Telangiectatic Osteosarcoma

Etiology

The exact etiology of telangiectatic osteosarcoma is still unknown, and so are the predisposing factors. It becomes challenging to conduct epidemiological studies and investigate the etiologic factors due to the rare occurrence of the disease. However, some anecdotal reports described genetic components due to the presence of the disease in family members.[5] Telangiectatic osteosarcoma was described in the metaphysis of the distal tibia in an 11-year-old girl and the lamina of the thoracic vertebra in an 8-year-old boy who was a cousin. On histopathological evaluation, dilated and proliferated blood cavities were seen along with anaplastic tumor cells and osteoid production, favoring the diagnosis of telangiectatic osteosarcoma. The clinical outcome was favorable in both cases.[5] Also, three well-documented cases of extraskeletal telangiectatic osteosarcoma of the soft tissues were described; the daughter of one of the cases had died previously of high-grade intramedullary bone osteosarcoma.[6]

Epidemiology

Telangiectatic osteosarcoma is predominantly seen in children, adolescents, and young adults. The mean age at presentation of telangiectatic osteosarcoma is 17.5 years (range from 15 to 20 years) with a male-to-female ratio of 2 to 1.[2] The distal femoral metaphysis is the single most common anatomic site (42%), followed by the proximal tibia (17%), the proximal humerus (9%), and the proximal femur (8%).

Flat bone involvement is relatively rare, with around 8% incidence of non-appendicular non-spinal sites.[7][8] Uncommon sites of telangiectatic osteosarcoma include the scapula, the ribs, the sternum, the innominate bone, the cranial vault, and the mandible. Telangiectatic osteosarcoma of the spine represents 2% of all cases of primary vertebral osteosarcomas.[9] Extra-osseous telangiectatic osteosarcoma is rare, with telangiectatic osteosarcoma arising in the soft tissues of the thigh, the forearm, and the popliteal fossa.[6]

Pathophysiology

Histogenesis

Telangiectatic osteosarcoma is presumed to derive from either transformed osteoblasts or stem cells of mesenchymal origin. Angiosarcomatous features are present in addition to osteoblast-like and fibroblast-like cells at the ultrastructural level. Tight intercellular junctions, Weibel-Palade bodies, and pinocytic vesicles are visible within the cell cytoplasm. These features suggest that telangiectatic osteosarcoma derives from multipotential stem cells of mesenchymal origin.[10][2][11]

Cytogenetics

Only seven cases of telangiectatic osteosarcoma to date have had genetic studies. The cytogenetic analysis identified trisomy 3 in one case, and in three other tumors, more complex chromosomal changes were reported.[12][13] Metaphase CGH identified an average of 2.5 aberrations in two telangiectatic osteosarcomas, and array CGH identified only three regional gains at 1q21-23.2, 1q25.2-31.1, and 7q21.13-21.2 in one tumor.[14] This suggests that telangiectatic tumors are genetically less complex than conventional osteosarcoma.

Histopathology

On gross as well as microscopic appearance, telangiectatic osteosarcoma very closely resembles aneurysmal bone cysts.[4] Therefore, the resected surgical specimens of telangiectatic osteosarcoma must undergo meticulous sampling.[2] Because of the cystic and lytic nature of the tumor, a core-needle biopsy may not provide an adequate and appropriate sample for the diagnosis. Hence, the establishment of the diagnosis often gets delayed leading to delayed treatment with the outcome affected adversely.[15][16][2] The complete face of the bone must be sampled to document the percentages of the viable and necrotic tumors.[2] Yin et al. developed and described a diagnostic model for the differentiation of telangiectatic osteosarcoma from an aneurysmal bone cyst.[17] 

Macroscopic Findings

Macroscopic examination reveals a hemorrhagic multicystic lesion filled with blood clots. Telangiectatic osteosarcomas have the classic description as ''a bag of blood.'' They are, by definition, composed of approximately 90% cystic components before treatment.[8] A fleshy sarcomatous component is typically not present. The cystic spaces can vary considerably in size and may occasionally measure several centimeters in diameter. More often, there is a mixture of large cystic and spongy areas. The spongy areas represent tissue honeycombed with smaller cysts measuring up to several millimeters. The borders of the lesion are usually well-demarcated, but often there are features of invasive growth with extensive irregular cortical erosion, complete disruption of cortical continuity, and invasion of soft tissue.

