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Clinical Outcome of 38 Patients With Juxtacortical Osteosarcoma

Temple, H., Thomas*; Scully, Sean, P.**; O'Keefe, Regis, J.; Katapurum, Susan††; Mankin, Henry, J.§

Clinical Orthopaedics and Related Research: April 2000 - Volume 373 - Issue - p 208-217
Section II: Original Articles: Tumor

Thirty-eight patients presented with previously untreated, predominantly low-grade juxtacortical osteosarcoma. There were 12 (32%) men and 26 (68%) women with a mean age of 28.9 years. The most common sites of tumor were the distal femur (n = 28) and proximal tibia (n = 5). Twenty-five patients presented with Stage IB tumors. Twelve had Stage IIB, which although it was predominantly low-grade, had an area of high grade tumor, so the tumors were considered dedifferentiated. One patient had Stage III tumor. All patients were alive at 6.75 years' average followup. Negative but close margins were achieved in all but two patients (range, 1-80 mm). Intramedullary extension was seen in 17 (44.7%) patients, and the adjacent cortex was involved in 27 (71.1%) patients. There was no statistically significant difference between tumor size, site, radiographic appearance, cortical or intramedullary extension, grade, resection margin, or pretreatment duration of symptoms and local recurrence. Intramedullary extension of tumor does not seem to increase the risk of metastatic disease. Dedifferentiation of predominantly low-grade juxtacortical osteosarcoma in not previously treated tumors is uncommon. Based on these data, close but negative margins may be adequate in achieving local disease control and preventing metastases in these patients.

From the *Department of Orthopaedics and Rehabilitation, University of Miami School of Medicine, Miami, FL; **Department of Surgery-Orthopaedics, Duke University Medical Center, Durham, NC; Department of Orthopaedic Surgery, University of Rochester School of Medicine and Dentistry, Rochester, NY; and the Departments of ††Radiology and §Orthopaedics, Harvard Medical School, Massachusetts General Hospital, Boston, MA.

Reprint requests to Sean P. Scully, MD, PhD, Duke University Medical Center, Department of Surgery-Orthopaedics Box 3312, Durham, NC 27710.

Received: April 3, 1998.

Revised: December 3, 1998; December 7, 1999; July 29, 1999.

Accepted: September 9, 1999.

Parosteal osteosarcoma or low-grade juxtacortical osteosarcoma is a rare and less aggressive form of osteosarcoma, representing 1% to 6% of all cases of osteosarcoma.11,15,22 The peak incidence is later than high-grade intramedullary osteosarcoma, usually in the third and fourth decades, and it affects females more often than males. The first clinical series of patients with this disease was described by Geschicter and Copeland9 in 1951; however, the term parosteal osteosarcoma initially was adopted by the Bone Sarcoma Registry of the American College of Surgeons in 1928 and later included in Ewing's revised classification in 1939.8 Dwinnell et al5 popularized the term parosteal osteosarcoma in 1954.

Parosteal osteosarcoma or low-grade juxtacortical osteosarcoma is a malignant tumor arising adjacent to the cortex of long bones with well differentiated fibrous, osseous, and cartilaginous components.10,18 Lichtenstein described these peculiar lesions "as neoplasms [that] develop apparently through slow but progressive proliferation of bone-forming (and also cartilage forming) periosteal and/or parosteal connective tissue and present as smaller or larger hard masses on the surface of bones, rather than the interior with increasing size, they may in time extend into the underlying cortex and eventually penetrate the medullary cavity."13 Some authors believe that when the intramedullary cavity is violated, this lesion behaves more like its high-grade intramedullary counterpart and is at greater risk to metastasize,3,18,21,25 although others have disputed this point.1,11,14-16,19,23 In addition, areas of higher-grade tumor can be present within these otherwise low-grade lesions, and it is thought that patients with tumors that harbor these dedifferentiated foci are at greater risk to have metastases develop.1,3,4,16,21,23,25

The clinical courses of patients with primary low-grade parosteal osteosarcoma who were treated at one institution during a 25-year period were reviewed. The importance of focal high-grade tumor and the relationship of intraosseous and cortical extension of disease related to outcome were analyzed. Finally, surgical margins were evaluated for local and systemic disease control.

