Complex Lymphatic Anomalies (GLA, GSD, KLA and CCLA)

Generalised lymphatic anomaly, Gorham-Stout disease, kaposiform lymphangiomatosis and central conducting lymphatic anomaly

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. A class defined by complexity rather than by a gene

Complex lymphatic anomalies (CLA) are, in the glossary of the International Society for the Study of Vascular Anomalies (ISSVA), the lymphatic malformations that show structural complexity, multisystem involvement and functional impairment [9]. The 2025 ISSVA classification places them among the low-flow vascular malformations, in the lymphatic branch, alongside isolated lymphatic malformations (macrocystic, microcystic and mixed), generalised lymphatic dysplasia (GLD) and the lymphoedemas, and recognises four entities: generalised lymphatic anomaly (GLA), kaposiform lymphangiomatosis (KLA), Gorham-Stout disease (GSD) and central conducting lymphatic anomaly (CCLA), the last either isolated or syndromic, associated with RASopathies [9]. Orphanet created the clinical group ORPHA:719950 to bring them together, as yet without a definition or synonyms [8]. The four entities share symptoms, imaging findings and complications, which makes the differential diagnosis difficult and explains the frequency of late diagnoses, sometimes after years or decades [2, 35]. In clinical genetics, the classification and diagnostic algorithm for primary lymphatic dysplasias of Connell and colleagues (2013), reproduced in the Oxford Desk Reference, already singled out "lymphangiomatosis/Gorham" as a category of its own in the branch of anomalies with disturbed growth, cutaneous manifestations or vascular anomalies, alongside Parkes Weber syndrome (RASA1), CLOVE syndrome and fibroadipose hyperplasia (AKT/PI3K/mTOR pathway) and Klippel-Trenaunay syndrome, whereas multisegmental lymphatic dysplasia with systemic involvement and generalised lymphatic dysplasia/Hennekam syndrome occupy the branch of systemic or visceral involvement of prenatal or postnatal onset [36].

This article covers the whole class uniformly. Common lymphatic malformations due to PIK3CA and the PIK3CA-related overgrowth spectrum (PROS), the germline lymphatic dysplasias, including GLD due to PIEZO1, recessive CCLA due to MDFIC and Hennekam syndrome, capillary malformation-arteriovenous malformation syndrome due to EPHB4 and RASA1, Noonan syndrome and germline RASopathies, and mosaic cutaneous RASopathies appear only to the extent that they produce a CLA phenotype or enter the differential diagnosis.

1.2. Gorham-Stout disease: from "phantom" osteolysis to lymphatic anomaly

The first description attributed to GSD is that of Jackson, in 1838, in a patient with progressive osteolysis of the humerus [4]. In 1955, Gorham and Stout related massive osteolysis, which they called acute spontaneous absorption of bone, "phantom bone" or "vanishing bone", to haemangiomatosis, and the eponym became established [4, 12]. In Hardegger's classification of the idiopathic osteolyses, GSD corresponds to type IV: monocentric, non-hereditary osteolysis, with a non-specific age at onset, usually before 40 years, with lymphatics in bone [4]. The interpretation changed with the demonstration that normal bone contains no lymphatic vessels and that the GSD lesion is a proliferation of intraosseous lymphatics accompanied by osteoclast activation, so that ISSVA now classifies GSD as a CLA, defined by aggressive osteolysis with loss of cortical bone in the context of a lymphatic anomaly [2, 9]. OMIM entry 123880, entitled "diffuse cystic angiomatosis of bone", uses "Gorham-Stout disease" as an alternative title and describes under the same number a family with autosomal dominant transmission of asymptomatic cystic bone lesions, an entity different from sporadic GSD [12].

1.3. Generalised lymphatic anomaly and the abandonment of the term "lymphangiomatosis"

For decades GLA was called lymphangiomatosis, diffuse or disseminated lymphangiomatosis, diffuse lymphangioma and, when thoracic disease predominated, pulmonary lymphangiomatosis [1, 2]. The 2014 ISSVA update separated GLA and GSD as distinct systemic lymphatic malformations [2]. The distinction rests mainly on bone: in GLA the lytic lesions are multiple, confined to the medullary cavity, non-contiguous and non-progressive, without cortical destruction, whereas in GSD the osteolysis is progressive, infiltrative and destroys the cortex [2, 35]. The authors of the Cincinnati group recommend abandoning the term "lymphangiomatosis", because it is non-specific and may delay appropriate treatment or leave complications unanticipated [27]. Hennekam syndrome, which ISSVA calls "primary generalised lymphatic anomaly", is a germline recessive entity entirely distinct from GLA, despite the similarity of names [9].

1.4. Kaposiform lymphangiomatosis

Croteau and colleagues described in 2014, on the basis of 20 patients seen at Boston Children's Hospital between 1995 and 2011, a generalised lymphatic anomaly with its own histology: clusters or sheets of spindle-shaped, haemosiderotic, "kaposiform" lymphatic endothelial cells, arranged in parallel between dilated, abnormal lymphatic channels, with the lymphatic markers D2-40, LYVE-1 and PROX1, and with an aggressive course [5]. The same group had introduced the term in 2004 and, in 2022, brought together the pathology of 43 patients; several older cases of "pulmonary lymphangiomatosis" corresponded to KLA, with the spindle cells interpreted as smooth muscle [6]. In 2014, ISSVA treated KLA as a provisionally unclassified vascular anomaly and, in 2018, as a subtype of GLA, a position that remains under debate because of its almost tumour-like behaviour and its own genetics; the World Health Organization describes it as a rare tumour of lymphatic origin [2, 29]. The discovery, in 2019, of the somatic variant NRAS p.(Gln61Arg) in 10 of 11 lesions gave KLA its own molecular basis [21].

1.5. Central conducting lymphatic anomaly

CCLA comprises the disorders caused by dysfunction of the thoracic duct and/or the cisterna chyli, with reflux and leakage of lymph, mainly into the lungs and abdomen [9]. It was recognised as a distinct entity with the development of dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) and intranodal lymphangiography, which make it possible to see the thoracic duct, the direction of flow and the sites of leakage [2, 35]. Unlike the other three entities, CCLA is often germline, as a manifestation of RASopathies, aneuploidies or monogenic lymphatic dysplasias, and only partly somatic [23]. Liu and colleagues proposed naming each case by genotype and phenotype, for example "mosaic KRAS-related CCLA", as a step towards "precision lymphology" [23].

1.6. Milestones of molecular discovery

The sequence of discoveries was rapid. In 2018, a somatic NRAS p.(Gln61Arg) variant was detected in isolated endothelial cells from a patient with GLA, and a germline EPHB4 variant was associated with CCLA [2]. In 2019 the somatic PIK3CA variants in GLA (five of nine patients) and NRAS variants in KLA were published [17, 21], as was the recurrent ARAF variant in a CCLA treated with a MEK inhibitor [22, 28]. In 2020 KLA due to CBL treated with trametinib was described, and in 2021 GSD due to KRAS p.(Gly12Val) [20, 22]. In 2022 and 2023, the Philadelphia cohorts showed that RASopathies, germline or mosaic, are the main known cause of CCLA and that the same gene, such as KRAS or PIK3CA, can cause any of the four entities [18, 23]. These discoveries brought CLA closer to the neoplasms that share the same variants and opened the way to repurposing mTOR, PI3K and MEK inhibitors [37].

1.7. Operational definitions used in this article

2. Molecular Genetics and Pathophysiology

2.1. Two signalling pathways and a common mechanism: activating mosaicism

Lymphatic malformations are, as a rule, sporadic and caused by somatic alterations in components of the PI3K-AKT-mTOR and RAS-MAPK pathways, unlike the primary lymphoedemas, which are germline [2, 36]. Most CLA variants are identical to those that activate oncogenes in neoplasms: recurrent substitutions at hotspots that keep the protein in a ligand-independent active state [20, 41]. They are found only in a fraction of the cells in the lesion, mainly in lymphatic endothelial cells, with variant allele fractions (VAF) usually below 10% and often below 1%, and are generally absent from blood [18, 28]. Activation of PI3K by p110α increases the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3) and AKT-mTOR signalling, with aberrant vascular and lymphatic development; there is no enzyme deficiency or biochemical assay, and the excess activity is confined to the mosaic lineages [42]. In Saudubray's classification of inborn errors of metabolism, the PIK3CA-related overgrowth spectrum appears among the inborn errors of phosphoinositide phosphorylation, with somatic inheritance, alongside germline disorders of the same kinase family (PIK3CD, PIK3R1, PIK3R2), whose dominant features are overgrowth and tumours, immune dysfunction and neurological, skeletal and cutaneous anomalies [43]. RAS variants (KRAS, NRAS, HRAS) keep the GTPase bound to GTP and activate the RAF-MEK-ERK cascade, with cross-talk to the PI3K pathway [29, 41]. Activation of either pathway in lymphatic endothelial cells produces, in models, lymphatic hyperplasia, lymphatics in bone, regression of lymphatic valves and chylothorax [17, 20].

2.2. Generalised lymphatic anomaly

Rodriguez-Laguna and colleagues studied, in Madrid, nine patients with GLA, with paired blood and tissue samples and isolated lymphatic endothelial cells, first with a 1370-gene panel and then with a targeted panel [17]. They found four somatic PIK3CA variants (NM_006218.4:c.1624G>A p.(Glu542Lys), c.1636C>A p.(Gln546Lys), c.3140A>G p.(His1047Arg) and c.3140A>T p.(His1047Leu)) in five patients (55.6%), with mosaicism of 1.1% to 23.0% in tissue and of 28% to 33% in the isolated endothelial cells of two patients; in one patient, the variant appeared only in the second sample, which illustrates sampling heterogeneity [17]. These are the same variants as in PROS and in isolated lymphatic malformations, which requires GLA to be distinguished clinically from these entities [17]. Mice expressing Pik3ca p.His1047Arg in lymphatic endothelial cells developed hyperplastic lymphatics and lymphatics in bone, without bone loss within the lifespan of the model, and rapamycin prevented the hyperplasia and dysfunction [17]. The PIK3CA–GLA association was classified as strong evidence by the VASCERN VASCA group in 2024 [28]. GLA is genetically heterogeneous: in the Philadelphia cohort there were cases of GLA with KRAS (insertion p.Gln70_Tyr71ins15, published designation, without c. notation in the source) and with PIK3CA NM_006218.4:c.263G>A p.(Arg88Gln), and mixed GLA/CCLA phenotypes with BRAF NM_004333.6:c.1799T>A p.(Val600Glu), HRAS and PIK3CA p.(Met1043Ile) (published protein designation; the c. change is not unambiguous) [18]; in 2026 a GLA due to a postzygotic insertion in HRAS was described [19]; and the NRAS p.(Gln61Arg) variant was detected in a patient diagnosed with GLA but with features overlapping KLA [2, 29].

2.3. Kaposiform lymphangiomatosis

Barclay and colleagues identified, by exome and high-depth sequencing, the somatic variant NRAS c.182A>G p.(Gln61Arg) in lesional tissue from 10 of 11 patients with KLA, with VAF of 1% to 28%; in the single negative case, calls in other genes were not convincing [21, 29]. The Boston pathology series confirmed the variant in 9 of 10 patients tested [6]. p.(Gln61Arg) is an oncogenic hotspot, present in 29% of cutaneous melanomas and in 10% of pyogenic granulomas, and NRAS codon 61 variants also cause epidermal naevi, multiple congenital melanocytic naevi and cutaneous-skeletal hypophosphataemia syndrome [21, 29]. Human endothelial progenitor cells expressing NRAS p.Gln61Arg acquire a spindle-shaped morphology, proliferate and migrate more, phosphorylate ERK1/2 and form enlarged vascular channels in xenografts, which reproduces the kaposiform cells [29]. KLA has other genes: CBL c.2322T>G p.(Tyr774Ter) at 4% in CD31+ cells from a chylous effusion, HRAS, KRAS NM_004985.5:c.35G>A p.(Gly12Asp) and PIK3CA NM_006218.4:c.1633G>A p.(Glu545Lys) and c.3140A>G p.(His1047Arg) [18, 22, 44]. The genetics of KLA thus converges on RAS activation, but is not exclusive to NRAS [29].

2.4. Gorham-Stout disease

The first causal variant in GSD was described in 2021 by Homayun-Sepehr and colleagues: KRAS c.35G>T p.(Gly12Val), present in 23% of alleles (142 of 620 reads) in bone with abnormal lymphatics from a woman with osteolysis of multiple bones of the right upper and lower limbs and of T10, confirmed by paired exome (28% in tissue) and absent from blood, with no other candidate variants [20]. p.Gly12Val is one of the most frequent KRAS variants in cancer, recorded more than 10,000 times in COSMIC [20]. The mouse model with KRAS p.Gly12Asp in lymphatic endothelial cells developed lymphatics in bone, regression of lymphatic valves and fatal chylothorax in all animals (median survival 26 days), and trametinib suppressed valve regression [20]. The Philadelphia cohort refers to other studies of KRAS in GSD and concludes that KRAS variants can cause all four types of CLA [18]. A review of about 350 cases mentions a germline GATA2 splice variant in a patient with a clinical diagnosis of GSD [4]. The pathophysiology of the osteolysis is multifactorial: ectopic lymphatics and endothelial cells stimulate osteoclastogenesis through interleukin-6 (IL-6), macrophage colony-stimulating factor and receptor activator of NF-κB ligand (RANKL), through macrophages producing vascular endothelial growth factors (VEGF-A, VEGF-C, VEGF-D) and, possibly, through mechanical compression [2, 4]. Serum from a patient with GSD increased the formation of osteoclastic cells and resorption lacunae in culture, an effect attributed to IL-6 [12]. Mice overexpressing VEGF-C in bone develop bone lymphatics and osteoclastic resorption similar to GSD [2].

