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Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: A novel clue to the pathogenesis of a rare syndrome
Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: A novel clue to the pathogenesis of a rare syndrome Daniela Bruch-Gerharz, MD,a Claus-Dieter Gerharz, MD,b Helger Stege, MD,a Jean Krutmann, MD,c Michael Pohl, MD,d Rainer Koester, MD,e and Thomas Ruzicka, MDa Duesseldorf, Duisburg, and Neuss, Germany Background: Gorham-Stout disease is an unusual, progressive syndrome of unknown etiology characterized by mono- or polyostotic osteolysis most often affecting children and young adults. The onset is insidious and the disease progresses to extensive and potentially disabling osteolysis often unresponsive to therapeutic intervention. Although bone and soft tissue lesions are the most frequent manifestations of Gorham-Stout disease, skin lesions can occur and may provide a clue to the pathogenesis of this rare syndrome. Objective: Our aim was to describe characteristics of vascular skin lesions of this rare condition using magnetic resonance imaging and histomorphological analysis. Methods: The case of a 36-year-old man with Gorham-Stout disease of the left leg and foot is reported. Results: This case was remarkable for its prominent lymphatic vascular malformations involving the skin and soft tissues adjacent to the diseased bone—a previously undescribed abnormality, which preceded osteolysis for several years. Magnetic resonance imaging played a key role in defining the extent of disease in skin and soft tissues. Limitations: It is difficult to assess the true incidence of hemangiomatosis in the earlier reports on GorhamStout disease in which hemangiomatous cutaneous lesions were mentioned but not described or illustrated. Conclusion: A vascular process with angiomatous histological features is considered to be the pathological hallmark of Gorham-Stout disease, but the specific type of this vascular process is still under debate. Our report highlights a lymphatic malformative nature of Gorham-Stout disease, thereby contributing to a better understanding and characterization of this rare disease entity. ( J Am Acad Dermatol 2007;56:S21-5.)
G
orham-Stout disease, first described in 1838, is a rare, but potentially disabling osteolytic condition, occurring in children and young adults. The onset is insidious and disease progresses to extensive monostotic or polyostotic osteolysis that
From the Departments of Dermatologya and of Radiology,d Heinrich-Heine-University of Duesseldorf; Institute of Pathology, Bethesda-Krankenhaus Duisburgb; Institute for Environmental Medical Research, Duesseldorf c; and Department of Radiology, Lukas-Krankenhaus Neuss.e Funding sources: None. Conflicts of interest: None identified. Reprint requests: Daniela Bruch-Gerharz, MD, Department of Dermatology, Heinrich-Heine-University, PO Box 101007, D-40001 Duesseldorf, Germany. E-mail: bruch-gerharz@med. uni-duesseldorf.de. Published online September 19, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.01.063
may ultimately lead to disappearence of entire bones.1,2 Little is known of the origin and pathology of this disorder. It is thought to relate to a vascular process with hemangiomatous histologic features in some patients, but others appear to have an underlying lymphangiomatous disorder. Characteristically, patients present with nonspecific symptoms such as muscular weakness and limb tenderness, pathologic fractures, or both.1-3 Other associated symptoms include localized or widespread skin and soft tissue lesions. Soft tissue lesions are not uncommon, and are present in about 60% of patients with GorhamStout disease.2 The soft tissues in the immediate vicinity of the diseased bone are the most commonly affected. Cutaneous symptoms, however, were explicitly noted in only 5 of the 220 patients with Gorham-Stout disease reported so far.4-8 These 5 patients also had symptoms of extensive osteolysis in addition to hemangioma-like skin lesions. Widespread lymphatic malformative lesions of the skin S21
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Fig 1. A, Radiography of lower left femoral shaft showing extensive osteolysis. B, Histopathologic aspect of osseous lesions showing thin-walled, sinusoidal vessels (stars). Bar = 0.5 mm.
and soft tissue as an extraosseous manifestation in Gorham-Stout disease have not been reported previously by other authors. Our case illustrates the limitations of the traditional terminologies used to describe the vascular lesions in Gorham-Stout disease as hemangiomatosis or lymphangiomatosis, and suggests that lymphatic vascular malformations could be the primary cause of extensive osteolysis in this unusual disorder.
