A 45-year-old woman presented with recent onset of left-sided chest pain. On clinical examination, these symptoms seemed to be strictly localized to a region that was marked by a long-standing cutaneous erythematous lesion. Laboratory results showed no gross abnormalities. Radiological imaging including conventional X-ray, MRI scans, and 3D CT reconstruction of the rib cage revealed circumscript destruction of the left lateral ribs 9–11. Histological analysis of a rib biopsy showed angiomatous hypervascularization and intracortical fibrosis. In keeping with these findings, the patient's condition was diagnosed as Gorham-Stout disease, a rare condition with localized, often unilateral, bone destruction. Monotherapy with bisphosphonates (pamidronate 30 mg IV every 3 months) was initiated, leading to rapid disappearance of local pain. Follow-up over 24 months documented a stable clinical and radiological picture without evidence of progressive bone destruction.
GORHAM-STOUT DISEASE (GSD; synonyms: vanishing bone disease, massive osteolysis, phantom bone disease) is a rare condition of unknown etiology characterized by local proliferation of small vascular or lymphatic vessels resulting in progressive destruction and resorption of bone. Massive osteolysis was first described by Jackson, who reported a case of a “boneless arm”,(1) and later became known as Gorham-Stout disease, when Gorham and Stout reviewed 24 cases from the literature in 1955.(2) GSD may affect one or more, often contiguous, bones with predominant sites of manifestation including the pelvis, shoulder girdle, spine, ribs, and skull. GSD occurs sporadically and usually affects children and young adults without sex preference. Diagnosis is based on clinical, laboratory, radiological, and histopathological findings.
A 45-year-old white woman presented with left-sided thoracic pain, which had gradually increased over the last 9 months. Medical history included a primary lymphedema of the left arm, which had developed 26 years ago. Physical examination showed an erythematous skin lesion spanning parts of the left breast, chest, and upper abdomen, with a centrally located angiomatous plaque (3.7 × 5.5 cm) on the left lateral chest wall with an irregular-shaped surface and central atrophy (Fig. 1A). These skin changes had initially appeared after her second pregnancy 15 years ago and had slowly increased in size ever since. Histopathological examination after a skin biopsy of the plaque and erythema showed marked proliferation of lymphatic vessels in the dermis and subcutis without endothelial atypia (Fig. 1B).
Conventional X-ray studies of the left lateral thorax showed marked thinning and a heterogeneous trabecular structure of ribs 9–11 (Fig. 2A). Bone scintigraphy revealed an increased uptake of all ribs of the left hemithorax (Fig. 2B). Destruction of ribs was confirmed by CT scans including 3D reconstruction (Fig. 2C). MRI scan of the thorax showed angiomatous soft tissue formation around the ribs of the left hemithorax (Fig. 2D). Histopathological analysis of a rib biopsy showed a dispersed cortical and irregular trabecular structure with intracortical fibrosis and hypervascularization, and trabecular microcallus formation (Figs. 3A-3C). Based on these findings, the diagnosis of GSD was established.
Notably, serum calcium and phosphorus levels at presentation were within the respective midnormal ranges, and neither intact parathyroid hormone (PTH) nor PTH-related peptide was elevated. Similarly, serum alkaline phosphatase and bone alkaline phosphatase were normal, whereas serum TRACP was slightly elevated (4.6 U/liter; reference range, 2.5-4.5 U/liter). Urinary cross-links were within the upper normal range (pyridinoline [PYD], 232 μg/g creatinine; reference range, 160–280 μg/g; desoxypyridinoline (DPD), 51 μg/g creatinine; reference range, 26–56 μg/g).
An intravenous bisphosphonate infusion (30 mg pamidronate) led to swift disappearance of local pain. Follow-up of the patient during 2 years of bisphosphonate treatment (pamidronate 30 mg IV every 3 months) showed a stable clinical picture. Imaging studies including conventional X-ray after 3, 9, 12, and 24 months and CT scans after 3 and 9 months of treatment did not show any progression of bone destruction, thereby providing radiological evidence for stabilization of disease. After initiation of bisphosphonate treatment, serum TRACP levels normalized, varying between 2.8 and 3.8 U/liter on trimonthly measurements during 24 months of follow-up. Similarly, urinary cross-link excretion decreased to the lower normal range during ongoing bisphosphonate treatment (Fig. 4).
