Telangiectatic Osteosarcoma 

Updated: May 01, 2018
Author: Nirag C Jhala, MD, MBBS; Chief Editor: Omohodion (Odion) Binitie, MD 

Overview

Background

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. When first recognized, telangiectatic osteosarcoma was proposed to be a distinct clinical and pathologic entity.[1] On the basis of subsequent findings that provided a better understanding of the condition's presentation and prognostic implications, telangiectatic osteosarcoma should be considered a variant of osteosarcoma.[2]  It is an uncommon variant, accounting for 0.4-12% of all osteosarcomas.[3, 4, 5, 6, 7]

Telangiectatic osteosarcoma appears as a painful, radiographically lytic mass lesion in the metaphyseal portion of the long bones. It is characterized by dilated, blood-filled vascular spaces lined by malignant osteoblasts. These osteoblasts are separated by fibrous septa, which contain the malignant cells, multinucleated giant cells, and tumor osteoid.[8]

Etiology

Because of the rarity of this lesion, the etiologic factors that promote malignant transformation have not been extensively investigated. Telangiectatic osteosarcomas are presumed to originate from transformed osteoblasts or from stem cells that are of mesenchymal derivation.

Results from transmission electron microscopic examination show that in addition to undifferentiated osteoblastlike and fibroblastlike tumor cells, angiosarcomatous elements may be observed in this malignant bone tumor. Endothelial cell–like structures, including pinocytotic vesicles, tight intercellular junctions, fine fibrils, and Weibel-Palade bodies, are seen in the cytoplasm of these cells.[9] Such observations suggest that telangiectatic osteosarcoma may be derived from multipotential mesenchymal cells, with possible differentiation along various pathways.[10]

Familial occurrence has been reported at least once.[11] In all cases of telangiectatic osteosarcoma, familial genetic changes may be responsible, but other causes are more likely. Molecular and cytogenetic studies are necessary to resolve these issues.[12]

Epidemiology

Telangiectatic osteosarcoma occurs in a male-to-female ratio of 2:1. Although disease can be found in patients as young as 3 years and as old as 71 years, it rarely occurs in persons older than 25 years. Most patients present between the ages of 10 and 20 years.[13]

Prognosis

Historically, local recurrence has been found to be more common than metastasis.[14, 15, 6, 16] With the use of preoperative chemotherapy, however, this observation is probably less accurate than it was. Telangiectatic osteosarcomas have vascular spread and therefore, similar to conventional osteosarcomas, metastasize to the bones and lungs.[14, 15]

 

Presentation

History and Physical Examination

The clinical presentation of telangiectatic osteosarcoma closely resembles that of conventional osteosarcoma. However, local pain, soft-tissue masses, and fractures are the most common presenting symptoms and signs.[6, 17, 18, 19]

Telangiectatic osteosarcoma lesions are usually osseous, but extraosseous lesions have been reported. In the long bones, these tumors usually occur in the metaphyseal region within the medullary cavity. As the tumors expand and destroy the cortex, blowout fractures may occur. These lesions may also occur in a diaphyseal location.[20]

The distribution pattern of telangiectatic osteosarcomas in the long bones is as follows[15] :

  • Distal femur - 48%
  • Proximal humerus - 12%
  • Proximal tibia - 10%
  • Proximal femur - 8%
  • Fibula - 5%
  • Midfemur - 2%
  • Midhumerus - 2%

These tumors have also been known to occur in the mandible[21, 22]  and, rarely, the rib.[23]

Potentially, telangiectatic osteosarcomas can arise in bones involved with Paget disease,[24, 25] where it can mimic other forms of conventional osteosarcoma.[26]

Telangiectatic osteosarcomatous differentiation has been reported in parosteal osteosarcoma,[27] in dedifferentiated chondrosarcoma arising in the background of osteochondroma,[28] in association with aneurysmal bone cysts,[29, 30, 31] and in osteitis deformans.