CASE REPORT A 21-year-old man with a 7-year history of cutaneous lymphatic malformations of the left lower extremity was hospitalized for diffuse pain in the left leg secondary to a recent minor trauma. There was no personal or family history of systemic vascular processes, and no associated constitutional symptoms were observed. Without a definite diagnosis being made, he developed difficulty in walking and severe progresssive bone pain in the left leg, exacerbated by physical activity. One year after his initial symptoms, he was transferred to a specialist radiologic center for further investigation. Radiographs and computed tomography scans now showed extensive resorption of the lower left femoral shaft (Fig 1, A) and the midshaft phalanges of the left foot suggestive of extensive osteolysis. All laboratory investigations failed to reveal any underlying
primary metabolic or infectious disorder. An open biopsy was performed and histologic examination of the involved bone revealed a widespread vascular malformation showing ectatic, thin-walled, sinusoidal vessels within zones of almost completely vanishing bone structures (Fig 1, B). The pathomorpologic aspect was consistent with Gorham-Stout disease. Skeletal survey did not reveal any other osteolytic lesion. Fractionated irradiation was applied to the involved bones (40 Gy in 2-Gy fractions). Twelve months later, his symptoms were improved with no recurrence of pain and normal radiologic appearance of the irradiated bones. No attempt was made to treat the cutaneous and soft tissue lesions. Ten years after bone irradiation, the patient was referred to our hospital with increasing discomfort and slowly progressive vascular skin lesions. At this time, he reported recurrent episodes of local cutaneous infection. Examination revealed numerous small and skin-colored papules and vesicles (diameter: 1 mm-1 cm) on the inner part of the left thigh extending from the gluteal region to the popliteal fossa (Fig 2, A). Similar lesions of widespread lymphatic malformations were noted on the left foot and toes with associated dystrophic nail changes. There was extensive cutaneous swelling and a palpable tumorous soft tissue mass in the involved areas. In addition, dilated vascular channels of varying calibers were found on the back aspect of the left foot (Fig 2, B). These channels were easily compressible and measured 2 to 3 cm in diameter. Careful examination did not reveal any other abnormalities. Magnetic resonance imaging delineated a continuous spread of the vascular malformative process from the skin into the adjacent connective tissue, the striated muscle, and the fat (Fig 2, C and D), which were riddled by diffuse and intercommunicating vascular networks. Repeated radiographs and computed tomography scans of adjacent bones were unremarkable. Skin biopsy specimens of the left leg showed histologic changes resembling the vascular lesions of the bone (Fig 2, E ). Remarkably, during the biopsy procedure the cutaneous vesicles that originally contained a clear fluid became dark red as a result of intralesional bleeding, which gave these lymphatic vascular lesions the appearance of hemangiomas the following day (Fig 2, F ). Within 6 weeks, the hemangiomatous appearance resolved spontaneously, and the original lymphatic aspect returned. During the next 4 years, treatment with firm compression of the left leg by bandages and manual massage gradually improved the lymphatic clearance and protected the skin and soft tissues from inflammation.
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Fig 2. A, Small, skin-colored papules and vesicles on inner part of left thigh (box, area shown in Fig 2, F, 1 day after skin biopsy). B, Easily compressible vascular channels measuring 2 to 3 cm in diameter on back aspect of left foot. C, Magnetic resonance image (MRI) showing continuous spread of vascular malformative process (arrows) from skin the adjacent connective tissue and fat. D, MRI showing dilated vascular channels of varying calibers (arrows) on back aspect of left foot. E, Histopathologic aspect of cutaneous lymphatic malformations showing large cavernous lymph spaces and ectatic lymph vessels (stars). Bar = 0.5 mm. F, Hemangiomatous aspect of vascular skin lesions 1 day after skin biopsy as result of bleeding into lymphatic vessels, giving rise to red coloration of lymphatic skin lesions.