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This is a retrospective study of 38 patients treated at the Massachusetts General Hospital for predominantly low-grade juxtacortical osteosarcomas from February 1977 to June 1992 with a minimum 4-year followup. Twelve patients with predominantly high-grade juxtocortical osteosarcomas were excluded from the study. Inpatient and outpatient charts were reviewed for variables including gender, age, tumor site, presenting symptoms, duration of symptoms to diagnosis, date of surgery, date of latest followup, type of resection, tumor stage at presentation, and oncologic outcome. Oncologic outcome was measured in disease-free survival, survival with disease, disease-free interval, and the presence or absence of metastatic disease or local recurrence during the surveillance period. Patients with low-grade juxtacortical osteosarcoma with a minimal 4-year followup were included. Patients with high-grade juxtacortical2,20 or intramedullary osteosarcoma24 were excluded from the analysis.

Standard radiographs on all patients were evaluated by a musculoskeletal radiologist (SK). In most patients, axial imaging studies consisting of computed tomography (CT) or magnetic resonance imaging (MRI) were available. Computer-assisted integration was used to assess the cross sectional area of the lesion and the area of mineralization, and the ratio was expressed as a percentage of the entire lesion. Radiographs also were used to define the site of the lesion, its location within the bone, and the presence or absence of cortical or intramedullary extension of disease.

Pathology reports were reviewed on each patient. These documents contained information on the predominant histologic subtype and grade, areas of focal intermediate-grade to high-grade tumor, the closest resection margin measured in millimeters, and exact tumor dimensions. Tumors were graded according to degree of differentiation and designated Grades 1, 2, or 3 for low-grade, intermediate-grade, and high-grade, respectively. The differentiation between histologic grades was made on the basis of the cellularity of the lesion, the pleomorphism, and the mitotic activity present. Dedifferentiation was defined as limited areas of high-grade tumor (3) in a lesion that predominantly was low-grade (1). In assessing margins and adequacy of resection the criteria of Enneking et al7 was used for what constituted intracapsular, marginal, wide, and radical resections. The Musculoskeletal Tumor Society staging system was used to assess stage, with Grade 1 lesions assigned to Stage I and Grades 2 and 3 to Stage II.6

Patients with metastatic disease or with a high-grade dedifferentiated component were treated with systemic chemotherapy. Patients treated with adjuvant chemotherapy were treated off protocol on standard osteosarcoma regimens within toxicity tolerances.

Variables were analyzed using means and standard deviations, Student's t test, and a nonparametric one-way analysis of variance for unequal groups.

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Data pertaining to 38 patients with low-grade juxtacortical osteosarcoma were analyzed to assess the relationship of local recurrence, distant metastases, surgical margins, and cortical and intramedullary extension to oncologic outcome (Table 1). There were 12 (32%) male and 26 (68%) female patients, with a mean age of 28.9 years (range, 16-57 years). The most common site of disease was the distal femur (n = 28), followed by the proximal tibia (n = 5) (Fig 1). Most of the lesions occurred in the metaphyseal or metadiaphyseal portion of long bones. The average followup was 6.75 years. The average duration of symptoms was 2 months (range, 1 day-1.4 years), although most patients presented with pain (52.6%), stiffness (5.3%), or an asymptomatic mass (42.1%).



Fig 1

Fig 1

The typical histologic appearance showed malignant but well-differentiated osseous and fibrous tissue arising on the surface of bone (Fig 2). Although all patients had predominantly Grade 1 disease, 11 patients had Grade 2 (intermediate) focal areas of tumor, and in one patient there were focal areas of Grade 3 (high-grade) tumor. There were 26 Stage IB lesions, 11 Stage IIB lesions because of a focal area of high-grade (3) tumor,6 and one Stage III lesion. Because of the attenuated periosteal layer that separates the tumor from the surrounding soft tissue, all lesions were considered extracompartmental.

