Lymphatic Malformations



Clinical Features

Gorham-Stout disease (GSD) is a rare disease of unknown etiology characterized by the presence of lymphatics in bone and massive bone loss. GSD may occur at any age, but it is most commonly observed in children and young adults [1]. It affects males and females of all races and does not exhibit a clear inheritance pattern [1]. The clinical course of GSD is unpredictable. GSD may rapidly progress or spontaneously arrest [2]. Symptoms are typically nonspecific such as weakness or acute pain and swelling [2]. In some cases, the first symptom is bone fracture following minor trauma [2]. Although GSD can affect any bone in the body, it frequently affects the shoulder, pelvis, jaw, ribs, and vertebrae [3]. Thoracic involvement tends to carry a poor prognosis and can be associated with chylothorax [2, 4-7]. This complication can have dire consequences such as respiratory distress and failure.

Histological Changes

Old case reports on massive osteolysis prompted Gorham and Stout to evaluate the histological changes in 8 prior cases of massive osteolysis [8]. In their groundbreaking paper, Gorham and Stout reported that angiomatosis is associated with the complete disappearance of bone(s) [8]. In some cases, the abnormal vessels appeared to be blood vessels, whereas in other cases, the abnormal vessels appeared to be lymphatic vessels. The presence of lymphatic vessels could not be confirmed at the time because there were no immunohistochemical markers of lymphatics. LYVE-1 and podoplanin are two markers of lymphatics. Importantly, numerous LYVE-1 and podoplanin positive lymphatic vessels are present in GSD lesions [4, 9, 10]. Vessels in pathological specimens taken from patients with GSD have also been reported to express VEGFR3, CD31, PDGFRβ and endoglin [10, 11]. Together, these observations demonstrate that patients with GSD have lymphatics in their bones.

The International Society for the Study of Vascular Anomalies (ISSVA) has developed a system to classify vascular anomalies. According to the ISSVA classification system, vascular malformations can be distinguished from vascular tumors by the expression of markers of cell proliferation. Although numerous vessels are present in GSD, the endothelial cells show low a labeling of the proliferation marker MIB-1 [11-13]. Therefore, GSD is considered to be a vascular malformation [12].


The cause of excessive bone resorption in GSD is unclear. Gorham and Stout maintained that osteolysis could be due to hyperemia, changes in pH, or mechanical forces [8]. Heyden suggested that sluggish blood flow may trigger hypoxia, lower tissue pH and favor the activity of acid hydrolases [14]. Endothelial dysplasia has also been proposed to drive the progression of GSD [15]. More recently, it has been suggested that osteoclasts contribute to the pathology of GSD. Osteoclasts are bone-degrading cells whose role and even presence in GSD has remained controversial. Gorham and Stout failed to identify osteoclasts in the pathological specimens used in their original investigation. Several other reports also document an absence of osteoclasts in GSD [8, 14, 16-18]. Conversely, osteoclasts have been noted by others [19-21]. This inconsistent observation has been proposed to be due to the evaluation of different phases (active or remission) of the disease [19]. Despite the inconsistency in the literature concerning their presence, changes in GSD appear to directly affect osteoclasts and their activity. Osteoclast progenitor cells isolated from a GSD patient were found to be more sensitive to the osteoclastogenic factors RANKL and M-CSF [20]. Furthermore, serum from a GSD patient stimulated the formation of osteoclast-like cells better than normal serum and this activity was blocked by an IL-6 neutralizing antibody [22]. These data suggest that circulating factors could influence osteoclast activity and bone resorption in GSD.

The crosstalk between lymphatic endothelial cells (LECs) and resident bone cells could affect bone turnover or formation. In vitro studies have revealed that LECs can stimulate the formation and activity of

osteoclasts [23]. Mechanistically, LECs produce M-CSF, which promotes the development of osteoclasts [23]. LECs did not affect the development or activity of osteoblasts [23]. Therefore, ectopic lymphatics in bone in GSD patients could induce osteoclast-mediated bone resorption by secreting M-CSF.


There is growing evidence that circulating factors could function as biomarkers of disease activity in GSD. IL-6 is a cytokine involved in bone resorption and has been found to be elevated in two different patients with GSD and to normalize following bisphosphonate treatment alone [18] or in combination with radiation [22]. However, a recent report questions the use of IL-6 as a biomarker of disease activity because the authors found that the levels of IL-6 did not correlate with the state of the disease [4]. VEGF-A, a growth factor with hem/lymphangiogenic properties [24, 25], is also a potential biomarker for GSD. VEGF-A was reported to be elevated in 2 patients with active disease and its levels dropped following disease stabilization [4]. Furthermore, VEGF-A was elevated in the plasma of another GSD patient and its levels decreased following treatment with interferon alpha 2b [26]. More recently, CTX-1 (a fragment of collagen-1 created by osteoclasts) has been found to be elevated in several GSD patients [27]. This circulating biomarker could potentially be used to monitor bone disease in patients with GSD. Further exploration of cytokines may lead to the identification of molecules to monitor disease activity in patients with GSD.