2.5. Central conducting lymphatic anomaly

CCLA has two genetic architectures. In the retrospective cohort of the Fishman Center in Philadelphia (115 participants with lymphangiography and clinical genetic testing, 2016–2019), 26% had a definitive molecular diagnosis: germline RASopathies (PTPN11 in six, RAF1 and RIT1 in two each, SOS1, HRAS and BRAF in one each), mosaic RASopathies (BRAF in an abdominal lymphatic malformation, ARAF in the pleura, KRAS in a naevus sebaceous and in a plexiform neurofibroma), trisomy 21 (six), 22q11.2 deletion (two, with LZTR1 in the region), biallelic PIEZO1 (two), FOXC2 (one) and storage disorders (glycogen storage disease type IV and Gaucher disease type III) [23]. The prospective cohort of 104 patients with primary CLA added, in CCLA, somatic variants in KRAS (NM_004985.5:c.35G>A p.(Gly12Asp), c.35G>T p.(Gly12Val), c.436G>A p.(Ala146Thr)), PIK3CA (NM_006218.4:c.3140A>T p.(His1047Leu) and c.3140A>G p.(His1047Arg)), BRAF NM_004333.6:c.1799T>A p.(Val600Glu) and MAP2K1 NM_002755.4:c.158T>G p.(Phe53Cys) as a candidate gene [18]. Sheppard and colleagues described four patients with CCLA, lymphoedema and microcystic lymphatic malformation due to mosaic KRAS variants, several in the context of naevus sebaceous or oculoectodermal syndromes; the variants NM_004985.5:c.35G>A p.(Gly12Asp) and c.38G>A p.(Gly13Asp) increased ERK phosphorylation, disrupted endothelial junctions and increased sprouting in lymphatic endothelial cell organoids, changes almost reversed by MEK inhibitors [24]. Among the germline forms, EPHB4 (autosomal dominant, variable expressivity, with fetal hydrops of lymphatic cause, atrial septal defect and varicose veins) alters the arteriovenous boundary and the development of lymphatic and venous valves, and MDFIC (autosomal recessive) and PIEZO1 (autosomal recessive) cause generalised lymphatic dysplasias with chylothorax [13–15, 45]. These germline forms enter the differential diagnosis.

2.6. Level of evidence for gene–disease associations

2.7. Variant spectrum and nomenclature

The most relevant variants were normalised in VariantValidator (GRCh38, MANE Select transcripts) [46]. In KLA, NRAS NM_002524.5:c.182A>G p.(Gln61Arg) (NC_000001.11:g.114713908T>C). In GSD and CCLA, KRAS NM_004985.5:c.35G>T p.(Gly12Val) and c.35G>A p.(Gly12Asp) (NC_000012.12:g.25245350C>A and C>T). In GLA, PIK3CA NM_006218.4:c.3140A>G p.(His1047Arg), c.3140A>T p.(His1047Leu), c.1624G>A p.(Glu542Lys), c.1633G>A p.(Glu545Lys) and c.1636C>A p.(Gln546Lys); the Madrid study used version NM_006218.2, with the same numbering [17]. In CCLA, ARAF NM_001654.5:c.640T>C p.(Ser214Pro) and BRAF NM_004333.6:c.1799T>A p.(Val600Glu). In KLA due to CBL, NM_005188.4:c.2322T>G p.(Tyr774Ter), a premature termination variant which, like the CBL variants in leukaemia, activates the RAS-MAPK pathway [29]. The minimum regions that a diagnostic panel should cover for these genes are defined by VASCERN: whole PIK3CA; KRAS exons 2–4 (codons 5, 12, 13, 22, 61, 64, 146); NRAS exons 3–4 (codons 61 and 146); HRAS exons 2–3; BRAF exon 15 (codon 600); ARAF exon 7 (codon 214); CBL exon 15 (codon 774); MAP2K1 exons 2–3 [28].

2.8. Genotype-phenotype correlations

The initial correlations (GLA with PIK3CA, KLA with NRAS, GSD with KRAS) hold as a trend, but are not absolute: PIK3CA has been found in KLA and CCLA, KRAS in all four types and HRAS and BRAF in GLA [18, 44]. Panel sequencing may therefore not discriminate the entity, but it guides targeted therapy [44]. In CCLA, the genotype is associated with flow patterns on DCMRL: germline RASopathies and mosaic BRAF show dilated "beaded" lymphatics, retrograde posterior intercostal flow, pulmonary perfusion and thoracic duct anomalies; mosaic KRAS p.Gly12Asp shows dilated channels and extensive pulmonary perfusion, without posterior intercostal flow; trisomy 21 shows disorganised central lymphatics and dilated cervical channels [23]. Expressivity probably depends on the timing of the mutation, the cell type affected and the variant; the same PIK3CA p.Glu542Lys occurs in isolated lymphatic malformation, venous malformation and PROS [28].

2.9. Penetrance, inheritance and allelic disorders

In the somatic forms, the concept of penetrance does not apply: the disease results from a postzygotic event, with no known transmission [17, 21]. In GSD there are no documented familial cases, and the OMIM entry describing an autosomal dominant family refers to cystic angiomatosis of bone, not to GSD [4, 12, 25]. In germline CCLA, inheritance follows the gene: autosomal dominant in the RASopathies and in EPHB4 (variable expressivity, with asymptomatic carriers or carriers with varicose veins), autosomal recessive in PIEZO1 and MDFIC [13–15]. The genes of the somatic CLA have very different germline and somatic allelic disorders: germline KRAS variants cause Noonan and cardiofaciocutaneous syndromes, mosaic NRAS codon 61 variants cause epidermal and congenital melanocytic naevi, and PIK3CA causes PROS and is involved in multiple cancers [21, 36, 42]. In the OMIM gene entries, the recorded allelic spectrum is as follows: KRAS, Noonan syndrome 3 and cardiofaciocutaneous syndrome 2 (germline), oculoectodermal syndrome, Schimmelpenning-Feuerstein-Mims syndrome and cerebral arteriovenous malformation (mosaic) and various cancers (somatic) [47]; NRAS, Noonan syndrome 6 (germline), congenital melanocytic naevus syndrome, neurocutaneous melanosis, epidermal naevus and RAS-associated autoimmune lymphoproliferative syndrome (somatic) [48]; BRAF, cardiofaciocutaneous, Noonan 7 and LEOPARD 3 syndromes and somatic cancers [49]; CBL, Noonan syndrome-like disorder with or without juvenile myelomonocytic leukaemia [50]; PIK3CA, CLOVE syndrome (MIM 612918), megalencephaly-capillary malformation-polymicrogyria syndrome, CLAPO and multiple somatic cancers [51, 52]; EPHB4, CM-AVM2 and lymphatic malformation 7 [53]; PIEZO1, dehydrated hereditary stomatocytosis (autosomal dominant) and lymphatic malformation 6 (autosomal recessive) [54]; MDFIC, lymphatic malformation 12 [55]. The OMIM entry for ARAF records no Mendelian phenotype, and the association with CCLA rests on the two published patients [23, 56]. Noonan syndrome has lymphoedema in about half of patients with PTPN11 and in 63% with SOS1, and the Noonan, cardiofaciocutaneous and Costello syndromes present with chylothorax, chylous ascites and intestinal lymphangiectasia [36, 57–59].

3. Clinical Spectrum and Manifestations by System

3.1. Common features of the class

CLA involve several organs, have diverse symptoms and manifest mainly in children and adolescents [2]. The common lesions are skeletal (osteolysis), thoracic (chylothorax, pleural or pericardial effusion, mediastinal mass, retroperitoneal mass), abdominal (ascites, splenic lesions, retroperitoneal mass) and cutaneous (lymphoedema and lymphorrhoea) [2]. Loss of lymph causes hypoalbuminaemia, hypoproteinaemia, hypogammaglobulinaemia, lymphopenia and anaemia; surgical drainage of effusions can multiply these losses, with immunosuppression, generalised oedema and growth failure [2, 27]. Effusions worsen with common viral infections and during periods of growth and hormonal change, such as puberty and pregnancy [27]. In the Freiburg registry (2015–2021; 32 patients: 15 GLA, 10 GSD, 3 KLA and 4 CCLA), 84% had symptoms by the age of 15 years and 25 had complications [60].

3.2. Generalised lymphatic anomaly

GLA is a rare congenital multisystem disease, with diffuse proliferation of lymphatic channels in bone and extraosseous tissues and skeletal and visceral involvement without cortical involvement [9]. It presents mainly in infancy and childhood, and deterioration of lung function is the main cause of morbidity and mortality [1]. The appendicular skeleton is preferentially affected, at several non-contiguous sites, and the spleen and liver are frequently involved [27]. In the Madrid cohort, the malformations were mainly mixed macro- and microcystic, and five of the nine patients had medullary bone loss, axial or axial and appendicular [17]. Small, multiple bone lesions may be painless, and many are incidental findings or come to light through fracture; chronic pain is a frequent presentation in adolescents and adults [2, 27]. Pleural effusions, with an approximate prevalence of 40% to 70%, are the most common respiratory presentation [27]. Effusions are associated with involvement of the rib cage: in the Cincinnati study, 86% of patients with pleural effusion and 75% of those with pericardial effusion had rib and/or mediastinal involvement, and rib fractures can directly injure the lung, heart and thoracic duct [35]. Vertebral extension into the spinal canal can cause intracranial hypertension, spinal cord compression and cerebrospinal fluid fistulas [35]. GLA can present as protein-losing enteropathy: a 25-year-old woman with steatorrhoea, weight loss, anasarca and hypoalbuminaemia had diffuse peritoneal lesions mimicking carcinomatosis, and omental biopsies and lymphangiography established a GLA due to HRAS [19]. GLA is also a possible complication of the lymphatic malformations of PROS, with an aggressive course when close to vital structures of the head and neck [26].

3.3. Gorham-Stout disease

GSD can affect any bone, in a monostotic or polyostotic form, and the most common symptom is localised pain; it may come to light through a pathological fracture [3]. The bones most often involved are the ribs, spine, pelvis, skull, clavicle and mandible, with a predilection for the maxillofacial bones, and the hand is rarely affected; as a rule it affects one bony segment, and the distribution of multiple lesions tends to be contiguous [4, 27]. The review of about 350 cases found a mean age at diagnosis of 25 years, more than half of cases before 18 years (80 up to 10 years and 79 between 11 and 18), without racial or regional preference and with male predominance in some series [4]. In the Chinese series of 67 histologically confirmed cases, 64.2% were men, the mean age was 28 years (1.5–71), the most common symptoms were pain (59.7%), functional impairment (19.4%) and swelling (17.9%), and 55.2% had disappearance of part of the bone on radiography [61].

Orthopaedic manifestations include pain, swelling, fractures that are spontaneous or follow minor trauma, deformity and shortening of long bones, gait difficulty and kyphosis [4]. Neurological complications arise with vertebral involvement (paraplegia, neurological deficits) and cranial involvement: cerebrospinal fluid fistula of the skull base or spine causes rhinorrhoea, otorrhoea, headache, nausea, vomiting and intracranial hypotension, and may be associated with Chiari I malformation and recurrent meningitis [4, 27]. Involvement of the temporal bone causes hearing loss, tinnitus and egophony, and involvement of the temporomandibular joint facial deformity, difficulty opening the mouth and loose teeth [4]. Chylothorax occurs in about 25% of patients and is the most serious complication, due to lymphatic leakage into the pleural cavity or from the thoracic duct or to a duropleural fistula; mortality in patients with chylothorax was about 43.6%, much higher than in the others [4]. Pericardial effusions and mediastinal masses are rare in GSD (fewer than 10 published cases) [4]. Soft-tissue lesions adjacent to the osteolysis cause chronic pain, lymphoedema, lymphorrhoea, asymmetry, leg-length discrepancy and scoliosis, and chronic lymphoedema can be complicated by infection, haemorrhage, ulceration and, rarely, angiosarcoma (Stewart-Treves syndrome) [2]. Asymptomatic splenic cysts are frequent [4]. In a recent Chinese series of seven adults with GSD (median age 27 years), all had pleural effusion (four chylothorax), five had dyspnoea and the extensive osteolysis of ribs, spine and pelvis was generally painless [62].

3.4. Kaposiform lymphangiomatosis

In the founding Boston series (20 patients), the median age at onset was 6.5 years (from birth to 44 years) and the median age at diagnosis 8.5 years, with 13 male patients [5]. The presentation was respiratory in 50% (cough and dyspnoea, three treated as asthma without response), haemorrhagic in 50% (epistaxis, scleral haemorrhage, bruising, vaginal bleeding, epidural haematoma, haemorrhagic effusion) and a soft, painless subcutaneous mass in 35% (flank, scapula, neck, chest wall) [5]. All had thoracic and mediastinal disease; 80% had microcystic disease of the pleura and lung, half of them asymmetric; 50% had lytic bone lesions with cortical preservation, mainly vertebral (70%), and 50% multiple hypoechoic splenic lesions [5]. Almost all developed pericardial (70%) and/or pleural (85%) effusions, with drainage volumes of 400 to 1500 mL (pericardium) and 1000 to 3000 mL (pleura), sometimes more than 1 L per day, of milky, serosanguineous or haemorrhagic fluid [5]. Thrombocytopenia was moderate (mean 78,000/μL at presentation; mean nadir 44,000/μL), with prolonged prothrombin time, D-dimers above 8000 ng/mL and fibrinogen below 100 mg/dL in severe cases; two patients were followed for months as thrombocytopenia with splenomegaly [5]. Over the years, the subcutaneous masses may progress to tense, violaceous oedema with lymphatic vesicles, with pain and functional limitation [5].

