Kaposiform lymphangiomatosis: Unifying features of a heterogeneous disorder

Fernandes, Violet M.; Fargo, John H.; Saini, Surbhi; Guerrera, Michael F.; Marcus, Leigh; Luchtman‐Jones, Lori; Adams, Denise M.; Meier, Emily Riehm

doi:10.1002/pbc.25278

Cited by 49 publications

(47 citation statements)

References 11 publications

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“…Although the NRAS variant was present in the tissue of the majority of patients analyzed in Barclay's study, the allelic frequency ranged from 1% to 28% and so not all cells in the lesions had the mutation. It remains unclear what cell type(s) in the KLA lesions harbor the NRAS mutation and also which cell type actually drives the disease process, although spindle cells and abnormal LEC are potential contributors . We did not find the NRAS gene mutation (p.Q61R) in the cells from the KLA patients in our study.…”

Section: Discussioncontrasting

confidence: 61%

“…Patients with KLA suffer from high morbidity and mortality, with 51% survival after five years and overall survival rate of 34% . This poor prognosis is due to a constellation of life‐threatening symptoms including pleural and/pericardial effusions and ascites, consumptive coagulopathy, and hemorrhage . Pulmonary and abdominal involvement is especially associated with poor outcome.…”

Section: Introductionmentioning

confidence: 99%

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Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Boscolo

Pastura

Glaser

et al. 2019

Pediatric Blood & Cancer

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Background Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of “kaposiform” spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. Procedure Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells. Results Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK‐1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K–AKT and MAPK–ERK‐1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K–AKT–mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. Conclusions Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K–AKT–mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.

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Section: Discussioncontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Boscolo

Pastura

Glaser

et al. 2019

Pediatric Blood & Cancer

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“…One is patient 5, who has Noonan syndrome, which has an established association with coagulopathy and recurrent bleeding (19,20). However, the combination of coagulopathy, recurrent bleeding ,and chylous effusions in the other two patients lead us to believe that these patients could instead have kaposiform lymphangiomatosis (21)(22)(23). These patients' biopsies would need to be reviewed to confirm this conclusion.…”

Section: Need Of a New Classificationmentioning

confidence: 99%

Primary Intestinal Lymphangiectasia and its Association With Generalized Lymphatic Anomaly

Marugán

López‐Gutiérrez

2016

J Pediatr Rev

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Background: Lymph is a fluid originating in the interstitial spaces of the body that contains cells, proteins, particles, chylomicrons, and sometimes bacteria. Objectives: The aim of the present study is to demonstrate that primary intestinal lymphangiectasia (PIL) results from a disruption of lymphatic circulation, thus corresponding to a secondary rather than a primary event in the context of generalized lymphatic anomaly. Materials and Methods:In this case series and record review, an analysis of intestinal lymphatic involvement was performed on patients diagnosed with PIL between 1965 and 2013. Of the 21 patients included in the study, 10 had been diagnosed before 5 years of age (1 prenatal), 8 between 5 and 18 years of age, and 3 while older than 18 years of age. The follow-up period varied between 1 and 34 years. Clinical data, blood and fecal parameters, imaging studies, endoscopy results, biopsy analyses, treatment details, and outcome information were collected from medical records. Endoscopy, histological studies, magnetic resonance imaging, and lymphoscintigraphy were performed on all patients. Dynamic intranodal lymphangiography was performed on 8 patients. Results: Central lymphatic channel obstruction was identified in 12 patients (57%). Associated lymphatic malformation (LM) was present in 16, diarrhea in 10, chylothorax in 11, chylous ascites in 10, pericardial effusion in 6, coagulopathy in 3, and osteolysis in 7. Conclusions: We consider intestinal lymphangiectasia not as an entity in itself, but as a consequence of lymphatic flow impairment in the thoracic duct, producing chylous reflux into the intestinal lymphatics.

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“…The elements mentioned above may be encountered in patients affected by CLA . A standardized report that includes possible specific findings present in the CLA will be helpful for patient management, performing meta‐analyses of published cases, and comparison of patient outcomes.…”

Section: Recommendationsmentioning

confidence: 99%

Multidisciplinary guidelines for initial evaluation of complicated lymphatic anomalies—expert opinion consensus

Iacobas

Adams

Pimpalwar

et al. 2019

Pediatric Blood & Cancer

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Objective Complicated lymphatic anomalies (CLAs) are chronic, progressive, and debilitating conditions that share clinical features, yet key elements for optimal evaluation and management have not been established. We aimed to formulate expert opinion consensus‐based guidelines for comprehensive evaluation of CLAs. Study Design Patient support groups dedicated to CLAs organized an international conference for vascular anomaly experts from 16 specialties to address the objective. Participants received a set of questions before the meeting and reviewed the literature. Data extracted from international lymphatic anomaly registries were presented and the group separated for panel discussions during the conference. The recommendations achieving consensus within the panel were presented to the entire audience. Open debate occurred until majority approval was achieved. Results The expert group was composed of 52 physicians who defined the clinical elements required to evaluate and diagnose a CLA. The radiology panel established the preferred anatomical and functional imaging methods for diagnosis and the elements required to be described during interpretation. Two medical panels compiled the metabolic and hematologic tests at diagnosis and also recommended functional studies. The surgical group recommended precautions for biopsy and the pathology panel provided biopsy specimen processing guidelines. Conclusions Patients with CLAs require a comprehensive and targeted diagnostic plan for appropriate management, prevention of complications, and conservation of resources. As this population is managed by diverse medical and surgical specialties, we offer an expert multidisciplinary consensus‐based opinion on the current literature and on data extracted from international lymphatic anomaly registries.

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Kaposiform lymphangiomatosis: Unifying features of a heterogeneous disorder

Cited by 49 publications

References 11 publications

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Primary Intestinal Lymphangiectasia and its Association With Generalized Lymphatic Anomaly

Multidisciplinary guidelines for initial evaluation of complicated lymphatic anomalies—expert opinion consensus

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