C. Parker Gibbs

Giant cell tumor of bone.

Objective:To discuss the treatment and outcomes for giant cell tumor (GCT) of bone. Materials and Methods:Review of the pertinent literature. Results:GCT is a rare benign bone lesion most often found in the extremities of women in the third and fourth decades of life. Surgery is the mainstay of treatment and usually consists of intralesional curettage; local control rates range from 80% to 90% after this procedure. Patients with extensive, recurrent, and/or biologically more aggressive tumors may require wide excision. A small subset of patients with incompletely resectable GCTs or with lesions that are surgically inaccessible may be treated with moderate-dose radiotherapy (45–50 Gy) and have a 65% to 80% likelihood of being locally controlled. Conclusion:The majority of patients with GCTs are effectively treated with intralesional curettage. Wide excision or radiotherapy is necessary to cure a relatively limited subset of patients with extensive, aggressive, and/or incompletely resectable GCTs.

Expression of an Exogenous Human Oct-4 Promoter Identifies Tumor-Initiating Cells in Osteosarcoma

We explored the nature of the tumor-initiating cell in osteosarcoma, a bone malignancy that predominately occurs in children. Previously, we observed expression of Oct-4, an embryonal transcriptional regulator, in osteosarcoma cell cultures and tissues. To examine the relationship between Oct-4 and tumorigenesis, cells from an osteosarcoma biopsy (OS521) were stably transfected with a plasmid containing the human Oct-4 promoter driving a green fluorescent protein (GFP) reporter to generate the transgenic line OS521Oct-4p. In culture, only approximately 24% of the OS521Oct-4p cells were capable of activating the transgenic Oct-4 promoter; yet, xenograft tumors generated in NOD/SCID mice contained approximately 67% GFP(+) cells, which selectively expressed the mesenchymal stem cell-associated surface antigens CD105 and ICAM-1. Comparison of the tumor-forming capacity of GFP-enriched and GFP-depleted cell fractions revealed that the GFP-enriched fractions were at least 100-fold more tumorigenic, capable of forming tumors at doses of <300 cells, and formed metastases in the lung. Clonal populations derived from a single Oct-4/GFP(+) cell were capable of forming tumors heterogeneous for Oct-4/GFP expression. These data are consistent with the cancer stem cell model of tumorigenesis in osteosarcoma and implicate a functional link between the capacity to activate an exogenous Oct-4 promoter and tumor formation. This osteosarcoma tumor-initiating cell appears highly prolific and constitutes a majority of the cell population in a primary xenograft tumor, which may provide a biological basis for the particular virulence of this type of cancer.

Aneurysmal bone cyst of the extremities. Factors related to local recurrence after curettage with a high-speed burr.

BACKGROUND Aneurysmal bone cyst is a benign, locally destructive lesion of bone. The rates of local recurrence after curettage have varied widely. Therefore, we performed a retrospective study of patients who had had an aneurysmal bone cyst in order to identify the rate of local recurrence and the prognostic factors related to local recurrence after use of contemporary methods of curettage with a high-speed burr. METHODS We reviewed the cases of forty patients who had been managed by the same surgeon for an aneurysmal bone cyst, as diagnosed on the basis of the latest pathological review, between January 1, 1976, and December 31, 1993. The patients were evaluated with regard to age, gender, the duration and type of symptoms, the presence or absence of pathological fracture, the status of the growth plate, the bone and part of the bone that were involved, the type of operative procedure, the outcome, the radiographic stage, the findings on magnetic resonance imaging and computerized tomography (when it became available) and on bone scintigraphy, and histological parameters. The median duration of follow-up was eighty-seven months (range, fifteen to 267 months). According to the criteria of Enneking, no patient had a stage-1 lesion (one with a surrounding rim of cortical bone), twenty-four had a stage-2 lesion (one with a clearly defined border but no cortical bone), and sixteen had a stage-3 lesion (one with no clearly defined border). RESULTS Of the forty patients, thirty-four had curettage with use of a high-speed burr. Of these thirty-four, twenty-two had filling of the defect with a cancellous autogenous graft; four, with a cancellous allograft; and three, with polymethylmethacrylate. In five patients, no material was put into the defect. The remaining six patients had resection through the margin of the lesion. Four (12 percent) of the thirty-four patients who had curettage had a local recurrence. No patient who had an excision through the margin of the lesion had a local recurrence. All local recurrences were in skeletally immature girls who were three, four, ten, and eleven years old. Univariate analysis with use of the chi-square, Fisher exact, and Wilcoxon log-rank tests showed that local recurrence was associated only with a young age (p = 0.0036) and open growth plates (p = 0.039). All local recurrences occurred within two years postoperatively, at two, seven, nine, and twenty-four months, and all were treated successfully with a second operation. CONCLUSIONS Rates of local control of almost 90 percent can be achieved with thorough curettage with use of a mechanical burr and without use of liquid nitrogen, phenol, or other adjuvants in patients who have an aneurysmal bone cyst of an extremity. A young age and open growth plates are associated with an increased risk of local recurrence.

