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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Genetics · Isolated Lymphatic Malformation

How Lymphatic Malformations Work: Biology and Subtypes

At a Glance

Isolated lymphatic malformations are caused by a random, non-inherited genetic mutation (usually in the PIK3CA gene) that overactivates the mTOR pathway. This causes abnormal, fluid-filled lymphatic cysts classified as macrocystic (large) or microcystic (small).

To understand a lymphatic malformation, it helps to think of the lymphatic system as a network of plumbing that carries clear fluid throughout the body. In a malformation, some of these “pipes” don’t develop correctly, leading to fluid-filled spaces rather than smooth channels [1][2].

The ISSVA Classification: Size Matters

Doctors use a standard system created by the International Society for the Study of Vascular Anomalies (ISSVA) to describe these malformations [1]. The main way they are classified is by the size of the fluid-filled spaces (cysts):

  • Macrocystic LMs: These consist of large, distinct pockets of fluid [3]. They are often easier to see on the surface and are frequently treated with sclerotherapy (injecting medicine directly into the cyst to shrink it) [4][5].
  • Microcystic LMs: These are made of many tiny, sponge-like channels that weave through healthy tissue [3]. Because they are more diffuse, they can be more challenging to treat and may require a combination of approaches [4].
  • Mixed LMs: Many children have a combination of both large and small cysts [3].

Why This Happens: The Biology of “Glitch”

A lymphatic malformation is caused by a somatic mutation [6]. This is a random genetic “glitch” that happens in a single cell after an egg is fertilized [7][8].

  • Not Inherited: Because the mutation happens late in development, it is only present in the malformed area, not in the rest of the child’s body or their DNA [9][10]. It is not something you passed down to your child [8].
  • Mosaicism: This means the child has two types of cells: healthy ones and ones with the mutation [9]. This is why the malformation is usually localized to one spot.

The PIK3CA and mTOR Connection

In most isolated lymphatic malformations, the “glitch” occurs in a gene called PIK3CA [11][12]. You can think of this gene as an “on” switch for cell growth.

When PIK3CA is mutated, it stays stuck in the “on” position, which hyperactivates a biological pathway called PI3K/AKT/mTOR [6][13].

  • mTOR acts like a master controller for cell growth and survival.
  • When it is constantly “hyper” or overactive, it tells the lymphatic cells to keep growing and expanding, which creates the malformed channels and cysts you see [14][6].

Understanding this pathway has been a breakthrough in medicine. It has allowed doctors to use emerging “targeted therapies”—medications that act like a “dimmer switch” to turn down that overactive growth signal [15][16]. This helps manage the malformation from the inside out, rather than just treating the surface.

Learn more about Location, Staging, and Airway Risk.

Common questions in this guide

What is the difference between macrocystic and microcystic lymphatic malformations?
Macrocystic malformations have large fluid-filled pockets and are often treated with sclerotherapy. Microcystic ones consist of tiny, sponge-like channels woven into healthy tissue, making them more challenging to treat.
Are lymphatic malformations passed down from parents?
No, they are not inherited. They are caused by a somatic mutation, which is a random genetic change that happens in a single cell after conception. This means the mutation is only in the affected area, not in your child's overall DNA.
What role does the PIK3CA gene play in lymphatic malformations?
A mutation in the PIK3CA gene acts like a stuck 'on' switch for cell growth. It overactivates the mTOR pathway, telling lymphatic cells to constantly grow and form abnormal cysts.
Will a regular blood test show a PIK3CA mutation?
Often, a standard blood test will be normal because the somatic mutation is only present in the malformed tissue itself. Testing usually requires a biopsy or fluid sample from the actual malformation to find the genetic glitch.
How does genetic testing change the treatment plan for a lymphatic malformation?
Understanding the specific genetic cause, like an overactive mTOR pathway, allows doctors to use emerging targeted therapies. These medications work from the inside out to 'turn down' the overactive growth signal, rather than just treating the surface cysts.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on the imaging, is my child's malformation macrocystic, microcystic, or a mix of both?
  2. 2.Since this is a somatic mutation, does that mean genetic testing of a blood sample might come back 'normal' even if the mutation is present in the tissue?
  3. 3.If my child has a PIK3CA mutation, are they a candidate for targeted therapies like sirolimus or alpelisib?
  4. 4.How does the size and location of these lymphatic channels affect my child's long-term treatment plan?
  5. 5.Are there any other signs of PIK3CA-related overgrowth (PROS) we should be looking for in other parts of the body?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Infiltration of M2-polarized macrophages in infected lymphatic malformations: possible role in disease progression.

