Initially described by Jackson in 1838 as a boneless arm,12 a range of osteolytic bone lesions including regional osteolysis in association with thin-walled vascular channels have been described. In 1955, Gorham and Stout reviewed 24 cases of osteolysis with histologic angiomatosis, describing the clinical syndrome now called Gorham's disease.7 It is characterized by massive osteolysis and disappearing bone disease.7
Although this disease process can be limited to the involved bone and can be self-limited, if the thoracic cavity or the thoracic duct is involved there is the possibility of formation of a chylothorax. Maintaining control of these chylothoraces has been shown to be difficult and the resulting complications often are devastating.3 Our patient died as a result of complications of an uncontrolled chylothorax and pneumonia.
A general feature in the reported histologic studies of patients with Gorham's disease is the presence of proliferative and/or dilated vascular (including lymphatic) channels in association with the osteolysis.3 However, the relationship between the two and underlying biologic mechanisms is elusive.
There have been few autopsy reports of Gorham's disease,6,8-10,13 and the pathogenesis is unclear. We describe autopsy findings stressing the importance of the abnormalities of lymph drainage and their anatomic association with osteolysis. We suggest a possible pathophysiologic mechanism underlying this condition.
A 35-year-old healthy amateur weight lifter presented with a 2-month history of episodic abdominal pain, nausea, and postprandial bloating associated on occasion with fever and vomiting. The patient was admitted to the general surgery department; he received oral antibiotics, cimeti-dine, and Maalox without relief. He reported acholic stools and a 16-lb weight loss not associated with anorexia.
An upper gastrointestional (GI) series was performed with findings suggestive of diffuse jejunal and ileal polyposis (Fig 1). He had no contributing medical history and was admitted with the diagnosis of malabsorption syndrome for a complete GI workup.
The patient was a well-developed, well-nourished, 6′3″; 217 lb muscular male. Laboratory examination revealed a hemoglobin of 14 g/dL, a leukocyte count of 6700 cu/mm with a normal differential, albumin of 4.4 g/dL, cholesterol of 195 mg/dL, and serum calcium of 10 mg/dL. Stool quantitative and qualitative fat and occult blood examinations were negative, serum carotene and vitamin A levels were normal, and D-xylose absorption and Schilling tests were normal.
The barium enema was negative. Abdominal and pelvic computed tomography (CT) and sonography suggested lymphoma with multiple hypoechogenic and splenic mesenteric defects, and a paracolic gutter and pelvic mass. A flat-plate abdominal radiograph showed a missing trans-verse process at L4 (Fig 2). Computed tomography of the chest revealed a left paravertebral mass at the carina extending to the upper abdomen consistent with lymphadenopathy. The final segment of the thoracic duct was absent on CT scans. He was diagnosed with lymphoma and then had an exploratory laparotomy.
Operative findings included approximately 1.5 L chylous ascitic fluid and small bowel mesentery covered with small nodular cysts which when incised released the same milky, chylous fluid. The liver, large bowel, kidneys, bladder, stomach, and omentum all appeared grossly normal. A small bowel biopsy showed normal small bowel mucosa with large dilated submucosal lymphatic channels (Fig 3).
The patient was diagnosed with small bowel lymphangiomatosis. A bone survey revealed multiple well-circumscribed radiolucent lesions involving the C3, L3, and L4 vertebral bodies, the transverse process of L4, the junction of the left interior pubic ramus and ischium, the left proximal humerus, the tip of the left scapula, and the left temporoparietal area (Fig 4). There was no increased uptake at any of the multiple lesion sites on Gallium and technetium bone scans. At this point, the patient was diagnosed with Gorham's disease. Although the orthopaedists were consulted regarding the bone lesions, clinical attention remained focused on the lymphangiomatosis of the bowel. He initially did well and was discharged 13 days postoperatively on a low-fat diet, but was readmitted 6 months later with a 2-day history of a 104° fever, chills, and whitish sputum. A chest radiograph revealed bilateral pleural effusions, and the physical examination revealed fundings consistent with abdominal ascites. A lymphangiogram showed abnormalities and partial obstruction of what was considered the thoracic duct at the T8-T9 level. The patient received a Levean shunt, had multiple thoracenteses, and a chest tube was inserted. His hospital course was complicated by pneumonia, peritoneal sepsis, acute respiratory distress syndrome, respiratory failure, and eventual death 5 weeks later (9 months after his initial presentation).
Lymphangiomatous or lymphangiectatic changes were documented in the lungs (interstitial and multifocal), visceral and parietal pleura, diaphragm, small bowel, pancreas, spleen, thymus, thyroid, and the L3 vertebra. The thoracic duct was not identifiable. Lymphangiomatous masses were seen in supradiaphragmatic (2.5 cm), anterior mediastinal (4.5 cm), and paraaortic (4.5 cm) locations at the tracheal bifurcation (Fig 5). Tracheobronchial lymph nodes showed lymphangiectatic change (Fig 6). The kidney, large bowel, adrenals, and parathyroid glands were normal. The heart showed left ventricular hypertrophy and the liver was congested. The lungs showed marked acute and chronic bronchopneumonia.
