Abstract
Abstract
“Lymphangiomatosis” is a general term for excessive growth of aberrant lymphatic vessels. The impact of lymphangiomatosis can be devastating due to osteolysis and/or multi-organ involvement. The disorders are heterogeneous, and treatment is dependent upon disease location and symptoms. Most reports are single cases or small case series, predominantly in the orthopedic and radiologic literature. Basic research focused on lymphatic disorders may translate into new therapies for these disorders.
Introduction
Focal lymphatic malformations may be small and discrete or involve contiguous structures, and may be associated with adjacent bony hypertrophy and consequent skeletal deformity. Cervicofacial lesions may lead to temporomandibular and maxillary problems as well as difficulties with speech, orthodonture, and pain. Balakrishnan et al. review potential modulators of osseous changes in lymphatic disorders. 8
Two subtypes of lymphatic disease (which are often overlapping) are lymphangiomatosis and Gorham's disease.9–11 The former can be limited to a define organ or structure (eg, spleen, liver, thoracic) or involve a more generalized process. Gorham's syndrome, Gorham-Stout disease, disappearing/vanishing/phantom bone disease are interchangeable names for cases of lymphangiomatosis concomitant with bony destruction. Most reports are from the radiologic and orthopedic literature.9,12–18 Histologic features include thin-walled lymphatic vessels positive for lymphatic markers (eg, LYVE-1, VEGFR-3).6,19
Symptoms of lymphangiomatosis and Gorham's syndrome are site-dependent and often progressive, although rare cases of spontaneous regression have been reported.20–22 Bony involvement leads to musculoskeletal pain, decreased bone density, pathologic fractures, bony distortion, and other orthopedic concerns.
Lymphangioleiomyomatosis (LAM) is a separate disorder, mainly affecting females and patients with tuberous sclerosis. Primarily manifesting as progressive pulmonary compromise due to abnormal proliferation of lymphangioleiomyomatous (smooth muscle) cells, extrapulmonary involvement is also commonly seen.23,24 LAM research may contribute to relevant insights applicable to Gorham's syndrome and lymphangiomatosis.25,26
Table 1 lists informative resources for these disorders.
Assessment and Evaluation
As with any disorder, a thorough history and physical examination is essential. Symptoms include pain, respiratory distress, and abdominal discomfort. Evaluation often includes radiologic studies (eg, x-ray, MRI) with characteristic osteopenia, lytic bone lesions, pathologic fractures, peribronchial thickening, chylous effusions, chylous ascites, and organ-specific changes, depending on disease extent.27–32 Both Gorham's syndrome and lymphangiomatosis may appear cystic.33–36
The differential diagnosis includes disorders causing lymphatic dysfunction such as: lymphangiectasia, lymphatic malformation, chyle leak syndromes, and disorders associated with osteolysis including malignancies, histiocytosis X, fibrous dysplasia, fibrous cortical defect, non-ossifying fibroma, osteoid osteoma, Hajdu-Cheney syndrome, idiopathic multicentric osteolysis with nephropathy, and heritable osteolysis syndromes.37–40 Three cases patients have been reporting with lymphangiomatosis and concomitant Chiari I malformation.41–43
Therapy
Treatment is dictated by the nature of the symptoms, anatomic location, and associated problems. Table 2 lists the range of published therapies for these disorders. There is no consistent sequence of therapies and no uniform response rate.11,19 Note that most cases require concomitant or sequential therapy in that there is not one treatment that stands out as most effective. To date, there is no set treatment protocol for these disorders, and few clinical trials (see Table 3).
Systemic therapy
Bisphosphonates and Vitamin D have been utilized in many cases, with results ranging from stabilization to lack of response.11,44–49 Direct intralesional instillation of bisphosphonates into diseased bone has been proposed. 50 Interferon alpha in addition to other interventions was successful in some cases. 11 Adjunctive therapy with interferon-alpha-2b, low anticoagulant, low molecular weight heparin, radiotherapy, and surgery was beneficial in two cases. 51 There are single case reports of patients treated adjunctively with tyrosine kinase inhibitors, bevacizumab or propranolol.52,53 A clinical trial investigating the safety and efficacy of sirolimus for complex vascular anomalies including lymphangomatosis and Gorham's syndrome is underway (http://clinicaltrials.gov/ct2/show/NCT00975819 last accessed December 10, 2011.).
Surgery
Sclerotherapy with bleomycin, doxycycline, OK-432, and other agents have been reported, with variable results.54–56 Orthopedic surgery including bone grafts and reconstruction, arthroplasty, fracture management, and allograft-resurfacing composite (ARC) have been described.7,57–62 Lung and liver transplantation for lymphangiomatosis have been reported, with variable results.63–67
Radiation therapy
Radiation therapy to disease foci has been described in several publications,47,54,68–71 and was found to prevent disease progression and result in stable or improved disease in 80% of a series of 8 cases, and in 77.3% of 44 previously published cases. 47
Discussion
Hirayama et al. propose that bone resorption by osteoclasts in patients with Gorham's have an increased responsiveness to factors that stimulate osteoclastogenesis and bone resorption. 72 Insights into the mechanism of Gorham's syndrome may arise from studies of osteolysis syndromes for which mutations have been discovered (eg, matrix metalloproteinases).38,40 New therapies may derive from research in lymphatic endothelial biology and studies targeting malignancy-associated osteolysis.73–75 The roles of interleukins, lymphatic growth factors, and signaling pathways (including mTOR and Alk-1) shed light on potential mechanisms, which can be exploited therapeutically.23,74,76–78 Lymphangiomatosis and Gorham's syndrome are relatively rare elusive heterogeneous diseases. Improved classification, risk stratification, and basic/clinical research will better define these disorders and help guide effective therapies.