DISCUSSION Gorham-Stout disease, also known as disappearing bone disease, vanishing bone, or phantom bone, is a rare syndrome belonging to the primary idiopathic osteolyses. First described in 1838 by Jackson,1 who reported the case of a young man with a progressively disappearing humerus, the syndrome became known as Gorham-Stout disease in 1955, when their review of 16 cases was published in the Journal of Bone and Joint Surgery.2 The syndrome may occur in any bone, but common sites include the long bones, the shoulder, and pelvic girdle. Enhanced osteoclast activity, which may be mediated by interleukin-6 (IL-6), has been implicated in the pathogenesis of increased bone resorption.9,10 In addition, it has been demonstrated in vitro that the increase in osteoclast formation in Gorham-Stout
disease is not because of an increase in the number of circulating osteoclast precursors, but rather an increase in the sensitivity of these precursors to IL-6 and other humoral factors that promote osteoclast formation and bone resorption.11 Gorham and Stout2 described these features: progressive osteolysis of one bone or a number of bones occurring in children and young adults; history of minor trauma, often associated with a fracture sometimes of pathologic type; and angiomatosis, usually interpreted as hemangiomatosis, in the affected bones or in the surrounding soft tissues. Since its original description, the changes in bone have always held the focus of attention, and histologic observations have mainly been limited to the bone and adjacent soft tissues. Conversely, the presence and significance of cutaneous lesions in Gorham-Stout disease has so far
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been underestimated. Localized or widespread vascular skin lesions, however, may herald an underlying osteolytic process, as with our patient. Originally, the term ‘‘hemangiomatosis’’ had been used to describe the underlying vascular process in Gorham-Stout disease.2,12-14 Our observations, however, are in line with the more current concept that several types of vascular malformative processes (including capillary, venous, or lymphatic malformations) can cause osteolysis characteristic for this disease. In this context it is important to note that for more than a decade the classification of Mullicken and Glowacki,15 dividing vascular anomalies into hemangiomas and vascular malformations, has been widely accepted. According to this classification the term ‘‘hemangiomatosis’’ is misleading and not appropriate to describe the vascular lesions in GorhamStout disease, because it does imply that they are proliferative, ie, neoplastic. Thus, hemangiomas usually exhibit a history of rapid neonatal growth and later regress spontaneously to a variable extent. Conversely, developmental vascular malformations including capillary, lymphatic, and venous malformations do worsen over time and express themselves in more tissues (witness our case) without being true neoplasms. Pathologically, they can be distinguished by their lack of endothelial cell proliferation and clinically by their frequent late onset and their lack of any tendency to spontaneous resolution (several expand with onset of puberty as in our patient). Therefore, in contrast to almost all previous reports on Gorham-Stout disease discussing hemangiomatous lesions within skin or bone, the current case with insidious progression of skeletal abnormalities along with soft tissue and skin lesions is consonant with the currently accepted terminology that vascular malformative rather than angiomatous lesions can cause progressive osteolysis. This distinction is not an academic one, but may have important implications for the diagnosis and management of Gorham-Stout disease. It is also interesting to note that the current case strongly suggests a key role for vascular lesions of lymphatic origin in the osteolytic process characteristic for this disease. Thus, lymphatic vascular lesions of the bone and soft tissues are not a new observation and have been noted in previous published series.2-4,16 In addition, Gorham-Stout disease is often complicated by thoracic duct occlusion with chylothorax, again implying an underlying lymphatic disorder.3,12,17 No hitherto proposed histologic features have been found to invariably distinguish blood from lymphatic vascular lesions.4,18 Moreover, the presence of erythrocytes within vascular spaces, long held to be pathognomonic of
