Last updated:
June 17, 2021
Years published: 1989, 2000, 2002, 2011, 2016, 2019, 2021
NORD gratefully acknowledges Sheila Ganti, PhD, Clinical Research Coordinator, Vascular Anomalies/Otolaryngology, Research Coordinator Core/CCTR, Seattle Children’s Hospital, and Jonathan A. Perkins, DO, Professor of Otolaryngology/Head and Neck Surgery, University of Washington, Attending Pediatric Otolaryngologist, Seattle Children’s Hospital, for assistance in the preparation of this report.
Summary
Lymphatic malformations are rare, non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system. These malformations are usually apparent at birth or by two years of age. Lymphatic malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. When evident at birth (congenital), lymphatic malformations tend to be soft, spongy, non-tender masses. The specific symptoms and severity of lymphatic malformations varies based upon the size and specific location of the malformation. Some lymphatic malformations can be massive. Lymphatic malformations, regardless of size, can potentially cause functional impairment of nearby structures or organs and disfigurement of affected areas.
Introduction
The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that transport a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it passes through a network of lymph nodes that help the body remove sources of infection (e.g., viruses, bacteria, etc.) and inflammation (e.g. antigens). Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows and in the chest, abdomen and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells.
Several different terms were once used to describe conditions now grouped under the umbrella term “lymphatic malformations.” Such terms include cystic hygroma, lymphangioma, cavernous lymphangioma, cystic lymphangioma and lymphangioma circumscriptum. These terms have been abandoned because some of the outdated terms imply a relationship to cancer. Lymphatic malformations are not cancerous and there is no known risk of malignant transformation.
Generally, symptoms from lymphatic malformations arise from compression or obstruction of nearby structures. Lymphatic malformations can involve any tissue. Usually they are found in only one area of the body (localized), but occasionally can be widespread (diffuse). When lymphatic malformations are widespread in bone and soft tissue, the condition may be referred to as lymphangiomatosis. Lymphatic malformations usually slowly grow larger as the patient grows, but sometimes get smaller spontaneously. Certain events such as puberty, infection, trauma or bleeding into a lymphatic malformation can cause them to grow rapidly.
It is important to note that affected individuals may not have all of the symptoms discussed below and that one child’s experience can vary dramatically from another child’s experience. Parents of affected children should talk to their physician and medical team about their child’s specific case, associated symptoms and overall prognosis. The specific symptoms that develop depend upon the size and exact location of a lymphatic malformation.
Lymphatic malformations are associated with overgrowth (hypertrophy) and swelling of any affected area including the lips, tongue, jaws, cheeks, arms, legs, fingers or toes. Malformations affecting the tongue, windpipe (trachea) or mouth can cause difficulty breathing (dyspnea), difficulties with speech and difficulty swallowing (dysphagia) and feeding problems. If the eye socket (orbit) is involved, double vision (diplopia) or displacement of the eyeball can occur (proptosis). Lymphatic malformations affecting the chest can cause wheezing, chest pain, chest pressure, shortness of breath, difficulty breathing and potentially airway compromise. Lymphatic malformations affecting the gastrointestinal tract or pelvis can cause constipation, bladder obstruction, recurrent infection or protein loss. Lesions in bone can be associated with bone overgrowth or bone loss.
Certain complications can occur with lymphatic malformations including recurrent inflammation or bleeding (hemorrhaging) into the malformation. When lymphatic malformations become inflamed, they swell, and the skin in the involved area becomes red and warm. This is known as cellulitis. Recurrent cellulitis can cause pain and disfigurement of the affected area. Some patients with lymphatic malformation have abnormally low numbers of lymphocytes which make them prone to cellulitis. Bleeding into a lymphatic malformation can cause rapid pain, hardening, and swelling or enlargement of the malformation in the affected area.
Radiographically lymphatic malformations have been categorized into three subtypes – macrocystic, microcystic or mixed (a combination of the other two). Macrocystic and microcystic lymphatic malformations are differentiated by the size of the fluid-containing portion of the malformation. The macrocystic type is made up of large cysts, more than 2 centimeters in diameter; the microcystic type is made up of smaller cysts or soft tissue enlargement without cyst formation. Most lymphatic malformations have both macrocystic and microcystic portions and histologically there is no difference between these categories. Macrocystic lymphatic malformations are characterized by a single or multiple fluid-filled pockets or cysts that occur most commonly in the nape of the neck. Macrocystic lymphatic malformations generally form soft, large translucent masses that can involve any area of the neck or chest. Overlying skin may have a bluish tinge. Although macrocystic lymphatic malformations typically appear on the back of the neck, they can, less frequently, originate near the armpits (axilla), in the groin, in the rear of the abdominal cavity, in the chest wall or in the hip or tailbone region. Macrocystic lymphatic malformations can potentially be extremely large, even large enough to obstruct the airway at delivery.
Microcystic lymphatic malformations may appear as several small, raised sacs (vesicles) on the skin that contain clear or bloody (hemorrhagic) fluid. They generally grow slowly usually in proportion with a growing child. Microcystic lymphatic malformations can thicken or swell causing enlargement of surrounding soft tissue and bones. They can be found on any area of skin or mucous membrane.
