Complex lymphatic anomalies, comprising generalized lymphatic anomaly, kaposiform lymphangiomatosis (KLA), Gorham-Stout disease (GSD), and central conducting lymphatic anomaly (CCLA), are congenital lymphovascular disorders with high morbidity and mortality. These conditions are rare, variable in terms of clinical morphology, and lack standardized diagnostic and therapeutic algorithms.
KLA is an aggressive lymphatic anomaly that typically involves the thorax, bones and spleen.1 It presents in young children, often with life-threatening complications such as pleural or pericardial effusions. An associated consumptive coagulopathy similar to Kasabach–Merritt phenomenon is seen.1 Histologically, abnormal lymphatics are seen, with focal spindled endothelial cells. These “Kaposiform” endothelial cells stain with D2-40 and PROX-1.1
A 2-year-old girl presented with a 2-month history of progressive shortness of breath and abdominal distension. Laboratory investigations revealed a consumptive coagulopathy with platelets 89 × 109/L (reference range 150–450), prothrombin time 21.9 seconds (10.6–11.4), activated partial thromboplastin time 41.3 seconds (24.0–36.0), fibrinogen 0.56 g/L (1.7–4.05), and D-Dimer 22.02 µg/mL (0.0–0.5). Abdominal ultrasonography revealed ascites. Pulmonary and splenic infiltrates were seen on computed tomography (CT) of the thorax and abdomen. Echocardiography showed a large pericardial effusion, from which serosanguinous fluid was drained. Whole-body magnetic resonance imaging confirmed pulmonary infiltrates and splenomegaly (Figure 1). Multiple well-defined areas of high STIR and low T1 intensity bony lesions were seen in the right humerus and bilateral femora. These corresponded to areas of lucency on CT without associated cortical destruction. Prominent cervical lymphadenopathy was identified as a potential target for tissue biopsy.
Histologically, lymph node architecture was unremarkable, but lymphangiectasia of the surrounding soft tissue was noted. Immunohistochemical stains for CCD31 and D2-40 were positive, confirming the presence of lymphatic vessels. Cytological atypia and spindle cell components were not identified.
The overall clinical picture was that of a complex lymphatic anomaly. Cell-free DNA was extracted from plasma using just 2.7 mL of patient blood. Digital droplet PCR was performed to detect the NRAS Q61R (c.182A>G) somatic mutation (Centogene, Rostock, Germany). The pathogenic variant was detected at a low allele frequency (0.362%) and, in conjunction with the consumptive coagulopathy, supported a diagnosis of KLA.2
Oral sirolimus was initiated at 0.8 mg/m2 twice daily, with subsequent dose adjustment aiming for trough levels of 5–15 ng/mL. Four months later, the recurrent Kasabach–Merritt phenomenon necessitated the addition of vincristine infusions (0.05 mg/kg weekly for 4 weeks, then monthly for 4 months) and oral prednisolone (2 mg/kg once daily). Over time, the coagulopathy and ascites resolved, and recurrent pericardial effusions ceased. Prednisolone was gradually tapered and 3 years later, the patient remains stable on sirolimus and low-dose prednisolone.
NRAS Q61R (c.182A>G) is a variant previously identified in several neoplasms, including melanoma. In 2019, Barclay et al identified this somatic mutation in lesional tissue from ten out of eleven individuals with KLA.3 The identification of somatic mutations is important for diagnostic purposes, but also for directing therapeutic strategies. We note with interest a recent case of KLA with the NRAS Q61R mutation that was successfully treated with the MEK inhibitor trametinib.4 We have opted to continue with a combination of sirolimus and low-dose prednisolone as the patient remains clinically stable, however if needed treatment with trametinib can be considered as an alternative to target RAS-MAPK pathway.
Tissue sampling is risky in KLA, due to the associated coagulopathy, and the anatomically challenging nature of lesions in the pleura or peritoneum, where a biopsy may precipitate lymphatic leakage or hemorrhage.2 Accordingly, noninvasive diagnostic techniques are preferable. This patient was diagnosed using a commercially available noninvasive assay, based on the prior identification of pathogenic NRAS mutations in KLA using cell-free DNA from plasma or pleural fluid by two prior groups.2,4
Here, we present a further case of KLA diagnosed using cell-free DNA from peripheral blood, and highlight the utility of this noninvasive test with important diagnostic and therapeutic implications.
1. Ricci KW, Iacobas I. How we approach the diagnosis and management of complex lymphatic anomalies [published online ahead of print, 2021 Apr 12]. Pediatr Blood Cancer. 2021;69(Suppl 3):e28985. doi: 10.1002/pbc.28985.
2. Ozeki M, Aoki Y, Nozawa A, et al. Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis
. Orphanet J Rare Dis. 2019;14:215.
3. Barclay SF, Inman KW, Luks VL, et al. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis
. Genet Med. 2019;21:1517–1524.
4. Chowers G, Abebe-Campino G, Golan H, et al. Treatment of severe Kaposiform lymphangiomatosis
positive for NRAS mutation by MEK inhibition [published online ahead of print, 2022 Mar 4]. Pediatr Res. 2022:10.1038/s41390-022-01986-0. doi:10.1038/s41390-022-01986-0