hemangiomatosis in Gorham-Stout disease, is of limited value as a diagnostic tool, as evidenced for the first time from our case: blood may be forced into lymph spaces during the manipulation of biopsy or even necropsy, artificially evoking the appearance of a hemangioma. It is difficult, therefore, to assess the true incidence of hemangiomatosis in the earlier reports on Gorham-Stout disease in which hemangiomatous cutaneous lesions were mentioned, but not described or illustrated.4,6,7 Our observation may, thus, provide a novel clue to the pathogenesis and natural history of this unusual syndrome. The diagnosis of Gorham-Stout disease may be delayed, especially in cases of atypical presentation, leading to protracted illness and serious complications. These range from minimal disability to death by chest wall or spinal localization.3,16 Fractionated irradiation (40-45 Gy in 2-Gy fractions) is considered as a first-line therapy in Gorham-Stout disease and ought to be commenced as soon as diagnosis has been established.16 When serious or irreparable mutilations have been caused by the process of bone destruction, Gorham-Stout disease is often unresponsive to radiation therapy or surgical intervention. In addition, most reports conclude that the presence of extraosseous involvement in GorhamStout disease carries a poor prognosis.3 If GorhamStout disease is suspected as the cause of massive osteolysis, the best methods of investigation are computed tomography and magnetic resonance imaging,19,20 because these modern imaging techniques may provide a better view into the soft tissues and the skin. In conclusion, our case suggests that lymphatic vascular malformations of the skin and soft tissues are a further criterion to establish the diagnosis of Gorham-Stout disease. Knowledge of the clinical pattern and cutaneous findings of Gorham-Stout disease is crucial for an early therapeutic intervention, and may allow to further elucidate the natural history of this clinically challenging condition. REFERENCES 1. Jackson J. A boneless arm. Boston Med Surg J 1838;18:368-9. 2. Gorham L, Stout A. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone): its relation to hemangiomatosis. J Bone Joint Surg Am 1955; 37A:985-1004. 3. Pedicelli G, Mattia P, Zorzoli AA, Sorrone A, de Martino F, Sciotto V. Gorham syndrome. JAMA 1984;252:1449-51. 4. Halliday DR, Dahlin DC, Pugh DG, Young HH. Massive osteolysis and angiomatosis. Radiology 1964;82:637-44. 5. Frost JF, Caplan RM. Cutaneous hemangiomas and disappearing bones with a review of cutaneovisceral hemangiomatosis. Arch Dermatol 1965;92:501-8. 6. Fornasier VL. Hemangiomatosis with massive osteolysis. J Bone Joint Surg Br 1970;52B:444-51.
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7. Jones GB, Midgley RL, Smith GS. Massive osteolysise disappearing bones. J Bone Joint Surg Br 1958;40B:494-6. 8. Bruch-Gerharz D, Gerharz CD, Stege H, Krutmann J, Pohl M, Koester R, et al. Cutaneous vascular malformations in disappearing bone (Gorham-Stout) disease. JAMA 2003;289:1479-80. 9. Devlin RD, Bone HG, Roodman GD. Interleukin-6: a potential mediator of the massive osteolysis in patients with GorhamStout disease. J Clin Endocrinol Metab 1996;81:1893-7. 10. Moller G, Priemel M, Amling M, Werner M, Kuhlmey AS, Delling ´ s massive osteolysis): G. The Gorham-Stout syndrome (Gorham a report of six cases with histopathological findings. J Bone Joint Surg Br 1999;81B:501-6. 11. Hirayama T, Sabokbar A, Itonaga I, Watt-Smith S, Athanasou NA. Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease. J Pathol 2001;195:624-30. 12. Choma ND, Biscotti CV, Bauer TW, Mehta AC, Licata AA. Gorham’s syndrome: a case report and review of the literature. Am J Med 1987;83:1151-6. 13. Heyden G, Kindblom LG, Moeller-Nielsen J. Disappearing bone disease: a clinical and histological study. J Bone Joint Surg Am 1977;59A:57-61.