The exact cause of lymphatic malformations is unknown. Lymphatic malformations result from abnormalities in the development of the lymphatic vascular system during embryonic growth. In a large number of patients, the lymphatic malformations have an activating mutation in the PIK3CA gene. This is a somatic (non-inherited) mutation isolated to the lymphatic endothelial cells lining the fluid filled channels. PIK3CA is known to play a role in regulating cell growth by signaling through the PI3K/mTOR pathway. Five different point mutations in DNA from lymphatic malformation tissue have been identified. It is unclear, however, if mutations in the PIK3CA gene alone cause lymphatic malformations. Sometimes the term “PROS” (PIK3CA-related overgrowth syndrome) is used to describe instances when both a PIK3CA mutation has been detected and overgrowth of the affected area is present.
Lymphatic malformations may occur in-utero as a part of a larger syndrome. These include: Noonan syndrome, Turner syndrome and Down syndrome. Usually, lymphatic malformations detected prenatally regress and are absent at birth. Lymphatic malformations are also a feature of CLOVES syndrome and Klippel-Trenaunay syndrome (KTS). (For more information these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Lymphatic malformations affect males and females in equal numbers. Most lymphatic malformations are evident at birth or within two years of age. However, in some patients, lymphatic malformations may not become apparent until adulthood. The exact prevalence of lymphatic malformations in the general population is unknown, but is thought to be approximately 1:4000 live births.
A diagnosis of lymphatic malformation can often be made before birth (prenatally) using ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. After birth, a diagnosis of a lymphatic malformation is made based upon a physical examination along with a detailed patient history.
Advanced imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT) scanning and ultrasound may be used to evaluate the extent of a lymphatic malformation after birth. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
Genetic testing of malformation tissue for PIK3CA or other gene variants is available and can be used direct treatment planning (https://www.ncbi.nlm.nih.gov/gtr/tests/570484/).
Treatment
The treatment of lymphatic malformations is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric surgeons, neurosurgeons, ear-nose-throat specialists (otolaryngologists), speech pathologists, eye specialists (ophthalmologists) and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment.
Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the exact size and location of a lymphatic malformation; the presence or absence of certain symptoms; the child’s age and overall health; the child’s tolerance of certain medications or treatments; personal preference and/or other elements. Decisions concerning the use of particular drugs and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient and/or parents based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. For lymphatic malformations of the head and neck, staging systems have been developed that help guide treatment planning and predict treatment outcome.
The main therapeutic options for treating a lymphatic malformation are active observation, percutaneous drainage, surgery, sclerotherapy, laser therapy, radiofrequency ablation or medical therapy. These different treatment options may be used in various combinations. Some lymphatic malformations have gone away without any therapy (spontaneous resolution), so observation is a viable treatment option in some cases.
Percutaneous drainage is a procedure during which an incision is made into a lymphatic malformation and the fluid is drained, usually through a catheter or similar device. Percutaneous drainage is often performed along with surgery or sclerotherapy, as the drained cyst fluid can re-accumulate.
Generally, macrocystic lymphatic malformations can be treated effectively and usually do not recur. Mixed and microcystic lymphatic malformations are often more difficult to treat as they do not respond as well to conventional therapies. There is a risk of recurrence of lymphatic malformations regardless of the treatment choice. Mixed and microcystic lymphatic malformations are more likely to recur and may require repeated therapies. In some cases, lymphatic malformations require lifelong therapy.
Sclerotherapy is a procedure in which a solution called a sclerosant or sclerosing agent, is injected directly into the macrocystic lymphatic malformation. This solution causes scarring within the lymphatic malformation, which eventually causes it to shrink or collapse. Most moderately sized macrocystic lymphatic malformations can be easily treated with sclerotherapy. Although the popularity of sclerotherapy for lymphatic malformations is increasing, there is no specifically favored or agreed upon sclerosing agent used. Agents that have been used include alcohol, bleomycin, picinabil (OK-432), doxycycline, acetic acid and hypertonic saline. Sclerotherapy may require multiple sessions to be effective, especially in extensive malformations.
Some lymphatic malformations, especially those that are localized to one area of the body, may be surgically removed (excised). The aim of surgery to remove a lymphatic malformation is to regain function of an affected area and prevent disfiguring complications. The exact location of a lymphatic malformation, such as proximity to a vital organ, may dictate only partial removal of the malformation. However, partial removal of a malformation may be sufficient to prevent complications. In some cases, the involvement of vital organs or structures makes surgical removal of a lymphatic malformation impossible.
Laser therapy is sometimes used to treat individuals with lymphatic malformations that involve the skin or mucous membranes. Multiple treatments spaced out over time may be required, and laser therapy is usually used in combination with other treatment options.
Radiofrequency ablation has been used to treat individuals with superficial skin or mucosal lymphatic malformations. During this procedure, a small needle is inserted into a lymphatic malformation. The needle is used to deliver a high-frequency alternating current (radiofrequency waves) that destroys (ablates) affected lymphatic vessel tissue. Initial reports show marked improvement or complete resolution of individuals treated with radiofrequency ablation. More research is necessary to determine the long-term safety and effectiveness of this potential therapy and other therapies for individuals with lymphatic malformations.