The pathology series of 43 patients (1999–2020) widened the range of onset from 29 weeks of gestation to 41 years (mean 8.2; median 6 years), with 23 male patients and only three older than 21 years; the areas involved were the mediastinum (31), skeleton (30), lungs (29), spleen (20), retroperitoneum and mesentery (17), soft tissues (8), liver (4) and kidneys (2) [6]. Coagulopathy ranged from minimal, with normal platelets, to platelets below 50,000/μL and fibrinogen below 60 mg/dL [6]. The 2023 review adds fatigue, fever, back, joint or bone pain, genital swelling mistaken for hernia, and rare manifestations such as pseudotumour cerebri and a fistula between cerebrospinal fluid and lymphatics with spontaneous intracranial hypotension; effusions are often haemorrhagic even without coagulopathy [29]. Frequent misdiagnoses are pneumonia, cancer, bone marrow failure, other vascular anomalies and immune thrombocytopenia [27, 29]. KLA is diagnosed mainly in children, but there are rare reports in adults with a similar presentation [22].

3.5. Central conducting lymphatic anomaly

In CCLA, channel dilatation, dysmotility or distal obstruction lead to stasis and reflux of lymph, with effusions, cutaneous vesicles, bone lesions and lymphangiectasia [35]. Pleural and pericardial effusions, ascites and generalised oedema can cause organ dysfunction, protein loss and infections [9]. In the Philadelphia cohort, the most common presentation was chylothorax (47%), followed by chylous ascites (24%), with a mean age of 3.7 years at lymphangiography (14 days to 26 years) and no consanguinity [23]. Chylothorax was the dominant presentation in the RASopathies (47%), in trisomy 21 (50%) and in GLD due to PIEZO1 (100%); the mosaic RASopathies due to KRAS and lymphoedema-distichiasis presented with oedema; 22q11.2 deletion and the metabolic disorders with chylous ascites [23]. In the RASopathies, lymphatic anomalies have a lifetime prevalence of about 37% in Noonan syndrome and may manifest before birth (increased nuchal translucency, hydrothorax, hydrops) or after (chylothorax, protein-losing enteropathy, lower-limb lymphoedema, chylopericardium) [32, 57]. In the forms due to mosaic KRAS, CCLA is associated with lymphoedema, microcystic lymphatic malformation and cutaneous and ocular phenotypes (naevus sebaceous, oculoectodermal syndrome), and a scrotal chylous leak has been described in an adolescent [24]. In linear naevus sebaceous syndrome, caused by activating somatic variants in HRAS (mainly NM_005343.4:c.37G>C p.(Gly13Arg)) or KRAS (p.(Gly12Asp) or p.(Gly12Val)), lymphatic malformations are among the occasional anomalies, and hypophosphataemic rickets, a variant of tumour-induced osteomalacia, regresses after excision of the skin lesions [63]. Germline CCLA due to EPHB4 can manifest as fetal hydrops that improves spontaneously in survivors, atrial septal defect or varicose veins in adulthood; in one family, the proband had recurrent pleural effusions from birth, a lung biopsy showing "pulmonary lymphangiomatosis" and diffuse lymphatic reflux [13].

3.6. Manifestations by system

3.7. Natural history and treated disease

The Boston and Japanese series mainly describe natural history in the era before targeted drugs. In KLA, 5-year survival was 51% and overall survival 34% in the 1995–2011 series, with death from cardiorespiratory failure at a mean interval of 2.75 years after diagnosis [5]. In the 1999–2020 series, 30 of the 38 patients with follow-up were alive (0.7 to 17 years after onset, mean 4.9) and 8 had died, a survival of 79% attributed in part to new therapies [6, 29]. In the Japanese national survey of 85 patients (35 GLA, 41 GSD and 9 KLA), mortality was 20% (17 of 85) over a mean observation of 7 years, all deaths associated with thoracic lesions; no patient without thoracic lesions died, and of the 69 children 50 had thoracic lesions and 13 died [31]. In the same series, mortality in KLA (55.6%, 5 of 9) was higher than in GLA (28.6%, 10 of 35; p=0.0268), and GSD had fewer effusions and mediastinal masses [2]. In the Freiburg registry there was one death (GLA) despite multimodal treatment and one spontaneous regression in an untreated KLA [60]. These figures come from referral-centre cohorts and do not represent the natural history of the population, and the improvement in survival in KLA coincides with the widespread use of sirolimus and, more recently, of MEK inhibitors [29].

3.8. Common cystic lymphatic malformation: presentation and natural history

Common cystic lymphatic malformation (MLK in the French protocol; the term "lymphangioma" has been abandoned) is the localised, non-complex form of lymphatic malformation and is the main borderline entity of CLA: it shares the mechanism (activating somatic PIK3CA variant in some cases) and sirolimus, but has no osteolysis or multisystem disease [34, 40]. The 2021 French national protocol (PNDS) deals mainly with the superficial forms, which are the most frequent and the most stereotyped; the deep forms (visceral: spleen, thorax, liver) are exceptional and are discovered incidentally or through a complication [34].

Presentation. The lesion is congenital, but not always visible at birth: about 90% are diagnosed before 5 years, often in the first two years on the occasion of an inflammatory flare that makes it apparent [34]. About 75% are located in the head and neck; these are followed by the roots of the limbs (axillae, groins), the gluteal region and the external genitalia [34]. Macrocystic forms (cysts of about 1 cm or more, theoretically amenable to puncture) present as round or lobulated subcutaneous masses several centimetres in size, under normal skin, of elastic or soft consistency; they predominate in the parotid, submandibular, cervical, axillary and inguinal regions [34]. Microcystic forms (cysts of less than about 1 cm) may be subcutaneous swellings clinically indistinguishable from macrocystic ones, or manifest on the surface as lymphangiectasias: translucent or haemorrhagic millimetric vesicles, scattered or in plaques, which may keratinise over time; they predominate in the oral cavity, tongue and orbit [34]. On dermoscopy, lymphangiectasias show pink, red, brown or violaceous lacunae separated by pale septa, which helps to distinguish them from condylomas on the genitalia [34]. Mixed forms combine large and small cysts. There is no difference by sex or ethnic origin [34].

Complications by site. The most serious complication is compression of the upper airway by a cervicofacial lesion, with immediate threat to life in the newborn; apart from this, cervicofacial lesions cause respiratory difficulty, dysphagia and impaired swallowing and speech through pharyngeal and laryngeal infiltration or compression [34]. In the orbit, the main symptoms are exophthalmos (usually unilateral), binocular diplopia and deep orbital pain due to raised pressure; the Valsalva manoeuvre is negative in an isolated lymphatic lesion, and a positive manoeuvre suggests an associated venous component [34]. The main orbital complication is compressive optic neuropathy, acute (intracystic haemorrhage, rarely infection) or chronic, recognised by reduced visual acuity, relative afferent pupillary defect, papilloedema (inconstant), visual field changes and dyschromatopsia [34]. In the foot, the lesion makes walking and wearing shoes difficult. In the visceral forms, chylous effusions (chylothorax, chylous ascites) or haemorrhage (splenic lesions) occur [34].

Flares. The course alternates asymptomatic periods with inflammatory flares, infections or intracystic haemorrhages, of variable frequency [34]. Flares cause sudden, painful and transient enlargement, sometimes with cutaneous inflammatory signs and fever; they last from 48 hours to one month (on average about ten days) and follow trauma or regional infections, often viral or trivial (otitis) [34]. It is difficult to distinguish an inflammatory flare from infection of a macrocyst, which is rarer. Intracystic haemorrhage makes the swelling tense, painful and sometimes bluish [34]. Sex and site do not appear to alter progression; puberty is often a peak of progression, without a demonstrated hormonal role [34].

Course by component. Macrocystic components may regress spontaneously, through fibrosis after inflammatory flares or haemorrhages ("natural sclerosis") [34]. In the Seattle series of Perkins and colleagues, 13 of 104 children with cervicofacial lesions (12.5%) had spontaneous regression; the French protocol places it between 2 and 7 months, and in the series of Phang and colleagues spontaneous remissions were concentrated in congenital cervical macrocystic lesions, at about 24 months after appearance [34, 64]. The most recent cohort from the same centre (298 patients aged 0 to 21 years, 2003–2022, later than the protocol) estimated complete spontaneous regression at 9.1% (27 patients), at a median of 12.0 months (interquartile range 6.7–27.4) after onset; the lesions that regressed were mainly macrocystic, cervical, focal and de Serres stage I, and no lesion of the upper or mid face, mixed or microcystic, or extensive unilateral or bilateral lesion regressed; the authors propose one year of observation for asymptomatic lesions with these favourable features [65]. Microcystic and mixed components tend to progress: they thicken, the vesicles multiply, and lymph exudation, bleeding (with iron-deficiency anaemia from repeated micro-losses) and odour from bacterial colonisation increase, and erosions open the way to cellulitis, bacteraemia or severe sepsis [34]. Microcystic lesions and disfiguring forms have a relevant psychological and social impact and affect the quality of life of the patient and family [34].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion arises from the combination of three groups of findings: lymphatic lesions at more than one site (splenic cysts, mediastinal or retroperitoneal masses, soft-tissue lymphatic malformation), lytic bone lesions and chylous effusions or protein losses without an evident cause [2, 27]. A history of a "cyst" excised in childhood that turns out to be a lymphatic malformation, associated with lytic rib lesions and chylothorax, is a clue to GLA [27]. KLA should be considered in the presence of unexplained hypofibrinogenaemia, thrombocytopenia and bleeding, especially with haemorrhagic ascites, pleural or pericardial effusion, and in a GLA with haemorrhagic effusion, extensive retroperitoneal or mediastinal involvement, clinical deterioration or haematological changes [5, 27]. GSD should be considered in unexplained massive osteolysis, especially when it progresses across the cortex or is associated with chylothorax or cerebrospinal fluid fistula [4, 61]. CCLA should be considered in chylothorax, chylous ascites, protein-losing enteropathy or generalised lymphoedema in patients with a RASopathy, trisomy 21, 22q11.2 deletion, previous fetal hydrops or mosaic skin lesions [23, 24].

4.2. Recognition by age

4.3. Warning and emergency signs

The emergency signs are pericardial effusion with tamponade, pleural effusion with mediastinal shift and respiratory failure, haemorrhage due to consumptive coagulopathy in KLA (fibrinogen below 100 mg/dL, falling platelets), meningitis associated with cerebrospinal fluid fistula in GSD of the skull base, spinal cord compression due to vertebral osteolysis and hypovolaemia or shock due to large-volume drainage [5, 27, 67]. Infection of a chylous effusion, such as empyema due to Streptococcus pneumoniae or bacteraemia due to Staphylococcus aureus, may be the first manifestation and mask the underlying disease [27, 39]. Catheter-associated central venous thrombosis worsens lymphatic leakage and should be sought when output increases [39]. In patients already diagnosed, effusions may worsen with viral infections and with puberty or pregnancy, and invasive interventions (rib biopsy, mediastinal surgery, osteosynthesis) may precipitate refractory leaks [5, 27].

4.4. Signs pointing to another entity

A unifocal purpuric skin lesion with severe thrombocytopenia in an infant points to kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon and not to KLA [5, 68]. Expansile metadiaphyseal bone lesions with deafness and tooth resorption in a family point to familial expansile osteolysis, and "Gorham disease is not familial" [25]. Congenital lymphoedema with Stemmer sign (inability to pinch the skin fold at the base of the second toe), "ski-jump" nails and a family history point to primary lymphoedema, and lymphoedema with intestinal lymphangiectasia, facial dysmorphism and intellectual disability to Hennekam syndrome [36, 69].

4.5. Newborn screening

There is no newborn screening for CLA. Prenatal detection of hydrops or cystic hygroma should lead to karyotype or array and to a panel or exome including RAS-MAPK pathway genes [66].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles

There are no validated formal diagnostic criteria for GLA, KLA or CCLA; diagnosis rests on the combination of history, examination, imaging, laboratory tests and, when necessary, histology and genetics [27, 44]. An international consensus of 52 experts from 16 specialties, organised by patient associations and supported by registry data, defined in 2020 the clinical elements, the preferred anatomical and functional imaging methods, the elements that the radiology report should describe, the metabolic and haematological tests at diagnosis, the functional studies, the precautions for biopsy and the processing of the sample [70]. The Freiburg registry applied these guidelines retrospectively and showed that osteolysis and periosseous infiltration distinguish GSD, ascites and protein-losing enteropathy CCLA, and consumptive coagulopathy KLA, with no differences in the number of bones, the distribution of lesions or fractures [60]. The diagnosis should be reviewed when new complications arise, especially in young children, in whom the initial presentation may not offer all the clues [27].

5.2. Initial assessment

5.3. Imaging and histological distinction between the four entities

The bone pattern is the most useful element for separating GSD from GLA and KLA: in GLA and KLA the lesions are lytic, medullary, multiple, non-contiguous and non-progressive, with preserved cortex, and the vertebrae (mainly lumbar) are frequently involved; in GSD the osteolysis is progressive and infiltrative, destroys the cortex, may cross joints and concentrically taper tubular bones ("sucked candy"), and involves the skull, ribs, clavicle and cervical spine more often [2, 4, 35]. In GSD, radiographs initially show "patchy" intramedullary and subcortical lucencies, resembling osteoporosis, and later osteolysis without sclerosis or periosteal reaction; MRI shows a lesion hypointense on T1 and hyperintense on T2, with a reticular soft mass and enhancement in the region of active osteolysis [4]. In KLA, chest CT shows smooth peribronchovascular and interlobular thickening and infiltration of mediastinal fat without macrocysts, and MRI shows T2-hyperintense infiltrative tissue with moderate to intense enhancement along the bronchovascular bundles and in the retroperitoneum [27, 29]. KLA and CCLA share retroperitoneal and mediastinal infiltrative tissue and signs of stasis and reflux on lymphangiography, but thoracic disease and soft-tissue enhancement are more marked in KLA; bone lesions are better delimited in GLA and more permeative in KLA and CCLA [6]. Splenic cysts occur in all three, more in KLA and GLA [6]. On PET/CT, GSD lesions take up little 18F-FDG (SUVmax below 2.5 in six of seven patients) but intensely take up 18F-labelled fibroblast activation protein inhibitor (18F-FAPI; SUVmax 4.0–17.6) [62].

