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Because it is rare and has a wide spectrum of clinical, histological, and imaging features, diagnosing GLA can be challenging. Plain x-rays reveal the presence of lytic lesions in bones, pathological fractures, interstitial infiltrates in the lungs, and chylous effusions that may be present even when there are no outward symptoms.
The most common locations of GLA are the lungs and bones and one important diagnostic clue is the coexistence of lytic bone lesions and chylous effusion. An isolated presentation usually carries a better prognosis than does multi-organ involvement; the combination of pleural and peritoneal involvement with chylous effusions and lytic bone lesions carries the least favorable prognosis.
When lung involvement is suspected, high resolution computed tomography (HRCT) scans may reveal a diffuse liquid-like infiltration in the mediastinal and hilar soft tissue, resulting from diffuse proliferation of lymphatic channels and accumulation of lymphatic fluid; diffuse peribronchovascular and interlobular septal thickening; ground-glass opacities; and pleural effusion.
Pulmonary function testing reveals either restrictive pattern or a mixed obstructive/restrictive pattern.
While x-rays, HRCT scan, MRI, ultrasound, lymphangiography, bone scan, and bronchoscopy all can have a role in identifying GLA, biopsy remains the definitive diagnostic tool. However, there are reports of biopsy resulting in serious complications, such as chylothorax.
Microscopic examination of biopsy specimens reveals an increase in both the size and number of thin walled lymphatic channels along with lymphatic spaces that are interconnecting and dilated, lined by a single attenuated layer of endothelial cells involving the dermis, subcutis, and possibly underlying fascia and skeletal muscle.
Additionally, Tazelaar, et al., described a pattern of histological features of lung specimens from nine patients in whom no extrathoracic lesions were identified, which they termed “diffuse pulmonary lymphangiomatosis” (DPL).
Recognition of the disease requires a high index of suspicion and an extensive workup. Because of its serious morbidity, GLA must always be considered in the differential diagnosis of lytic bone lesions accompanied by chylous effusions, in cases of primary chylopericardium, and as part of the differential diagnosis in pediatric patients presenting with signs of interstitial lung disease.
In 1983 Heffez and colleagues published a case report in which they suggested eight criteria for a definitive diagnosis of GSD:
- Positive biopsy with the presence of angiomatous tissue
- Absence of cellular atypia
- Minimal or no osteoblastic response or dystrophic calcifications
- Evidence of local bone progressive osseous resorption
- Non-expansile, non-ulcerative lesions
- No involvement of viscera
- Osteolytic radiographic pattern
- Negative hereditary, metabolic, neoplastic, immunologic, or infectious etiology.
Recognition of the disease requires a high index of suspicion and an extensive workup. Because of its serious morbidity, GSD must always be considered in the differential diagnosis of osteolytic lesions. Diagnosis relies on radiographic findings revealing progressive osteolysis and cortical destruction. Magnetic resonance imaging (MRI) shows complete resorption of bone and replacement with infiltrative soft tissue that is of low signal intensity on T1-weighted imaging and high signal intensity on T2, with intense enhancement on contrast imaging.
Immunohistochemical markers of lymphatic endothelial cells (LYVE-1, podoplanin/D2-40) reveal presence of lymphatic vessels in medullary and cortical regions of bones, and in affected soft tissues. Rib lesions should not be biopsied, as this procedure may elicit a refractory chylous effusion.
Differential diagnosis includes generalized lymphatic anomaly (the major distinguishing characteristic, is the progressive osteolysis seen in GSD), acroosteolysis dominant type, multicentric carpo-tarsal osteolysis with or without nephropathy, autosomal recessive carpotarsal osteolysis, hereditary sensory and autonomic neuropathy type 2, Farber lipogranulomatosis, Torg-Winchester syndrome, idiopathic phalangeal acroosteolysis (see these terms). Other causes of osteolysis such as infection, cancer (primary or metastatic), inflammatory or endocrine disorders should also be considered.