Microscopic Findings

Histologically, telangiectatic osteosarcoma is composed of blood-filled or empty cystic spaces resembling aneurysmal bone cysts. The septa are populated by pleomorphic cells with important nuclear hyperchromasia and also contain osteoclast-like giant cells. Osteoid formation is usually focal and confluent. Because telangiectatic osteosarcoma is sometimes not adequately sampled by core-needle biopsy due to its lytic and cystic nature, cellular atypia and osteoid formation may be absent, which may lead to misdiagnosis.[2] Previously, the osteoid production by the malignant cells was deemed essential for diagnosing telangiectatic osteosarcoma. However, later various cases were reported with a lack of osteoid production.[4] Thickened septa with nodularity, along with the presence of malignant cells with nuclear pleomorphism and cellular atypia, microscopically differentiate telangiectatic osteosarcoma from aneurysmal bone cysts.[17]

Immunochemistry

No immunohistochemical studies are useful in the diagnosis of telangiectatic osteosarcoma.

History and Physical

There is no difference in the clinical presentation of telangiectatic and conventional osteosarcoma. Local pain and/or soft tissue mass are the most common symptoms of telangiectatic osteosarcoma. Sometimes, the patients may present with a pathologic fracture.[18][19] Occasionally, a vascular bruit may be heard over the tumor. As with any other malignant tumor, a thorough general physical and systemic clinical examination is mandatory to look for evidence of any metastases.

Evaluation

Several imaging modalities are available for establishing the diagnosis of telangiectatic osteosarcoma. They include:

• Plain radiographs
• Computed tomography (CT)
• Magnetic resonance imaging (MRI)

Radiographic Findings

Telangiectatic osteosarcoma is typically a purely lytic lesion with a permeative destructive growth pattern. This rapidly growing tumor often expands the contour of bone and shows features of cortical disruption with minimal or no periosteal new bone formation. The massive expansile growth pattern of telangiectatic osteosarcoma can superficially simulate an aneurysmal bone cyst. Telangiectatic osteosarcoma can have a deceptively innocent radiographic appearance with sharply demarcated margins, simulating a benign bone cyst. Aneurysmal bone cysts generally have type 1A or 1B patterns of geographic bone destruction.[20] Presence of soft tissue mass, Codman triangle, and matrix mineralization point towards the diagnosis of telangiectatic osteosarcoma. MRI best documents the multilocular cystic nature of the lesion and the so-called fluid level sign.[21]

T1-weighted MRI shows heterogeneous low signal intensity, and T2-weighted images show high signal intensity with several cystic foci, fluid levels, and an extra-skeletal extension of the tumor, similar to an aneurysmal cyst, but with irregular walls, septae, and nodular and solid components.[7] Zishan et al. described that presence of fluid-fluid levels in the lesion was the most useful differentiating MRI feature between telangiectatic osteosarcoma and aneurysmal bone cyst. As compared to 74% of the osteosarcomas demonstrating a fluid level, 95% of the bone cysts had the presence of fluid levels. Also, only aneurysmal bone cysts had lesions that were completely filled with a fluid-fluid level.[20]

The criteria for diagnosing telangiectatic osteosarcoma include the following:

• Radiographically, a destructive, osteolytic tumor with little or no matrix mineralization or periosteal new bone formation
• Cystic/cavitary gross specimen with little solid tumor tissue and no areas of a dense bone
• Histologically, a tumor with single or multiple cystic cavities containing blood or necrotic tissue, with thickened septa composed of anaplastic tumor cells[4]

