Generalized Lymphatic Anomaly and Gorham–Stout Disease: Overview and Recent Insights

Abstract

Significance: Generalized lymphatic anomaly and Gorham–Stout disease are extremely rare diseases with severe symptoms and poor prognosis. The etiology and clinical presentation of the patients remain poorly defined, but recent research has attempted to determine the pathogenesis of these diseases. Recent Advances: In recent years, the characteristics of complex lymphatic anomalies have been revealed. Kaposiform lymphangiomatosis is recognized as a new entity that has an aggressive course and poor prognosis. Genetic analysis revealed somatic mutations in genes associated with the phosphoinositide 3-kinase (PI3K) pathway in lymphatic malformation lesions. Somatic NRAS mutation in lymphatic endothelium from a generalized lymphatic anomaly patient was also detected as a potential cause of disease. Furthermore, studies demonstrated the efficacy of the mammalian target of rapamycin (mTOR) inhibitor sirolimus for these lymphatic diseases. Critical Issues: These diseases have overlapping symptoms, imaging features, and complications, leading to difficulty in their differential diagnosis. In addition, there are no standard therapies. Therefore, we need to determine the differences among these diseases to not only diagnose but also treat them appropriately. Future Directions: Further investigations should reveal differences in the clinical features and findings of radiological, pathological, and genetic examinations to manage each disease appropriately. Somatic mutation in genes encoding RAS/PI3K/mTOR signaling pathway components could be associated with the pathogenesis of these diseases and may be novel targets for drug therapies.

A case report of Gorham-Stout disease diagnosed during the course of recurrent meningitis and cholesteatoma

“…Gorham-Stout disease is a rare condition that is difficult to diagnose, as there is no specific test or procedure. Diagnosis is made by excluding other diseases, particularly lymphadenopathies, bone manifestations of systemic diseases, or other neoplastic lesions [7]. Previous studies proposed the following criteria to establish a diagnosis of for disease: 1) positive biopsy for presence of angiomatous tissue; 2) absence of cellular atypia; 3) minimal or no osteoblastic response and absence of dystrophic calcification; 4) evidence of local, progressive osseous resorption; 5) no expansile, nonulcerative lesion; 6) absence of visceral involvement; 7) an osteolytic radiographic pattern; and 8) no evidence of hereditary, metabolic, neoplastic, immunologic, or infectious etiology [8].…”

“…Previous studies proposed the following criteria to establish a diagnosis of for disease: 1) positive biopsy for presence of angiomatous tissue; 2) absence of cellular atypia; 3) minimal or no osteoblastic response and absence of dystrophic calcification; 4) evidence of local, progressive osseous resorption; 5) no expansile, nonulcerative lesion; 6) absence of visceral involvement; 7) an osteolytic radiographic pattern; and 8) no evidence of hereditary, metabolic, neoplastic, immunologic, or infectious etiology [8]. Despite variations in the histological appearance of this disease, typical histological findings reveal resorbed bone structures, which are replaced by thinwalled endothelium-lined capillaries of vascular or lymphatic origin [7]. A biopsy is also helpful for ruling out other entities during differential diagnosis.…”

Dental management of lymphangiomatosis: case report

“…The biomarkers angiopoietin‐1 and ‐2 have been used to identify patients with similar vascular pathologies with high sensitivity and specificity. Bone‐specific alkaline phosphatase (BAP), serum C‐terminal telopeptide‐1, tartrate‐resistant acid phosphatase and serum interleukin‐6 have also been reported as potential biomarkers. There is evidence suggesting that infection with Mycobacterium avium paratuberculosis may have a pathogenic link to lymphangiomatosis, warranting further investigation into potential infectious sources of this disease.…”

“…The use of antiangiogenic medications including inhibitors of mTOR, VEGF and MAPK kinase enzymes (MEK) has shown promise in mitigating disease progression. Sirolimus is an mTOR inhibitor which exerts its effects via kinase activity inhibition leading to cell death. A variety of VEGF inhibitors, including bevacizumab and pazopanib, have also been demonstrated as effective therapies through inhibition of lymphangiogenesis.…”

“…Genetic abnormalities in the RAS/mitogen‐activated protein (MAPK) and phosphoinositide 3‐kinase (PI3K)/mammalian target of rapamycin (mTOR) signalling pathways have been reported as potential mechanisms of these lymphatic diseases. Pathogenesis has also been linked with the receptor for vascular endothelial growth factor (VEGF) which is a key regulator of angiogenesis.…”