On histology, GLA shows anastomosing lymphatic channels of variable size, lined by flat endothelium, PROX1- and D2-40-positive; GSD shows the same type of channels with cortical destruction and numerous osteoclasts; KLA shows, in addition to the dysmorphic channels, scattered clusters of spindle-shaped lymphatic endothelial cells, often haemosiderotic, D2-40-, PROX1- and LYVE-1-positive, sometimes with expression of mesenchymal markers (CD73, CD90, CD105, CD146) [5, 27, 29]. In KLA, the spindle cells are in poorly delimited clusters, and in kaposiform haemangioendothelioma they form rounded confluent nodules with glomeruloid foci and microthrombi [5, 68]. A biopsy may contain only abnormal vessels without clusters, and a second sample may be diagnostic [6].

5.4. Biopsy: indications and precautions

The characteristics of the bone lesions, the visceral distribution and the laboratory tests often allow the diagnosis without biopsy [27]. When necessary, soft-tissue biopsy is preferable; rib and vertebral biopsies should be avoided because of the risk of refractory pleural effusion and cerebrospinal fluid fistula, and in KLA biopsy may worsen the coagulopathy and cause haemorrhage [27, 29]. Bone biopsies are small and often crushed, with a risk of error [2]. The decision should be taken by the multidisciplinary team, weighing the diagnostic benefit against the risk, and the combination of advanced imaging, biomarkers and cell-free DNA genetics may make biopsy unnecessary [29, 39]. Before any procedure with a non-low bleeding risk in KLA, fibrinogen should be corrected to more than 150 mg/dL [27].

5.5. Criteria for Gorham-Stout disease

The Heffez criteria, used in the GSD literature, are eight: biopsy with angiomatous tissue, abnormal lymphatic channels and numerous osteoclasts; absence of cellular atypia; minimal or absent osteoblastic response and absence of dystrophic calcifications; progressive local bone resorption; non-expansile, non-ulcerative lesion; absence of visceral involvement; osteolytic radiological pattern; and exclusion of hereditary, metabolic, neoplastic, immunological and infectious causes [4]. The criterion of "absence of visceral involvement" predates the recognition of GSD as a multisystem CLA, which may present with chylothorax and splenic cysts [4, 9]. Laboratory tests are almost always normal, with alkaline phosphatase sometimes slightly raised; increases in bone alkaline phosphatase, CTX-1, tartrate-resistant acid phosphatase, IL-6, RANKL and osteoprotegerin have been described, which fell after bisphosphonates [2, 4].

5.6. Biomarkers

Serum angiopoietin-2 is raised in KLA (about 9-fold in a group of 7 patients and about 10-fold in a group of 11, with soluble VEGF receptor type 3 about 7-fold) and in kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon, but not, or only slightly, in GLA; it falls with sirolimus and tracked the clinical response in one case of KLA [6, 29, 71]. In an adult patient with KLA, the value was 4519 pg/mL (reference 1434–4141 pg/mL) [18]. CTX-1 may be raised in KLA with bone disease [29]. None of these biomarkers has a validated diagnostic threshold.

5.7. Genetic testing: sample, technique and limitations

The variants of the somatic CLA are in the affected tissue and not in peripheral blood; testing should be done on tissue or on fluids that contain cells or DNA from the lesion [27, 28]. The VASCERN VASCA group recommends at least 4 mm of affected tissue (surgical specimen or skin biopsy with abnormal vasculature), fresh, frozen or formalin-fixed paraffin-embedded (FFPE); histological examination to estimate representativeness; next-generation sequencing with unique molecular identifiers (UMI); a detection threshold of 1%; validation of variants with VAF below 5% by digital PCR or a second sequencing run; and points out that standard exome sequencing lacks the depth to detect 1% mosaicism and that C>T/G>A deamination artefacts in FFPE limit the threshold [28]. Blood is not recommended because of the low yield; cell-free DNA (cfDNA) from plasma or lymph is promising but still requires validation, because the VAF is often below 1% [28].

In the Philadelphia cohort, the stepwise strategy (germline exome, deep tissue exome, amplicon panels and UMI panels at more than 80,000-fold depth) on fresh or FFPE tissue, on CD31+ cells isolated from lymphatic fluid and on cfDNA from lymph or plasma detected variants down to 0.15% VAF and gave a molecular diagnosis in 41% of patients with primary CLA; the germline exome found pathogenic variants in 16.3% and variants of uncertain significance (VUS) in 5.8%; FFPE gave a diagnosis in 22 of 43 cases (51.2%; VAF 0.52–31.5%); endothelial cells from chylous fluid gave a diagnosis in 9 of 24 (VAF 0.21–44%); and in 24 patients the VAF was 1% or less, including a BRAF variant at 0.21%, below the reportable limit of the clinical laboratory [18]. In KLA, NRAS p.(Gln61Arg) was detected in cfDNA from plasma and pleural effusion by droplet digital PCR in four of five patients, and in one patient only in plasma cfDNA, at 0.2%, after negative exome sequencing of leucocytes and skin lesions and a negative lung tissue panel [30, 72]. In a child with presumed KLA, a 26-gene somatic panel at about 500-fold depth on pleural fluid was negative and cfDNA from the same fluid, on a 51-gene panel, found the variant at 4.69% [39]. In isolated lymphatic malformations, cfDNA from cyst fluid detected PIK3CA variants in seven of seven patients, and plasma in none of 26 [73].

The limitations should be stated in the report. A negative result does not exclude the disease: the variant may be below the threshold, the sample may not contain lesional cells, the gene may not be on the panel or the cause may not be known, as happens in about half of GLA and most CCLA [17, 18, 23]. The proportion of patients with a detected variant in one series is not equivalent to the clinical sensitivity of the test in another population. The report should state the gene, the transcript and version, the HGVS nomenclature, the VAF, the coverage, the regions below the quality standard, the methods, the limitations, the gene list and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) with the adaptations for somatic variants; potentially germline variants should be reported with a recommendation for germline testing and genetic counselling [28]. In CCLA, testing should include germline genes (RASopathy panel, EPHB4, PIEZO1, MDFIC, FOXC2) and karyotype or array, in addition to somatic testing [18, 23].

5.8. Practical algorithm

5.9. Prenatal and preimplantation diagnosis

Somatic CLA cannot be diagnosed before birth by genetic testing, because the variant is not in the parents' germline. Prenatal ultrasound may show hydrops, effusions or hygroma; the recommended investigation includes karyotype or array, a panel or exome with RAS-MAPK pathway genes and exclusion of immune and infectious causes and fetal anaemia [66]. In germline forms of CCLA with a known familial variant, prenatal diagnosis and preimplantation genetic testing are possible, as in any monogenic disorder [36].

In common cystic lymphatic malformation, fetal ultrasound detects the lesion in 50 to 65% of cases and postnatal ultrasound in about 90%; medium to large lesions may be seen in the 1st trimester and, in most cases, on the 2nd-trimester anomaly scan [34]. The French protocol distinguishes lymphatic malformation from cystic hygroma and increased nuchal translucency (delayed lymphatic resorption), which are associated with aneuploidies (mainly trisomy 21), heart defects and syndromes; an increased translucency does not predict cystic lymphatic disease [34]. As no association between cystic lymphatic malformation and chromosomal anomalies has been described, amniocentesis for karyotype or array is not systematic and is left to the reasoned decision of the prenatal diagnosis centre [34]. The recommendations are: follow-up in a multidisciplinary prenatal diagnosis centre (CPDPN, the only accredited centres in France); combine fetal MRI (usually after 28 weeks of gestation, with heavily T2-weighted sequences) with the reference ultrasound; assess precisely the locoregional extent and the relationship with the aerodigestive axis to estimate the prognosis; and systematically look for associated anomalies, in particular segmental hypertrophy and anomalies of the extremities (macrodactyly, abnormal gap between the 1st and 2nd toes, sandal gap), which suggest PROS [34]. The microcystic, pseudo-solid and infiltrative component is difficult to delimit on both examinations; cysts separated by echogenic supporting tissue suggest a mixed form [34]. In the differential with teratoma, the presence of calcifications in the solid components (absent in lymphatic malformation) and progressive, continuous growth throughout pregnancy favour teratoma [34]. Other associated vascular malformations, especially capillary ones, cannot be excluded before birth, and the couple should be informed [34]. For giant lesions, fetal delivery is planned jointly by obstetricians, neonatologists and interventional radiologists (section 7.15) [34].

5.10. Common cystic lymphatic malformation: assessment and classifications

The diagnosis of common cystic lymphatic malformation is clinical and radiological [34]. The initial clinical examination should identify the risk of life-threatening (cervicofacial site), functional (orbit, extremities) and aesthetic complications, and reassess it during follow-up [34]. The clinical picture guides interpretation of the imaging: a sudden, bluish swelling suggests a macrocyst with intracystic haemorrhage; a bluish lesion that grows in the first months with local warmth suggests a hypodermal infantile haemangioma; a bluish lesion without warmth, compressible and of variable volume suggests a venous malformation; dermal vesicles suggest a microcystic component [34].

Imaging. Doppler ultrasound is the first-line examination, because it involves no radiation and is accessible; in macrocysts it shows septated, anechoic fluid-filled lesions, sometimes heterogeneous or with a fluid-fluid level after haemorrhage, and in microcystic forms an echogenic infiltration without hypervascularity on Doppler, sometimes with millimetric cysts [34]. MRI is the reference examination for extent and for characterisation before any treatment: fat-suppressed T2 sequences in at least two planes (axial and coronal), complemented by T1 (haemorrhage, fat infiltration); gadolinium is reserved for diagnostic doubt, because it enhances the septa of macrocysts but not their contents, unlike venous malformation; angiographic sequences are of no value [34]. CT, arteriography, phlebography, lymphography and lymphoscintigraphy are of no value in common cystic lymphatic malformation, which separates it from CLA, in which lymphangiography and scintigraphy are central [34]. For periorbital lesions, brain MRI is requested to look for associated developmental venous anomalies [34]. In paediatric follow-up, ultrasound is preferred; MRI usually requires sedation below 6 years of age [34].

Laboratory tests, cytology and histology. In an isolated lesion there is no laboratory test useful for diagnosis; tests are used for complications (iron-deficiency anaemia due to repeated bleeding, metabolic impact of extensive lesions) and for the work-up before sirolimus [34]. In combined or syndromic forms with a venous component, consumptive coagulopathy (raised D-dimers and low fibrinogen) is present in about half of cases and justifies periodic measurements [34]. Fine-needle aspiration, rarely diagnostic, is performed before sclerotherapy and shows straw-coloured fluid rich in lymphocytes, sometimes slightly blood-stained; in venous malformation the fluid is purely blood [34]. Biopsy is rarely necessary and is reserved for doubtful cases (some microcystic and deep forms); it shows thin-walled vessels and cysts with empty lumens, with lymphatic markers (podoplanin recognised by the D2-40 antibody, CD34, LYVE-1, VEGFR-3); a wide surgical biopsy may leave prolonged lymphorrhoea from the scar [34]. Testing for somatic PIK3CA variants in tissue, with a blood sample taken in parallel, is done for nosological investigation or before targeted therapy; such variants are found in syndromic forms (CLOVES, Klippel-Trenaunay) and in some isolated forms [34]. Depending on the site, ophthalmological, ear, nose and throat or orthopaedic assessments are requested, together with repeated quality-of-life assessments [34].

Cervicofacial classifications and severity scales. The French protocol brings together three classifications with prognostic value and two scales used mainly in clinical studies (table 5.10a) [34].

6. Differential Diagnosis

6.1. Differential within the class

The first task is to distinguish the four CLA from one another, because prognosis and treatment differ; overlap is considerable and some patients have features of two entities, such as GLA with conduction anomalies on lymphangiography [18, 35].

6.2. Differential with other entities

6.3. Comments on the main differentials

Kaposiform haemangioendothelioma shares with KLA the spindle cells, the coagulopathy and, when thoracic, the effusions, but presents earlier (mean age 4.1 months versus 26.7 months in a West China series), is unifocal, rarely involves the mediastinum, lung and several bones, and responds to therapy with regression and haematological normalisation, unlike KLA [5, 68]. In the Kasabach-Merritt phenomenon, thrombocytopenia and hypofibrinogenaemia are more profound, and ISSVA reserves the term for kaposiform haemangioendothelioma and tufted angioma [9, 29]. The thrombocytopenia of KLA is often labelled as immune and treated with transfusions or splenectomy before diagnosis, and platelet transfusions may worsen the hypofibrinogenaemia [27].

In osteolysis, GSD is partly a diagnosis of exclusion: neoplasms, infection, inflammatory diseases and hereditary osteolyses must be excluded [4]. Familial expansile osteolysis is distinguished by bone expansion, deafness and tooth resorption and familial transmission [25]. In a child with multiple well-delimited lytic lesions, the main differential is Langerhans cell histiocytosis (calvaria and temporal bone more than the central skull base) and multiple enchondromas; the presence of a mediastinal lymphatic malformation or splenic cysts favours CLA [27].

