Introduction

Prostate adenocarcinoma ranks as the second most common cancer diagnosed in males worldwide and a leading cause of cancer-related mortality [1]. Its incidence escalates sharply with age, remaining rare before 40 years but surging particularly after the seventh decade [2]. Early-stage disease exhibits heterogeneous behavior, with many tumors remaining indolent over years, while others progress aggressively, leading to death within a few years. In contrast, benign prostatic hyperplasia (BPH) affects 20% of men at the age of 40 years and nearly 90% by the eighth decade, causing substantial urological morbidity via lower urinary tract symptoms but lacking malignant potential [3]. Both conditions predominantly afflict elderly men, yet prostate adenocarcinoma differs markedly from BPH in its morbidity. Pathogenesis involves hormonal, genetic, and environmental factors, culminating in sequential genetic alterations, including early inactivation of tumor-suppressor genes [4].

Diagnosis integrates digital rectal examination, serum prostate-specific antigen (PSA) testing, multiparametric MRI, and biopsy [5]. Grading is performed using the modified Gleason system and World Health Organization (WHO) Prognostic Grade Groups. Grade Group 1 (≤6) indicates low-risk; Group 2 (3+4=7) and Group 3 (7) represent intermediate-risk; and Group 4 (8) and Group 5 (9-10) signify high-risk, poorly differentiated tumors [6]. The molecular pathogenesis of prostate adenocarcinoma centrally involves dysregulation of the PI3K/AKT/mTOR pathway, occurring in 30-50% of cases. Normally, receptor tyrosine kinases activate PI3K to generate PIP3, which recruits and activates Akt to promote cell growth and survival [7]. The tumor suppressor PTEN negatively regulates this pathway by dephosphorylating PIP3. PTEN loss - through deletion, mutation, or epigenetic silencing - causes Akt hyperactivation, driving uncontrolled proliferation [8]. Additionally, inactivation of the TP53 tumor suppressor, through mutation or deletion, contributes to genomic instability and resistance to apoptosis [9]. This pathway dysregulation, alongside ETS gene fusions, facilitates tumor progression and the development of castration-resistant prostate adenocarcinoma.

Prostate adenocarcinoma has a relatively low frequency of TP53 mutations, which are of two types: wild-type p53 protein that shows weak, focal, or heterogeneous nuclear staining because of transient physiological stabilization in response to cellular stress, and mutant p53 protein that commonly demonstrates strong, diffuse nuclear accumulation owing to its prolonged half-life. Conversely, certain TP53 mutations may result in complete absence of p53 staining (null pattern), but this rate increases substantially in castrate-resistant, locally advanced, and metastatic tumors. Loss of p53 is associated with higher tumor grade, advanced stage, increased lymph node metastasis, and poorer response to therapy. Immunohistochemical studies demonstrate that abnormal p53 expression due to accumulation of dysfunctional protein and correlates with aggressive clinical behavior, lymphovascular invasion, and extra-prostatic spread [10]. Ki-67 expression rises progressively from normal prostate through premalignancy to carcinoma, exceeding that in BPH, while p53 overexpression correlates with advancing stage and Gleason score [11].

Ki-67 and p53 show promise but yield inconsistent independent prognostic value in prostate adenocarcinoma. Therefore, this study evaluates immunohistochemical expression of p53 and Ki-67 in BPH and prostate adenocarcinoma, correlating findings with Gleason score and serum PSA levels.