrosis, and cell to stromal ratio |
Click here to view
Twelve cases had serum PSA levels above 100 ng/mL and Gleason score ranged from 6 to 9. Necrosis was consistently present. Tumor mass to stroma ratio ranged from 1:1 to 9:1, cell size was large with abundant pale pink cytoplasm to clear cytoplasm [Figure 2] in four cases. The normal, borderline, and high serum PSA values in carcinoma prostate had no relation with age [Table 3].
|Figure 2: Poorly-differentiated carcinoma with Gleason score of 8 (4 + 4), sheets of large-sized cells with abundant cytoplasm, and very high PSA (851 ng/ml)|
Click here to view
| Discussion|| |
PSA is synthesized in the ductal epithelium and prostatic acini. It is found in normal, hyperplastic, and malignant prostatic tissue.  Patients with prostatic cancer have, in general, elevated serum PSA levels compared to men without prostatic carcinoma. The most commonly used cutoff serum level for PSA is 4 ng/mL. When serum PSA concentrations are 4-10 ng/mL (borderline levels), the incidence of cancer detection on a prostate biopsy with a normal digital rectal examination is approximately 25%. With serum PSA levels over 10 ng/mL, the incidence of prostate cancer on a biopsy increases to approximately 67%. With a serum PSA levels of <2 ng/mL, the probability of cancer is <2%, and raises to approximately 18% for PSA values of 2.5-4 ng/mL. Other factors such as prostatitis, infarct, and instrumentation of the prostate also increase serum PSA value. Benign prostate tissue also contributes to serum PSA levels, although not to the same extent as cancer. 
Age specific PSA reference ranges - as men age, their prostates tend to enlarge with benign prostatic hyperplasia. One would then anticipate that overall older men would have higher serum PSA levels than younger men. Recommended age-specific upper reference ranges for serum PSA are 2.5 ng/ml for men 40-49 years of age, 3.5 ng/mL for men 50-59 years, 4.5 ng/mL for men 60-69 years, and 6.5 ng/ml for men 70-79 years. , The Gleason grading system is one of the more powerful prognostic indicators in prostate cancer. Gleason score correlates with all of the important pathologic parameters seen in the radical prostatectomy specimens. ,,, Grade on biopsy can influence what type of definitive treatment is to be given (watchful waiting vs surgery or radiation). Since normal and hyperplastic prostate differs from neoplastic prostate in terms of anaplasia minimal to marked and cell mass, anaplasia will be the defining factor between hyperplasia and malignant tumors. So increasing anaplasia (grade) may increase the serum PSA value. Hence, with increasing Gleason grade and score with increasing anaplasia increases the serum PSA level as found in this study. Infarction in benign prostate increases serum PSA value.  So it is not surprising to find high PSA value in carcinoma with necrosis as in the present study, because in malignancy the necrosis is infarction type. Cell size increases cell mass and increasing cell mass compared to stroma increases PSA production,  which in turn elevates serum PSA level. These findings explain increased serum PSA value in four of the cases with large cell size in the study. Hence, serum PSA value in any particular case depends on how many histomorphological variables are on the positive side. The present study is mainly done to understand the correlation between histomorphological variables like pattern, Gleason grade and score, amount of necrosis, ratio of cell mass to stroma, and cell size. Study of independent clinical variables like obesity, administration of drugs like statins, nonsteroidal anti-inflammatory drugs, thiazide diuretics, and anti-androgens, all of which lower the serum PSA level even in patients with carcinoma prostate, has not been done in this study. ,,, This would have explained normal PSA in three cases and borderline PSA in one case of carcinoma prostate, provided the history of intake of above mentioned drug was available. Another factor which decreases the specificity of PSA in some cases of carcinoma prostate is that PSA is not exclusively secreted by the prostate gland. It has been detected in lower concentration in other tissues like urethral glands, endometrium, normal breast tissue, and salivary glands and also detected in serum of women with breast, lung, or uterine cancer and in some patients with renal cancer.  The present study is done on men with diagnosed cases of adenocarcinoma of prostate. None of the patients were suffering from any other cancer. Hence, the elevated level of PSA in the present study is exclusively due to carcinoma prostate.
