Osseous vascular anomalies can be characterized as vascular tumors or malformations. Classification is vital for prognosis and treatment. Much remains unknown about conditions such as Gorham–Stout disease. Treatments target the proposed genetic pathways such as PI3KCA/AKT/mTOR pathway.
Key points
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Osseous vascular tumors are rare and are classified based on their biological potential.
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Gorham-Stout disease is a rare disease marked by the disintegration of bone structure, the growth of lymphatic vascular formations, and extensive localized bone degradation.
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Treatment of vascular and lymphatic malformations involves the use of embolic agents, surgery, laser, and developing medical therapies.
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The PI3KCA/AKT/mTOR pathway may yield future therapeutic potential for vascular anomalies and Gorham–Stout disease.
Osseous vascular anomalies
Osseous vascular tumors are categorized based on their biological potential: benign hemangiomas, epithelioid hemangiomas (intermediate-locally aggressive), pseudomyogenic hemangioendothelioma (intermediate-rarely metastasizing), malignant epithelioid hemangioendothelioma, and angiosarcoma ( Table 1 ). Vascular tumors arise from abnormalities in endothelial cell proliferation. The most common osseous vascular tumors of the cranium are benign hemangiomas, which commonly present as radiolucencies in the spine and long bones, with a prevalence of about 10%, and rarely leading to neurologic deficits. Conversely, infantile hemangiomas, which do not usually involve bone, typically seem early in infancy and undergo proliferation until approximately 1 year of age when they begin to involute, a process that can take many years.
| Hemangioma | Epithelioid Hemangioma | Pseudomyogenic Hemangioendothelioma | Epithelioid Hemangioendothelioma | Angiosarcoma | ||
|---|---|---|---|---|---|---|
| Biological Potential | Benign | Intermediate-locally aggressive | Intermediate-rarely metastasizing | Malignant | ||
| Clinical features | Prevalence | Common (∼10%) | Rare (≤1 in 1,000,000) | |||
| Percentage of patients with multifocal presentation | <20 | ∼20 | >90 | >50 | >50 | |
| Percentage 5-y overall survival | 100 | >95 | ∼75 | <40 | ||
| Radiographic features | Lytic (“corduroy like”) | Lytic to mixed lytic–sclerotic | Lytic and aggressive | |||
| Histologic features | Border | Smooth | Smooth | Infiltrative and ragged | Infiltrative and ragged | Infiltrative and ragged |
| Lobulation | Yes | Yes | No | No | No | |
| Vasoformation | Yes | Yes | No | Usually no a | Variable | |
| Cytologic features | Spindled | Epithelioid | Spindled-to-epithelioid | Epithelioid-to-spindled | ||
| Necrosis | Uncommon | Occasional | Occasional | Occasional | Frequent | |
| Immunohistochemistry | Cytokeratins | Positive in a subset of all vascular tumors | ||||
| Diagnostic markers for distinction | None | FOSB (in a subset of tumors) | FOSB | CAMTA1 (rarely TFE3) | None | |
| Recurrent genetic mutations | None | FOS (rarely FOSB rearrangement) | FOSB rearrangement | WWTR 1-CAMTA1 (rarely YAP1-TFE3 or other) fusion | Diverse | |
a Although most epithelioid hemangioendotheliomas lack vasoformative features, well-formed vascular channels are present in a small subset of tumors (that harbor the YAP1-TFE3 fusion).
The role of the age is significant in that most benign osseous hemangiomas are asymptomatic and found in pediatric populations, whereas metastatic lesions are found more commonly in adults. , Primary vascular lesions of the jaws are rare in children, with most involving other tissues. Aneurysmal bone cysts and central vascular malformations (eg, Rendu–Osler–Weber syndrome) have been reported as primary vascular lesions of the jaws in the pediatric population.