The vertebra examined showed lymphangiectatic changes with active osteoclastic resorption but few osteo-blasts were seen. Grossly, well-circumscribed space-occupying defects were evident where the involved verte-brae were sectioned (Fig 7A), which on histologic analysis, revealed resorption of the cortical bone (Fig 7B) and profound thinning of the cancellous bone (Fig 7C) with active osteoclastic resorption (Fig 7D). The lymphangiectatic membranes were often in direct contact with active osteoclastic resorption sites (Fig 8), and can be characterized as thin and sinewy or cellular and sponge-like (Fig 9). Because the family limited the extent of the autopsy, the paracolic gutter and pelvic masses and the lytic lesions of the proximal left humerus, left scapula, left transverse process of the L4 vertebra, and the inferior pubic ramus were not histologically examined.
The final anatomic diagnosis was extensive lymphangiomatosis with multifocal soft tissue, visceral, pulmonary, abdominal, and osseous involvement. Death was attributable to uncontrolled chylothorax and ensuing pulmonary pneumonia.
Classic Gorham's disease is characterized by marked osteolysis,7 but its etiology remains obscure. There is substantial documentation that the disease has vascular or lymphatic proliferation with or without fibrosis.3,16 Ramani and Shah, in a report focusing on lymphangiomatosis as the key finding, described significant bone involvement18 and, conversely, Choma et al described massive osteolysis with abnormal vascular tissue, including lymphatic tissue.3 We think the lymphatic variant of Gorham's disease deserves its own subcategory.
We documented abnormalities of the lymphatic system including lymphangiomatous masses, lymphangiectatic dilations (small bowel, spleen, pancreas, thymus, and bones), and absence of a portion of the thoracic duct. These findings are important because therapeutic attempts focusing on identification and ligation of the duct may be futile as has been reported.15,19,20 Podevin et al recognized this futility by using the term, thoracic lymphatic dysplasia not further defined.17
Our findings of dilated lymphatic channels (lymphangiectasia) or accumulation of lymphangiomatous tissues in the pleural and peritoneal tissues, the diaphragm, mediastinum, and spleen correspond to known anatomic tracking of the thoracic duct.5
There were several common findings during autopsies of five patients with Gorham's disease (Table 1).6,8-10,13
All had abnormal vascular proliferation that involved bone sites, some described as lymphatic and some admixed with fibrosis. Sites of involvement include pleural tissue, spleen, nodes, and vertebrae as in our case. There is a predilection for osseous involvement of the clavicle, scapula, ribs, and vertebrae as revealed by autopsy or premortem imaging. Numerous patients died from chylous effusions and pneumonia.
Our findings combined with results in isolated clinical reports suggest the lymphatic variant of Gorham's disease is a distinct entity. In one study, approximately 17% of patients with Gorham's disease had chylothoraces develop,20 and approximately ½ died. Gorham's disease generally affects younger patients and seems to have no racial or gender predilection, and most osseous involvement occurs in the shoulder region and vertebrae.2 In our patient and in reported cases, chylous effusions were frustrating to treat, with a poor prognosis.15,7
Hirayama et al think that the bone resorption is related to osteoclast activity.11 Our autopsy findings suggest an etiology of active osteoclastic resorption. Because the parathyroid glands were normal, hyperparathyriodism was not the causative mechanism. Although hyperemia has been proposed in other diseases as a contributing factor to bone resorption, and has been proposed as causative factor in Gorham's disease, our patient's normal bone scans did not support this pathogenesis. We think the causative factor in our patient most likely was production of a local tissue factor related to the lymphatic proliferation or dilatation. Because endothelial cells of vascular tissue may mediate local tissue events, the abnormal, lymphatic changes, and associated lining cell activation may have been the source of osteolysis.
The endothelium of lymphatic vessels has been linked to toll-like receptors shown to upregulate cytokines such as tumor necrosis factor-alpha and interleulin-6, which are associated with osteolysis.1,14 Devlin et al observed elevated levels of interleukin-6 in the serum of a patient with Gorham's disease involving the skull and facial bones.4
Our findings suggest a distinct variant of Gorham's disease. We based our proposed pathogenesis on autopsy findings (Table 2). A maldeveloped (or totally absent) thoracic duct may lead to development of an aberrant collateral lymphatic circulation including dilated lymphatic channels (lymphangiectasia) and lymp-rich soft tissue masses (lymphangiomas). Collateral lymphatic circulation develops and extends to the nascent intraosseous lymphatic system. This bone lymphatic tissue contains activated endothelial lymphatic cells leading to increased activity of osteoclasts, which lead to marked osteolysis.
Although there is no consensus regarding treatment of Gorham's disease,16 therapeutic attempts must focus on the morbid and deadly chylous effusions. Surgical interventions in patients with Gorham's disease complicated by chylous effusions have been unsuccessful.6 Surgical inter-
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