Telangiectatic osteosarcoma also has been noted to arise in extraosseous soft tissues in the forearm, thigh, and popliteal fossa.[32] Although rare, telangiectatic osteosarcomatous differentiation has been seen in cases of malignant phyllodes tumor of the breast[33] and in cases of ovarian sarcoma.[34]

 

DDx

 

Workup

Imaging Studies

In patients with suspected bone tumors, imaging studies are the initial examinations for determining the nature and extent of the lesion. Plain radiography, magnetic resonance imaging (MRI), computed tomography (CT), and radionuclide bone imaging (ie, bone scanning) help in the differential diagnosis. Patient treatment is often based on the findings from these studies.

On conventional radiographs, pure lytic lesions define these tumors. The tumor margins are frequently permeative; however, well-defined margins have been noted. A sclerotic rim suggests another diagnosis. The lytic lesions may have fluid-filled spaces. Cortical destruction and infiltration into the surrounding soft tissues can occur. This tumor may also evoke a periosteal bone reaction, and it can be associated with the Codman triangle. A pattern of parallel striations is highly suggestive of telangiectatic osteosarcoma.

The literature regarding CT and MRI features of telangiectatic osteosarcoma is relatively sparse.

The differential diagnosis of telangiectatic osteosarcoma, based on imaging studies, often includes the following[35] :

  • Aneurysmal bone cyst
  • Ewing sarcoma
  • Langerhans cell histiocytosis
  • Fibrosarcoma
  • Malignant fibrous histiocytoma

Histologic Findings

The use of fine-needle aspiration biopsy (FNAB) and the pathologic evaluation of tissue sections obtained during surgery in the diagnosis of telangiectatic osteosarcoma have been reviewed.[4, 5, 36]

Fine-needle aspiration biopsy

The examination of samples obtained by means of FNAB reveals sheets of highly polymorphous cells. The cells include spindled cells reminiscent of fibroblasts, as well as round or oval malignant cells. Multinucleated cells also are frequently identified. Nuclear hyperchromasia, nuclear membrane irregularity, and prominent nucleoli are noted in the malignant cells. Increased mitotic activity may be noted as well. The cytoplasm is variable and granular.

Although FNAB results, in conjunction with highly suggestive clinical and radiographic findings, may be of value in determining the malignant nature of the underlying process, they are not the mainstays in the diagnosis of telangiectatic osteosarcomas. Rather, core-needle or conventional biopsy permits a definitive diagnosis of telangiectatic osteosarcoma.

Gross appearance of the resected tumors

The tumors, which may be 10-20 cm in diameter, have the appearance of a hemorrhagic mass. An aneurysmal bone cyst is often suspected. Sometimes, these lesions have multicystic channels filled with blood that correspond to the radiographic appearance of fluid-filled spaces. A solid, fleshy, sarcomalike appearance is not appreciated in these lesions.

Microscopic features

Malignant cells are noted in a background of blood and necrotic debris. Because the pleomorphic hyperchromatic malignant cells may be diluted in the necrotic and hemorrhagic background, a careful examination to recognize these elements is imperative. Blood lakes, rather than endothelium-lined spaces, are present (see the image below).

Large blood lakes seen at a low magnification are Large blood lakes seen at a low magnification are reminiscent of findings in an aneurysmal bone cyst (hematoxylin and eosin, original magnification X4).

In some cases, an osteoid matrix may not be visualized except within the septal walls, which may be thin and difficult to find. In such cases, a characteristic radiographic appearance, when correlated with a careful microscopic search for features suggestive of malignancy, helps in the correct interpretation of the findings.[37] Occasionally, low-power examination reveals a morphologic pattern that is reminiscent of an aneurysmal bone cyst.

A potential trap is created by a radiologic impression of an aneurysmal bone cyst and the characteristic gross features of that cyst. However, examination of the cyst lining reveals overt malignant cells, often with increased mitotic activity (see the first image below). These cells may lie adjacent to the benign osteoclastic giant cells. In some cases, these giant cells are numerous, and the tumor mimics a giant cell–rich osteosarcoma (see the second image below).