For additional studies, we assessed serum interleukin-6 (IL-6) using an assay from DPC Biermann (Bad Nauheim, Germany). We also determined the concentrations of the osteoclastic regulators osteoprotegerin (OPG) and the free soluble RANKL using assays from Imundiagnostik (Bensheim, Germany), as previously described.(3) Of note, serum IL-6 was found to be elevated at the initial assessment (8.4 ng/liter; reference range, <5.4 ng/liter), but normalized after 6 months of bisphosphonate treatment (<5.0 ng/liter) and stayed normal during subsequent follow-up over 18 months. We noted an increase in serum OPG from 1.42 pM at baseline to 1.59 pM after 3 months and 1.93 pM after 9 months of treatment. Concurrently, a significant drop in sRANKL from 0.19 to 0.004 and 0.008 pM, respectively, occurred, which resulted in a marked increase of the calculated OPG/free sRANKL ratio from 7.7 to 198.8 and 247.8, respectively.
Our patient is a prismatic case with clinical and radiological findings impressively showing the dramatic presentation of Gorham-Stout disease (GSD). This rare condition is characterized by localized, pathologically enhanced bone resorption leading to bone destruction, attributed to proliferation of abnormal lymphatic vessels. The differential diagnosis of GSD includes other forms of idiopathic or secondary osteolysis.(4) Clinical signs at presentation include pain, swelling, and spontaneous fractures. Osteolysis may stop progressing at any time, but often osseous tissue completely disappears, leaving only a residual fibrous band, a dramatic development inspiring the term “vanishing bone disease.”(2) Regeneration of bone to a notable extent rarely occurs.(5, 6) Death is not uncommon when osteolysis involves the spine or thorax, leading to spinal cord compression and chylothorax, respectively.(7–10)
The etiology and pathogenesis of GSD is still unknown. Osteolysis in GSD occurs in a monocentric fashion affecting single or contiguous bones in the same anatomical region, as typically seen in our patient with the affection of the left side of the rib cage. It is unclear whether proliferation of lymphatic vessels in GSD leads to activation of osteoclasts and thus to excessive bone resorption or whether the expansion of vascularized fibrous tissue is secondary to enhanced resorption of bone. However, our case argues in favor of the former hypothesis because proliferation of lymphatic tissue was found in adjacent soft tissue beyond the affected ribs as confirmed by the skin biopsy. In addition, the skin lesion was noted for the first time after a traumatic delivery, 15 years before the actual disease manifestation. A similar case with cutaneous vascular malformations in the medial aspect of the left thigh in GSD affecting the left femoral shaft has been reported recently.(11)
Of further debate is the role of osteoclasts in GSD. Histopathological analyses of affected bones commonly show fibrous tissue consisting of dilated endothelial vessels that sometime contain red blood cells, but presence of osteoclasts is inconsistent. Thus, it has been speculated that presence or absence of osteoclasts might be explained by different phases of the syndrome.(12) From a clinical and radiological point of view, our patient clearly presented with active disease, but surprisingly only few osteoclasts were found on histopathological analysis of the rib biopsy.
Formation, differentiation, and activation of osteoclasts is greatly dependent on cytokines, growth factors, and hormones. IL-6 has been implicated in the pathogenesis of GSD. A previous report showed that serum from a GSD patient with markedly increased serum IL-6 levels could trigger formation and activation of osteoclasts in vitro, and this effect was blunted by pretreatment with neutralizing antibody against IL-6.(13) In keeping with these findings, our patient presented with elevated IL-6 levels that normalized after bisphosphonate treatment and subsequent clinical and radiological stabilization of disease. The observed increase in the OPG/free sRANKL ratio in our patient may reflect the bone protective effect of bisphosphonate treatment.
No standardized treatment of GSD has been established yet, certainly attributable to the rarity of the disease and to the lack of understanding of its underlying pathogenetic mechanisms. Reports of clinical courses involving assessment of treatment are scarce, and the significance of treatment effects needs careful evaluation, because spontaneous stabilization has been described.(2) GSD has been previously treated by radiotherapy,(6, 11, 14) surgical resection, and orthopedic stabilization.(15–17) Watchful waiting, especially in children, might be an alternative option, but requires careful monitoring.(18, 19)
To our knowledge, there have been only two reports of antiresorptive treatment using bisphosphonates in GSD. However, in these cases, bisphosphonates were either used in combination with calcitonin and radiation therapy(13) or with α2b-interferon.(20) In our patient, an immediate clinical improvement of local pain and a stable clinical and radiological picture during 2 years of follow-up suggests effectiveness of low-dose pamidronate treatment alone. Longer-term follow-up and additional studies employing bisphosphonates in GSD will help to evaluate this therapeutic approach in further detail.
We thank U Freund for excellent technical assistance. LCH is supported by DFG Grants 1875/3-1 and 1875/4-1. WA is a MRC Senior Clinical Fellow.