PHACE(S) is a syndrome that includes posterior fossa malformation, hemangioma, arterial anomalies, coarctation of aorta and cardiac anomalies, and eye defects (and sternal raphe). Most (90%) of the patients with this syndrome have more than one extracutaneous manifestation, with significant head and neck involvement. About 40% of these patients have infantile hemangiomas, and many become symptomatic. Importantly, the hemangiomas can be subglottic or involve the airway. MRI/MRA can be used to evaluate cerebral malformations.
It is important to determine whether a maxillofacial vascular abnormality is a tumor versus a malformation, as this can affect prognosis and treatment. , Malformations grow by expanding the bone and causing dilation. Most vascular lesions involving bone are malformations that will cause bony destruction or distortion. Vascular malformations are present at birth and will grow proportionately with the patient; however, intraosseous malformations typically do not become evident until later in life.
Vascular anomalies occur frequently in children; however, confusing nomenclature and a lack of pathophysiologic understanding has led to difficulty in diagnosis and treatment of these lesions. Mulliken and Glowacki proposed a biologic classification of vascular anomalies in 1982, separating vascular tumors from vascular malformations (slow vs fast flow).
The radiographic features of all vascular tumors of bone are typically lytic and occasionally lytic-mixed sclerotic ( Fig. 1 ). Hemangiomas can often be diagnosed by radiographic appearance alone, but angiosarcomas are aggressive and infiltrative in appearance. Histologic features are usually smooth borders, lobulation, and vasoformation in the benign subtypes, with more infiltrative and ragged appearance in the malignant subtypes, with the absence of lobulation or vasoformation. Epithelioid hemangiomas may be mistaken for common hemangiomas, but histology shows more than half of the tumors cells as epithelioid, as opposed to a majority of bland endothelial cells.
The Fos gene family, encoding for the transcription factor FOS (Fos Proto-Oncogene, AP-1 Transcription Factor Subunit) and its parlogue, F OSB , have been described in osseous vascular tumors, such as osteoblastoma and pseudomyogenic hemangioendothelioma. Epithelioid hemangiomas, on some occasions, share similar mutations. YAP1-TFE3 (Yes1 Associated Transcriptional Regulator – Transcription Factor Binding To IGHM Enhancer 3) and WWTR1-CAMTA1 (WW Domain Containing Transcription Regulator 1 – Calmodulin Binding Transcription Activator 1) genetic rearrangements are known to cause epithelioid hemangioma endotheliomas. Additionally, EWSR1-NFATC1 (EWS RNA Binding Protein 1 – Nuclear Factor Of Activated T Cells 1) fusion variations have been documented in hemangioma of the bone. Endothelial cells are used for immunohistochemical markers for occasional confirmation of skeletal lesions.
The markers prox1 (Prospero Homeobox 1), podpplanin, ERG (ETS Transcription Factor ERG), FLI1 (Fli-1 Proto-Oncogene), surface antigens CD34 and CD31 are commonly used. Future work is being performed to look for bone-specific immunohistochemical markers.
Prognosis
Primary hemangioma of the bone is rare and often misrepresented. Venous intraosseous lesions are managed by “insightful neglect” if the lesion is not of a significant volume with no substantial clinical problems. Epithelioid hemangioma is commonly mistaken for hemangioma as more than half of the neoplastic cellular content is epithelioid unlike hemangiomas which contain bland endothelial cells and fewer epithelioid cells.
Angiosarcoma which is the other interosseous vascular tumor is an aggressive and infiltrative malignancy causing significant clinical symptoms and with a high suspicion adequate imaging and biopsy could confirm.
Gorham–Stout disease
Gorham–Stout disease (GSD) is a sporadic bone disorder characterized by progressive bone resorption and possible malignant proliferation of vascular (lymphatic) structures. GSD is also known as disappearing bone disease, vanishing bone disease, and more than a dozen other terms in medical literature. As such, it is closely related to lymphangiomatosis.
