Molecular Pathology of Endometrial, Ovarian, Prostatic, and Renal Cell Carcinomas

The topography of cancer diagnosis and treatment has completely changed with the introduction of molecular pathology into routine practice. That was homogeneous disease entities are nowadays molecularly diverse neoplasms that are needed to have tailored therapy. The review scrutinizes critically molecular bases of endometrial, ovarian, prostatic, and renal cell cancers, with focus on clinically significant alterations and therapy.

Endometrial Carcinoma

Molecular Classification: Beyond Traditional Histopathology

The TCGA-based molecular classification of endometrial carcinoma represents a significant advancement over traditional histomorphologic categorization, though its implementation presents considerable challenges in routine practice:

1. POLE ultramutated: Carrying pathogenic mutations within the exonuclease domain of DNA polymerase epsilon, these tumors exhibit unprecedented mutation burdens (>100 mutations/Mb). Despite frequently ominous histopathological characteristics, these lesions uniformly exhibit excellent outcomes. The underlying mechanisms of this paradoxical behavior are incompletely understood but are likely due to increased immunogenicity.

2. Microsatellite instability (MSI)-hypermutated: Dysfunctional mismatch repair apparatus, largely due to MLH1 promoter hypermethylation (sporadic) or MMR gene germline mutations (Lynch syndrome), creates a hypermutator phenotype. Important distinctions between sporadic and inherited MMR deficiency need to be established, since genetic counseling implications are vastly different.

3.Copy-number low (endometrioid): This molecularly diverse group is often found to have CTNNB1 mutations that activate Wnt signaling. In fact, new data indicate that CTNNB1-mutated tumors in this group might constitute a clinically distinct entity with increased recurrence risk in early-stage disease—a paradigm that undermines traditional risk stratification paradigms.

4.Copy-number high (serous-like): Exhibiting high levels of chromosomal instability and nearly universal TP53 mutations, these high-grade tumors exhibit molecular characteristics in common with high-grade serous ovarian carcinomas. This molecular convergence implies shared oncogenic pathways independent of divergent tissues of origin.

Therapeutic Implications: From Molecular Classification to Precision Medicine

The molecular stratification of endometrial carcinoma has significant therapeutic implications:

•POLE-mutated tumors: There is emerging evidence to support de-escalation of adjuvant therapy, with a view to avoiding patients unnecessary treatment toxicity. Prospective validation is however yet to be completed.

•MMR-deficient tumors: Aside from their known function in Lynch syndrome screening, MMR status is now emerging as a predictive biomarker for immune checkpoint inhibition. Pembrolizumab has impressive clinical activity in recurrent/metastatic MMR-deficient tumors, with response rates up to 40-50%—dramatically better than standard chemotherapy in the recurrent setting.

•PI3K/AKT/mTOR changes: Although PI3K pathway changes are common in endometrial carcinoma (~80% of endometrioid types), single-agent PI3K pathway inhibitors have been associated with modest activity. The redundancy of pathways and complexity of feedback mechanisms require combination approaches, some of which are being explored.

Ovarian Carcinoma

Molecular Heterogeneity: Reframing a Multifaceted Disease Spectrum

Ovarian carcinoma includes heterogeneous disease entities that are anatomically located but are fundamentally different in pathogenesis:

1. High-grade serous carcinoma (HGSC): These highly aggressive cancers uniformly carry TP53 mutations and have widespread chromosomal instability. About half have homologous recombination deficiency (HRD), with BRCA1/2 mutations being the prototypical, though not sole, etiology. The phenomenon of "BRCAness"—functional HRD independent of germline BRCA mutations—has broadened the therapeutic import of this pathway.

2. Low-grade serous carcinoma: Exhibiting indolent course and MAPK pathway activation (KRAS/BRAF/NRAS mutations), these tumors exhibit poor responsiveness to standard chemotherapy. Their unique molecular pathogenesis from HGSC highlights the fallacy of viewing all "serous" carcinomas as an undifferentiated whole.

3. Clear cell carcinoma: Most often occurring in endometriosis, such carcinomas present ARID1A mutations, PIK3CA alterations, and MET amplifications. Their tumor molecular profile presents similarities to other organs' clear cell carcinomas, pointing to tissue-agnostic oncogenic patterns.

Critical Assessment of Therapeutic Targets

• PARP inhibition: The synthetic lethality principle underlies the activity of PARP inhibitors in HRD-positive ovarian cancer. Although BRCA1/2 mutations were originally the only biomarkers for PARP inhibitor efficacy, the therapeutic window has widened to encompass HRD-positive tumors, irrespective of BRCA status. Nevertheless, the best HRD assay is controversial, with varying commercial platforms exhibiting imperfect concordance.

•Antiangiogenic approaches: In spite of global approval of bevacizumab for advanced ovarian cancer, predictive biomarkers are still lacking. Clinical benefit versus toxicity requires careful patient selection beyond current clinical criteria.

•New synthetic lethality strategies: ARID1A-mutant tumors exhibit sensitivity to EZH2 inhibition, ATR inhibition, and HDAC6 inhibition in preclinical models—demonstrating how molecular weaknesses can be targeted therapeutically.

Prostatic Carcinoma

Molecular Taxonomy: Beyond Gleason Grading

Molecular classification of prostate cancer identifies distinctive oncogenic drivers with therapeutic relevance:

1. Androgen receptor (AR) signaling: Even with castration resistance, the majority of advanced prostate cancers remain AR-signaling dependent through several mechanisms: AR amplification, mutations that allow promiscuous activation, splice variants that lack the ligand-binding domain, and changes in co-regulatory factors. Elucidation of these mechanisms of resistance has propelled next-generation AR-targeted therapeutic development.