Malignant bone tumors.

Malignant bone tumors represent a small percentage of cancers nationwide and also are much less common than malignant soft-tissue tumors. The rarity of the condition makes it imperative that orthopaedic surgeons in nononcologic practices are able to recognize the symptoms that suggest a possible bony malignancy to avoid inappropriate or delayed treatment. The most common primary malignant bone tumors, osteosarcoma and Ewings sarcoma, occur in childhood. Chondrosarcoma occurs more frequently in older adults. Rare tumors such as chordoma and adamantinoma have anatomic predilections for the sacrum and tibia, respectively. The primary symptom of a patient with a malignant bone tumor is pain, which often occurs at rest or at night. There are also characteristic findings on physical examination such as swelling or decreased joint range of motion. Patients with a likely malignancy require thorough staging to determine the extent of disease and a well-planned biopsy for accurate diagnosis. The biopsy can be an image-guided needle biopsy or an open incisional biopsy. Knowledge of specific tumor characteristics and treatment options for osteosarcoma, Ewings sarcoma, chondrosarcoma, malignant fibrous histiocytoma, chordoma, and adamantinoma is important. Patients with osteosarcoma and resectable Ewings sarcoma are treated with chemotherapy followed by surgical resection. Secondary sarcomas can occur in previously benign bone lesions and require aggressive treatment. Specific techniques are available for the resection of malignant bone tumors from the upper extremities, lower extremities, pelvis, and spine. Reconstruction options include the use of allografts, megaprostheses, and vascularized autografts. There has been a trend toward more prosthetic reconstructions because of early complications with allografts. The care of patients with primary malignant bone tumors requires a multidisciplinary approach to treatment. The orthopaedic oncologist is a vital member of a team composed of musculoskeletal radiologists and pathologists, radiation oncologists, medical and pediatric oncologists, and microvascular surgeons.

The management of adult soft tissue sarcomas.

Soft tissue sarcomas are a relatively rare, heterogeneous group of tumors arising from mesenchymal tissues and occurring almost anywhere in the body. The rate of progression and likelihood of hematogenous dissemination, usually to the lung, is determined primarily by tumor grade. The likelihood of regional spread is low. Pretreatment evaluation includes computed tomography of the primary site and chest and magnetic resonance imaging of the primary tumor. The mainstay of treatment is surgery; wide excision for low-grade lesions and wide or radical (compartmental) resection for high-grade tumors. Often, these procedures cannot be achieved either because of the location and extent of the sarcoma or anticipated functional deficit. Adjuvant preoperative and/or postoperative radiotherapy improves the likelihood of local control and preserves function when adequate margins cannot be achieved with surgery alone. The role of adjuvant chemotherapy is unclear; however, some data suggest the doxorubicin containing regimens may improve the likelihood of cure for high-grade lesions, particularly large tumors arising in the extremities. Prognosis is influenced by a variety of factors, including age, tumor size, histologic grade, depth (superficial or deep), histologic subtype, and site. Approximately 90% and 98% of recurrences are observed within 5 years and 10 years, respectively. Five-year overall survival rates range from approximately 60% to 80%.