Careful examination of the lining of blood-filled Careful examination of the lining of blood-filled lakes shows overt malignant cells. Atypical tripolar mitosis is noted in the field (hematoxylin and eosin, original magnification X20).
Numerous giant cells may be noted in the tumor, wh Numerous giant cells may be noted in the tumor, which mimics a giant, cell–rich osteosarcoma (hematoxylin and eosin, original magnification X20).

Unlike an aneurysmal bone cyst, telangiectatic osteosarcoma has an osteoid matrix that is delicate and lacelike in appearance. Also, the stroma between the dilated vascular spaces often contains malignant cells.

Role of pathologists

A high degree of suspicion is necessary with a purely destructive long-bone lesion in adolescents. Examinations of bone tumors and tumorlike conditions have been reviewed.[12] Briefly, in the resected specimen, the size and location of the tumor and the extent of disease should be noted. The involvement of the resected margins and of the vessels, nerves, skin, and soft tissues along the biopsy tract should be included in the report.

After preoperative chemotherapy, the resected specimen should be mapped, and multiple sections representing the complete face of the bone should be obtained to document the amount of necrosis and viable tumor in the specimen. This observation is particularly important because the amount of necrosis has strong prognostic significance and affects the subsequent management of telangiectatic osteosarcoma. Tumor necrosis in more than 95-98% of the resected specimen is considered a good response to chemotherapy.[38, 39]

Staging

The American Joint Committee on Cancer (AJCC) staging system for primary bone tumors is based on a combination of the primary tumor (T), regional lymph node involvement (N), distant metastasis (M), and histopathologic grade (G). Because regional lymph node involvement is rare in bone tumors, the pathologic stage grouping involves any combination of these four grades.

With respect to these bone tumors, AJCC definitions for primary tumor characteristics are as follows:

  • TX - The primary tumor cannot be assessed
  • T0 - No evidence of a primary tumor is present
  • T1 - The tumor is confined within the cortex
  • T2 - The tumor invades beyond the cortex

Definitions for regional lymph node involvement are as follows:

  • NX - Regional lymph nodes cannot be assessed
  • N0 - No regional lymph node metastasis is present
  • N1 - Regional lymph node metastasis is present

Definitions for distant metastasis are as follows:

  • MX - Distant metastasis cannot be assessed
  • M0 - No distant metastasis is present
  • M1 - Distant metastasis is present

Definitions for histopathologic grades are as follows:

  • GX - Grade not assessable
  • G1 - Well differentiated, low grade
  • G2 - Moderately differentiated, low grade
  • G3 - Poorly differentiated, high grade
  • G4 - Undifferentiated, high grade

Definitions for pathologic stages are as follows:

  • Stage IA - G1 or G2, T1, N0, M0
  • Stage IB - G1 or G2, T2, N0, M0
  • Stage IIA - G3 or G4, T1, N0, M0
  • Stage IIB - G3 or G4, T2, N0, M0
  • Stage III - Not defined
  • Stage IVA - Any G, any T, N1, M0
  • Stage IVB - Any G, any T, any N, M1

Enneking initially proposed a system for staging bone tumors that was based on the histopathologic grade, the site of the lesion, and evidence of metastasis (see Table 1 below).

Table 1. Initial Enneking Clinical Staging System for Primary Malignant Bone Tumors (Open Table in a new window)

Stage

Grade

Location

Metastasis

IA

Low grade, G1

T1

M0, intracompartmental

IB

Low grade, G1

T2

M0, intracompartmental

IIA

High grade, G2

T1

M0, intracompartmental

IIB

High grade, G2

T2

M0, extracompartmental

IIIA

Low or high grade, G1 or G2

T1

M1, intracompartmental with metastasis

IIIB

Low or high grade, G1 or G2

T2

M1, extracompartmental with metastasis

In the Enneking method of staging malignant bone tumors, histologic grade is defined as follows:

  • Low grade, G1 - Well-differentiated tumor with few mitoses and moderate nuclear atypia
  • High grade, G2 - Poorly differentiated tumor with high cell-to-matrix ratio, many mitoses, and marked nuclear atypia

The site of the lesion is specified as follows:

  • Intracapsular, T0 - Lesion surrounded by an intact capsule of fibrous tissue or reactive bone
  • Extracapsular, T1 - Lesion within the compartment of its origin (the lesion remains within an intraosseous, intrafascial and/or muscular plane or periosteal or parosteal compartment)
  • Extracapsular, T2 - Lesion extension beyond its compartment of origin or lesion origin within an incompletely bound space, such as the popliteal fossa, axilla, or groin

Metastasis is specified as follows:

  • M0 - No known metastasis
  • M1 - Metastasis present

More recently, another system, the Birmingham classification, has been proposed for the surgical staging of high-grade osteosarcoma.[40] Further study will be requried to assess the validity of this system.

 

Treatment

Medical Therapy

Advances in diagnosis and chemotherapeutic regimens have improved the prognosis of patients with telangiectatic osteosarcoma.[6, 14, 41, 42, 43] Because of neoadjuvant chemotherapy, the continuous disease-free survival for patients with telangiectatic osteosarcoma is similar to or better than that for persons with conventional osteosarcoma.[14, 41, 44, 45]

Regarding the choice of chemotherapeutic agents, the treatment of telangiectatic osteosarcoma is similar to that of high-grade osteogenic sarcomas. Reported below are two protocols that are used specifically for the treatment of telangiectatic osteosarcoma.

Although no standard recommendations for chemotherapy in telangiectatic osteosarcoma exist, generalizations can be made regarding the modern treatment of this disease, as follows:

  • Preoperative chemotherapeutic agents can be administered intravenously (IV) or intra-arterially for two to six cycles
  • Chemotherapy should include at least two of the following drugs: doxorubicin, methotrexate, cisplatin or carboplatin, and ifosfamide [46]
  • For adjuvant chemotherapy, two to six cycles of the same drugs are used; however, non–cross-reacting drugs may be selected for use in patients with a poor response to neoadjuvant chemotherapy
  • As always, and particularly in the case of rare diseases such as telangiectatic osteosarcoma, experimental treatment options that advance scientific knowledge and ensure high-quality patient care should be considered

Chemotherapeutic approach A

Two cycles of IV methotrexate are administered over 6 hours, beginning on days 1 and 21. This agent is followed by citrovorum factor or leucovorin rescue and, after 9 days, by continuous intra-arterial administration of cisplatin for 72 hours. Surgery follows, and depending on the tumor response (good vs poor), further neoadjuvant therapy may be continued.

Postoperative chemotherapy for patients who have a good response may include at least three cycles of IV doxorubicin for 2 days. On day 21, IV methotrexate is infused over 6 hours, followed by citrovorum factor or leucovorin rescue. Continuous intra-arterial cisplatin administration follows this course on day 28 for 72 hours. Such cycles are administered beginning on days 1, 49, and 105, at least.

For patients who have a poor response, (ie, tumor necrosis in <95% of the tumor in the resected specimen), five cycles of IV doxorubicin are administered for 2 days. On day 21, a combination of bleomycin, cyclophosphamide, and IV dactinomycin is administered for 2 days.

Chemotherapeutic approach B

Preoperative chemotherapy involves two cycles of IV methotrexate over 6 hours, followed by citrovorum factor or leucovorin rescue. This is followed by the administration of cisplatin on day 7 for 72 hours. After 48 hours of cisplatin therapy, the patient should receive IV doxorubicin for 8 hours. The second cycle begins on day 28, and surgery follows this cycle.

If the response to chemotherapy is good, as determined by the amount of tumor necrosis in the resected specimens, at least three cycles of IV doxorubicin may be administered for 2 consecutive days in a 4-hour period on each day. This step is followed by IV methotrexate administered over 6 hours on days 21 and 27, followed by citrovorum factor or leucovorin rescue and intra-arterial cisplatin infusion for 72 hours. This course is repeated after 17 days for at least two additional cycles.