In CCLA, the main distinction is between primary and secondary forms: in the Philadelphia cohort, 88 patients with lymphatic conduction anomalies secondary to congenital heart disease or raised central venous pressure were separated from the primary CLA [18]. Cardiac catheterisation may be necessary to exclude haemodynamic causes of chylothorax [39]. The germline lymphatic dysplasias, Hennekam syndrome and the primary lymphoedemas are distinguished by family history, the distribution of lymphoedema and germline testing [36, 69]. In protein-losing enteropathy, ascites or hydrops without a thoracic duct anomaly on lymphangiography, inborn errors of metabolism enter the differential: MPI-CDG, autosomal recessive and with about 35 patients described, presents between the 1st and 11th months with hepato-intestinal disease, protein-losing enteropathy, thromboses and hypoglycaemia, shows a type 1 pattern on transferrin isoelectric focusing and is the only CDG with effective treatment, oral mannose at a dose of 1 g/kg per day divided into four to six doses (no maximum dose defined in the source), which makes the symptoms disappear rapidly but does not always control the liver disease [79]. Lysosomal disorders, glycogen storage disease IV and several CDG cause non-immune fetal hydrops, and PLVAP and DGAT1 variants cause protein-losing enteropathy of neonatal onset [78]. Primary intestinal lymphangiectasia (Waldmann disease), a lymphatic anomaly with dilated intestinal channels that manifests as protein-losing enteropathy, also enters this differential, with endoscopic and histological diagnosis and dietary treatment [2].

6.4. Common cystic lymphatic malformation: differential and syndromic forms

In children, a cystic lymphatic malformation presenting as a mass is distinguished mainly from congenital cysts (thyroglossal duct, thymic, branchial, bronchogenic, gastrointestinal duplications), superficial venous malformations, deep infantile haemangiomas and other malformations or tumours (teratomas, lipomas, neuromas, soft-tissue sarcomas) [34]. Genital or perianal microcystic forms are confused with angiokeratomas, pyogenic granulomas (botryomycomas), molluscum contagiosum or condylomas [34]. Ultrasound, MRI, fine-needle aspiration and biopsy are the tools for exclusion in case of doubt [34].

Most cystic lymphatic malformations are simple, that is, purely lymphatic; others are combined with low-flow capillary or venous components, and some are part of syndromes, in somatic mosaicism or, more rarely, germline and transmissible [34]. Table 6.4a brings together the syndromes listed in the French protocol, with the OMIM numbers confirmed in the sources for each entity; for Bannayan-Riley-Ruvalcaba syndrome the protocol gives MIM number 15480, which does not correspond to the correct entry (153480) [34].

7. Treatments and Risk Management Strategies

7.1. Principles and level of evidence

CLA have no cure, and the aim is to halt progression, control complications and improve quality of life [27]. Patients should be followed at an experienced centre and by a multidisciplinary team, with paediatric haematology or oncology, interventional radiology, surgery, respiratory medicine, cardiology, orthopaedics, neurosurgery, genetics, nutrition, dermatology and palliative care as needed [2, 29]. The evidence is low: there are no randomised trials in CLA, and the only completed prospective trial that included them is the phase II trial of sirolimus in complicated vascular anomalies [80]. The 2017 Japanese guidelines assigned strength 2 (weak) and evidence D (very weak) to the recommendation on chylous effusions in GLA and GSD; the 2022 edition maintains that no treatment is consistently effective, but considers sirolimus promising as first line [31, 67]. Local interventions rarely control extensive disease, so treatment is multimodal; it should start with conservative measures when there is no threat to life and include drugs and procedures in moderate to severe forms [2]. Disease-modifying drugs should, whenever possible, precede surgery: osteosynthesis in bone affected by CLA often fails, with leakage of lymph or cerebrospinal fluid and infection [27].

7.2. Sirolimus

Mechanism and rationale. Sirolimus (rapamycin; Rapamune®) inhibits the mammalian target of rapamycin (mTOR), downstream of PI3K and AKT; it inhibits lymphangiogenesis and, in mouse models, reduces abnormal lymphatics without damaging normal ones [2]. In the GLA model due to Pik3ca p.His1047Arg, it prevented lymphatic hyperplasia and dysfunction [17]. Patients without a PIK3CA variant and with RAS pathway variants also respond, which is attributed to cross-talk between the pathways [17, 29].

Pivotal trial. In the Cincinnati and Boston phase II trial (NCT00975819; 2009–2013), 61 patients aged 0 to 31 years with complicated vascular anomalies and at least one complication received continuous oral sirolimus, starting at 0.8 mg/m² per dose twice daily, with a target trough of 10 to 15 ng/mL guided by pharmacokinetics, for 12 cycles of 28 days [80]. At the end of cycle 6, 47 of 57 evaluable patients had a partial response, 3 stable disease and 7 progression; none had a complete response [80]. Among the CLA, GLA had a partial response in 7 of 7 patients at cycles 6 and 12; GSD in 3 of 3 at cycle 6 and in 1 of 2 evaluated at cycle 12 (1 progression); KLA in 5 of 7 at cycle 6 (1 stable, 1 progression) and in 6 of 7 at cycle 12; and central lymphatic channel anomalies progressed in all 3 patients [80]. Attributable grade 3 or higher toxicities were haematological in 27%, metabolic and gastrointestinal in 3% each, infectious, lymphatic and respiratory in 2% each; two patients withdrew because of toxicity, the dose was reduced in two and there were no related deaths [80].

Series by entity. In the combined analysis of the trial and a retrospective Cincinnati series (18 patients, 13 GLA and 5 GSD; trough 8–15 ng/mL), 83% improved in at least one domain (92% of GLA, 60% of GSD), with functional improvement in 83% and improvement in quality of life in 78%, on average at 2.7 and 4.2 months, but radiological improvement in only 28%; no patient progressed on imaging, no bone lesion progressed and there were no fractures during the study; 5 of 7 pleural effusions decreased (2 resolved) and 2 pericardial effusions resolved [35]. In the Madrid series, seven patients with GLA treated with 0.8 mg/m² twice daily for a mean of 16 months had reduced pain, three functional improvement, without improvement of chylothorax or bone regeneration [17]. In the prospective Gifu series (20 patients with cystic lymphatic malformation, KLA, GLA, GSD or CCLA; once-daily dosing, trough 5–15 ng/mL), 50% had a partial radiological response at 6 months, with significant improvement in severity and quality of life only in that group; one patient with GSD and one with CCLA died from progression [38]. In KLA, the West China series and the literature together gave a partial response in 58.3%, stable disease in 25.0% and progression in 16.7% [81]. In a systematic review of nine adults with GSD and bone lesions, sirolimus produced a response in seven (two complete) and halted active osteolysis, with local bone formation but without complete reossification [82]. The 2022 Japanese guidelines estimate a response rate of about 80% in series of 18 to 41 patients, without complete remissions [31].

Dose. There is no guideline dose for CLA; the doses used come from the phase II trial and from institutional protocols [27, 80]. The Cincinnati and Texas Children's protocol proposes 0.8 mg/m² per dose every 12 hours orally, with a target trough of 8 to 12 ng/mL, indefinite duration or transition to another targeted therapy; in children under 2 years, the dose follows the developmental pharmacokinetics of Mizuno and colleagues [27]. In KLA, the 2023 review indicates age-based dosing with a trough of 10 to 15 ng/mL and individualisation to the lowest effective dose [29]. In Japan, once-daily dosing with a trough of 5 to 15 ng/mL is used [38]. None of the sources sets a maximum dose in mg: the dose is titrated to the trough, and the operational limit is the protocol target trough, with toxicity described above 15 ng/mL [27, 35]. For comparison, the US label and the Portuguese and European SmPC for Rapamune® indicate, in lymphangioleiomyomatosis, 2 mg per day in adults with a trough of 5 to 15 ng/mL measured 10 to 20 days later, with no paediatric dose established below 18 years; use in CLA is off-label in the United States, the European Union and Portugal [83–85]. Dose changes should not be made before 7 to 14 days, because of the long half-life, and the trough should be monitored [83].

Adverse effects and their management. The most common are mucositis or stomatitis, hypertriglyceridaemia and hypercholesterolaemia, myelosuppression and infections [35, 38]. In the Gifu series, 80% had adverse effects, including three grade 3 infections (upper airway, cellulitis, pneumonia), without discontinuation [31]. Laryngeal oedema with supratherapeutic levels (above 15 ng/mL), pancreatitis and hypertension have been described [35, 39, 67]. In newborns and infants, dyslipidaemia is almost constant (hypertriglyceridaemia in 10 of 10 and hypercholesterolaemia in 9 of 10 in a Nagoya series), with a pharmacovigilance signal much higher than in adults and median onset at 11 days [86]. It is recommended to consider prophylaxis against Pneumocystis jirovecii pneumonia, especially in infants, and to monitor levels [2, 27]. The label also includes the risk of lymphoma and infections due to immunosuppression, angioedema, impaired wound healing, proteinuria, non-infectious pneumonitis, embryofetal toxicity, male infertility and contraindication of live vaccines [83]. Long-term complications (metabolic, growth, fertility, immunity, neoplasms) have not been studied, and it is not known when to stop [35]. In the low-flow malformations of the European VASE trial, 54% of patients who completed 2 years of sirolimus had symptomatic relapse at a median of 13 months after discontinuation [87].

7.3. MEK inhibitors

Rationale. Variants in NRAS, KRAS, HRAS, BRAF, ARAF, MAP2K1 and CBL activate the MAPK pathway, and MEK inhibitors reverse the changes in lymphatic endothelial cells, organoids, zebrafish and mice [20, 24, 37]. There are no published trials; the evidence comes from case reports and small series [29].

Clinical results. An 18-year-old woman with refractory KLA and a CBL variant responded to trametinib within four weeks (resolution of cough, dyspnoea and orthopnoea), with reduction of effusions at 3 months and remodelling of the central lymphatic system on DCMRL at 6 months [22]. A 9-year-old boy with severe KLA, end-stage restrictive lung disease and NRAS p.(Gln61Arg) detected only in cfDNA improved with trametinib 0.025 mg/kg per day: 10% weight gain in 2 months, withdrawal of night-time oxygen at 6 weeks, normalisation of platelets and an increase in forced expiratory volume in the first second from 32% to 52% of predicted at 4 months [30]. Another 9-year-old boy with KLA due to NRAS had a fall in D-dimers from 37 to less than 5 mg/L and resolution of pleural effusions [18]. A 4-year-old child with refractory chylous effusions and presumed KLA due to NRAS recovered with trametinib (section 10) [39]. In eight Dutch patients with Noonan-type RASopathy and CCLA, trametinib was effective with variable individual responses, including congenital chylothorax treated with 0.01 mg/kg per day and early discontinuation [32]. The combination of sirolimus 1 mg and trametinib 1 mg per day, after sequential failure of each, produced rapid and sustained improvement in an adolescent with CLA [37]. In the Philadelphia cohort, the molecular diagnosis led to new therapy in 63% of patients and to improvement in 63% of those treated, including with MEK inhibitors [18].

Dose. There is no approved dose in CLA; the doses used are extrapolated from paediatric oncology [24, 27]. The most cited target is 0.025 mg/kg once daily (maximum 2 mg), also adopted in the VATCH trial, often with a lower starting dose (0.01 mg/kg or 0.5 mg per day) for tolerability [22, 30, 88]. For comparison, the US label for Mekinist® indicates 2 mg per day in adults and, in children from 1 year of age with low-grade glioma (in combination with dabrafenib), weight-based doses: tablets 1 mg (26–37 kg), 1.5 mg (38–50 kg) and 2 mg (51 kg or more), and oral solution from 0.3 mg (8 kg) to 2 mg (51 kg or more) [89]. In the European Union, Mekinist® tablets are approved in adults and adolescents from 12 years of age with melanoma (weight-based doses equal to those above), and the oral formulation Spexotras® for paediatric glioma from 1 year of age since January 2024 [90, 91]. The Dutch series cites 0.025 mg/kg per day below 6 years and 0.032 mg/kg per day from 6 years as paediatric phase I trial doses in refractory solid tumours, and the adult dose of 2 mg per day, equivalent to 0.025 mg/kg per day for 80 kg [32]. Use in CLA is off-label in all jurisdictions.

Adverse effects and monitoring. Rash, acneiform dermatitis, dry skin, diarrhoea, fatigue, hypertension and ventricular dysfunction are the most cited in CLA, and there was one case of rhabdomyolysis requiring discontinuation [24, 29, 39]. The label requires assessment of ejection fraction before treatment, at the first month and then every 2 to 3 months, ophthalmological assessment in the event of visual changes (permanent discontinuation if retinal vein occlusion) and surveillance for haemorrhage, colitis, thromboembolism, pneumonitis and severe skin toxicity [89]. In KLA treated in Israel, monitoring included laboratory tests, ophthalmology with optical coherence tomography, electrocardiogram, echocardiogram, lung function tests and chest CT [30]. In juvenile rats, trametinib reduced bone length and delayed sexual maturation [89].

