Skip to main content

Complex lymphatic anomalies (CLA)

Complex lymphatic anomalies (CLA) comprise several high-risk disorders. These disorders can involve the soft tissue, lungs, liver, spleen, intestines, and bones. They can also cause a conduction problem in which the "plumbing system" of the lymphatics is abnormal leading to pleural effusion, pericardial effusion, ascites and edema of the extremities. These conditions can also cause loss of bone and stability leading to infection, paralysis, and death.

Includes Several diagnoses:

Generalized Lymphatic Anomaly (GLA)

  • Multifocal LMs that commonly involves bone, viscera (liver, spleen, lungs), soft tissues, thoracic and abdominal cavities
  • Bone involvement is typically appendicular, osteolytic (“punched out” lesions with intact cortex)
  • Clinical severity depends on location and extent (thoracic involvement has worse prognosis)
  • Associated with variants in PIK3CA and BRAF

Gorham Stout Disease (GSD)

  • “Vanishing bone disease”
  • Progressive osteolysis and complete loss of bone due to abnormal lymphatic proliferation/invasion of bone
  • Favors axial skeleton (including cervical spine, skull)
  • Regional disease (can progress to involve adjacent bones, soft tissues, viscera), not multifocal
  • Results in pain, loss of function, CNS issues (CSF leak, meningitis, neurologic injury)
  • Associated with variants in KRAS

Kaposiform Lymhangiomatosis (KLA)

  • Clinically similar to GLA, with multifocal LMs that commonly involves bone, viscera (liver, spleen, lungs), soft tissues, thoracic and abdominal cavities
  • Histologically distinct, with kaposiform spindle-shaped lymphatic endothelial cells
  • Commonly associated with hemorrhagic effusions and coagulopathy (though not always)
  • Higher morbidity and mortality than GLA (survival rate 34% when first described), secondary to multi-organ system dysfunction, respiratory failure, hemorrhage, infection
  • Associated with variants in NRAS, KRAS, CBL, PIK3CA

Central Conducting Lymphatic Anomaly (CCLA)

  • Encompasses a wide range of disorders with primary issue being an abnormal central conducting anomaly. CCLA can be associated with KLA, GSD and GLA but also germline issues and associated with other syndromes such as Noonan syndrome, Turner syndrome, and down syndrome to name a few.
  • Dysfunction of thoracic duct and/or cisterna chylae, resulting in reflux or leakage of lymphatic fluid
  • Can lead to pleural effusion, pericardial effusion, ascites, anasarca, bony lesions, PLE
  • Can result in life-threatening infection, organ dysfunction, coagulopathy/thrombosis, nutritional deficiencies
  • Can be primary or secondary; associated with multiple genes (ARAF, EPHB4, BRAF, KRAS, RASA-1, PIEZO1, GATA2, MDFIC, HRAS etc.) and genetic syndromes (e.g., Noonan syndrome)
  • Treatment: procedural and pharmacologic interventions and supportive measures.

References

Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015 Feb;167A(2):287-95. doi: 10.1002/ajmg.a.36836. Epub 2014 Dec 31. PMID: 25557259; PMCID: PMC4480633.

Qiao C, Richter GT, Pan W, Jin Y, Lin X. Extracranial arteriovenous malformations: from bedside to bench. Mutagenesis. 2019 Dec 19;34(4):299-306. doi: 10.1093/mutage/gez028. PMID: 31613971.

Borst AJ, Britt A, Adams DM. Complex lymphatic anomalies: Molecular landscape and medical management. Semin Pediatr Surg. 2024 Jun;33(3):151422. doi: 10.1016/j.sempedsurg.2024.151422. Epub 2024 May 22. PMID: 38833763.

Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, Burrows P, Frieden IJ, Garzon MC, Lopez-Gutierrez JC, Lord DJ, Mitchel S, Powell J, Prendiville J, Vikkula M; ISSVA Board and Scientific Committee. Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics. 2015 Jul;136(1):e203-14. doi: 10.1542/peds.2014-3673. Epub 2015 Jun 8. PMID: 26055853.

Kunimoto K, Yamamoto Y, Jinnin M. ISSVA Classification of Vascular Anomalies and Molecular Biology. Int J Mol Sci. 2022 Feb 21;23(4):2358. doi: 10.3390/ijms23042358. PMID: 35216474; PMCID: PMC8876303.

Reynolds G, Cardaropoli S, Carli D, Luca M, Gazzin A, Coppo P, La Selva R, Piglionica M, Bagnulo R, Turchiano A, Ranieri C, Resta N, Mussa A. Epidemiology of the disorders of the Pik3ca-related overgrowth spectrum (Pros). Eur J Hum Genet. 2023 Nov;31(11):1333-1336. doi: 10.1038/s41431-023-01414-9. Epub 2023 Jun 26. PMID: 37365400; PMCID: PMC10620148.

Penington A, Phillips RJ, Sleebs N, Halliday J. Estimate of the Prevalence of Vascular Malformations. Journal of Vascular Anomalies. 4(3):p e068, September 2023. | DOI: 10.1097/JOVA.0000000000000068

Ryu JY, Chang YJ, Lee JS, Choi KY, Yang JD, Lee SJ, Lee J, Huh S, Kim JY, Chung HY. A nationwide cohort study on incidence and mortality associated with extracranial vascular malformations. Sci Rep. 2023 Aug 25;13(1):13950. doi: 10.1038/s41598-023-41278-z. PMID: 37626114; PMCID: PMC10457363.

Rosenberg M. Most Populous Metropolitan Areas in the United States. ThoughtCo. Jun. 7, 2024.

Montez JK, Beckfield J, Cooney JK, Grumbach JM, Hayward MD, Koytak HZ, Woolf SH, Zajacova A. US State Policies, Politics, and Life Expectancy. Milbank Q. 2020 Sep;98(3):668-699. doi: 10.1111/1468-0009.12469. Epub 2020 Aug 4. PMID: 32748998; PMCID: PMC7482386.

Lawton MT, Rutledge WC, Kim H, Stapf C, Whitehead KJ, Li DY, Krings T, terBrugge K, Kondziolka D, Morgan MK, Moon K, Spetzler RF. Brain arteriovenous malformations. Nat Rev Dis Primers. 2015 May 28;1:15008. doi: 10.1038/nrdp.2015.8. PMID: 27188382.