Several different strategies have been employed to treat GSD. Surgical interventions such as pleurodesis and thoracic duct ligation have been widely used to manage the accumulation of fluid in the pleural cavity in GSD patients [2]. Radiation therapy has also been used to control thoracic involvement and disease progression. Hyed et al. [28], recently reviewed radiation therapy in 44 GSD patients and found disease progression, arrest, and remission occurred in 22.7%, 50%, and 27.3% of patients, respectively.

Bisphosphonates inhibit osteoclasts and have been used to treat GSD. Disease stabilization has been noted in cases which used bisphosphonates to treat lesions affecting the hand [29], jaw [30], pelvic girdle [31], and ribs [6, 18]. However, disease progression has been observed even in the presence of long- term use of bisphosphonates [32].

Therapeutic strategies targeting the deranged endothelium in bones have also been used to treat GSD. Interferon alpha-2b as a single agent exerted a noticeable clinical benefit in a patient with GSD that previously received radiation therapy and ligation of the thoracic duct [33]. Interferon alpha-2b combined with clondronate also showed a therapeutic benefit; however, since both agents were given simultaneously, it is unclear which drug was more important for the improvement in the patient’s condition [17]. Clinical improvement has also been noted in cases where pegylated interferon alpha-2b has been combined with zoledronic acid [6] or surgery [34]. Interferon alpha with steroid therapy also induced disease remission in a patient [35]. The anti-VEGF-A antibody bevacizumab has also been used to successfully treat a case of GSD [36]. In recent years, sirolimus has grown in popularity for treating GSD. Several cases have been published reporting positive outcomes in GSD patients treated with Sirolimus [37-41; 52].

Genetics and Animal Models

Transgenic mice that overexpress VEGF-C in bone exhibit a phenotype that resembles GSD. Osx- tTA;TetO-Vegfc mice have lymphatics in their bones and they have porous cortical bone [42]. Osx- tTA;TetO-Vegfc mice also have more osteoclasts than control mice and zoledronic acid can attenuate bone loss in Osx-tTA;TetO-Vegfc mice [42].

Lineage-tracing studies with Osx-tTA;TetO-Vegfc and Prox1-CreERT2;LSL-Pik3caH1047R mice revealed that LECs in bone come from preexisting LECs located outside of bone [43]. A time course experiment was performed to further characterize bone lymphatic development in Osx-tTA;TetO-Vegfc mice. This revealed that bone lymphatics develop is a stepwise process where regional lymphatics grow, breach the periosteum, and then gradually invade bone [43]. It was also reported that loss of osteoclasts impaired the development of bone lymphatics in Osx-tTA;TetO-Vegfc mice and that rapamycin can suppress the growth of bone lymphatics in Osx-tTA;TetO-Vegfc mice [43].

A somatic activating mutation in KRAS (p.Q61R) was recently identified in one patient with GSD [44]. Potential disease-causing variants were not identified in 5 other GSD patients included in the study [44]. It remains unclear from this study whether additional GSD patients have mutations in KRAS and whether active KRAS signaling in LECs is sufficient to drive GSD.


Clinical Features

Generalized lymphatic anomaly (GLA) is rare disease of the lymphatic system [45]. Although GLA can present at any age, it is typically diagnosed in children [45]. This condition may affect a single organ, but commonly involves multiple organs [45]. Thoracic involvement frequently presents with chylous effusions and is associated with a poor prognosis and a high mortality rate, especially in children [45, 46]. Symptoms of GLA are nonspecific and include wheezing, cough, dyspnea, and chest pain [47]. These nonspecific symptoms cause pulmonary GLA to be misdiagnosed as asthma in many individuals [48]. However, imaging (MRI and CT) and histological analysis can assist in the correct diagnosis of GLA.

Approximately 40% of patients with GLA have bone involvement [48]. GLA patients with bone involvement exhibit loss of medullary bone, but not cortical bone [49]. GLA patients with bone involvement tend to have more bones affected than GSD patients and the appendicular skeleton is more frequently involved in GLA than GSD [49].

Histological Changes

The histological features of pulmonary GLA are distinct from other diseases of the lung. GLA specimens contain numerous anastomosing vessels comprised of flattened-endothelial cells that stain positive for factor VIII-related antigen [50] and D2-40 [51]. A biobank of formalin-fixed paraffin-embedded material from 23 GLA/GSD patients has been created [52]. Analysis of pulmonary and pleural samples from this biobank revealed that lesions in young patients are more proliferative than lesions from old patients [52]. Importantly, this biobank is reported to be open for collaborative ventures on GLA and GSD [52].


