Neoplasms of Bone

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Chapter 495 Neoplasms of Bone

495.1 Malignant Tumors of Bone

Carola A.S. Arndt

The annual incidence of malignant bone tumors in the USA is approximately 7 cases/million white children <14 yr of age, with a slightly lower incidence in African-American children. Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, followed by Ewing sarcoma (Table 495-1; Fig. 495-1). In children <10 yr of age, Ewing sarcoma is more common than osteosarcoma. Both tumor types are most likely to occur in the second decade of life.

Table 495-1 COMPARISON OF FEATURES OF OSTEOSARCOMA AND THE EWING FAMILY OF TUMORS

FEATURE OSTEOSARCOMA EWING FAMILY OF TUMORS
Age Second decade Second decade
Race All races Primarily whites
Sex (M : F) 1.5 : 1 1.5 : 1
Cell Spindle cell–producing osteoid Undifferentiated small round cell, probably of neural origin
Predisposition Retinoblastoma, Li-Fraumeni syndrome, Paget disease, radiotherapy None known
Site Metaphyses of long bones Diaphyses of long bones, flat bones
Presentation Local pain and swelling; often, history of injury Local pain and swelling; fever
Radiographic findings Sclerotic destruction (less commonly lytic); sunburst pattern Primarily lytic, multilaminar periosteal reaction (“onion-skinning”)
Differential diagnosis Ewing sarcoma, osteomyelitis Osteomyelitis, eosinophilic granuloma, lymphoma, neuroblastoma, rhabdomyosarcoma
Metastasis Lungs, bones Lungs, bones
Treatment Chemotherapy Chemotherapy
Ablative surgery of primary tumor Radiotherapy and/or surgery of primary tumor
Outcome Without metastases, 70% cured; with metastases at diagnosis, ≤20% survival Without metastases, 60% cured; with metastases at diagnosis, 20-30% survival
image

Figure 495-1 A, Age and skeletal distribution of 1,649 cases of osteosarcoma in the Mayo Clinic files. B, Age and skeletal distribution of 512 cases of Ewing sarcoma in the Mayo Clinic files.

(From Unni KK, editor: Dahlin’s bone tumors: general aspects and data on 11,087 cases, ed 5, Philadelphia, 1996, Lippincott-Raven. Reprinted by permission of the Mayo Foundation.)

Osteosarcoma

Pathogenesis

Although the cause of osteosarcoma is unknown, certain genetic or acquired conditions predispose patients to development of osteosarcoma. Patients with hereditary retinoblastoma have a significantly increased risk for development of osteosarcoma. The sites of osteosarcoma in these patients were initially thought to be located only in previously irradiated areas, but later studies have shown them to arise in sites far from the radiation field. Predisposition to development of osteosarcoma in these patients may be related to loss of heterozygosity of the RB gene. Osteosarcoma also occurs in the Li-Fraumeni syndrome, which is a familial cancer syndrome associated with germline mutations of the p53 gene. Kindreds with Li-Fraumeni syndrome have a spectrum of malignancies in 1st-degree relatives, including carcinoma of the breast, soft tissue sarcomas, brain tumors, leukemia, adrenal cortical carcinoma, and other malignancies. Rothmund-Thomson syndrome is a rare syndrome associated with short stature, skin telangiectasia, small hands and feet, hypoplasticity or absence of the thumbs, and a high risk of osteosarcoma. Osteosarcoma also can be induced by irradiation for Ewing sarcoma, craniospinal irradiation for brain tumors, or high-dose irradiation for other malignancies. Other benign conditions that can be associated with malignant transformation to osteosarcoma include Paget disease, enchondromatosis, multiple hereditary exostoses, and fibrous dysplasia.

The pathologic diagnosis of osteosarcoma is made by demonstration of a highly malignant, pleomorphic, spindle cell neoplasm associated with the formation of malignant osteoid and bone. There are four pathologic subtypes of conventional high-grade osteosarcoma: osteoblastic, fibroblastic, chondroblastic, and telangiectatic. No significant differences in outcome are associated with the various subtypes, although the chondroblastic component of that subtype may not respond as well to chemotherapy. The role in prognosis of various genes such as drug resistance-related genes, tumor suppressor genes, and genes related to apoptosis is being evaluated.

