To the Editor:
Kaposiform lymphangiomatosis (KLA) is a rare disease classified as a
subtype of lymphatic malformations. It affects multiple organs,
including the mediastinum, lungs, bones, spleen, and soft tissues and is
often associated with thrombocytopenia and coagulopathy. Currently, no
treatments have been established for this disease. It is often a
progressive disease with poor prognosis.1-4
A previously healthy 10-year-old male was found to be thrombocytopenic
(70 000/µL) in a preoperative examination for acute appendicitis and was
diagnosed with immune thrombocytopenia by a local physician.
Additionally, abnormal infiltrates were observed on his chest
radiographs. One year later, his platelet count decreased to 30 000/µL.
After an additional 6 months, hemoptysis was observed, leading to the
patient’s referral to our department at the age of 12 years. At the
initial visit, laboratory investigation indicated an oxygen saturation
of 95% on room air, platelet count 43 000/µL, and an elevated level of
fibrin-fibrinogen degradation product (FDP) (26.6 µg /mL). The pulmonary
function test indicated a percentage-predicted vital capacity of 66.8%,
and the percentage-predicted forced expiratory volume in 1 s was 80.9%.
Magnetic resonance imaging (MRI) showed that lesions with high signal
intensity on both T1- and T2-weighted images ascended through the
peritracheal region and extended to the extrapulmonary regions involving
the subcutaneous neck. It extended caudally into the pelvic cavity (Fig.
1A and B). Chest computed tomography (CT) revealed a diffusely spread,
low-density area in the mediastinum. Thickening of the interlobular
septal wall and pleura were also observed. (Fig. 1C and D). A lung
biopsy was not able to be performed due to chronic disseminated
intravascular coagulation. Subcutaneous tissue and neck lymph nodes were
biopsied instead of the lungs. Pathological examination revealed dilated
lymphatic channels in the fatty connective tissue (Fig. 1E), which lead
to the diagnosis of diffuse pulmonary lymphangiomatosis. A multimodal
treatment regimen consisting of interferon-alpha, thalidomide, and
propranolol was ineffective (Fig. 2). Propranolol was discontinued due
to frequent and recurrent asthma-like attacks, which are considered as
the adverse effects. Subsequently, fluticasone followed by inhaled
budesonide-formoterol was administered to control the asthma-like
attacks. After 1 year and 2 months of inhaled combined
budesonide-formoterol (1 280 µg of budesonide and 36 ug of formoterol),
the platelet count suddenly increased from 28 000 to 43 000/µL during a
month without any triggers at the age of 20 years. Surprisingly, during
the following 3 months, platelet counts and FDP levels rapidly returned
to their normal ranges. The pathology was re-evaluated, and a focal
cluster of D2-40 positive spindle cells was observed, leading to a final
diagnosis of KLA (Fig. 1F). The respiratory function gradually
recovered. The MRI findings also improved, but slight deterioration was
observed after the inhalation dose was reduced. Seventeen years after
the onset of respiratory symptoms, the patient rarely complained of
dyspnea or bleeding while receiving inhaled budesonide-formoterol
therapy.
KLA is a progressive disease that worsens over time, and respiratory
failure is the primary cause of death. Approximately 20% of patients
survive for 7 years after the onset of respiratory
symptoms1. Previous reports have indicated that
various medical treatments, including corticosteroids, vinblastine,
interferon-alpha, doxycycline, thalidomide, and octreotide, as well as
surgical interventions such as pleurodesis, chest tube ligation, and
tumor resection, have been temporizing1-4. Activation
of the RAS/PI3K/mTOR signaling pathway has been observed in KLA
tissues5. Although sirolimus, an mTOR inhibitor, has
been reported to be effective6, its efficacy rate is
insufficient, with 58.3% of patients achieving partial response, 25%
experiencing stable disease, and 16.7% showing disease
progression7. Recent case reports have shown its
effectiveness in treating sirolimus-resistant patients with either the
PIK3CA inhibitor, alpelisib, for somatic PIK3CAmutations8 or the MEK inhibitor trametinib for somaticNRAS p.Q61R mutations9,10. Corticosteroids are
used for their anti-inflammatory effects and typically administered
systemically. Previous reports have shown only transient improvements in
coagulation abnormalities, imaging findings, and pulmonary function
tests even with systemic administration10,11. No
reports have indicated the efficacy and long-term improvements induced
by corticosteroid-beta-2 receptor agonist inhalation therapy, as
observed in the present case. The mechanism underlying the improvement
in coagulopathy and regression of abnormal mediastinal soft tissue and
lung parenchyma remains unknown.
This case is a significant example of the prognosis of KLA and gathering
more cases using this treatment is crucial.
