What is the etiology of malignant ascites?

Etiology of Malignant Ascites

Malignant ascites is primarily caused by extensive infiltration, metastasis, and growth of cancer cells in the peritoneal cavity, leading to abnormal fluid accumulation through multiple biological mechanisms including epithelial-mesenchymal transition, altered adhesion molecules, and complex interactions with the peritoneal microenvironment. 1, 2

Primary Cancer Types Associated with Malignant Ascites

• Ovarian cancer (26% of cases) is the most common cause of malignant ascites, followed by pancreatic (20%), gastric (17%), and colorectal cancers (14%) 3
• Gastric cancer peritoneal metastasis (GCPM) is a significant cause, accounting for between one-fifth and three-fifths of all metastatic recurrences after gastrectomy 1
• Lobular breast cancer has a unique propensity to metastasize to the peritoneum, similar to gastric cancer, due to specific molecular characteristics 1, 4
• Other primary tumors that commonly cause malignant ascites include colorectal and ovarian cancers 1

Pathophysiological Mechanisms

Tumor-Related Factors

• Epithelial-mesenchymal transition (EMT) is a critical process where epithelial cells transform into a mesenchymal phenotype with increased migratory and invasive capabilities 1, 4
• Primary gastric tumors of the EMT subtype develop peritoneal metastasis more frequently and have worse prognosis compared to non-EMT subtypes 1
• Downregulation of intercellular adhesion molecules, particularly E-cadherin, facilitates tumor cell detachment and promotes peritoneal carcinomatosis 1, 4
• High expression of discoidin domain receptor 2 (DDR2) in primary gastric tumors is significantly associated with EMT and peritoneal dissemination 1

Genomic Drivers

• TP53 mutations occur at similar rates in peritoneal metastases as in primary tumors, while CDH1 mutations are more frequent, particularly in diffuse-type gastric cancers 1
• Novel drivers such as PIGR and SOX9 have been identified in tumor cells derived from malignant ascites 1
• Somatic copy number analysis has identified amplifications in potential therapeutic targets including KRAS, FGFR2, MET, ERBB2, EGFR, and MYC 1
• Single-cell RNA sequencing has revealed that tumor cells in malignant ascites are derived from only a single clone per patient or just a few subclones 1

Paracrine Factors in the Ascitic Fluid

• Malignant ascites contains various growth factors, cytokines, chemokines, and other soluble factors that create a tumorigenic environment 1
• The TGF-β pathway is upregulated within tumor cells, with elevated levels of TGF-β1 cytokine detected in peritoneal washings of patients with gastric cancer peritoneal metastasis 1
• Inflammatory cytokines including tumor necrosis factor-α, interferon-γ, IL-6, and IL-1β increase expression of adhesion molecules on mesothelial cells 1
• Chemokines including CXCL1/CXCR1, CCL2/CCR4, and CXCL12/CXCR4 play important roles in migration, chemotaxis, proliferation, and adhesion of tumor cells 1

Peritoneal Microenvironment Factors

• The peritoneum consists of a basement membrane, mesothelial cells, and connective tissue including hyaluron, collagen, proteoglycans, and interstitial cells 1
• Localization of free-floating tumor cells to the peritoneal mesothelial lining is regulated by adhesion molecules such as CD44 and integrin and selectin superfamilies 1
• Cancer-associated fibroblasts (CAFs) and other stromal cells influence the metastatic process through crosstalk mediated by cytokines and growth factors 1, 4
• Growth factors including endothelial growth factor, hepatocyte growth factor, and VEGF induce mesothelial cell contraction, exposing the peritoneal basement membrane 1

Diagnostic Considerations

• Ascitic fluid cytology is positive only in the setting of peritoneal carcinomatosis with a sensitivity of 96.7% if three samples are sent and processed promptly 1
• The first cytology sample is positive in 82.8% of cases and at least one of two samples is positive in 93.3% 1
• Patients with peritoneal carcinomatosis usually have a history of a breast, colon, gastric, or pancreatic primary carcinoma 1
• Serum CA125 is elevated in essentially all patients with ascites of any cause and is very nonspecific; testing is not recommended in patients with ascites 1

Prognostic Implications

• Malignant ascites is associated with poor prognosis (median survival of 5.7 months following diagnosis) and significant reduction in quality of life 3, 5
• Ovarian cancer has a more favorable prognosis compared to other malignancies causing ascites 5
• Independent prognostic factors for survival include cancer type, presence of liver metastases, and serum albumin levels 5
• Low serum albumin, low serum protein, and liver metastases adversely affect survival 5