الفهرس 
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Abstract
The present work was carried out to evaluate immunohistochemical expression of Metallothionein-2A and P63 in prostate adenocarcinomas versus benign prostatic hyperplasia then correlate their expression with different clinico-pathological parameters.
To achieve the aim, retrospective 50 cases of prostatic adenocarcinoma and 23 cases of benign prostatic hyperplasia, obtained by either transurethral resection specimens of prostate (TURP) or, transrectal core needle biopsy (NB), were randomly selected from Pathology Department, Medical Research Institute, Alexandria University in the period January 2018 to January 2019.
Five micron thick sections from the formalin-fixed, paraffin- blocks were prepared and examined by light microscopy after applying Haematoxelin and eosin staining, and immunohistochemical staining (P63 monoclonal antibody which is ready to use, and Anti-metallothionein-1 monoclonal antibody at a dilution of 1:100).
After Examination of H&E stained sections, the studied 50 cases of prostatic adenocarcinomas were classified according Johns Hopkins Hospital grading system into five distinct Grade Groups based on the modified (2005 and 2014) Gleason score.
Total MT expression whethercytoplasmic or nuclearwas evaluated using a semi-quantitative immunoreactivity scores (IRS) system, which took into account percentage of positively stained cells (value A: 0 points, no cells with positive reaction; 1, fewer than 10% of cells stained positively; 2, 10% to 50% of positive cells; 3, 51% to 80% of positive cells; and 4, more than 80% of cells positively stained) and the intensity of the color reaction (value B: 0, no reaction; 1, weak reaction; 2, moderate reaction; and 3, strong reaction). The final score represented a product of scores representing the two variables (IRS = A x B) and ranging from 0 to 12 points, where a weak reaction ranges from 0 to 4 points and a strong reaction from 6 to 12 points.
P 63 The nuclear staining pattern for the basal cell marker p63 was interpreted as negative/ positive. Staining was interpreted as negative when less than 10% of the tumor cells showed light nuclear staining while any nuclear staining in at least 10% of the tumor cells was considered positive. Positive cases were further subclassified into diffuse/ foci pattern.
In the studied 23 cases of benign prostatic hyperplasia (BPH), the ages of the patients ranged from 44 to 78 years, with a mean of 66.52 ± 8.93years. In the studied 50 cases of prostatic adenocarcinoma group, the ages of the patients ranged from 48 to 90 years with a mean of 72.0 ± 10.79 years. Significant difference was found between the ages of the two studied groups (p=0.037). So that patients were more elder in malignant group.
In the studied 23 benign cases, the total serum PSA levels ranged 0.3 -23 ng/dl; with a mean of 8.07 ± 5.77 ng/dl. In studied 50 cases of prostatic adenocarcinoma, the total serum PSA levels ranged from 3.6 -134 ng/dl with a mean of 62.60 ± 35.84 ng/dl. There was a highly significant increase in serum PSA levels in prostatic adenocarcinoma cases compared to benign cases (p < 0.001).
In different subgroups of prostatic adenocarcinoma according to Gleason’s score, a variation of PSA serum levels was statistically significant. (p=0.004).
The studied 23 benign cases by H&E showed Benign nodular hyperplasia of prostate either singly (5 cases, 21.73%) or in combination with other lesions (18 cases, 78.26 %) such as basal cell hyperplasia, atypical adenomatous hyperplasia, sclerosing adenosis and focal prostatic atrophy. For statistical purposes, the benign lesions were considered altogether as benign group.
The studied 50 cases of prostatic adenocarcinomas were classified according Johns Hopkins Hospital grading system into five distinct Grade Groups: Grade group 1 (Gleason score ≤ 6) (4 cases,8%), Gradegroup 2 (Gleason score 3 + 4 = 7) (4 cases, 8%), Grade group 3 (Gleason score 4 + 3 = 7) (4 cases, 8%), Grade group 4 (Gleason score 4+4=8; 3+5=8; 5+3=8) (14 cases, 28%), Grade group 5 (Gleason scores 9 and 10) (24cases, 48%).
Metallothionein- expression (MT-2A) was detected in 15 out of 23 cases ofBPH (65.21%); either nuclear (5 cases, 33.33%) or cytoplasmic and nuclear (10 cases, 66.66%). Immunoreactivity scores (IRS) expression ranged from mild (11 cases, 73.33%) to strong (4 cases, 26.66%).
All 50 cases ofadenocarcinoma (100%) demonstrated that MT-2A expressed in all cases (100%) either both cytoplasmic and nuclear (27cases, 54%) or only nuclear (23cases, 46%). According to immunoreactivity scores (IRS) system, Metallothionein-2A expression ranged from mild (20 cases, 40%) to strong (30 cases, 60%).
There was a significant difference in of the MT-2A expression between the two studied groups (benign Vs malignant) (p < 0.0001). Also as separate study, (total MT-2A expression according to IRS) the number of cases with mild expression were more in malignant cases than benign cases (20 malignant versus benign 11cases), but as percentage of mild cases benign were more than malignant (73.3% benign versus 40% malignant); Cases with strong expression as (percentage, number) were more in prostatic adenocacimoma (60%, 30 malignant versus 26.7%, 4 benign).
In five sub-grade Groups of the studied 50 cases prostatic adenocarcinoma, total MT-2A expression showed a significant difference (p<0.05).
On comparing the degree of nuclear expression of MT-2A between the studied benign group (23 cases) and malignant group (50 cases), there was a marked significant difference (p< 0.05)on other hand,the degree of nuclear expression of MT-2A in five subgroups of prostatic adenocarcinoma could not be significantly different.
A Receiver operating characteristics (ROC) curve demonstrated the diagnostic accuracy of MT-2A expression as a predictive test for prostatic adenocarcinomawith sensitivity of 76.92 % .and specificity of 100%.The positive predictive value of 100% and the negative predictive value of 34.8% and an overall accuracy of 88% were calculated.
In studied 23 cases of BPH, P63 was detected in 22 cases (95.7%)while one case was negative. In the 22 positive cases 18 of them (81.8%) showed diffuse nuclear expression of basal cells, and 4 of them (18.2%) showed focal nuclear expression of basal cells.
In studied 50 cases of prostatic adenocarcinoma, all cases (100%) were negative for basal nuclear cell expression. Of this 19 showed total negative staining whereas other 31(62%) showed cytoplasmic positivity of luminal cells.
On comparing the P63 expression between the studied benign group (23cases) and malignant group (50 cases), there was a marked significant difference (p< 0.001).
On studing the relation between p63 and five malignant subgroups according to Gleason’s score we cannot statically analyse the finding.
A Receiver operating characteristics (ROC) curve demonstrated the diagnostic accuracy of P63 expression as a predictive test for prostatic adenocarcinoma. There was a significant value of P63expression in prediction and detection of prostatic adenocarcinoma in comparison with benign cases, the sensitivity was 41.51% the specificity was 95.0% the positive predictive value was 95.7% and the negative predictive value was 38.0 % and an overall accuracy was 68%.
Combined use of both metallotheinin and P63 expression as a predictive test for prostatic adenocarcinomaincreased the area under the curve (AUC) into 0.776 and the p- value was highly significant (<0.001).
There was significant difference between the level of PSA and total expression of MT-2A in both benign and malignant groups, but no significant difference was found between level of PSA and expression of P63in both benign and malignant groups.