In 1838, J B S Jackson, an American surgeon and pathologist, first reported the condition titled “A Boneless Arm” in The Boston Medical and Surgical Journal (now The New England Journal of Medicine). Although the humerus bone had diminished in size and shortened length, the patient reported using the arm well. In 1954, Dr Gorham and Dr Stout hypothesized that angiomatosis was responsible for this unusual bone resorption after publishing two case series and reviewing 16 similar cases. They presented the abstract to the American Association of Physicians in the same year. In October 1955, “Massive Osteolysis (Acute Spontaneous Absorption of Bone, Phantom Bone, Disappearing Bone): Its Relation to Hemangiomatosis” was published in The Journal of Bone and Joint Surgery . In a series of 24 patients, it was hypothesized that this disease is associated with angiomatosis of blood and sometimes of lymphatic vessels.
Genetics/Etiology/Epidemiology
The etiology and pathophysiology of GSD remains poorly understood, with no environmental or genetic risk factors having been identified. Gorham and Stout defined the disease as hemangiomatosis, which includes hyperemia and bone destruction. Heyden suggested that local hypoxia and acidosis caused increased activity of hydrolytic enzymes, and Young thought the osteolysis came from local endothelial dysplasia. , Recent hypotheses consider the enhanced osteoclastic activity secondary to increased IL-6, IL-1, and TNF. IL-6 is capable of stimulating osteoclast activity and increasing sensitivity of osteoclast precursors to humoral factors, such as IL-1 and TNF. , The strong activity of both acid phosphatase and leucine aminopeptidase in mononuclear perivascular cells that are in contact with remaining bone, perhaps indicating these cells are important in the process of osseous resorption. Several reports also described an overlap between visceral and bone lymphangiomatosis.
GSD occurs sporadically, with symptoms appearing at any age, any race, and any gender. Most cases have been reported under age 40 years, with children and young adults mostly affected. Symptoms vary depending on the bones affected and can range from mild to severe, even life-threatening.
There is currently no standardization for diagnosing GSD. Currently, the diagnosis is made by histopathological and clinical correlation, with the following eight diagnostic criteria.
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Positive histologic findings for proliferation and angiomatous dysplasia
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Absence of osteoblastic reaction and/or dystrophic calcifications
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Evidence of local bone progressive resorption
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Exclusion of cellular atypia
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Non-ulcerative lesion
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Absence of visceral involvement
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Osteolytic radiographic pattern
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Negative hereditary, metabolic, neoplastic, immunologic, and infectious etiology
Clinical Presentation and Subtypes
GSD may affect multiple bones, but in most cases, it stays in one region of the body. , The most common symptoms are pain and swelling in the affected area, with no apparent cause. In some cases, pathologic fractures may be the first presenting symptom. Pathologic fractures may be characterized by sclerosis around the fracture site, and screening for post-fracture acceleration of bone resorption in these patients is important. Bones commonly affected by GSD include ribs, spine, pelvis, skull, clavicle, shoulder, and jaws. , Approximately 30% of affected patients had maxillofacial involvement, with mandible being the most frequently affected jawbone. The most common finding is pain and swelling on the affected area. Other findings include mobile teeth, malocclusion, deviation of mandible, facial deformity, and occasional pathologic fractures. Laboratory studies can be completely within normal limits. Patients with spine and skull involvement may experience neurologic complications, acute spinal pain, and paralysis, with occasional spinal fluid leakage. If the ribs or thoracic vertebrae are involved, the known findings include breathing difficulty, chest pain, weight loss, and chylothorax.
Radiographic Findings
The radiologic appearance of bone lesions reveals intramedullary and subcortical radiolucency. The classic radiologic features of GDS are tapering bone ends or a “mouse tail” appearance. GSD can be categorized into four distinct radiographic stages: The first stage shows patchy osteopenia in the intramedullary or subcortical regions resembling osteoporosis. At the second stage, confluent radio-lucencies produce new broader radiolucent areas. The third stage is characterized by the involvement of adjacent soft tissue after cortical breakage. At the final stage, the involved bone is completely resorbed and replaced by fibrous tissue ( Fig. 2 ).
