What is the etiology of peritoneal carcinomatosis?

Etiology of Peritoneal Carcinomatosis

Peritoneal carcinomatosis arises primarily through transcoelomic spread from intra-abdominal malignancies, most commonly gastrointestinal and gynecological cancers, through a complex multistep process involving tumor cell dissociation, peritoneal cavity dissemination, and implantation on peritoneal surfaces. 1, 2

Primary Cancer Origins

The most common primary malignancies causing peritoneal carcinomatosis include:

• Gastrointestinal cancers are the predominant source, with gastric cancer accounting for peritoneal metastases in nearly one-third of patients at diagnosis 3
• Colorectal cancer frequently presents with peritoneal carcinomatosis as the second most common site of distant metastasis 4
• Gynecological malignancies, particularly ovarian cancer, demonstrate high propensity for peritoneal spread 3
• Lobular breast cancer represents a unique entity with peritoneal metastatic patterns similar to gastric cancer, driven by specific molecular characteristics 3, 1

Pathophysiologic Mechanisms

Three Major Molecular Pathways

Peritoneal carcinomatosis develops through three primary mechanisms that may occur independently or in combination 5:

1. Direct dissemination from the primary tumor through breach of the serosal surface (pT4a disease) 3
2. Primary peritoneal malignancy arising de novo from peritoneal tissues 5
3. Independent origins where primary tumor and peritoneal implants develop through separate molecular events 5

Tumor Cell Dissociation and Spread

Epithelial-mesenchymal transition (EMT) is the critical initial process enabling peritoneal carcinomatosis 3, 1, 2:

• EMT transforms epithelial cells into a mesenchymal phenotype with increased migratory capacity, invasive capability, and resistance to anoikis (detachment-induced cell death) 3
• Primary gastric tumors of the EMT subtype develop peritoneal metastases more frequently and demonstrate the worst prognosis compared to non-EMT subtypes 3, 2
• Downregulation of E-cadherin and other intercellular adhesion molecules facilitates tumor cell detachment from the primary site 3, 1

Genomic Drivers

Specific genetic alterations promote peritoneal carcinomatosis 3, 2:

• CDH1 mutations occur more frequently in peritoneal metastases, particularly in diffuse-type gastric cancers 3, 2
• TP53 mutations are present at similar rates in peritoneal metastases as primary tumors 3, 2
• Novel drivers including PIGR (polyimmunoglobulin receptor) and SOX9 (embryonic developmental pathway gene) have been identified in malignant ascites 3, 2
• Amplifications in KRAS, FGFR2, MET, ERBB2, EGFR, and MYC represent actionable therapeutic targets 3

Peritoneal Microenvironment Interactions

Anatomical Factors

The peritoneum provides a unique microenvironment that facilitates tumor implantation 3, 1:

• The peritoneum consists of basement membrane, mesothelial cells, and connective tissue (hyaluron, collagen, proteoglycans) that tumor cells exploit for adhesion 3
• Tumor implants preferentially locate in areas of physiological peritoneal fluid stasis: pelvic reflections, paracolic gutters, sigmoid mesocolon, ileocolic area, and right subdiaphragmatic space 6

Paracrine Signaling

Malignant ascites creates a tumorigenic environment through soluble factors 3, 2:

• Growth factors, cytokines (IL-6, IL-8), and chemokines (CXCL1/CXCR1, CCL2/CCR4) promote tumor cell survival and proliferation 3, 1
• TGF-β pathway activation increases collagen and fibronectin deposition, facilitating tumor cell adhesion to peritoneal surfaces 1
• Cancer-associated fibroblasts and stromal cells influence metastatic progression through cytokine-mediated crosstalk 1

Routes of Peritoneal Seeding

Direct Serosal Breach

Tumor infiltration through the peritoneal surface (pT4a) represents the most common mechanism 3:

• Requires tumor cells visible on the peritoneal surface, free in the peritoneal cavity, or separated from the peritoneal surface only by inflammatory cells 3
• Tumor perforation is classified as pT4a without requiring documented tumor cells on the peritoneal surface 3
• Discontinuous peritoneal deposits must be distinguished from direct peritoneal involvement, as the former represents distant metastatic disease (pM1c) 3

Transcoelomic Spread

Following serosal breach, tumor cells disseminate through three main pathways 1:

• Lymphatic spread through peritoneal lymphatic channels
• Hematogenous dissemination via blood vessels
• Direct cavity dissemination with free-floating tumor cells in peritoneal fluid 1

Clinical Presentation Patterns

Synchronous vs. Metachronous Disease

• Synchronous peritoneal carcinomatosis occurs simultaneously with primary cancer diagnosis, with increasing incidence (18% to 26.5% over 2008-2017 in gastric cancer) 3
• Metachronous peritoneal carcinomatosis develops 7-32% of the time after curative gastrectomy, typically within 8.5-26 months post-surgery, accounting for one-fifth to three-fifths of all metastatic recurrences 3, 2

Critical Pitfalls

Imaging limitations create diagnostic challenges 3:

• CT sensitivity for peritoneal metastases is only 28-51% despite 97-99% specificity 3
• Diffuse-type gastric cancers (mucinous, signet ring cell) demonstrate lower 18F-FDG uptake on PET-CT, limiting detection 3
• Diagnostic laparoscopy with peritoneal washings should be strongly considered before initiating systemic chemotherapy in all patients with proven gastric cancer to detect occult peritoneal disease 3

Molecular heterogeneity affects treatment response 3:

• Peritoneal metastases may harbor different genomic alterations than the primary tumor, necessitating separate tissue profiling for targeted therapy selection 3
• The peritoneal-plasma barrier and poor cancer tissue vascularity result in poor response to systemic chemotherapy, requiring consideration of peritoneal-directed strategies 3