14. Cannon SR. Massive osteolysis: a review of seven cases. J Bone Joint Surg Br 1986;68B:24-8. 15. Mullicken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69: 412-20. 16. Drewry GR, Sutterlin CE, Martinez CR, Brantley SG. Gorham disease of the spine. Spine 1994;19:2213-22. 17. Mendez AA, Keret D, Robertson W, MacEwen GD. Massive osteolysis of the femur (Gorham’s disease): a case report and review of the literature. J Pediatr Orthop 1987;7:96-9. 18. Gallagher PJ. Blood vessels. In: Sternberg SS, editor. Histology for pathologists. Philadelphia and New York: Lippincott-Raven; 1997. pp. 763-86. 19. Vine´e P, Tanyue O, Hauenstein KH, Sigmund G, Sto¨ver B, Adler CP. CT and MRI of Gorham syndrome. J Comput Assis Tomogr 1994;18:985-9. 20. Ceroni D, De Coulon G, Regusci M, Kaelin A. Gorham-Stout disease of costovertebral localization: radiographic, scintigraphic, computed tomography, and magnetic resonance imaging findings. Acta Radiol 2004;45:464-8.
G
orham-Stout disease, first described in 1838, is a rare, but potentially disabling osteolytic condition, occurring in children and young adults. The onset is insidious and disease progresses to extensive monostotic or polyostotic osteolysis that
From the Departments of Dermatologya and of Radiology,d Heinrich-Heine-University of Duesseldorf; Institute of Pathology, Bethesda-Krankenhaus Duisburgb; Institute for Environmental Medical Research, Duesseldorf c; and Department of Radiology, Lukas-Krankenhaus Neuss.e Funding sources: None. Conflicts of interest: None identified. Reprint requests: Daniela Bruch-Gerharz, MD, Department of Dermatology, Heinrich-Heine-University, PO Box 101007, D-40001 Duesseldorf, Germany. E-mail: bruch-gerharz@med. uni-duesseldorf.de. Published online September 19, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.01.063
may ultimately lead to disappearence of entire bones.1,2 Little is known of the origin and pathology of this disorder. It is thought to relate to a vascular process with hemangiomatous histologic features in some patients, but others appear to have an underlying lymphangiomatous disorder. Characteristically, patients present with nonspecific symptoms such as muscular weakness and limb tenderness, pathologic fractures, or both.1-3 Other associated symptoms include localized or widespread skin and soft tissue lesions. Soft tissue lesions are not uncommon, and are present in about 60% of patients with GorhamStout disease.2 The soft tissues in the immediate vicinity of the diseased bone are the most commonly affected. Cutaneous symptoms, however, were explicitly noted in only 5 of the 220 patients with Gorham-Stout disease reported so far.4-8 These 5 patients also had symptoms of extensive osteolysis in addition to hemangioma-like skin lesions. Widespread lymphatic malformative lesions of the skin S21
S22 Bruch-Gerharz et al
J AM ACAD DERMATOL FEBRUARY 2007
Fig 1. A, Radiography of lower left femoral shaft showing extensive osteolysis. B, Histopathologic aspect of osseous lesions showing thin-walled, sinusoidal vessels (stars). Bar = 0.5 mm.
and soft tissue as an extraosseous manifestation in Gorham-Stout disease have not been reported previously by other authors. Our case illustrates the limitations of the traditional terminologies used to describe the vascular lesions in Gorham-Stout disease as hemangiomatosis or lymphangiomatosis, and suggests that lymphatic vascular malformations could be the primary cause of extensive osteolysis in this unusual disorder.