7.4. Alpelisib (PI3Kα inhibitor)

Alpelisib (Vijoice®) inhibits the p110α subunit and is approved in PROS: in the United States by accelerated approval since 5 April 2022, for patients from 2 years of age with severe manifestations requiring systemic therapy, at 50 mg once daily with food from 2 to 17 years (125 mg from 6 years after 24 weeks) and 250 mg in adults [26, 42]; in the European Union, with conditional marketing authorisation from the European Commission of 15 July 2026, for patients from 2 years of age with severe or life-threatening manifestations of PROS, on the basis of a retrospective study of 57 compassionate-use patients in which 12 of 32 evaluated (37.5%) had a reduction of at least 20% in one to three lesions at 24 weeks [92]. In CLA with a PIK3CA variant that do not meet the criteria for PROS, use is off-label. A 20-year-old man with KLA due to PIK3CA p.Glu545Lys, whose response to sirolimus had plateaued, improved with alpelisib 125 mg per day [18]; in a series of four KLA, GLA and CCLA with PIK3CA, responses were modest [44]. Frequent adverse effects in PROS are hyperglycaemia, diarrhoea, headache, stomatitis, alopecia, dermatitis, dry skin and nausea [92].

7.5. Other drugs

The vincristine and interferon doses come from the Cincinnati and Texas Children's institutional protocol and the zoledronate dose from a case report; there are no guideline or label doses for CLA, and use is off-label [27, 71]. In KLA, initial combination of two or three drugs (oral sirolimus, corticosteroid and vincristine) is preferred by these authors [27].

7.6. Supportive treatment

Chylous effusions and ascites. Drainage is indicated only if there is cardiorespiratory compromise; a large asymptomatic effusion or one with tolerable symptoms does not need to be drained, and sirolimus reduces drain output and the risk of reaccumulation after drain removal [27]. Repeated or continuous drainage causes losses of protein, immunoglobulins and lymphocytes, and sometimes hypovolaemic shock requiring albumin, immunoglobulin, coagulation factors, transfusion and vasopressor support [27, 67]. In refractory chylous ascites, the Japanese guidelines recommend starting with fasting, parenteral nutrition and a medium-chain triglyceride (MCT) diet and, if ineffective, considering drugs, sclerotherapy and surgery (strength 2, evidence D) [67]. In CLA, nutritional therapy alone rarely controls the effusions [31]. Replacement of albumin and immunoglobulins and compression garments are the mainstay of treatment of CCLA [27].

Coagulopathy in KLA. Platelet transfusions should be limited to uncontrolled active bleeding or to the period immediately before or during a procedure with a non-low bleeding risk, because they can worsen the coagulopathy and fail to raise platelets; fresh frozen plasma or cryoprecipitate are indicated if fibrinogen is below 100 mg/dL, and before procedures or in active bleeding fibrinogen should be corrected to more than 150 mg/dL; red cell concentrates have no negative effect [27, 29]. Splenectomy normalised platelets in two of three patients in the founding series, with variable results in another series [5, 6].

Infection and thrombosis. Infections of effusions (pneumococcal empyema, staphylococcal bacteraemia) and meningitis associated with cerebrospinal fluid fistulas require antibiotic therapy and, when possible, closure of the defect [27, 39]. Central venous thrombosis worsens lymphatic leakage and has been treated with therapeutic-dose heparin [39].

7.7. Lymphatic interventions, surgery and radiotherapy

7.8. Approach by entity

GLA. Sirolimus is first line when there is pain, symptomatic bone lesions, effusions or progression, with a bisphosphonate if there is bone disease; alpelisib is an off-label option if there is a PIK3CA variant, and MEK inhibitors in the rare GLA due to KRAS, HRAS or BRAF [18, 19, 27]. Local interventions treat effusions and symptomatic lesions.

GSD. Sirolimus with zoledronic acid is the most frequently reported combination, with radiotherapy in refractory cases and surgery for fractures, vertebral instability, deformity and chylothorax; in GSD of the skull base with recurrent meningitis, peginterferon and zoledronate were used before sirolimus for fear of immunosuppression [4, 27]. Chylothorax is the main poor prognostic factor and justifies early treatment [4].

KLA. Without a genetic diagnosis, first line is sirolimus, usually combined with a corticosteroid and vincristine in exacerbations and coagulopathy, with zoledronate if there is bone disease; in the presence of resistance or a known RAS-MAPK variant (NRAS, CBL, HRAS, KRAS), trametinib [27, 29, 30]. Biopsy, mediastinal surgery and drainage require caution because of haemorrhage and prolonged leaks [5, 29].

CCLA. Treatment is mainly supportive and interventional (embolisation, lymphovenous anastomosis, thoracic duct reimplantation), and the response to sirolimus is uncertain (progression in all three patients in the phase II trial) [27, 80]. In forms due to a germline RASopathy or to mosaic KRAS, BRAF or ARAF, trametinib is the most studied targeted option, and the Dutch authors recommend it in severe, refractory CCLA in the Noonan-type RASopathies [24, 32].

7.9. Regulatory status

Authorisation is not equivalent to marketing or reimbursement; the sources consulted do not indicate the reimbursement status of alpelisib in Portugal. In Brazil, the open data of the National Health Surveillance Agency (ANVISA) show active registration of Rapamune® (sirolimus; Pfizer) and Mekinist® (trametinib; Novartis), and of alpelisib only as Piqray® (antineoplastic class), with no registration of Vijoice® or Spexotras®; this dataset does not include the approved indications [96].

7.10. Main trials and studies

These studies do not allow indirect comparisons: populations, response criteria and durations differ, and composite partial responses (function, quality of life, imaging) are not equivalent to disease regression, which is rare on imaging [35, 80]. Case results with MEK inhibitors are subject to publication bias, and there are cases of modest response or failure, as with alpelisib in CLA due to PIK3CA and with trametinib alone before the addition of sirolimus [37, 44]. No phase 3 trial specific to GLA, GSD, KLA or CCLA was identified [88].

7.11. Developments in the last 12 months

7.12. Guideline recommendations and divergences

The 2017 Japanese guidelines recommended no specific treatment for chylous effusions in GLA and GSD (weak strength, very weak evidence) and noted that the drugs were not recognised by national insurance; those of 2022, after the coverage of sirolimus, consider it the only drug approved for these diseases in Japan and promising as first line, and judge interferon-α, octreotide and propranolol ineffective [31, 67]. In the United States, the 2020 consensus deals with initial assessment and not with treatment, and the published protocols are institutional; the authors stress that there is no consensus on indications, starting dose, adjustments, monitoring or duration [27, 70]. Sirolimus trough targets differ between 5–15 ng/mL (Japan, LAM label), 8–12 ng/mL (Cincinnati protocol) and 10–15 ng/mL (phase II trial and KLA review) [27, 29, 38, 80]. The clinical genetics reference books do not address the treatment of CLA, and the recommendations follow the guidelines and recent series [25, 36].

The 2021 French national protocol deals with common cystic lymphatic malformation and not with CLA; its recommendations and the divergences from the other sources are in section 7.15 [34].

7.13. Agents and procedures to avoid

Rib and vertebral biopsy, resection of mediastinal masses in KLA and osteosynthesis without prior medical treatment should be avoided, because of the leaks and haemorrhages they may trigger [5, 27]. In KLA, platelet transfusions outside active bleeding or a procedure may worsen the coagulopathy [27]. With sirolimus, live vaccines and cytochrome P450 3A4 inducers and inhibitors should be avoided [80, 83]. Prolonged corticosteroids worsen osteoporosis and growth [29, 81].

7.14. Pregnancy, lactation, perioperative care and transition

Sirolimus may cause fetal harm, and highly effective contraception is recommended during treatment and until 12 weeks after the last dose; it may cause azoospermia or oligospermia [83]. Trametinib is embryotoxic in animals and may cause fetal harm [89]. CLA effusions may worsen in pregnancy [27]. The effects of the disease and the drugs on ovarian reserve and fertility are poorly understood, and an oocyte preservation cycle during treatment had a lower than expected yield, which justifies early referral to reproductive medicine [98]. Perioperatively, fibrinogen should be corrected to more than 150 mg/dL in KLA, lymphatic losses and slower wound healing under sirolimus should be taken into account, and orthopaedic surgery should be planned after the disease has been controlled with drugs [27, 83]. Transition to adulthood requires continuity of treatment, which is chronic and often lifelong, and management of chronic pain, which persists in long-term survivors [5, 29].

In common cystic lymphatic malformation, pregnancy appears to alter the course little, but flares and enlargement after delivery have been described; background treatments should be avoided in pregnancy, and sirolimus should be stopped a few weeks before a planned conception [34]. Adolescence and leaving secondary school are periods at risk of loss to follow-up: transition should include discussion of contraception, sexuality, body image, relationships and life plans [34].

7.15. Common cystic lymphatic malformation: treatment according to the French protocol (2021)

Principles. Not all cystic lymphatic malformations need treatment: an asymptomatic, minimally deforming lesion may be kept under surveillance [34]. Apart from small lesions that are resected entirely, the aim is not cure, but to maintain function, control symptoms, preserve appearance and prevent worsening, with the least possible impact on quality of life [34]. Decisions, except for minimal forms, are taken at a multidisciplinary meeting (vascular medicine, dermatology, genetics, paediatrics and neonatology, respiratory medicine, radiology, ophthalmology, ear, nose and throat surgery, orthopaedics, maxillofacial, visceral and plastic surgery, obstetrics, pain clinic, physiotherapy, psychology, nursing) and depend on age, comorbidities, type (macrocystic, microcystic or mixed), isolated or syndromic nature, volume, extent, site, functional impact and impact on quality of life [34]. The protocol separates emergency treatment of flares from background treatment, which aims to reduce volume or prevent worsening; lesions that are not small or spontaneously regressing require lifelong follow-up [34].

Sclerotherapy. This is the first-line treatment for most lymphatic malformations, more effective in macrocystic than in microcystic lesions, less invasive than surgery and with faster recovery [34]. It is usually performed under ultrasound guidance: the fluid is aspirated (and may be sent for cytology), the lesion is opacified to exclude communication with the systemic venous system and the sclerosant is injected in a volume of about one third to one half of the aspirated volume [34]. The response (fibrosis) is assessed after at least 4 to 6 weeks; it is often partial, owing to insufficient diffusion into the microcysts, and several sessions are often needed, almost always as monotherapy [34]. The sclerosants used are sodium tetradecyl sulfate, sodium morrhuate, OK-432, polidocanol or lauromacrogol 400 (Aetoxisclérol® 3% in France), absolute ethanol (also in gel form), doxycycline (in France, Vibraveineuse® 100 mg/5 mL, the only parenteral presentation) and bleomycin; the choice depends on the experience of the centre, the type and size of the cysts and availability, and use in this indication is outside the marketing authorisation, validated by practice and the literature [34]. The larger the lesion, the more potent the sclerosant (for example, ethanol), bearing in mind toxicity: cardiac arrests have been described with absolute ethanol and, exceptionally, with polidocanol, mainly in venous malformations and in infants and newborns under general anaesthesia; gelled ethanol is viscous, passes little into the circulation and maintains inflammation for 2 to 3 weeks [34]. Bleomycin causes less inflammation, so it is used in the orbit to reduce the risk of optic nerve compression, and is of value in microcystic forms by interstitial injection; it is a cytotoxic agent with restricted handling (preparation in a specialised pharmacy unit, gloves, goggles and mask) and has cumulative toxicity that limits repetitions [34]. For comparison, the US label for injectable bleomycin states that pulmonary toxicity increases markedly with total doses above 400 units, which should be given with great caution, although it also occurs in young patients and at low doses [99].

Results and complications of sclerotherapy. In the meta-analysis by De Maria and colleagues on the orbit (13 studies, 154 patients with low-flow, lymphatic and venous, orbital and periocular vascular malformations), complete cure was 54.9% (95% CI 34.2–75.7%), emergency decompressive surgery 3.4% and loss of vision 2.7%, with high heterogeneity; the French protocol presents these figures as referring only to lymphatic malformations [34, 100]. In the same group's meta-analysis on the head and neck (25 studies, 726 patients with lymphatic malformation), complete cure was 50.5% (95% CI 36.6–64.3%), 53.1% in macrocystic, 35.1% in microcystic and 31.1% in mixed lesions; doxycycline had the highest cure rate (62.4%), and permanent morbidity was 1.2%, with no deaths [101]. In the Boston series of Chaudry and colleagues (31 patients with a microcystic or combined form, mean age 13.4 years, 1 to 4 sessions, mean 1.7), with bleomycin up to 1 U/kg per session and a maximum of 15 U, the response was complete (reduction greater than 90%) in 38%, partial (25–90%) in 58% and minimal or none in 3%, without complications, with lung function tests at 6 and 12 months and an annual chest radiograph over a mean follow-up of 3.2 years [102]. The adverse effects common to sclerosants are swelling, pain, skin ulceration and nerve palsy; haemolytic haemoglobinuria occurs in almost 50% of patients after absolute ethanol, and the risk of significant complication (nerve injury, skin necrosis, pulmonary vasospasm, arrhythmia, cardiorespiratory collapse) is 0 to 3%, ethanol being the agent with the most serious complications [34]. The post-injection inflammatory reaction transiently enlarges the lesion and should be anticipated in retro-ocular (optic nerve) and peripharyngeal sites (acute respiratory distress in patients without a tracheostomy) [34].

Anaesthesia. Sclerotherapy can be performed under local anaesthesia (infiltration or anaesthetic cream), moderate conscious sedation, hypnoanalgesia or general anaesthesia; general anaesthesia is preferable with absolute ethanol, because of the intense pain, and should be considered, with airway protection, for lesions of the oral cavity, pharynx, hypopharynx or larynx, in which a prophylactic tracheostomy may be planned [34].

Surgery. Except for small, well-delimited lesions, complete excision is almost always impossible because of infiltration, so surgery is usually partial, palliative and second line [34]. A 2014 retrospective study (174 patients with cervicofacial lesions) showed no superiority of sclerotherapy over surgery, with biases that limit interpretation; resection of low-stage, small to intermediate cervical macrocystic lesions has good results with few complications [34]. In microcystic forms, debulking ("contouring") surgery reduces deforming lesions, can be repeated and often complements sclerotherapy; the postoperative course may include prolonged lymphatic exudation and reappearance of lymphangiectasias [34].

