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Clinical Presentation and Diagnosis

Patients can present with cystic lymphatic malformations of the thorax or abdomen, effusions (pericardial, pleural, or peritoneal), chyloptysis or plastic bronchitis, chyluria, or protein losing enteropathy [31]. Pulmonary parenchymal disease is not uncommon and presents with thickened bronchovascular bundles and pleural surfaces. Bony lymphatic lesions can cause pain and impaired mobility [28, 32].

LMs in GLA share several radiological ndings with common cystic lymphatic malformations, although splenic and hepatic involvement appears to be more common [28, 33]. Bone lesions can be characterized by plain radiographs, CT, MRI, or bone scintigraphy. CT is more sensitive than radiographs at identifying and characterizing bony lesions associated with GLA, and MRI is the most sensitive; in addition, MRI is preferred for its ability to demonstrate soft tissue components, such as lymphatic malformations. Typically, on MRI the bone marrow is hypointense on T1 in affected areas with hyperintense T2 signal noted in osseous lesions. GLA may be associated with multiple lytic abnormalities in the medullary compartment of bone. In contrast to GSD, however, GLA does not cause cortical destruction, although pathologic fractures can still occur. Lesions in GLA more commonly involve a greater number of bones than GSD and are non-contiguous. They can include the appendicular skeleton­ though are most frequently identi ed as multiple lesions throughout the pelvis and vertebrae [25, 28, 32, 33].

In patients with GLA, CT scan of the chest can demonstrate bilateral interstitial in ltrates with diffuse smooth thickening of interlobular septa and bronchovascular bundles, with extensive involvement of mediastinal connective tissue and perihilar regions (Fig. 21.6) [25, 28–30, 32, 33].

Course/Prognosis

GLA diagnosed earlier in life carries a worse prognosis with mortality of up to 39% described in a review of patients under 16 years of age [34]. Thoracic involvement in GLA is generally associated with a worse prognosis. Bone fractures and recurrent effusion in the pleural or pericardial spaces add to morbidity. There are few data available regarding prognosis in adults, but a recent study of 35 patients with GLA that included adults (median age 18 years) showed >60% survival over 10 years [32].

Management

Recent advances in therapy, including the use of mTOR inhibitors with addition of bisphosphonates for symptomatic

or high-risk bony disease, can provide signi cant improvement in morbidity and mortality.

Sirolimus is a direct inhibitor of mTOR complex 1 and blocks downstream signaling and protein synthesis [29, 30, 35, 36]. Adams et al. reported an 85% response rate in complicated vascular anomalies at the end of approximately 12 months [37]. All seven patients with GLA reported partial responses. The most common adverse event was bone marrow­ suppression (27%). Many physicians prescribe prophylaxis for PJP for patients with GLA on sirolimus, particularly if there is hypogammaglobulinemia or lymphopenia from lymph or chyle losses [28, 38]. Notably the heterogeneity in GLA disease manifestations in these populations can confound interpretation of many of these studies. A phase 3 study of sirolimus is currently underway and will provide valuable information regarding the topic (NCT02638389).

Newer therapies with more targeted agents, such as inhibitors of PI3K-alpha (the product of the PIK3CA gene), have the potential to improve disease control in cases where a speci c genetic mutation is identi ed [39].

Interferon alpha 2b was one of the rst treatments reported to be effective for GLA. The mechanism of action is thought to be regulation of VEGF expression. Administration can be associated with a fu-like syndrome [40, 41]. In addition, side effects, including severe depression and mood issues, can limit is use in adults.

Zoledronic acid is a potent bisphosphonate that inhibits osteoclast-mediated bone resorption and induces osteoclast apoptosis. There are several reports of improvement in bone pain in patients with GLA [28, 40]. It is often used in combination with sirolimus when bony disease is present, particularly when patients report pain or pathologic fracture [42].

Sclerosis and surgical resection have been used to debulk large LMs associated with GLA. Sclerotherapy is usually guided by direct real-time imaging to help differentiate healthy lymphatic tissue from diseased tissue. Pleurectomy, pleurodesis, and ligation of the thoracic duct can be performed to address recurrent pleural effusions.

Successful treatment with irradiation for unresectable LMs causing signi cant symptoms has been reported but carries risk of malignant conversion to angiosarcoma (or lymphangiosarcoma).

Kaposiform Lymphangiomatosis

Kaposiform Lymphangiomatosis (KLA) is an aggressive subtype of GLA that was rst identi ed by Croteau et al. at Boston Children’s Hospital in 2015 [43]. They reported histopathological characteristics of spindled lymphatic endothelial cells accompanying malformed lymphatic channels in 20 patients with lymphatic anomalies. Although the clinical presentations of GLA and KLA can be similar, hematologic

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and coagulation abnormalities should raise suspicion for KLA and biopsy con rmation should be sought [44]. While KLA shares some histological features with kaposiform hemangioendothelioma (KHE), its clinical features are distinct [45]. The nding that multiple different genetic mutations can cause KLA, including RAS mutations, favor classi cation as a neoplasm rather than a malformation.

