Prostate cancer is a biologically heterogeneous disease that affects the prostate gland, a small gland in males located below the bladder and in front of the rectum. The prostate plays a critical role in producing seminal fluid. Prostate cancer can range from slow-growing tumors that may never cause symptoms or require treatment, to highly aggressive forms that metastasize rapidly and result in significant morbidity and mortality. It is the second most common cancer in men worldwide and remains a major public health concern, especially in aging populations.
Histological Grading: Gleason Score and Grade Group
One of the most fundamental aspects of prostate cancer diagnosis and prognosis is the histologic grading of the tumor, typically determined via a prostate biopsy. The Gleason scoring system, developed in the 1960s by Dr. Donald Gleason, is still in widespread use (with refinements). It is based on the architectural patterns of prostate cancer cells under a microscope, assigning two grades: the most prevalent pattern (primary) and the second most prevalent (secondary), each ranging from 1 (well differentiated) to 5 (poorly differentiated). These are summed to produce a Gleason score from 6 (3+3) to 10 (5+5).
In modern pathology, Gleason patterns 1 and 2 are rarely diagnosed, so clinically relevant Gleason scores start from 6. The International Society of Urological Pathology (ISUP) has since introduced a Grade Group system to simplify prognostic communication:
- Grade Group 1: Gleason score 6 (3+3)
- Grade Group 2: Gleason 7 (3+4)
- Grade Group 3: Gleason 7 (4+3)
- Grade Group 4: Gleason 8 (4+4, 3+5, or 5+3)
- Grade Group 5: Gleason 9–10 (4+5, 5+4, 5+5)
Higher Gleason scores and Grade Groups correlate with worse prognosis and greater likelihood of metastasis.
Molecular and Genetic Characteristics
Prostate cancer has a complex and varied genomic landscape, with different molecular alterations driving tumor initiation and progression. These changes can be used for classification, risk stratification, and even targeted therapy in some cases.
Common Genetic Alterations:
- TMPRSS2-ERG Fusion: Present in about 50% of prostate cancers, this fusion gene results from the androgen-responsive TMPRSS2 gene fusing with the ERG oncogene, promoting invasion and cancer progression. It is more common in European populations.
- PTEN Loss: A tumor suppressor gene involved in regulating the PI3K/AKT pathway. PTEN loss is associated with aggressive disease and resistance to therapy.
- TP53 Mutations: Often found in advanced or castration-resistant prostate cancer (CRPC), TP53 mutations impair DNA repair and cell cycle regulation.
- BRCA1/BRCA2 Mutations: While commonly associated with breast and ovarian cancer, these mutations also significantly elevate prostate cancer risk. BRCA2 in particular is associated with early-onset, aggressive disease.
- HOXB13 Mutations: The G84E variant of the HOXB13 gene is linked to hereditary prostate cancer and may serve as a genetic marker for familial risk.
Epigenetic Changes and Methylation Patterns:
Hypermethylation of promoter regions (e.g., GSTP1) is a common and early event in prostate carcinogenesis, used in molecular diagnostics like the ConfirmMDx test to predict repeat biopsy necessity. Epigenetic regulation also influences tumor heterogeneity and progression.
Molecular Subtypes and Genomic Classifiers
Large-scale genomic studies, including The Cancer Genome Atlas (TCGA), have led to the classification of prostate cancer into distinct molecular subtypes, including:
- ETS-fusion positive (e.g., TMPRSS2-ERG)
- SPOP mutant
- FOXA1 mutant
- IDH1 mutant
These subtypes have implications for prognosis and therapy. Tools such as Decipher, Oncotype DX, and Prolaris are genomic classifiers used in clinical practice to guide decision-making, particularly for determining the benefit of adjuvant therapy or the suitability of active surveillance.
Metabolic Characteristics of Prostate Cancer
Unlike many other cancers that primarily rely on aerobic glycolysis (Warburg effect), prostate cancer has unique metabolic features. Normal prostate cells have an unusual metabolic phenotype in which they accumulate and secrete high levels of citrate. This is due to suppression of mitochondrial aconitase activity by high zinc levels. During malignant transformation, cancerous cells lose the ability to accumulate zinc, leading to restored aconitase activity and a shift toward oxidative phosphorylation and lipid synthesis.
This metabolic reprogramming supports rapid cell proliferation and can serve as a potential therapeutic target. Moreover, prostate cancer cells often exhibit increased lipid metabolism, particularly de novo fatty acid synthesis (mediated by enzymes like FASN – fatty acid synthase). PET imaging using radiolabeled acetate or choline takes advantage of this metabolic shift for tumor visualization.
Tumor Microenvironment and Immune Evasion
The prostate cancer microenvironment is immunosuppressive, which makes immunotherapy less effective compared to cancers like melanoma or non-small cell lung cancer. Key characteristics include:
- Low tumor mutational burden (TMB): Fewer neoantigens make immune recognition harder.
- Poor T-cell infiltration: Tumors are often “cold,” lacking cytotoxic T-cell presence.
- Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs): These immunosuppressive cells are enriched in the prostate tumor microenvironment.
However, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, though rare in prostate cancer (~3%), are responsive to immune checkpoint inhibitors like pembrolizumab.
Androgen Receptor (AR) Signaling and Resistance
Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer, exploiting the dependency of most prostate tumors on androgen receptor signaling. However, castration-resistant prostate cancer (CRPC) eventually develops, characterized by:
- AR gene amplification or overexpression
- AR splice variants (e.g., AR-V7) that are constitutively active and insensitive to traditional anti-androgens
- Intratumoral androgen synthesis
These adaptations allow cancer cells to continue proliferating despite systemic androgen deprivation. Next-generation androgen pathway inhibitors like enzalutamide, apalutamide, and abiraterone have been developed to overcome some of these mechanisms, but resistance remains a major clinical hurdle.
Neuroendocrine and Variant Histologies
In a subset of advanced cases, prostate cancer undergoes lineage plasticity and transforms into neuroendocrine prostate cancer (NEPC), a highly aggressive variant that does not rely on AR signaling. This form often emerges after intense AR pathway inhibition and is characterized by:
- Loss of RB1 and TP53
- Expression of neuroendocrine markers like synaptophysin and chromogranin
- Resistance to conventional hormone therapy
NEPC is typically managed with platinum-based chemotherapy, similar to small-cell lung cancer.
Future Directions and Emerging Therapies
The landscape of prostate cancer therapy is rapidly evolving with advances in precision medicine. Promising areas include:
- PARP inhibitors: Particularly effective in BRCA-mutated and HRR-deficient tumors (e.g., olaparib, rucaparib).
- Radioligand therapy: PSMA-targeted agents like [177Lu]Lu-PSMA-617 (Pluvicto) deliver targeted radiation to PSMA-expressing tumor cells.
- Bispecific T-cell engagers (BiTEs) and CAR-T therapies targeting PSMA or other prostate antigens.
- Combination therapies: Pairing immunotherapy with radiation, PARP inhibitors, or anti-androgens to synergistically overcome resistance.
Conclusion
Prostate cancer is a multifaceted disease that spans a spectrum from indolent to highly lethal forms. The modern understanding of its biology, encompassing histologic grading, genomic profiling, metabolic shifts, and treatment resistance mechanisms, allows for increasingly personalized treatment. Yet, challenges remain, especially in managing advanced and resistant disease. Ongoing research into tumor evolution, immune evasion, and molecular vulnerabilities promises to reshape the future of prostate cancer management, offering hope for more effective and durable therapies.
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