CASE REPORT A 21-year-old man with a 7-year history of cutaneous lymphatic malformations of the left lower extremity was hospitalized for diffuse pain in the left leg secondary to a recent minor trauma. There was no personal or family history of systemic vascular processes, and no associated constitutional symptoms were observed. Without a definite diagnosis being made, he developed difficulty in walking and severe progresssive bone pain in the left leg, exacerbated by physical activity. One year after his initial symptoms, he was transferred to a specialist radiologic center for further investigation. Radiographs and computed tomography scans now showed extensive resorption of the lower left femoral shaft (Fig 1, A) and the midshaft phalanges of the left foot suggestive of extensive osteolysis. All laboratory investigations failed to reveal any underlying
primary metabolic or infectious disorder. An open biopsy was performed and histologic examination of the involved bone revealed a widespread vascular malformation showing ectatic, thin-walled, sinusoidal vessels within zones of almost completely vanishing bone structures (Fig 1, B). The pathomorpologic aspect was consistent with Gorham-Stout disease. Skeletal survey did not reveal any other osteolytic lesion. Fractionated irradiation was applied to the involved bones (40 Gy in 2-Gy fractions). Twelve months later, his symptoms were improved with no recurrence of pain and normal radiologic appearance of the irradiated bones. No attempt was made to treat the cutaneous and soft tissue lesions. Ten years after bone irradiation, the patient was referred to our hospital with increasing discomfort and slowly progressive vascular skin lesions. At this time, he reported recurrent episodes of local cutaneous infection. Examination revealed numerous small and skin-colored papules and vesicles (diameter: 1 mm-1 cm) on the inner part of the left thigh extending from the gluteal region to the popliteal fossa (Fig 2, A). Similar lesions of widespread lymphatic malformations were noted on the left foot and toes with associated dystrophic nail changes. There was extensive cutaneous swelling and a palpable tumorous soft tissue mass in the involved areas. In addition, dilated vascular channels of varying calibers were found on the back aspect of the left foot (Fig 2, B). These channels were easily compressible and measured 2 to 3 cm in diameter. Careful examination did not reveal any other abnormalities. Magnetic resonance imaging delineated a continuous spread of the vascular malformative process from the skin into the adjacent connective tissue, the striated muscle, and the fat (Fig 2, C and D), which were riddled by diffuse and intercommunicating vascular networks. Repeated radiographs and computed tomography scans of adjacent bones were unremarkable. Skin biopsy specimens of the left leg showed histologic changes resembling the vascular lesions of the bone (Fig 2, E ). Remarkably, during the biopsy procedure the cutaneous vesicles that originally contained a clear fluid became dark red as a result of intralesional bleeding, which gave these lymphatic vascular lesions the appearance of hemangiomas the following day (Fig 2, F ). Within 6 weeks, the hemangiomatous appearance resolved spontaneously, and the original lymphatic aspect returned. During the next 4 years, treatment with firm compression of the left leg by bandages and manual massage gradually improved the lymphatic clearance and protected the skin and soft tissues from inflammation.
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Fig 2. A, Small, skin-colored papules and vesicles on inner part of left thigh (box, area shown in Fig 2, F, 1 day after skin biopsy). B, Easily compressible vascular channels measuring 2 to 3 cm in diameter on back aspect of left foot. C, Magnetic resonance image (MRI) showing continuous spread of vascular malformative process (arrows) from skin the adjacent connective tissue and fat. D, MRI showing dilated vascular channels of varying calibers (arrows) on back aspect of left foot. E, Histopathologic aspect of cutaneous lymphatic malformations showing large cavernous lymph spaces and ectatic lymph vessels (stars). Bar = 0.5 mm. F, Hemangiomatous aspect of vascular skin lesions 1 day after skin biopsy as result of bleeding into lymphatic vessels, giving rise to red coloration of lymphatic skin lesions.