This is a descriptive study with a small patient population which is a limitation. Hence, further studies with more number of cases are needed to come to a definite conclusion.
| References|| |
|1.||Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994;152:1732-6. |
|2.||Epstein JI, Netto GJ. Clinical correlates with biopsy: Serum prostate-specific antigen, digital rectal examination, and imaging techniques. In: Epstein JI, Netto GJ, editors. Biopsy Interpretation of the Prostate. Philadelphia: Lippincott Williams and Wilkins; 2007. p. 2-5. |
|3.||Stamey TA, Johnstone IM, McNeal JE, Lu AY, Yemoto CM. Preoperative serum prostate specific antigen levels between 2 and 22 ng./ml. correlate poorly with post-radical prostatectomy cancer morphology: Prostate specific antigen cure rates appear constant between 2 and 9 ng/ml. J Urol 2002;167:103-11. |
|4.||Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909-16. |
|5.||Gretzer MB, Partin AW. PSA markers in prostate cancer detection. Urol Clin North Am 2003;30:677-86. |
|6.||Anderson JR, Strickland D, Corbin D, Byrnes JA, Zweiback E. Age-specific reference ranges for serum prostate-specific antigen. Urology 1995;46:54-7. |
|7.||Dalkin BL, Ahmann FR, Kopp JB. Prostate specific antigen levels in men older than 50 years without clinical evidence of prostatic carcinoma. J Urol 1993;150:1837-9. |
|8.||Murphy GP, Busch C, Abrahamsson PA, Epstein JI, McNeal JE, Miller GJ, et al. Histopathology of localized prostate cancer. Consensus Conference on Diagnosis and Prognostic Parameters in Localized Prostate Cancer. Stockholm, Sweden, May 12-13, 1993. Scand J Urol Nephrol Suppl 1994;162:7-42. |
|9.||Epstein JI, Partin AW, Sauvageot JA, Walsh PC. Prediction of progression following radical prostectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol 1996;20:286-92. |
|10.||Epstein JI, Pizov G, Walsh PC. Correlation of pathologic finding with progression after radical retropubic prostatectomy. Cancer 1993;71:3582-93. |
|11.||Green GA, Hanlon AL, Al-Saleem T, Hanks GE. A Gleason score of 7 predicts a worse outcome for prostate carcinoma patients treated with radiotherapy. Cancer 1998;83:971-6. |
|12.||Banez LL, Hamilton RJ, Partin AW, Vollmer RT, Sun L, Rodriguez C, et al. Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer. JAMA 2007;298:2275-80. |
|13.||London S. Common medications tied to lower PSA levels[ Internet] 2010. Available from: http://www.medconnect.com.sg/tabid/92/s28/General-Medicine/ct1/c36141/Common-Medications-Tied-to-Lower-PSA-Levels/Default [Last accessed on 2013 January 12]. |
|14.||Popular drugs lower PSA levels [Internet] 2009 Jan 20. Available from: http://www.clinicaladvisor.com/popular-drugs-lower-psa-levels/article/126133/ Last accessed on 2013 January 12]. |
|15.||Negri C, Tosi F, Dorizzi R, Fortunato A, Spiazzi GG, Muggeo M, et al. Antiandrogen drugs lower serum prostate specific antigen (PSA) levels in hirsute subjects: Evidence that serum PSA is a marker of androgen action in women. J Clin Endocrinol Metab 2000;85:81-4. |
|16.||Prostate-specific Antigen [Internet] 2013 Mar 7. Available from: http://en.wikipedia.org/wiki/Prostate-specific_antigen [Last accessed on 2013 January 12]. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]