    Zhang W, He KF, Yang JG, et al.

    The British journal of dermatology 2016; (175(1)):102-12 doi:10.1111/bjd.14471.

    PMID: 26873524
  2. 2

    [Diagnosis and management of vascular malformations : Interdisciplinary teamwork in demand].

    Evert K, Kühnel T, Weiß KT, et al.

    Der Pathologe 2019; (40(4)):422-430 doi:10.1007/s00292-019-0625-0.

    PMID: 31243549
  3. 3

    Treatment of isolated lymphatic malformation with the herbal medicine "Eppikajyutsuto": a retrospective multicenter study.

    Hashizume N, Kawano T, Sugita K, et al.

    Pediatric surgery international 2025; (41(1)):257 doi:10.1007/s00383-025-06161-0.

    PMID: 40828383
  4. 4

    Bleomycin for Percutaneous Sclerotherapy of Venous and Lymphatic Malformations: A Retrospective Study of Safety, Efficacy and Mid-Term Outcomes in 26 Patients.

    Nevesny F, Chevallier O, Falvo N, et al.

    Journal of clinical medicine 2021; (10(6)) doi:10.3390/jcm10061302.

    PMID: 33809919
  5. 5

    Treatment of deep-seated facial microcystic lymphatic malformations with intralesional injection of pingyangmycin.

    Wu HW, Wang X, Zheng JW, et al.

    Medicine 2016; (95(37)):e4790 doi:10.1097/MD.0000000000004790.

    PMID: 27631231
  6. 6

    Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation.

    Le Cras TD, Goines J, Lakes N, et al.

    Angiogenesis 2020; (23(3)):425-442 doi:10.1007/s10456-020-09722-0.

    PMID: 32350708
  7. 7

    De novo mutations, genetic mosaicism and human disease.

    Mohiuddin M, Kooy RF, Pearson CE

    Frontiers in genetics 2022; (13()):983668 doi:10.3389/fgene.2022.983668.

    PMID: 36226191
  8. 8

    Mosaicism in health and disease - clones picking up speed.

    Forsberg LA, Gisselsson D, Dumanski JP

    Nature reviews. Genetics 2017; (18(2)):128-142 doi:10.1038/nrg.2016.145.

    PMID: 27941868
  9. 9

    Double somatic mosaicism in Cornelia de Lange syndrome.

    Pezzani L, Pezzoli L, Rosina E, et al.

    American journal of medical genetics. Part A 2024; (194(5)):e63512 doi:10.1002/ajmg.a.63512.

    PMID: 38135466
  10. 10

    Mosaicism in Cutaneous Disorders.

    Lim YH, Moscato Z, Choate KA

    Annual review of genetics 2017; (51()):123-141 doi:10.1146/annurev-genet-121415-121955.

    PMID: 29178821
  11. 11

    Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA-related tissue overgrowth syndromes.

    Horbach SE, Jolink F, van der Horst CM

    Dermatologic therapy 2016; (29(6)):466-469 doi:10.1111/dth.12398.

    PMID: 27502552
  12. 12

    Lymphatic Malformation Responsive to Sirolimus in Keratinocytic Epidermal Nevus Syndrome with KRAS Mutation: A Case and Brief Literature Discussion.

    Sideris E, Tng ETV, Chee P

    Case reports in dermatology 2021; (13(1)):195-201 doi:10.1159/000515247.

    PMID: 34703427
  13. 13

    PI3K/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating mutations.

    di Blasio L, Puliafito A, Gagliardi PA, et al.

    Cell death & disease 2018; (9(2)):45 doi:10.1038/s41419-017-0064-x.

    PMID: 29352118
  14. 14

    Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

    Castillo SD, Tzouanacou E, Zaw-Thin M, et al.

    Science translational medicine 2016; (8(332)):332ra43 doi:10.1126/scitranslmed.aad9982.

    PMID: 27030595
  15. 15

    Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly.

    Rodriguez-Laguna L, Agra N, Ibañez K, et al.

    The Journal of experimental medicine 2019; (216(2)):407-418 doi:10.1084/jem.20181353.

    PMID: 30591517
  16. 16

    Anticancer effects of alpelisib on PIK3CA-mutated canine mammary tumor cell lines.

    Yeom J, Cho Y, Ahn S, Jeung S

    Frontiers in veterinary science 2023; (10()):1279535 doi:10.3389/fvets.2023.1279535.

    PMID: 38033642

This page explains the biology and genetics of lymphatic malformations for educational purposes only. Always consult your child's medical team for specific diagnosis, genetic testing, and treatment planning.

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