Physical methods. Electrocoagulation, lasers (CO2, pulsed dye) and radiofrequency destroy superficial lesions, stop bleeding and reduce redness; they are palliative, repeated and painful, often requiring general anaesthesia [34]. The classic indication is microcystic malformation of the tongue (bleeding, pain, feeding difficulty, hypersalivation, protrusion), in which physical methods are the first alternative to partial glossectomy: in the series of Leboulanger and colleagues with low-energy radiofrequency (coblation), with follow-up of 3 to 13 months, all patients improved, bleeding disappeared in 5 of 7 and there was moderate local recurrence in 2 of 7 [34]. In cutaneous lymphangiectasias, the CO2 laser is safe and effective, with minor adverse effects (dyschromia, slight scarring), but frequent recurrence in the medium and long term [34].

Physiotherapy. Compression and manual lymphatic drainage have not demonstrated efficacy in cystic lymphatic malformation (systematic review by Langbroek and colleagues, 2018) and are proposed case by case [34]. Compression is indicated mainly in syndromic forms; in the growing child it is made to measure and renewed about every 3 months to avoid a tourniquet effect; several experts do not recommend it before 2 years of age; the recommended pressure is low (15–20 mmHg), increased according to tolerance [34]. Manual drainage has not been studied in this disease, but it is well tolerated and is continued if the patient finds it useful [34].

Systemic sirolimus. Sirolimus (Rapamune®) is the most used mTOR inhibitor, since 2011, as a palliative background treatment for complicated, diffuse or complex forms; it acts more on symptoms (pain, bleeding, lymphorrhoea) than on volume [34]. In France, the authorised indications are prevention of renal rejection and sporadic lymphangioleiomyomatosis (2 mg per day, trough of 5 to 15 ng/mL measured 10 to 20 days after starting and, once the dose has stabilised, at least every 3 months) [34, 83]. Bioavailability is 14% with the oral solution and slightly higher with the tablets, so it should always be taken either with or without food; it is a substrate of CYP3A4 and P-glycoprotein, and combination with potent inhibitors (voriconazole, itraconazole, telithromycin, clarithromycin) or inducers (rifampicin, rifabutin, St John's wort, carbamazepine), or grapefruit juice, is not recommended; the mean terminal half-life is 62 hours in adults, longer in hepatic impairment, shorter in children and unchanged in renal impairment [34]. The most frequent adverse effects (more than 10%) are aphthae or mucositis (close to 30%), digestive disturbances, asthenia and headache; less frequent are arthralgia, acne, hypertension, upper respiratory tract infections, hypersensitivity pneumonitis, venous thromboses, lymphoedema and lymphocele; on laboratory tests, thrombocytopenia, microcytic anaemia, neutropenia, lymphopenia, hyperglycaemia and dyslipidaemia [34]. A review of serious adverse effects in vascular anomalies described severe pulmonary infections; because of the lymphopenia, some specialists add pneumocystis prophylaxis, without consensus [34]. The attending physician checks that vaccinations are up to date (no live vaccines during treatment), the regularity of dental follow-up and signs of infection [34, 83].

Evidence for sirolimus in this disease. In the review by Nadal and colleagues (2016; 84 vascular anomalies), the response appeared between 2 weeks and 6 months, with heterogeneous criteria; in the phase II trial of Adams and colleagues (61 patients with complicated vascular anomalies; section 7.2), 47 of 57 evaluable patients had a partial response at cycle 6 and none had a complete response (the French protocol rounds this to about 90%); in the systematic review by Freixo and colleagues (73 publications, almost all retrospective, 317 patients on oral sirolimus), 94.9% of patients with lymphatic malformation had clinical improvement, with low-level evidence [34, 80, 103]. The PERFORMUS trial (NCT02509468; 59 children aged 6 to 18 years with low-flow vascular malformations at 11 French centres, 2015–2018; sirolimus with a target trough of 4 to 12 ng/mL after an observational period of randomised duration) showed, overall, no reduction in volume on MRI; in the subgroup of 18 children with pure cystic lymphatic malformation, the reduction in volume was significant, and sirolimus improved pain, bleeding, exudation and quality of life; 56 patients had 231 adverse effects (5 serious, none life-threatening), mainly oral ulcers (49.2%) [104]. The French protocol, written before publication, describes the result as no effect on volume; the published data show a volumetric effect in the pure lymphatic forms [34, 104]. The protocol advocates starting early, in early childhood, in microcystic forms at risk of functional complication [34]. In orbital lesions, the data suggest partial improvement in volume and functional signs; in newborns with large lesions, sirolimus alone or with sclerotherapy was effective and well tolerated in the short and medium term [34]. Duration is long, there are no criteria for stopping other than adverse effects (stopping may be a treatment holiday) and treatment may be resumed [34].

Topical sirolimus. Sirolimus 0.1%, applied 1 to 2 times a day, has been described in case reports as a palliative treatment for cutaneous lymphangiectasias; in France it is a compounded preparation, with stability problems, and was in a randomised multicentre trial (NCT03972592) at the time of the protocol [34]. The 3.9% formulation in the SELVA trial (section 7.10) is a distinct product [95].

Drugs without an indication. Sildenafil, after a case in 2012 and series without a control group (1 to 4 mg/kg per day in three doses; volume reduction in 4 of 7 children at 20 weeks in the series of Danial and colleagues, with an increase in the other 3; clear reduction in 9 of 21, moderate in 3 and none in 10 in the series of Wang and colleagues), did not confirm efficacy and is accepted only as a last resort [34]. Propranolol (2 mg/kg per day in two cases of Maruani, without effect; action on bleeding, but not on volume, in 3 of 4 patients with a tongue lesion) and bevacizumab (isolated cases, systemic or as a sclerosant, with frequent and sometimes serious adverse effects) do not have sufficient evidence, and the benefit-risk balance of bevacizumab appears unfavourable [34]. Targeted anti-PI3K therapies, such as alpelisib, were under clinical evaluation for forms with a PIK3CA variant (section 7.4) [34].

Neonatal emergency. For very large lesions detected in utero that may prevent delivery or obstruct the airway, the EXIT procedure (planned caesarean section with drainage of the lesion during delivery, with controlled access to the airway) is discussed [34]. In the Philadelphia series of Laje and colleagues (112 fetuses with prenatally diagnosed cervical lymphatic malformation, 1995–2013), 13 (11%) were delivered by EXIT, according to two criteria (deviation, compression or obstruction of the airway; involvement of the floor of the mouth); airway access was achieved in 12 of 13 (laryngoscopy in 7, rigid bronchoscopy in 4, tracheostomy in 1), one fetus with a massive lesion died, and 5 patients needed a tracheostomy later [105]. Outside EXIT, a symptomatic neonatal macrocystic lesion of the head and neck is treated first line by drainage followed by sclerotherapy; in the series of Chen and colleagues, 15 newborns underwent sclerotherapy at birth under local anaesthesia, without complications [34]. Tracheostomy is sometimes necessary and is poorly experienced by parents, who need information about the prognosis [34]. In giant lesions, combining sirolimus for 12 to 24 months with one or more sessions of sclerotherapy gave good results in several cases, to the point that the protocol presents it as an alternative to the terminations of pregnancy previously proposed for large prenatal forms [34].

Background treatment by type. In macrocystic forms, planned sclerotherapy (local or general anaesthesia) is first line if the lesion is troublesome; surgery is second line; abstention is acceptable for small, non-troublesome lesions, which may regress after flares [34]. In microcystic and mixed forms, which are more infiltrative, the strategy combines, sequentially or simultaneously and with periods of abstention, sclerotherapy (interstitial bleomycin), debulking surgery, sirolimus (background treatment of choice), laser or radiofrequency of the superficial components (CO2 laser or radiofrequency on mucosae; CO2 laser, pulsed dye laser or topical sirolimus on cutaneous lymphangiectasias) and targeted therapy; abstention is frequent for small lesions when pain is controlled with analgesics [34]. In syndromic forms (PROS, Proteus), treatment combines surgery, sclerotherapy, anticoagulation of recurrent intramalformation thromboses, physiotherapy, sirolimus and, increasingly, PI3K inhibitors, according to the French PROS protocol [34, 106].

Orbital lesion. Treatment depends on the visual impact (compressive optic neuropathy, diplopia, exophthalmos with corneal damage) [34]. In acute exophthalmos, usually due to intracystic haemorrhage, puncture (percutaneous or open) is the reference; if acuity does not recover or worsens after puncture, or if puncture is impossible, surgical orbital decompression with intravenous corticosteroids is performed; resection is the last resort, with a major bleeding risk, attenuated by biological glue and suction drains, and bone decompression is sometimes necessary [34]. Without an acute complication, background treatment is decided on the basis of progressive neuropathy, diplopia, chronic pain, aesthetic concern and quality of life, with sclerotherapy (bleomycin, polidocanol, doxycycline), early sirolimus or both; surgery is rarely complete [34].

Inflammatory flares. No study has compared treatments, and the recommendations are empirical [34]. The protocol regimen and the comparison with the labels are in table 7.15a. Drainage of macrocysts followed by sclerotherapy is an option in flares of macrocystic forms, if there is rapid access to interventional radiology; repeated flares justify longer antibiotic courses or prophylaxis (Wagner and colleagues propose at least three months) and, above all, a background treatment, in particular sirolimus, and referral to the reference or competence centre [34].

Complementary medicine, psychological and social support. The protocol, at the proposal of the patient association AMLA, accepts alternative and complementary medicine (medical hypnosis, meditation, sophrology, manual therapies, acupuncture, herbal medicine and others) as a complement for well-being, pain, sleep and anxiety, without demonstrated superiority over placebo and never replacing conventional treatment; oral herbal products require checking for interactions, in particular with sirolimus [34]. Regular psychological support should be offered to the patient, at any age and with appropriate tools (drawing and stories for children, sharing groups for adolescents and parents), and to carers; the protocol suggests developing therapeutic education programmes with coping strategies [34]. Physical activity and sport should be encouraged and, if necessary, adapted to the site and the discomfort [34].

Divergences from the other sources. The sirolimus target trough in the French protocol (about 3–12 ng/mL, with extremes of 3–4 to 12–15 ng/mL; 4–12 ng/mL in the PERFORMUS trial) is lower than those used in CLA (5–15 ng/mL in Japan and in the lymphangioleiomyomatosis label, 8–12 ng/mL in Cincinnati, 10–15 ng/mL in the phase II trial); the starting dose (1.6 mg/m² per day in two doses) coincides with the 0.8 mg/m² per dose every 12 hours of the phase II trial and the Cincinnati protocol [27, 34, 38, 80, 104]. The first trough measurement is at 15–30 days in the protocol and at 7–14 days after each adjustment in the US label [34, 83]. The protocol dose of co-amoxiclav (80–100 mg/kg/day) is about double the maximum of the standard paediatric formulations in the US label (45 mg/kg/day), but lower than the labelled paediatric maximum with the 14:1 formulation (Augmentin ES-600®, 90 mg/kg/day, only in recurrent or persistent acute otitis media), and the duration of 6 to 10 days differs from the 14 to 21 days of the French PROS protocol for infection of a lymphatic malformation [34, 106, 110]. The guideline is the reference for the dose, and the label serves for comparison.

8. Reproductive Options and Family Counselling

8.1. Somatic forms: mosaic GLA, GSD, KLA and CCLA

In CLA caused by postzygotic somatic variants, the variant is not present in blood or, in principle, in the patient's germline, and the parents are not carriers [17, 20, 21]. The recurrence risk for siblings is therefore that of the general population, and there is no indication to test relatives. GSD has no documented familial cases [4, 25]. The risk of transmission of a somatic variant to the patient's own offspring has not been quantified in CLA; experience in PROS indicates a very low risk for mosaic hotspot variants [42]. When somatic testing detects a variant with a VAF close to 50% in several tissues, or in a gene associated with germline disease, the laboratory should flag the possibility of germline origin and recommend germline testing and counselling [28].

In isolated common cystic lymphatic malformation, PIK3CA variants, when found, are somatic; demonstrating postzygotic origin greatly reduces the recurrence risk in offspring compared with germline disorders, and the French protocol considers the isolated forms non-hereditary and reassuring for parents [34]. In syndromic forms, counselling depends on the syndrome and on the somatic or germline origin of the variant (table 6.4a), with referral to the reference or competence centre [34].

8.2. Germline forms of CCLA

In germline CCLA, the risk follows the gene. In the autosomal dominant RASopathies (for example, PTPN11, SOS1, RAF1, RIT1), each child of a carrier has a 50% risk of inheriting the variant, with variable expressivity of the lymphatic phenotypes; many variants are de novo [23, 36]. In the EPHB4 form, autosomal dominant with variable expressivity, carriers may have anything from severe, sometimes fatal, fetal hydrops to atrial septal defect, varicose veins and lower-limb oedema in adulthood, and families with first-trimester miscarriages have been described [13]. In the PIEZO1 and MDFIC forms, autosomal recessive, the parents are carriers and the risk for each pregnancy is 25%, with frequent fetal hydrops and intrauterine death in some cases [14, 15]. Trisomy 21 and 22q11.2 deletion follow the usual chromosomal counselling [23]. Cascade testing of at-risk relatives and prenatal or preimplantation diagnosis are possible when the familial variant is known [36].

8.3. Prenatal diagnosis and pregnancy

In a pregnancy with fetal hydrops or effusions, investigation includes karyotype or array, a panel or exome with RAS-MAPK genes and exclusion of immune, infectious and haematological causes; lymphatic dysplasia was the cause in 5.7% of 5437 cases in a systematic review [66]. Women with CLA should know that pregnancy may worsen the effusions and that sirolimus and trametinib require effective contraception and planning of pregnancy with the team, because of embryofetal toxicity [27, 83, 89].