DISCUSSION Gorham-Stout disease, also known as disappearing bone disease, vanishing bone, or phantom bone, is a rare syndrome belonging to the primary idiopathic osteolyses. First described in 1838 by Jackson,1 who reported the case of a young man with a progressively disappearing humerus, the syndrome became known as Gorham-Stout disease in 1955, when their review of 16 cases was published in the Journal of Bone and Joint Surgery.2 The syndrome may occur in any bone, but common sites include the long bones, the shoulder, and pelvic girdle. Enhanced osteoclast activity, which may be mediated by interleukin-6 (IL-6), has been implicated in the pathogenesis of increased bone resorption.9,10 In addition, it has been demonstrated in vitro that the increase in osteoclast formation in Gorham-Stout
disease is not because of an increase in the number of circulating osteoclast precursors, but rather an increase in the sensitivity of these precursors to IL-6 and other humoral factors that promote osteoclast formation and bone resorption.11 Gorham and Stout2 described these features: progressive osteolysis of one bone or a number of bones occurring in children and young adults; history of minor trauma, often associated with a fracture sometimes of pathologic type; and angiomatosis, usually interpreted as hemangiomatosis, in the affected bones or in the surrounding soft tissues. Since its original description, the changes in bone have always held the focus of attention, and histologic observations have mainly been limited to the bone and adjacent soft tissues. Conversely, the presence and significance of cutaneous lesions in Gorham-Stout disease has so far
S24 Bruch-Gerharz et al
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been underestimated. Localized or widespread vascular skin lesions, however, may herald an underlying osteolytic process, as with our patient. Originally, the term ‘‘hemangiomatosis’’ had been used to describe the underlying vascular process in Gorham-Stout disease.2,12-14 Our observations, however, are in line with the more current concept that several types of vascular malformative processes (including capillary, venous, or lymphatic malformations) can cause osteolysis characteristic for this disease. In this context it is important to note that for more than a decade the classification of Mullicken and Glowacki,15 dividing vascular anomalies into hemangiomas and vascular malformations, has been widely accepted. According to this classification the term ‘‘hemangiomatosis’’ is misleading and not appropriate to describe the vascular lesions in GorhamStout disease, because it does imply that they are proliferative, ie, neoplastic. Thus, hemangiomas usually exhibit a history of rapid neonatal growth and later regress spontaneously to a variable extent. Conversely, developmental vascular malformations including capillary, lymphatic, and venous malformations do worsen over time and express themselves in more tissues (witness our case) without being true neoplasms. Pathologically, they can be distinguished by their lack of endothelial cell proliferation and clinically by their frequent late onset and their lack of any tendency to spontaneous resolution (several expand with onset of puberty as in our patient). Therefore, in contrast to almost all previous reports on Gorham-Stout disease discussing hemangiomatous lesions within skin or bone, the current case with insidious progression of skeletal abnormalities along with soft tissue and skin lesions is consonant with the currently accepted terminology that vascular malformative rather than angiomatous lesions can cause progressive osteolysis. This distinction is not an academic one, but may have important implications for the diagnosis and management of Gorham-Stout disease. It is also interesting to note that the current case strongly suggests a key role for vascular lesions of lymphatic origin in the osteolytic process characteristic for this disease. Thus, lymphatic vascular lesions of the bone and soft tissues are not a new observation and have been noted in previous published series.2-4,16 In addition, Gorham-Stout disease is often complicated by thoracic duct occlusion with chylothorax, again implying an underlying lymphatic disorder.3,12,17 No hitherto proposed histologic features have been found to invariably distinguish blood from lymphatic vascular lesions.4,18 Moreover, the presence of erythrocytes within vascular spaces, long held to be pathognomonic of
