A Short Note on Generalized Lymphatic Anomaly: A Lymphatic Disorder
Received: 02-Feb-2022, Manuscript No. Jbclinphar-22-53235; Editor assigned: 04-Feb-2022, Pre QC No. Jbclinphar-22-53235 (PQ); Reviewed: 18-Feb-2022 QC No. Jbclinphar-22-53235; Revised: 24-Feb-2022, Manuscript No. Jbclinphar-22-53235 (R); Published: 03-Mar-2022, DOI: 10.37532/0976- 0113.13.S(1).128
Citation: Suzuki T, Kamio Y. A Short Note on Generalized Lymphatic Anomaly: A Lymphatic Disorder. J Basic Clin Pharma 2021;13:128-129.
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Lymphatic disorders may be challenging to diagnose because of the limited number of cases and diversity of symptoms. Along with the clarification of pathogenesis, advancements in diagnostic nomenclature and scrutinized internationally standardized classifications have been observed. Several causal genes have been elucidated and included in the classification system. The International Society for the Study of Vascular Anomalies (ISSVA) has established a classification of lymphatic disorders. For example, simple vascular malformations (IIa) or Lymphatic Malformations (LMs) include Generalized Lymphatic Anomaly (GLA), Kaposiform Lymphangiomatosis (KLA), and Gorham– Stout Disease (GSD). Morbidity and mortality of LMs are induced by infection or significant compression of the circulatory, respiratory, and digestive organs. To relieve symptoms, pleurodesis and sclerotherapy may be effective in providing local control. However, complete surgical extirpation of all lesions is considered risky due to adhesions around vital organs, such as the lung and mediastinal large vessels. Thus, the role of surgery remains unclear. In patients with GLA, the disease-causing genes identified from endothelial cells have a somatic mutation in neuroblastoma RAS. Other genes such as PIK3CAm were advocated as causal genes of another subset of LMs. Therapeutic agents are being developed based on these germlines and somatic mutations.
Generalized lymphatic anomaly, Lymphatic malformation, Neuroblastoma RAS, ISSVA
CT: Computed Tomography; DPL: Diffuse Pulmonary Lymphangiomatosis; GLA: Generalized Lymphatic Anomaly; GSD: Gorham-Stout Disease; KLA: Kaposi form Lymphangiomatosis; LMS: Lymphatic Malformations; MRI: Magnetic Resonance Imaging; mTOR: mammalian Target of Rapamycin; NRAS: Neuroblastoma RAS; PIK3: Phosphatidylinositol-3 Kinase; VATS: Video- Assisted Thoracic Surgery; VEGFR: Vascular Endothelial Growth Factor Receptor.
About the Study
Generalized Lymphatic Anomaly (GLA), previously termed as lymphangiomatosis, presents as a subset of multifocal Lymphatic Malformations (LMs) that involve the skin, neck, abdomen, and thorax [1-5]. We previously reported a case of an adult female patient with GLA and bacteremia . She was successfully treated with an antibacterial drug and Video-Assisted Thoracic Surgery (VATS) debridement and drainage. Only palliative care was administered to the patient. To date, no fundamental treatment for GLA has been determined .
Etiology and genetics
The lymphatics form a delicate plexus of vessels that connect to the main lymphatic channels, including the cisterna chyli and thoracic duct. A disruption in this plexus of vessels may induce a variety of LMs. However, the exact etiology of LMs remains unclear.
Endothelial cells express Vascular Endothelial Growth Factor Receptors (VEGFRs). VEGF-C is considered to play an important role in lymphangiogenesis [4,6-11]. In patients with GLA, the disease-causing genes identified from endothelial cells have a somatic mutation in neuroblastoma RAS [7,12]. This mutation was proven to take part in the development of the lymphatic system. Other genes such as PIK3Cam were advocated as causative of LMs [12,13]. Therapeutic agents are being developed based on the germline and somatic mutations [8,10,12-14].
Symptoms and diagnostic investigations
LM symptoms vary depending on the site of occurrence and the LM subset. Patients with osteolytic bone diseases may present with pathologic fractures . GLA and Gorham–Stout Disease (GSD) are congenital disorders that commonly involve the bones, thorax, spleen, and gastrointestinal tract. Osseous disease is observed in both subsets. Osteolytic lesions in patients with GLA frequently exhibit cortical bone sparing. In contrast, patients with GSD show aggressive lytic lesions with cortical bone loss .
Thoracic involvement includes chylous effusion, such as chylothorax, chyloptysis, chylopericardium, and chylous ascites, and is believed to be induced by leakage from the thoracic duct [2,14,15]. Diffuse Pulmonary Lymphangiomatosis (DPL) is a disease characterized by diffuse interstitial infiltration of lymphatic vessels in the lung, pleura, and mediastinum [2,14,16]. Chest Computed Tomography (CT) reveals peribronchovascular and interlobular septal thickening . CT and Magnetic Resonance Imaging (MRI) lymphangiography reveal abnormal lymph flow around the thoracic duct . Both chylothorax and DPL cause cough, wheezing, and dyspnea, subsequently leading to respiratory failure and death. Open biopsy may be recommended.
Morbidity and mortality of LMs are induced by infection [2,3,18] or significant dysfunction of the circulatory, respiratory [19,20], and digestive organs [21-23] caused by the disruption in the lymphatic vessels. Cases in which bilateral lung transplant was successful for patients with DPL have been reported . Generally, resection of organs may be difficult when the extent of the required resection is large. The role of surgery remains unclear because of the limited extirpation . To relieve symptoms, pleurodesis and sclerotherapy may be effective in providing local control [25,26]. Our case had infection of several cysts of lymphangiomatosis along with bacteremia. We successfully performed debridement and irrigation of the lesions under VATS along with administration of an antibacterial drug, ultimately decreasing the cystic lesions and eradicating the infection . This technique is sometimes performed for severe empyema thoracis [27-29]. Therapeutic decisions depend on the site of presentation and severity of the disease . In our case, treatment was not initiated while the patient was asymptomatic .
The number of clinical drug trials evaluating the reduction of lymphatic proliferation has increased. Specifically, somatic mutations in genes encoding for the RAS/PI3K/mTOR signaling pathway have been identified as targets for drug development. Sirolimus, a mammalian target of rapamycin inhibitor, is used in the management of DPL [14,30].
Lymphatic disorders are difficult to diagnose and treat. However, the classification and nomenclature of these disorders have improved because of advancements in the field of genetics and the accumulation of case reports. Genetic characteristics of subsets of LMs have been elucidated. Novel treatment modalities that impede LM pathogenesis should be developed in the future.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors declare no conflicts of interest.
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