For patients with a poor response to the initial neoadjuvant chemotherapy, four cycles of IV doxorubicin are administered for 2 consecutive days in a 4-hour period each day. On day 21, ifosfamide plus mesna is infused for 5 consecutive days in 90 minutes. This step is followed with IV methotrexate administered over 6 hours on day 42 and then citrovorum factor or leucovorin rescue. On day 48, a combination of cisplatin, as given preoperatively, and etoposide (VP16) is administered in 1-hour infusions on 3 days. This cycle is repeated after 19 days for at least two cycles.

The addition of doxorubicin to preoperative neoadjuvant therapy results in a continuous disease-free survival rate of 82% at a follow-up of 2-7 years (mean, 4 years). This rate is significantly better than the continuous disease-free survival rate of 61% reported for conventional osteosarcomas treated with the same chemotherapeutic protocol.

The Children's Oncology Group and its precursor organizations, the Pediatric Oncology Group (POG) and the Cancer Strategies Group (CSG), have been pioneers with regard to studies aimed at establishing standardized neoadjuvant chemotherapeutic protocols for the treatment of osteosarcomas.[47] Because chemotherapeutic protocols are continually evolving, a knowledgeable investigator should always be consulted before such therapy is initiated.

Surgical Therapy

Surgical management of telangiectatic osteosarcoma depends on the tumor's location, the stage of the disease, and the tumor's response to neoadjuvant chemotherapy.

The primary goal of surgery is the complete resection of the tumor, using wide margins. With the success of current neoadjuvant chemotherapeutic protocols, this goal is usually achieved. However, cases in which the major neurovascular structures are involved or a pathologic fracture has occurred usually require wide excision or radical amputation to completely resect the primary tumor. Intraoperatively, the margins of surgical excision may be evaluated with intraoperative frozen-section examination as indicated.

Margins that are intralesional, marginal, or less than wide result in unacceptably high local recurrence rates that may indicate lower disease-free survival rates. In limb-salvage procedures, the type of reconstruction depends on the primary tumor's location, the structures being resected, the patient's age and activity level, and the surgeon's experience.[48] The resultant function of the patient with a salvaged limb should be determined by using standard Musculoskeletal Tumor Society (MSTS) functional outcome assessments. The local recurrence of disease after limb-salvage procedures is usually treated with wide excision or radical amputation to achieve local control of the disease.

Initial staging studies should include standard radiography, whole-body technetium-99m (99mTc) methylene diphosphonate (MDP) bone scanning, computed tomography (CT) of the chest, and magnetic resonance imaging (MRI) of the primary tumor. MRI scans should include not only the tumor but also the joint proximal to and the one distal to the tumor to detect any skip metastases.

After these studies, biopsy is performed in close consultation with the musculoskeletal oncologic surgeon and the radiologist, as well as with the surgical pathologist, the cytopathologist, or both. A sample can be obtained by means of open biopsy, fine-needle aspiration biopsy, or core-needle biopsy, with image guidance used as indicated. The biopsy incision or tract must be placed so that its site can be resected en bloc at the time of definitive surgery. Therefore, the musculoskeletal oncologic surgeon must be involved in the initial biopsy.

After the preoperative portion of neoadjuvant chemotherapy, the tumor stage is reassessed to determine the effect of the chemotherapy on the local extent of the disease and the presence of any distant metastatic disease. The staging system used by musculoskeletal oncologic surgeons is the surgical system introduced by Enneking, which is advocated by the MSTS. According to this staging system, most telangiectatic osteosarcomas are stage IIB—that is, high-grade, extracompartmental lesions. Some patients present with distant metastatic disease; their tumors are stage IIIB.

Postoperative Care

After successful resection with limb-salvage methods or amputation, the patient should be closely monitored for recurrence of the tumor and for distant metastatic disease. Standard radiographs should be obtained to assess local recurrence. CT scans of the chest and bone scans are periodically obtained to assess distant metastatic disease.