Sirolimus has been used to treat several cases of GLA [37, 40, 41, 53]. In a recent study, 18 patients (13 with GLA and 5 with GSD) were treated with sirolimus [54]. Eighty-three percent of patients had improvement in one or more aspects of their disease [54]. Boney disease did not progress in patients with bone involvement and effusions improved in most patients with either a pleural or pericardial effusion [54]. Taken together, sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA or GSD [54]. Other treatments for GLA include surgical resection [44], pleurodesis [46], lung transplantation [57], interferon alpha [56, 57], propranolol [58], and medium chain triglyceride diet [46].

Genetics and Animal Models

It was recently reported that somatic activating mutations in PIK3CA can cause GLA [59]. Mice that expressed an active form of PIK3CA (Prox1-CreERT2;LSL-PIK3CAH1047R) in their lymphatics developed

abnormal lymphatics in their skin and ectopic lymphatics in their bones [59]. Importantly, rapamycin inhibited lymphatic hyperplasia and dysfunction in Prox1-CreERT2;LSL-PIK3CAH1047R mice [59].

Transgenic mice were recently created to study lymphatic abnormalities in the lung. CCSP-rtTA;TetO- Vegfc mice develop irregular lymphatics in their lungs and chylothorax [60]. Surprisingly, the irregular lymphatics persisted following the withdrawal of VEGF-C [60]. Interestingly, rapamycin partially reversed the lymphatic abnormalities in CCSP-rtTA;TetO-Vegfc mice [61]. This work suggests that rapamycin can partially normalize irregular lymphatic vessels.


Clinical Features

Kaposiform lymphangiomatosis (KLA) is an aggressive lymphatic anomaly. KLA is typically diagnosed in children and the 5-year survival rate for the disease is 51% [62]. Patients with KLA exhibit diffuse lymphatic abnormalities in multiple tissues. The mediastinum, lung, pleura, spleen, and skeleton are frequently affected in patients with KLA [62]. Similar to GLA, bone involvement in KLA is associated with the loss of medullary bone, not cortical bone [48, 62]. However, hemorrhagic pleural or pericardial effusions are more common in KLA than GLA [48]. Thrombocytopenia is also more common in KLA than GLA [62].

Histological Changes

A distinguishing characteristic of KLA is the presence of spindle cells [62]. These spindle cells express podoplanin, a marker of lymphatic endothelial cells [62].


Angiopoietin-2 (Ang-2) is a hem/lymphangiogenic growth factor that can function as an agonist or antagonist of Tie-2. Ang-2 serum levels are elevated in KLA patients and can potentially be used to diagnose KLA [63, 64]. Interestingly, Ang-2 levels decrease in KLA patients following treatment with sirolimus [63]. Therefore, Ang-2 could function as a diagnostic biomarker for KLA and as a biomarker to monitor response to therapies.


Several therapies have been used to treat KLA. The most common treatments include vincristine, interferon-α, and sirolimus [41, 48, 62, 65].

Genetics and Animal Models

Lymphatic endothelial cells were recently isolated from a GLA/KLA patient [66]. Exome sequencing revealed that the cells harbored an activating mutation in NRAS (p.Q61R) [66]. These cells formed lesions when grown in mice and expression of mutant NRAS in endothelial cells impaired lymphatic development in zebrafish [66]. More recently, 10 additional patients with KLA were found to have the NRAS p.Q61R variant [67]. In the future, NRAS-mutant zebrafish and/or mice could be used to test therapies for KLA.


Central conducting lymphatic anomaly (CCLA) is a complex lymphatic anomaly that is characterized by the dilatation of lymphatic channels. It was recently discovered that somatic mutations in ARAF can cause CCLA [68]. ARAF is a serine/threonine protein kinase that activates MEK. The ARAF mutation (c.640T>C:p.S214P) that was found in two unrelated patients with CCLA is a gain-of-function mutation that promotes MEK/MAPK signaling [68]. The MEK inhibitor, trametinib, suppressed MAPK signaling in ARAF-mutant lymphatic endothelial cells and a different MEK inhibitor normalized lymphatics in ARAF-

mutant zebrafish [68]. One CCLA patient has been treated with trametinib and their pulmonary function test markedly improved following 12 months of therapy [68]. Lastly, an inactivating mutation in EPHB4 has been identified in a family with CCLA [69].


Although substantial progress has been made in field of lymphatic anomalies research, more work needs to be done. It is our hope that future investigations will: 1) shed light on the underlying mechanisms responsible for GSD, GLA, and KLA; 2) detect biomarkers for monitoring the progression/remission of GSD, GLA, and KLA; and 3) identify new treatments for patients and methods to assess patient outcomes.


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