Etiopathogenesis

Similar to many vascular anomalies with somatic activating variants in the RAS/PI3K/mTOR signaling pathways, Barclay et al. found an activating NRAS mutation (p.Q61R) in KLA [46, 47]. Recently a mutation in the Casitas B lineage lymphoma (CBL) gene, an inhibitor of the RAS pathway, was also identi ed in a patient with KLA [48]. NRAS is

a

c

a proto-oncogene that regulates proliferation via the MAPK and PI3k/AKT pathway. The nding that KLA can also be caused by mutations in the MAPK pathway could explain the non-responses or insuf cient responses to mTOR and PI3K targeted therapy in KLA patients who were initially diagnosed with GLA and treated with sirolimus or other Akt pathway inhibitors [1, 22, 28, 32, 36, 43, 46, 48–51]. One case of human papilloma virus RNA identi ed by PCR from tissue sampling of a KLA patient has also been reported [52].

Grossly, KLA demonstrates a pattern similar to primary diffuse lymphangiomatosis in the lung with the addition of hemorrhage. KLA morphology is dominated by malformed lymphatic channels within the pleura, pulmonary septa, and bronchoalveolar bundles. In addition, there are foci of intravascular and perivascular, spindle shaped to fat “kaposiform” endothelial cells which are occasionally hemosiderin laden and show platelet microthrombi (Fig. 21.11). Although

b

d

Fig. 21.11  Kaposiform Lymphangiomatosis (KLA). (a) Biopsy demonstrates H&E section of brocollagenous tissue with excessive, irregular slit-like vessels lined by a single layer of endothelial cells. Scattered foci of perivascular and intravascular spindles cells are present. (b)

These spindle cells are admixed with lymphocytes, extravasated red blood cells, and occasionally hemosiderin laden macrophages. (c) These spindle cells are diffusely immunoreactive to CD34, an endothelial cell marker, and (d) PROX-1, a lymphatic marker (insert)

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the clinical presentations of GLA and KLA can be similar, hematologic abnormalities should raise suspicion for KLA and biopsy con rmation should be sought. While KLA shares some histological features with kaposiform hemangioendothelioma, its clinical features are distinct and the latter has a prominent spindled endothelial cell component. The endothelial cells in KLA are immunoreactive to vascular markers, including CD31, CD34, and ERG, and lymphatic markers Podoplanin (D2–40) and PROX-1.

Clinical Presentation and Diagnosis

Although KLA is typically diagnosed in the pediatric population at a mean age of 6 years, the original cohort included patients as old as 44 years of age [43], and the disease is increasingly recognized in adults [53]. KLA is associated with coagulopathy, including hypo brinogenemia, thrombocytopenia and bleeding that are not present in GLA [44]. Bleeding can often be the presenting complaint. In addition, serum angiopoietin-2 is markedly elevated in cases of KLA (and KHE), allowing differentiation from GLA [54]. Angiopoietin-2 levels can also be used to follow response to therapy [55]. KLA has a stronger predilection than GLA for the thoracic cavity and on presentation most patients have pleural, posterior mediastinal and hilar disease. A typical pattern on imaging in KLA is contrast enhancing, in ltrative soft tissue thickening, and lung parenchymal involvement along the bronchovascular bundles (Fig. 21.12). Patients often have an associated pleural/pericardial effusion with both a chylous and hemorrhagic component. Lytic osseous lesions are typically similar to those in GLA with cortical sparing, and pathologic fractures have been noted as in GLA. The anatomic distribution often resembles that of central conducting lymphatic anomalies (CCLAs), and it can be

dif cult to differentiate the two on lymphangiography. Findings can include dilated and tortuous lymphatics with refux into different channels. This may explain why effusions, which are commonly seen and are often the presenting complaint, are associated with an aggressive course. The overall mortality rate for KLA in 43 patients with well-­ characterized pathology was approximately 21% [56].

Management

Sirolimus has been used with some bene t in many patients with KLA, although it is often not suf cient as a single agent. Zhou et al. report a partial response in 58.3% of their cohort with sirolimus [57]. Adams et al. reported good response in six of seven sirolimus treated patients [37]. As KLA was only recently identi ed as a distinct entity, it is likely that some patients classi ed as GLA in past studies actually had KLA [37, 55, 57].

When response to sirolimus is suboptimal, courses of vincristine and/or corticosteroids have often been added to treatment regimens during fares in an attempt to stabilize disease. Vincristine has been used for the coagulopathy in KLA based on shared pathophysiologic elements with Kasabach-Merritt phenomenon, which has been shown to be responsive to that therapy [28, 43, 58].

Bisphosphonates such as zoledronic acid are often added when there is signi cant bony involvement, similar to their use in GLA and GSD [42].

More recently, with the identi cation of activating NRAS or CBL mutations in affected tissues, therapies have been used to target the RAS/MAPK pathway. MEK inhibitors block signals in the distal elements of the RAS pathway, and are therefore useful for targeting most mutations in this signaling network. Foster et al. report resolution of pleural effu-

Fig. 21.12  Right hilar fullness and thickening of interlobular septa and bronchovascular bundles in a patient with KLA

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