ACKNOWLEDGMENTS
The authors would like to thank the patient and the parents for their
consent to publish this report. We would like to thank Editage
(www.editage.jp) for English language editing.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
REFERENCES
1. Croteau SE, Kozakewich HPW, Perez-Atayde AR, et al. Kaposiform
Lymphangiomatosis: A Distinct Aggressive Lymphatic Anomaly.Journal of Pediatrics . Feb 2014;164(2):383-388.
2. McDaniel CG, Adams DM, Steele KE, et al. Kaposiform
lymphangiomatosis: Diagnosis, pathogenesis, and treatment. Pediatr
Blood Cancer . Apr 2023;70(4):e30219.
3. Ozeki M, Fujino A, Matsuoka K, Nosaka S, Kuroda T, Fukao T. Clinical
Features and Prognosis of Generalized Lymphatic Anomaly, Kaposiform
Lymphangiomatosis, and Gorham-Stout Disease. Pediatr Blood
Cancer . May 2016;63(5):832-8.
4. Ozeki M, Fukao T. Generalized Lymphatic Anomaly and Gorham-Stout
Disease: Overview and Recent Insights. Advances in Wound Care .
Jun 2019;8(6):230-245.
5. Barclay SF, Inman KW, Luks VL, et al. A somatic activating
<i>NRAS</i> variant
associated with kaposiform lymphangiomatosis. Genetics in
Medicine . Jul 2019;21(7):1517-1524.
6. Wang Z, Li K, Yao W, Dong K, Xiao X, Zheng S. Successful treatment of
kaposiform lymphangiomatosis with sirolimus. Pediatr Blood
Cancer . Jul 2015;62(7):1291-3.
7. Zhou JY, Yang KY, Chen SY, Ji Y. Sirolimus in the treatment of
kaposiform lymphangiomatosis. Orphanet Journal of Rare Diseases .
Jun 2021;16(1)260.
8. Grenier JM, Borst AJ, Sheppard SE, et al. Pathogenic variants in
PIK3CA are associated with clinical phenotypes of kaposiform
lymphangiomatosis, generalized lymphatic anomaly, and central conducting
lymphatic anomaly. Pediatr Blood Cancer . May 17 2023:e30419.
9. Foster JB, Li D, March ME, et al. Kaposiform lymphangiomatosis
effectively treated with MEK inhibition. EMBO Mol Med . Oct 07
2020;12(10):e12324.
10. Chowers G, Abebe-Campino G, Golan H, et al. Treatment of severe
Kaposiform lymphangiomatosis positive for NRAS mutation by MEK
inhibition. Pediatric Research . 2022 Mar 2022;
11. Anthony MD, Swilling A, Jiwani ZM, et al. Multidisciplinary
Multiagent Treatment of Complex Lymphatic Anomalies with Severe Bone
Disease: A Single-Site Experience. Lymphatic Research and
Biology . Apr 2022;20(2):118-124.
Legend list
FIGURE 1
Coronal magnetic resonance imaging (MRI), computed tomography (CT)
images, and histopathological studies for a patient with KLA.
- Short-T1 inversion recovery (STIR) imaging of the chest in a
10-year-old male at the time of diagnosis showed significant
mediastinal thickening that ascended through the peritracheal region
and extended into both shoulders and the subcutaneous neck. It
extended caudally from the aorta to the abdominal cavity (white
arrows).
- T2 images at the age of 27 years showed high-intensity areas within
the mediastinum to the pulmonary hilum, and bronchovascular bundles
were decreased.
- Axial chest computed tomography (CT) of the pulmonary window revealed
a diffusely spread low-density area in the mediastinum.
- An axial chest CT scan in the mediastinal window shows variable
thickening of the peri-bronchial wall (yellow arrows), interlobular
septal wall (white arrows), and pleura (blue arrows). Continuity is
observed through the bilateral pulmonary hila to the diffuse
bronchovascular bundle thickening.
- Microscopic findings of biopsied lymph nodes demonstrated dilated
lymphatic channels in the fatty connective tissue with hematoxylin and
eosin staining.
- Microscopic findings of biopsied lymph nodes demonstrated clustered
spindle cells that stained positive for D2-40.
FIGURE 2
The clinical course and treatment
The upper panel shows the changes in platelet count (red) and
fibrin-fibrinogen degradation products (FDP) (blue) during the treatment
course. The lower panel shows the results of the pulmonary function
tests, including the percent predicted vital capacity (solid line) and
percent predicted forced expiratory volume in 1 s (dotted line). Inhaled
corticosteroids are shown in yellow. Budesonide-formoterol contains 160
μg of budesonide and 4.5 μg of formoterol per inhalation. Four
inhalations per day were initiated, and improvements in coagulopathy and
pulmonary function were observed after eight inhalations. When the dose
was reduced to two inhalations per day, the MRI findings worsened;
therefore, the dose was maintained at four inhalations per day.