8.4. Fertility and counselling of minors

Prolonged treatment with immunosuppressants and molecular inhibitors has poorly understood effects on fertility; sirolimus may cause azoospermia or oligospermia, and a patient with CLA under treatment had a suboptimal yield in oocyte preservation, so it is recommended to discuss fertility preservation before a possible decline in ovarian reserve [83, 98]. In the somatic forms there is no predictive testing of minors to offer. In the germline forms, testing of minors is justified when there is medical benefit (surveillance for manifestations in childhood), according to the general rules of counselling [36].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

There are no population prevalence studies of any of the four entities. Orphanet classifies the prevalence of GSD as less than 1 per 1,000,000, with about 300 published cases, and that of KLA and CCLA as unknown; it has no prevalence entry for GLA [1, 3, 10, 11]. The 2022 review counted more than 350 cases of GSD published since 1955, mostly isolated reports [4]. The estimate of 1 to 5 per 10,000 in Europe that Orphanet assigns to the group of rare lymphatic malformations refers mainly to common lymphatic malformations and not to CLA [116]. These figures are counts of published cases, not incidences.

For common cystic lymphatic malformation, the French protocol, based on the 2019 recommendations of the French Society of Otorhinolaryngology, gives an incidence of cervicofacial lesions of 1.2 to 2.8 per 1000 births, without describing the population or the method of estimation, so the figure should be read as a French position and not as a validated population incidence; superficial forms are much more frequent than deep ones [34]. The same range circulates in reviews and case reports; the 2023 meta-analysis on OK-432 attributes it to Lerat and colleagues, a retrospective single-centre French series of 23 patients operated on between 2004 and 2013, without a denominator of births; in the sources consulted, no population-based or registry study confirming it was identified [117].

9.2. Data by region and by cohort

In GSD there is no racial or regional preference, and some series describe male predominance, such as the 64.2% of men in the Chinese series [4, 61]. In KLA, the Boston series had a slight male predominance (13 of 20; 23 of 43) [5, 6]. No founder populations or founder variants are known, which is expected in somatic disorders. The sources consulted contain no data from Portugal or Brazil; the absence of data in these sources does not demonstrate the absence of cases.

9.3. Special populations

In young children, thoracic disease and young age are associated with a worse prognosis, and sirolimus requires pharmacokinetic dosing, close lipid monitoring and Pneumocystis prophylaxis [27, 35, 86]. In girls and women, puberty and pregnancy may worsen the effusions, and fertility should be discussed before prolonged treatments [27, 98]. In adults, GSD and KLA may present late, and osteolysis requires exclusion of myeloma and metastases [4, 27]. In the RASopathies, lymphatic disease is a frequent complication (lifetime prevalence of about 37% in Noonan syndrome) and often a CCLA [32].

9.4. Reference networks, registries and patient associations

In Europe, the reference network is VASCERN, whose VASCA working group has published patient pathways for lymphatic malformation (2020) and for kaposiform haemangioendothelioma (2024) and recommendations for somatic genetic testing [28, 33]. The specific patient associations are the Lymphangiomatosis & Gorham's Disease Alliance (LGDA, https://lgdalliance.org/) and the Lymphatic Education & Research Network (LE&RN, https://lymphaticnetwork.org/); for research, the CaNVAS consortium (https://www.research.chop.edu/canvas) [29]. In the United Kingdom, the Lymphoedema Support Network and the British Lymphology Society support patients with lymphoedema [36]. Active registries include the Lymphatic Anomalies Registry of Boston Children's Hospital (NCT02399527), the NICHD natural history study (NCT05731141; 1200 participants planned) and the Cincinnati biomarker study (NCT03001180) [29, 88].

In France, common cystic lymphatic malformation has had a national protocol (PNDS) since March 2021, coordinated by the rare disease health networks FIMARAD (dermatology; reference centres MAGEC-Nord, coordinated at Necker-Enfants Malades Hospital, and MAGEC-Sud, coordinated at Bordeaux University Hospital), TETECOU (head and neck; coordinated in the ear, nose and throat department at Necker) and FAVAmulti (rare vascular diseases; coordinated at the Georges Pompidou European Hospital) [34]. Follow-up alternates between the reference or competence centre and the attending physician; forms requiring regular, prolonged or costly follow-up may be recognised as a long-term condition (ALD, 100% coverage), with reimbursement of transport and, in lymphatic forms under ALD, of one spa treatment per year; disability benefits (AAH in adults with at least 80% disability, AEEH below 20 years, PCH) depend on the MDPH, and schools organise an individualised reception plan (PAI), a personalised schooling plan (PPS), a support worker (AESH) or home teaching (SAPAD) [34]. The French associations are AMLA (Agir pour les Malformations Lymphatiques en Alliance, http://asso-amla.org/fr/), the Association Syndrome CLOVES and AVML (Vivre Mieux le Lymphœdème, http://www.avml.fr/); emergency cards from the rare disease networks are available [34].

10. Illustrative Clinical Case

10.1. Kaposiform lymphangiomatosis due to NRAS p.(Gln61Arg) diagnosed from cell-free DNA in the effusion

Brown and colleagues, in Melbourne, described in 2026 a 4-year-old girl, previously healthy except for a small muscular ventricular septal defect, with 3 days of fever, respiratory distress and cyanosis [39]. She had a large purulent right pleural effusion and methicillin-sensitive Staphylococcus aureus bacteraemia, treated with cefazolin and clindamycin and chest drainage, and a large pericardial effusion requiring pericardiocentesis [39]. The pleural and pericardial fluids were chylous (raised triglycerides, lymphocyte predominance), and the output did not decrease with a low-fat diet, parenteral nutrition, intravenous methylprednisolone and octreotide; she had thrombocytosis and microcytic anaemia, with normal coagulation [39]. Occlusive thrombosis of the left subclavian, internal jugular and brachiocephalic veins, associated with a central catheter, increased chylous output and was treated with heparin [39].

Femoral intranodal MR lymphangiography was not diagnostic; repeated with intrahepatic, mesenteric and inguinal injection, it showed dilated, abnormal lymphatic channels in the mediastinum and upper abdomen, suggestive of GLA, and cardiac catheterisation excluded haemodynamic causes [39]. Single nucleotide polymorphism microarray on blood was normal, and a 26-gene somatic panel at about 500-fold depth on pleural fluid was negative; cell-free DNA from the pleural fluid, analysed in Philadelphia on a 51-gene vascular malformation panel, revealed NRAS NM_002524.5:c.182A>G p.(Gln61Arg) with a VAF of 4.69% [39]. Without histology, and without thrombocytopenia, bone lesions or a mediastinal mass, the diagnosis was revised to presumed KLA due to NRAS p.(Gln61Arg) [39].

While trametinib was being obtained through a compassionate access programme (not approved or reimbursed in Australia for this indication), she received sirolimus 1.12 mg/m² per day with a trough of 5 to 10 μg/L for 8 weeks, with reduced output but clinical deterioration and pancreatitis [39]. On day 137 of admission she started trametinib 0.5 mg enterally once daily, with about 3 weeks of overlap with sirolimus during weaning [39]. Soon afterwards she had drain obstruction, reaccumulation of effusions and tamponade, video-assisted thoracoscopic surgery, respiratory and multiorgan failure and high-frequency oscillatory ventilation; the family was informed of the poor prognosis and the drains were removed at their request, after which oxygenation unexpectedly improved [39]. With trametinib, the effusions resolved, parenteral nutrition was stopped and dietary fat was reintroduced, and she was discharged 7 weeks after starting the drug, after 186 days in hospital [39]. At 3 months she had only a small residual pleural effusion, at 6 months she had returned to school without symptoms and at 14 months she had normal growth and activity, with toxicity limited to dry skin and a mild follicular rash [39].

The figures of the article consulted show the clinical timeline with treatments and outputs (https://pmc.ncbi.nlm.nih.gov/articles/PMC13501887/figure/fig-0001/), coronal T1-weighted MR lymphangiography after intrahepatic injection, with dilated channels in the mediastinum and upper abdomen and pleural and pericardial effusions (https://pmc.ncbi.nlm.nih.gov/articles/PMC13501887/figure/fig-0002/), and a diagram of the RAS-MAPK and PI3K-AKT-mTOR pathways with the sites of action of trametinib and sirolimus (https://pmc.ncbi.nlm.nih.gov/articles/PMC13501887/figure/fig-0003/) [39].

10.2. Comment

The case brings together several points of this article: presentation as empyema masking the lymphatic disease, venous thrombosis as an aggravating factor for leakage, the limitation of moderate-depth clinical panels in the face of low-VAF variants, the value of cell-free DNA from effusions when biopsy is risky, revision of the phenotypic diagnosis (GLA) to a diagnosis integrated with the genotype (presumed KLA) and the response to the MEK inhibitor after a partial response to sirolimus [18, 28, 39]. An additive effect of sirolimus during the overlap cannot be excluded [39]. The measures described, such as trametinib at a fixed dose of 0.5 mg and removal of the drains in the context of end-of-life care, are individual decisions and not routine; trametinib in CLA is off-label and without a published trial, and the NRAS variant is not pathognomonic of KLA [29, 39].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends on the entity, the extent and, above all, thoracic involvement. In the Japanese survey, overall mortality was 20% at 7 years and all deaths occurred in patients with thoracic lesions [31]. In a study of 53 cases of thoracic GLA cited by the Cincinnati group, mortality was 39% below 16 years and nil above [35]. Pleural and pericardial effusions, involvement of ribs and vertebrae and young age are associated with a worse prognosis in GLA and GSD [35]. In GSD, chylothorax is the worst prognostic factor (mortality of about 43.6%), and among the children who died almost all had chylothorax; in the Chinese series, the disease was not fatal in most and 21 of 30 patients with follow-up had local control [4, 61]. KLA is the most severe entity: 5-year survival of 51% and overall survival of 34% in the 1995–2011 series, mortality of 55.6% in the Japanese survey, and survival of 79% in the pathology series extending to 2020 [2, 5, 6]. Death results from cardiorespiratory failure or coagulopathy [29]. Long-term survivors report chronic musculoskeletal pain [5]. In CCLA, prognosis depends on the cause and the response to interventions, and the sources do not describe survival by genotype [23].

Under sirolimus, the series describe stabilisation of bone disease and functional improvement, but infrequent radiological regression and relapse after discontinuation in low-flow malformations, which makes treatment prolonged or indefinite [27, 35, 87]. The apparent improvement in survival in KLA coincides with new therapies, but there are no controlled comparisons [29].

11.2. Surveillance

There is no consensus on surveillance after diagnosis or under treatment [27]. The table brings together the recommendations of the sources and, where these are lacking, the requirements of the drug labels.

11.3. Long-term follow-up

Follow-up is lifelong, by a multidisciplinary team and at an experienced centre, with attention to late complications of the disease (fractures, vertebral deformity, chronic pain, fistulas, protein losses) and of treatments (dyslipidaemia, infections, effects on growth, fertility, secondary neoplasms after radiotherapy) [4, 29, 35]. Patient associations and natural history registries help to support families and generate data [29].

12. Summary and Final Considerations

Complex lymphatic anomalies are four rare diseases of the lymphatic circulation, generalised lymphatic anomaly, Gorham-Stout disease, kaposiform lymphangiomatosis and central conducting lymphatic anomaly, which the 2025 ISSVA classification groups together by structural complexity, multisystem involvement and functional impairment [9]. The first three are, in the great majority, sporadic and caused by activating somatic variants in the PI3K-AKT-mTOR and RAS-MAPK pathways, mainly PIK3CA in GLA, NRAS p.(Gln61Arg) in KLA and KRAS in GSD; CCLA is often germline, as a manifestation of RASopathies, aneuploidies or lymphatic dysplasias, and sometimes somatic [17, 20, 21, 23]. The correlations between gene and entity are trends and not rules, because the same gene can cause more than one type [18].

Diagnosis rests on the bone pattern (progressive cortical destruction in GSD, non-contiguous medullary lesions in GLA and KLA), on the coagulopathy and spindle cells of KLA and on the demonstration of thoracic duct anomalies and reflux in CCLA, using dynamic MR lymphangiography [2, 27]. Molecular testing should be done on affected tissue or on cells and cell-free DNA from lymphatic fluid, with deep sequencing and a 1% threshold, because the variants are at low fraction and absent from blood; a negative result does not exclude the disease [18, 28]. Rib and vertebral biopsy should be avoided [27].

Treatment is multimodal and based on low-level evidence. Sirolimus is the most studied systemic therapy, with functional improvement in most GLA, GSD and KLA but infrequent radiological regression and no demonstrated effect in CCLA; it is approved for these diseases only in Japan [31, 35, 80]. MEK inhibitors, mainly trametinib, have produced responses in cases of KLA, CCLA and other forms with RAS-MAPK pathway variants and are in phase 1/2 and 2 trials; alpelisib is an option in forms with PIK3CA and was authorised in the European Union in 2026 for severe PROS [30, 32, 88, 92]. Bisphosphonates, vincristine, corticosteroids, lymphatic interventions, surgery and radiotherapy complete treatment according to the entity and the complications [4, 27]. Prognosis depends mainly on thoracic disease: KLA and GSD with chylothorax are the most severe forms, and survival in KLA appears to have improved with targeted therapies [4, 6, 31]. Prevalence studies, validated diagnostic criteria, surveillance consensus and controlled trials are lacking, and molecular diagnosis integrated with the phenotype is now the basis of therapeutic choice [18, 27].

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