Oncological Outcomes of Operative Treatment of Subcutaneous Soft-Tissue Sarcomas of the Extremities*

We reviewed the cases of sixty-two patients who had had a subcutaneous sarcoma to determine the effect of tumor and treatment-related variables on the rates of survival and local recurrence. Fifty-nine (95 per cent) of the patients had had an operation at another hospital before being referred to us. Twenty-nine (47 per cent) of the sixty-two tumors were high-grade, forty-two (68 per cent) were small (five centimeters or less), and thirty (48 per cent) were malignant fibrous histiocytomas. We followed a treatment strategy that consisted of repeat excision with the goal of obtaining wide margins. Excluding thirteen patients who had had a palpable local recurrence at the time of presentation, twenty (49 per cent) of forty-one patients who had had a marginal excision at another hospital had microscopic residual tumor on repeat excision. At a median of fifty-six months after the repeat excision, fifty (81 per cent) of the sixty-two patients had been continuously disease-free, one had no evidence of disease, eight had died of the disease, and three had died of other causes. The five-year rate of disease-free survival was 85 per cent (fifty-three of sixty-two patients). There were three local recurrences, all in patients who had had a marginal resection. No recurrences were noted in patients who had had a wide local excision of the tumor or of the previous operative field. Multivariate analysis revealed that a large tumor (greater than five centimeters), a marginal excision, and adjuvant radiation therapy were associated with a worse prognosis. Excellent rates of survival for patients who have a subcutaneous sarcoma, including those who have a large or high-grade tumor and those who have residual tumor following a previous operation, can be obtained with carefully planned operative treatment alone. We recommend operative excision or repeat excision with wide margins because of the high prevalence of residual tumor. Size is the most important tumor-related factor, and the operative margin is the most important treatment-related factor. The additional value of adjuvant radiation therapy remains unproved.

Pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder that affects the synovium in young and middle-aged adults. Although most believe that it is an inflammatory process, some believe that it is a benign neoplasm. The optimal treatment is surgery. The local recurrence rate after marginal excision for localized PVNS is low. In contrast, the local recurrence rate after open synovectomy for diffuse PVNS is relatively high. The intra-articular instillation of radioactive isotopes or external beam radiotherapy (approximately 35 Gy in 14–15 fractions over 3 weeks) may significantly improve the likelihood of local control and long-term function in patients with incompletely resected diffuse PVNS. The probability of complications after moderate-dose radiotherapy (RT) is low.

The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity

Marginal excision of soft tissue sarcoma (STS), defined as resection through the tumor pseudocapsule or surrounding reactive tissue, increases the likelihood of local recurrence and necessitates re‐excision or postoperative radiation. However, its impact after preoperative radiation therapy (RT) remains unclear. This study therefore investigated the significance of marginal margins in patients treated with preoperative RT for extremity STS, reporting long‐term local control and limb preservation endpoints.

Current Concepts Review - Evaluation and Staging of Musculoskeletal Neoplasms*

Staging is the process of classifying a tumor, especially a malignant tumor, with respect to its degree of differentiation as well as its local and distant extent, in order to estimate the prognosis for the patient. Evaluation of the histological and imaging studies of a tumor allows the physician to formulate a rational strategy for treatment with operative intervention, medical therapy, or radiation therapy. Staging a tumor is a valuable process in the management of individual patients. In contrast, staging systems are based on clinical, radiographic, and histological features that are believed to be of prognostic importance and may be useful when outcomes are compared between groups of patients. Staging systems may be used to compile data on patient survival and recurrence for tumors that have similar features and to evaluate the effectiveness of therapy for such tumors. The first staging system to be described, as far as we know, was for cervical carcinoma. The system, which was developed by the League of Nations nearly fifty years ago5, was based on the TNM system, in which T referred to the extent of the primary tumor; N, to the presence or absence of nodal metastases; and M, to the presence or absence of distant metastases. Staging systems such as this one have been valuable in the care of patients who have homogeneous and relatively common neoplasms. Treatment protocols based on the TNM system are used to determine which patients should be managed with an operation, radiation, or chemotherapy. There is no universally accepted staging system for musculoskeletal neoplasms because of the low incidence of such tumors, their heterogeneous nature and unpredictable behavior, and disagreement as to the relative importance of various prognostic factors. Also, an important prognostic variable in a staging system for malignant musculoskeletal tumors, unlike a system …

Animal Models in Osteosarcoma

Osteosarcoma (OS) is the most common non-hematologic primary tumor of bone in children and adults. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for non-metastatic disease approaching 70%. However, most OS tumors are high grade and tend to rapidly develop pulmonary metastases. Despite clinical advances, patients with metastatic disease or relapse have a poor prognosis. Toward a better understanding of the molecular pathogenesis of human OS, several genetically modified OS mouse models have been developed and will be reviewed here. However, better animal models that more accurately recapitulate the natural progression of the disease are needed for the development of improved prognostic and diagnostic markers as well as targeted therapies for both primary and metastatic OS.