2. DNA repair deficiency: An estimated 20-25% of metastatic prostate cancers carry DNA repair gene alterations (BRCA2, ATM, CDK12, etc.). Such alterations are predictors of response to PARP inhibition and possibly to platinum-based therapy. Importantly, germline DNA repair gene alterations are enriched in the metastatic setting, highlighting the value of germline testing even in absence of overtly hereditary disease.

3. Transformation to neuroendocrine phenotype: The convergent loss of RB1 and TP53 commonly underlies treatment-emergent neuroendocrine differentiation—a deadly variant with unique therapeutic vulnerabilities. This transformation is a major mechanism of resistance to AR-directed therapies.

Precision Therapeutics: Targeting Molecular Dependencies

•AR-targeted therapy sequencing: Simultaneous use of next-generation AR antagonists (enzalutamide, apalutamide, darolutamide) and androgen synthesis inhibitors (abiraterone) shows overlapping mechanisms of resistance. AR splice variant transcription and AR genomic structural changes can inform sequencing choices, but these require prospective validation.

•PARP inhibition: Olaparib and rucaparib have shown significant activity in DNA repair-deficient prostate cancer, with 40-50% response rates in BRCA2-mutated disease. The widening indications for PARP inhibitors highlight the essential role of comprehensive genomic profiling in advanced disease.

•PSMA-targeted therapies: Prostate-specific membrane antigen expression allows for both diagnostic imaging (PSMA-PET) and therapeutic targeting (177Lu-PSMA-617), a classic example of the theranostic paradigm in contemporary oncology.

Renal Cell Carcinoma

Molecular Diversity: Beyond Histological Subtypes

The molecular taxonomy of renal cell carcinoma shows specific driver mutations in histological subtypes:

1. Clear cell RCC: In addition to the conventional VHL mutations causing constitutive HIF activation, recent work has uncovered the prognostic and potentially predictive role of chromatin remodeling gene mutations (PBRM1, SETD2, BAP1). Importantly, PBRM1 mutations are associated with favorable responses to immune checkpoint inhibition, whereas BAP1 mutations predict an aggressive phenotype.

2. Papillary RCC: Molecular differentiation between type 1 (MET-driven) and type 2 (type 2 with silencing of CDKN2A, SETD2 mutations, and TFE3 fusions) offers a rational ground for therapeutic stratification. Identification of CpG island methylator phenotype (CIMP) in a subgroup of type 2 papillary RCC with poor prognosis underlines the significance of epigenetic mechanisms.

3. Chromophobe RCC: Mitochondrial impairment is a key characteristic of these tumors, with possible therapeutic significance through metabolic vulnerabilities.

Therapeutic Paradigms: Shifting Beyond VEGF Inhibition

• Immunotherapeutic strategies: Combination of checkpoint inhibitors with either VEGF-targeted therapy or a second immunotherapeutic modality has revolutionized first-line therapy for metastatic clear cell RCC. The intricate interplay between angiogenesis, immune evasion, and tumor metabolism is the basis for these effective combination regimens.

• HIF2α inhibition: HIF2α inhibitor (belzutifan) development is a mechanistically appealing method of directly targeting the key oncogenic driver in VHL-deficient clear cell RCC. Clinical response in Von Hippel-Lindau disease and sporadic RCC validates this strategy.

• MET inhibition: Selective MET inhibitors (savolitinib) show promising activity in MET-altered papillary RCC, illustrating the oncogene addiction principle in molecular subtypes of RCC.

Molecular Diagnostic Techniques: Strengths and Limitations

Next-Generation Sequencing (NGS)

•Uses: Extensive genomic profiling becomes more routine standard of care for advanced disease. Nevertheless, there are technical and interpretative challenges, especially between distinguishing driver versus passenger alterations.

•Platform considerations: Deciding on targeted panels, whole-exome, or whole-genome methodology has trade-offs of depth, breadth, or cost. Tailored panels concentrating on clinically actionable alterations is the reasonable compromise for most clinical scenarios.

Immunohistochemistry (IHC) for Biomarker Assessment

•Applications: Notwithstanding the technological progress, IHC is still irreplaceable for protein expression analysis. Digital pathology and quantitative image analysis are improving the objectivity and reproducibility of IHC interpretation.

•Limitations: Discrepancies between genomic changes and protein expression require integrated diagnostic strategies.

Fluorescence In Situ Hybridization (FISH)

•Applications: FISH still plays a key role in identifying gene rearrangements and copy number changes, especially in situations where NGS could be compromised by tissue quality or availability.

•Evolution: RNA-based NGS methods are increasingly being used to complement or supplant FISH for fusion detection, with greater throughput and the capacity to identify new fusion partners.

Methylation Analysis

•Applications: DNA methylation profiling offers valuable diagnostic and potentially predictive information, especially in epigenetically dysregulated tumors.

•Implementation challenges: Standardization of methods and interpretative criteria is still incomplete.

The incorporation of molecular pathology into classification and treatment planning of gynecologic and urologic neoplasias is a revolution in oncology. The evolving molecular taxonomy of the tumors delivers rational targets to intervene therapeutically and with more and more accurate prognostic stratification. As molecular and cellular anatomy is better elucidated, these classic distinctions on histological borders dissolve, becoming instead molecular groupings that define better underlying biology. The future is multimodal molecular evaluation methods that reflect the complexity of such neoplasms and guide genuinely personalized therapeutic interventions. Major challenges persist in applying these advanced methods uniformly across diverse healthcare environments and in managing the dynamic behavior of cancer evolution under therapeutic stress.