Murphie Price

Background: Meigs’ syndrome is characterized by benign ovarian tumors with associated ascites and pleural effusion that resolves after removal of the tumor.^1,2 Its etiology is currently unknown as the disease is very rare, but one testable hypothesis is that the primary tumor secretes large amounts of proinflammatory factors that are associated with increased vascular permeability which leads to accumulation of fluid in the pleural and peritoneal cavities.^1,2

Lymphatic malformation (LM) is characterized by abnormal lymphatic vessel proliferation. LM can manifest in various locations and disorders include Generalized Lymphatic Anomaly (GLA) and Gorham-Stout disease (GSD).³ These diseases can often present with similar symptoms as Meigs including tissue fluid accumulation and ascites. One of the pathways implicated in LM is the PI3K/AKT/mTOR pathway. Abnormal activation of PI3K is related to the occurrence of LM. mTOR plays a regulatory role which fosters cell growth, proliferation, and lymphangiogenesis, which contributes to the formation and progression of LM. The VEGFR3 receptor is also involved in mediating lymphangiogenesis.³ Approximately 80% of LMs have been connected to PIK3CA mutations and are localized to lymphatic malformation endothelial cells (LMECs). These mutations have been connected to cancer and result in receptor-dependent hyperactivation of PI3K, amplified downstream signaling of Akt, and hyperproliferation of LMECs. Cancer treatments targeting the PI3K pathway, such as sirolimus, have been repurposed to target LMs.⁴

Objective: In this narrative review, we explored the mechanisms of how sirolimus works in lymphatic malformations.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “Meigs’ syndrome”, “sirolimus”, “lymphatic malformation”.

Results: Studies indicate that treatment with sirolimus, an mTOR inhibitor, had the greatest reduction in viability of LMECs when combined with overexpressed Ang2 compared to just Ang2 overexpression or drug treatment.⁴ In a mutant mouse model with deleted Tie receptors, results demonstrated that Ang2 inhibition decreased the VEGF-C induced lymphangiogenesis.⁷ This indicated that both the Tie receptors and endogenous Ang2 were required for VEGF-C–induced lymphangiogenesis in adult mice.⁷ Conditional expression of a PIK3CA mutation in endothelial cells led to vascular overgrowth and mutations in mice.⁶ Mutant mice were treated with sirolimus, VEGF-C trap, and both sirolimus and the VEGF-C trap. While both treatments alone prevented LM growth, combined treatment additionally demonstrated regression of the vasculature.⁶ Furthermore, the efficacy of sirolimus as a treatment for GLA and GSD was measured through a prospective clinical trial and retrospective review study. Results demonstrated that 83% of the patients had an improvement in one aspect of the disease including tissue fluid accumulation. Overall, sirolimus appeared to reduce symptoms and improve quality of life.⁸

Conclusions: The mechanism behind the cause of Meigs’ syndrome is still not fully understood or known, but it is possible that there is a link to LMs due to the characteristic pleural effusion and ascites likely driven by vascular permeability and growth. Studies have shown that sirolimus is an effective treatment for rare diseases involving complex lymphatic anomalies by suppressing lymphatic growth through its inhibition of the signaling pathways that cause abnormal vessel growth.^5,8

Works Cited:

1. Argento AC, Gillespie CT. Pleural Disease in Women.Semin Respir Crit Care Med. 2019;40(3):402-409. doi:10.1055/s-0039-1695050
2. Ferreiro L, Toubes ME, Rodríguez-Núñez N, Valdés L. Benign obstetric and gynaecological diseases associated with pleural effusion: a narrative review.Breathe (Sheff). 2025;21(1):240238. Published 2025 Feb 25. doi:10.1183/20734735.0238-2024
3. Zhang C, Liu J, Wang Y, et al. Lymphatic Malformation: Classification, Pathogenesis, and Therapeutic Strategies.Ann Vasc Surg. 2025;121:35-46. doi:10.1016/j.avsg.2025.05.028
4. Sun RW, Zhang H, Mehdi SJ, et al. Rescue of Angiopoietin-2 Inhibits Proliferation of Lymphatic Malformation Endothelial Cells.FASEB J. 2025;39(24):e71308. doi:10.1096/fj.202502078R
5. Monroy M, McCarter AL, Hominick D, Cassidy N, Dellinger MT. Lymphatics in bone arise from pre-existing lymphatics.Development. 2020;147(21):dev184291. Published 2020 Apr 20. doi:10.1242/dev.184291
6. Martinez-Corral I, Zhang Y, Petkova M, et al. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation.Nat Commun. 2020;11(1):2869. Published 2020 Jun 8. doi:10.1038/s41467-020-16496-y
7. Korhonen EA, Murtomäki A, Jha SK, et al. Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression.J Clin Invest. 2022;132(15):e155478. doi:10.1172/JCI155478
8. Ricci KW, Hammill AM, Mobberley-Schuman P, et al. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease.Pediatr Blood Cancer. 2019;66(5):e27614. doi:10.1002/pbc.27614