hemangiomatosis in Gorham-Stout disease, is of limited value as a diagnostic tool, as evidenced for the first time from our case: blood may be forced into lymph spaces during the manipulation of biopsy or even necropsy, artificially evoking the appearance of a hemangioma. It is difficult, therefore, to assess the true incidence of hemangiomatosis in the earlier reports on Gorham-Stout disease in which hemangiomatous cutaneous lesions were mentioned, but not described or illustrated.4,6,7 Our observation may, thus, provide a novel clue to the pathogenesis and natural history of this unusual syndrome. The diagnosis of Gorham-Stout disease may be delayed, especially in cases of atypical presentation, leading to protracted illness and serious complications. These range from minimal disability to death by chest wall or spinal localization.3,16 Fractionated irradiation (40-45 Gy in 2-Gy fractions) is considered as a first-line therapy in Gorham-Stout disease and ought to be commenced as soon as diagnosis has been established.16 When serious or irreparable mutilations have been caused by the process of bone destruction, Gorham-Stout disease is often unresponsive to radiation therapy or surgical intervention. In addition, most reports conclude that the presence of extraosseous involvement in GorhamStout disease carries a poor prognosis.3 If GorhamStout disease is suspected as the cause of massive osteolysis, the best methods of investigation are computed tomography and magnetic resonance imaging,19,20 because these modern imaging techniques may provide a better view into the soft tissues and the skin. In conclusion, our case suggests that lymphatic vascular malformations of the skin and soft tissues are a further criterion to establish the diagnosis of Gorham-Stout disease. Knowledge of the clinical pattern and cutaneous findings of Gorham-Stout disease is crucial for an early therapeutic intervention, and may allow to further elucidate the natural history of this clinically challenging condition. REFERENCES 1. Jackson J. A boneless arm. Boston Med Surg J 1838;18:368-9. 2. Gorham L, Stout A. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone): its relation to hemangiomatosis. J Bone Joint Surg Am 1955; 37A:985-1004. 3. Pedicelli G, Mattia P, Zorzoli AA, Sorrone A, de Martino F, Sciotto V. Gorham syndrome. JAMA 1984;252:1449-51. 4. Halliday DR, Dahlin DC, Pugh DG, Young HH. Massive osteolysis and angiomatosis. Radiology 1964;82:637-44. 5. Frost JF, Caplan RM. Cutaneous hemangiomas and disappearing bones with a review of cutaneovisceral hemangiomatosis. Arch Dermatol 1965;92:501-8. 6. Fornasier VL. Hemangiomatosis with massive osteolysis. J Bone Joint Surg Br 1970;52B:444-51.
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7. Jones GB, Midgley RL, Smith GS. Massive osteolysise disappearing bones. J Bone Joint Surg Br 1958;40B:494-6. 8. Bruch-Gerharz D, Gerharz CD, Stege H, Krutmann J, Pohl M, Koester R, et al. Cutaneous vascular malformations in disappearing bone (Gorham-Stout) disease. JAMA 2003;289:1479-80. 9. Devlin RD, Bone HG, Roodman GD. Interleukin-6: a potential mediator of the massive osteolysis in patients with GorhamStout disease. J Clin Endocrinol Metab 1996;81:1893-7. 10. Moller G, Priemel M, Amling M, Werner M, Kuhlmey AS, Delling ´ s massive osteolysis): G. The Gorham-Stout syndrome (Gorham a report of six cases with histopathological findings. J Bone Joint Surg Br 1999;81B:501-6. 11. Hirayama T, Sabokbar A, Itonaga I, Watt-Smith S, Athanasou NA. Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease. J Pathol 2001;195:624-30. 12. Choma ND, Biscotti CV, Bauer TW, Mehta AC, Licata AA. Gorham’s syndrome: a case report and review of the literature. Am J Med 1987;83:1151-6. 13. Heyden G, Kindblom LG, Moeller-Nielsen J. Disappearing bone disease: a clinical and histological study. J Bone Joint Surg Am 1977;59A:57-61.
14. Cannon SR. Massive osteolysis: a review of seven cases. J Bone Joint Surg Br 1986;68B:24-8. 15. Mullicken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69: 412-20. 16. Drewry GR, Sutterlin CE, Martinez CR, Brantley SG. Gorham disease of the spine. Spine 1994;19:2213-22. 17. Mendez AA, Keret D, Robertson W, MacEwen GD. Massive osteolysis of the femur (Gorham’s disease): a case report and review of the literature. J Pediatr Orthop 1987;7:96-9. 18. Gallagher PJ. Blood vessels. In: Sternberg SS, editor. Histology for pathologists. Philadelphia and New York: Lippincott-Raven; 1997. pp. 763-86. 19. Vine´e P, Tanyue O, Hauenstein KH, Sigmund G, Sto¨ver B, Adler CP. CT and MRI of Gorham syndrome. J Comput Assis Tomogr 1994;18:985-9. 20. Ceroni D, De Coulon G, Regusci M, Kaelin A. Gorham-Stout disease of costovertebral localization: radiographic, scintigraphic, computed tomography, and magnetic resonance imaging findings. Acta Radiol 2004;45:464-8.