Telangiectatic osteosarcoma may be confused with aneurysmal bone cyst because of its lytic appearance on radiography. High-grade osteosarcoma typically arises in the diaphyseal region of long bones and invades the medullary cavity. It also may be associated with a soft tissue mass. Two variants of osteosarcoma, parosteal and periosteal osteosarcoma, should be distinguished from conventional osteosarcoma because of their characteristic clinical features. Parosteal osteosarcoma is a low-grade, well-differentiated tumor that does not invade the medullary cavity and most commonly is found in the posterior aspect of the distal femur. Surgical resection alone often is curative in this lesion, which has a low propensity for metastatic spread. Periosteal osteosarcoma is a rare variant that arises on the surface of the bone but has a higher rate of metastatic spread than the parosteal type and an intermediate prognosis.

Diagnosis

Bone tumor should be suspected in a patient who presents with deep bone pain often causing nighttime awakening in whom there is a palpable mass, and radiographs demonstrate a lesion. The lesion may be mixed lytic and blastic in appearance, but new bone formation is usually visible. The classic radiographic appearance of osteosarcoma is the sunburst pattern (Fig. 495-2). When osteosarcoma is suspected, the patient should be referred to a center with experience in managing bone tumors. The biopsy and the surgery should be performed by the same surgeon so that the incisional biopsy site can be placed in a manner that will not compromise the ultimate limb salvage procedure. Tissue usually is obtained for molecular and biologic studies at the time of the initial biopsy. Before biopsy, MRI of the primary lesion and the entire bone should be performed to evaluate the tumor for its proximity to nerves and blood vessels, soft tissue and joint extension, and skip lesions. The metastatic work-up, which should be performed before biopsy, includes CT of the chest and radionuclide bone scanning to evaluate for lung and bone metastases, respectively. The differential diagnosis of a lytic bone lesion includes histiocytosis, Ewing sarcoma, lymphoma, and bone cyst.

Treatment

With chemotherapy and surgery, the 5-yr disease-free survival rate of patients with nonmetastatic extremity osteosarcoma is 65-75%. Complete surgical resection of the tumor is important for cure. The current approach is to treat patients with preoperative chemotherapy in an attempt to facilitate limb salvage operations and to treat micrometastatic disease immediately. Up to 80% of patients are able to undergo limb salvage operations after initial chemotherapy. Some institutions use intra-arterial chemotherapy to infuse chemotherapy directly into an artery feeding the tumor, although this approach has not been shown to be better than conventional intravenous chemotherapy. It is important to resume chemotherapy as soon as possible after surgery. Lung metastases present at diagnosis should be resected by thoracotomies at some time during the course of treatment. Active agents currently in use in multidrug chemotherapy regimens for conventional osteosarcoma include doxorubicin, cisplatin, methotrexate, and ifosfamide.

One of the most important prognostic factors in osteosarcoma is the histologic response to chemotherapy. An international cooperative group is performing a randomized trial of the postoperative addition of high-dose ifosfamide with etoposide to standard three-drug therapy with cisplatin, doxorubicin, and methotrexate to improve the outcome of patients with a poor histologic response. Patients with good histologic response will be randomized to the addition of PEGylated interferon-α2b. For patients with metastatic disease, a new approach currently being investigated is the addition of zoledronic acid, a bisphosphonate, to intensive chemotherapy. After limb salvage surgery, intensive rehabilitation and physical therapy are necessary to ensure maximal functional outcome.

For patients who require amputation, early prosthetic fitting and gait training are essential to enable them to resume normal activities as soon as possible. Before definitive surgery, patients with tumors on weight-bearing bones should be instructed to use crutches to avoid stressing the weakened bones and causing pathologic fracture. The role of chemotherapy in parosteal and periosteal osteosarcomas is not well defined.

Prognosis

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