Medical therapy with the drugs sirolimus or sildenafil can be used to treat both localized and diffuse lymphatic malformations. Sirolimus is most commonly used to treat cancer and is only recently prescribed to treat lymphatic malformations. This drug is taken orally, and it works by inhibiting cell growth by targeting the PI3K/mTOR pathway. How long an individual should take sirolimus remains to be determined. Sildenafil is also taken orally. It has been shown, in a small number of patients, to shrink lymphatic malformations. This drug allows blood and lymphatic vessel walls to relax, and this leads to decreased fluid collection. Clinical trials are underway to establish dosing guidelines and to compare these drugs to other treatment options. In the future it may be possible to use targeted medical therapies to inhibit PIK3CA gene variant activity in lymphatic malformations.
Additional treatment for individuals with lymphatic malformations may be necessary based on the extent to which the malformation impairs normal breathing, eating and speaking. For example, airway compromise and difficulty breathing may ultimately require treatment with a tracheotomy, a procedure by which a tube is inserted into the throat through an incision in the windpipe, in order to achieve airway stabilization. If eating is impaired, a modified diet and/or gastrostomy tube may be necessary. Some children may require reconstructive surgery for the jaw bones because of overgrowth caused by the penetration of a lymphatic malformation. Infections may require antibiotics. Pain medication and anti-inflammatory medications may also be used in some cases.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXBOOKS
Gangi A, Guth S, Guermazi A, Eds. Imaging in Percutaneous Musculoskeletal Interventions. Springer, Germany;2009:378-379.
JOURNAL ARTICLES
Bertino F, Trofimova AV, Gilyard SN, Hawkins CM. Vascular anomalies of the head and neck: diagnosis and treatment. Pediatr Radiol. 2021. Online ahead of print.
Bonilla-Velez J, Whitlock KB, Ganti S, Theeuwen HA, Manning SC, Bly RA, Dahl JP, Perkins JA. Active observation as an alternative to invasive treatments for pediatric head and neck lymphatic malformations. Laryngoscope. 2021;131(6): 1392-1397.
Zenner K, Jensen DM, Cook TT, et al. Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations. Genet Med. 2021; 23(1): 123-130.
Venot Q, Blanc T, Rabia SH, et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018; 558(7711): 540-546.
Adams DM, Trenor CC, Hammill AM, et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics. 2016;137(2):e20153257.
Luks VL, Kamitaki N, Vivero MP, et al. Lymphatic and other vascular malformative/overgrowth disorders are cause by somatic mutations in PIK3CA. J Pediatr. 2015;166(4):1048-54.
Osborn AJ, Dickie P, Neilson DE, Glasser K, Lynch KA, Gupta A, Dickie BH. Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations. Hum Molec Genet. 2015;24(4):92-38.
Impellizzeri P, Romeo C, Borruto FA, et al. Sclerotherapy for cervical cystic lymphatic malformation. Our experience with computed tomography-guided 98% sterile ethanol insertion and a review of the literature. J Pediatr Surg. 2010;45:2573-2478.
Perkins JA, Manning SC, Tempero RM, et al. Lymphatic malformations: review of current treatment. Otolaryngol Head Neck Surg. 2010;142:795-803.
Perkins JA, Manning SC, Tempero RM, Cunningham MJ, Edmonds JL, Jr., Hoffer FA, Egbert MA. Lymphatic malformations: current cellular and clinical investigations. Otolaryngol Head Neck Surg. 2010;142(6):789-794.
Smith MC, Zimmerman MB, Burke DK, Bauman NM, Sato Y, Smith RJ. Efficacy and safety of OK-432 immunotherapy of lymphatic malformations. Laryngoscope. 2009;119(1):107-115.
Burrows PE, Mitri RK, Alomari A, et al. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Res Biol. 2008;6:209-216.
Perkins JA, Maniglia C, Magit A, Sidhu M, Manning SC, Chen EY. Clinical and radiographic findings in children with spontaneous lymphatic malformation regression. Otolaryngol Head Neck Surg. 2008;138(6):772-777.
Grimmer JF, Mulliken JB, Burrows PE, Rahbar R. Radiofrequency ablation of microcystic lymphatic malformation in the oral cavity. Arch Otolaryngol Head Neck Surg. 2006;132:1251-1256.
Tempero RM, Hannibal M, Finn LS, Manning SC, Cunningham ML, Perkins JA. Lymphocytopenia in children with lymphatic malformation. Archives of otolaryngology–head & neck surgery. 2006;132(1):93-97.
Lee S, Finn L, Sze RW, Perkins JA, Sie KC. Gorham Stout syndrome (disappearing bone disease): two additional case reports and a review of the literature. Archives of otolaryngology–head & neck surgery. 2003;129(12):1340-1343.
INTERNET
Cincinnati Children’s Hospital Medical Center. Lymphatic Malformations. Last Update 02/2020. Available at: https://www.cincinnatichildrens.org/health/l/lymphatic Accessed June 15, 2021.
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