Fig 2A

Fig 2A

Radiographically, all of the lesions were well-mineralized and closely apposed to the bone surface (Fig 3). The average tumor size was 53.1 cm2 (range, 10-225 cm2). The mean percent of tumor ossification was 77% (range, 15%-99%) There was no statistically significant difference between tumor size and grade (p = 0.53) or between percent ossification and grade (p = 0.15). Neither increased tumor size nor decreased tumor ossification were associated with increased risk of local recurrence; however, decreased tumor ossification was observed in both patients with metastatic disease (p = 0.05).

Fig 3

Fig 3

Negative surgical margins were achieved in all but two patients. One patient with positive resection margins had focal intermediate-grade disease but received no additional surgical or adjuvant treatment. She remained free of disease 4 years after surgery. The other patient with positive margins had a documented local recurrence at 4 years after her initial resection and was treated with reresection and no adjuvant treatment. This patient is alive without disease 7 years after reresection. There were four patients with locally recurrent disease, three of whom had negative resection margins. Overall, these patients had recurrent disease develop at an average of 91 months (7.6 years) after the index procedure. Treatment for local recurrence consisted of reexcision in two patients and amputation in two. All patients with recurrent disease had Grade 1 lesions with no evidence of increased focal tumor grade, two had cortical involvement by tumor, and only one had intramedullary extension of disease (Table 2). There was no statistically significant difference between tumor size, site, radiographic appearance (degree of ossification), cortical or intramedullary extension, grade, resection margin, or duration of symptoms, and local recurrence. At latest followup, all patients with local recurrence were alive without disease.



Chemotherapy was administered to only three patients with low-grade juxtacortical osteosarcoma; one with no areas of higher grade tumor but metastatic disease at the time of presentation, another with a large mass (80 cm2) with focal intermediate Grade 2 tumor, and the third with foci of high Grade 3, dedifferentiated areas of tumor. There were no adverse treatment outcomes, and all patients were free of disease at latest followup (average, 5.3 years). No patients had tumors recur locally or had new or recurrent distant metastases develop.

Seventeen (44.7%) patients had intramedullary tumor extension, although the lesion involved the adjacent cortex in most (71.1%) of the patients. There was no statistically increased risk of local recurrence (p = 0.14) or metastatic disease (p = 0.29) in patients in whom the cortex was involved. For tumors that invaded the medullary canal there also was no statistical association with local recurrence or metastasis (p > 0.1). There was increased tumor grade in six of the 17 patients with intramedullary disease extension (Grade 2 tumor foci). Two of these patients had metastatic disease develop; one presented with lung metastases, and the other had lung metastases develop after treatment. The grade, site, duration of symptoms, radiographic size, and percent ossification were not associated with more aggressive local disease, cortical erosion, or intramedullary extension.

There were two intralesional, 19 marginal, and 17 wide procedures performed on 38 patients. The closest margin was 2 mm or less in 21 (55%) patients. The margin was histologically positive in two patients. There was no difference in the type of resection performed based on site, radiographic size, patient age, tumor grade, or percent ossification (Table 3). The closest surgical margin in these patients usually was the soft tissue margin in lesions arising in or near the popliteal fossa with tumor abutting the neurovascular bundle.



Mean followup for this group of patients was 6.75 years. At latest followup all 38 patients had no evidence of clinical disease. Initially, all patients except one underwent limb salvage surgery. The one patient in this series who underwent amputation was a 47-year-old man with a large (16 × 9 × 8 cm) Grade 1 distal femoral lesion that involved the posterior neurovascular bundle and extended into the medullary canal. He had pulmonary metastases at the time of presentation and underwent pulmonary nodule resection and chemotherapy initially and again 7 years later for recurrent disease. He is alive without disease at latest followup.