The high alkaline phosphatase level frequently seen in osteosarcoma is not a feature of telangiectatic osteosarcoma. On the other hand, the evaluation of platelet count, white cell count, lactate dehydrogenase, and alkaline phosphatase have been described for differentiating telangiectatic osteosarcoma from aneurysmal bone cysts. The sarcomas had a higher value of platelet count, white cell count, alkaline phosphatase, and lactate dehydrogenase than the aneurysmal bone cysts.[17]

Treatment / Management

Previously, the prognosis and clinical outcome of telangiectatic osteosarcoma were considered to be poor. However, with the advent of chemotherapy, the prognosis has significantly improved, with around a 60% survival rate at ten years, which is similar to that of conventional osteosarcoma.[22] Patients with telangiectatic osteosarcoma receive neo-adjuvant chemotherapy followed by surgical excision, further followed by adjuvant chemotherapy/ radiotherapy. The pre-chemotherapy era required amputation in most cases of telangiectatic osteosarcoma. However, limb-sparing surgery is now possible in most cases, even with pathological fractures.[23][22][24] The extent of surgery depends on the size, location, and response to the neoadjuvant therapy. Adjuvant chemotherapy can offer some advantages if metastatic disease is present.(B2)

Colomina et al. reported the outcome of 8 patients with telangiectatic osteosarcoma with pathologic fractures. They described that the presence of a pathologic fracture did not worsen the outcome and had similar survival and recurrence rates.[24] Similarly, in a retrospective review of 87 cases of telangiectatic osteosarcoma, Angelini et al. reported a survival rate of 60% at ten years. The majority of the patients were cured with neoadjuvant chemotherapy and limb-sparing surgery. They found tumor response to chemotherapy as the only significant prognostic factor affecting survival.[22](B2)

Differential Diagnosis

The most common differential diagnosis is an aneurysmal bone cyst which closely mimics the radiographic, gross as well as microscopic features of telangiectatic osteosarcoma. This often delays the diagnosis leading to the delay in starting optimal treatment. Other differential diagnoses include:

• Giant cell tumor of bone
• Brodie abscess
• Blood clot
• Malignant fibrous histiocytoma
• Fibrosarcoma[4]

Treatment Planning

Chemotherapeutic protocols for telangiectatic osteosarcoma are similar to those of conventional osteosarcoma. Patients will have two to six cycles of chemotherapy administered before surgery. The common chemotherapeutic agents used include cisplatin, carboplatin, methotrexate, doxorubicin, and ifosfamide.[25] Among these, at least two agents need inclusion in a dual-drug therapy regimen. The effect of chemotherapy on telangiectatic osteosarcoma must undergo reassessment. The percentage of tumor necrosis needs to be assessed in the pathological evaluation of the surgical specimen, as <90% necrosis mandates a change in the chemotherapeutic regimen.[4]

Staging

The two common staging systems for telangiectatic osteosarcoma include the Enneking system for malignant bone neoplasms and the American Joint Committee on Cancer (AJCC) system for staging bone sarcomas. The Enneking system includes tumor histological grade, the local extent of the tumor- intracompartmental or extracompartmental and the presence of metastasis. The AJCC system considers tumor histological grade, tumor size, and the presence and location of metastases.[26]

Prognosis

Telangiectatic osteosarcoma usually shows a better response to chemotherapy than conventional osteosarcoma. Survival rates with current chemotherapy protocols are within the range of 65% after five years.[27] The pattern of metastatic spread of telangiectatic osteosarcoma is similar to that seen in conventional osteosarcoma.

Tumor necrosis greater than 95% is considered one of the most important prognostic factors.[28] Additionally, uninvolved neurovascular bundles and soft tissue and bone resection margins are essential for a favorable prognosis.[2] Yin et al. reported that the level of lactate dehydrogenase and tumor volume were predictive prognostic factors, and the presence of a pathologic fracture did not affect the outcome.[17]

Complications

The complications in managing telangiectatic osteosarcoma include local recurrence, metastases, decreased survival, implant failure, infection, and cardiotoxicity due to chemotherapy.[4]