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This study is unique in that only patients initially presenting with predominantly Grade 1 tumor were included for analysis. Patients with tumors with focal Grade 2 and Grade 3 areas were considered only if most of the lesion was Grade 1. Although the current study is retrospective, this fairly homogenous patient population treated during a 25-year period produced some important observations. As in previous studies, there was a predominance of female patients and a patient population that, on average, was older than that seen with conventional high-grade intramedullary osteosarcoma. Similarly, the site and location within the bone were not unlike those reported in other studies, with the distal femur and proximal tibial metaphysis or metadiaphysis being most common.

Areas of higher tumor grade are not uncommon in patients with parosteal osteosarcoma and were observed in 12 patients in this series; however, only one tumor was considered dedifferentiated.25 Several studies of parosteal or juxtacortical osteosarcoma have reported high-grade tumors or histologic characteristics that are not consistent with the overall histologic appearance of parosteal osteosarcoma.3,5,12,15,17,23,25 Wold et al25 described 11 such cases in 55 patients treated at the Mayo Clinic in which 10 of the 11 tumors were seen in patients after multiple recurrent lesions. A high rate of dedifferentiation (16%) also was reported by Okada et al,15 but unlike the reports of earlier studies, a large proportion of these lesions were found primarily not in association with disease recurrence.

In the current study, areas of higher tumor grade were observed in 12 of 38 (31%) patients, but only one patient (2.6%) had an area of high-grade tumor that qualified as dedifferentiated. The reason for this disparity is unclear. Each specimen in the current series was examined carefully grossly and microscopically. The pathology reports describe areas of increased cellularity, atypia, and mitotic activity. Analysis of tumor samples was not random but depended on close inspection of the macrosections and critical interpretation of histologic detail. Because most studies report an increased incidence of dedifferentiation with recurrent lesions, the fact that there were few secondary or recurrent lesions in this series may account for the small number of dedifferentiated tumors. Intermediate-grade tumors described as parosteal osteosarcoma may be at greater risk of transitioning to higher grade sarcomas than are Grade 1 tumors. Dedifferentiation in primary, not recurrent, Grade 1 juxtacortical osteosarcomas probably is less common.

Intramedullary involvement was common and occurred in 44.7% of patients, whereas tumor destruction or erosion of the adjacent cortex was observed in 71.1% of patients. Tumor extension into the medullary canal has been thought by some to affect prognosis adversely, although others have shown no significant difference in outcome. Campanacci et al3 described increased intramedullary invasion in tumors with higher-grade histologic features and reasoned that higher tumor grade leads to increased local aggressiveness and increased risk of pulmonary metastases. Intramedullary extension of disease was seen in 17 patients and focal increased tumor grade was seen in six of these patients. There was no increased risk of metastatic disease based on tumor grade alone in those lesions that extended into the medullary canal, and there was no increased risk of metastasis based on intramedullary extension alone. This was reaffirmed in the current report, for which there was no statistically significant correlation between cortical or medullary involvement and disease recurrence.

It is likely that small numbers in the current study preclude the statistical power to determine whether intramedullary extension is an independent prognostic factor. High-grade has been shown to serve as a prognostic indicator and has been shown in some studies more likely to be associated with intramedullary invasion. It may be that medullary involvement may be associated with higher-grade tumors and not be an independent prognostic indicator. The current study was unable to show a significant difference between grade and intramedullary extension and intramedullary extension and poor outcome as measured in local recurrence and survival. The one patient in this series with dedifferentiation did have intramedullary invasion; however, metastasis did not develop in this patient. Both patients with pulmonary metastases had evidence of focal intramedullary invasion, one patient with Grade 1 tumor only and the other with a limited area of Grade 2 tumor.

No radiographic features were associated with increased risk of local recurrence or of metastatic disease, except possibly the percent of tumor ossification. Tumors with less ossification tended to be less differentiated than were tumors with more abundant ossification. Both patients with metastasis had reduced ossification, and although this was statistically significant (p = 0.05), the small number of patients precludes a meaningful conclusion. Axial imaging studies, particularly MRI, are particularly useful in predicting intramedullary extension, thus guiding appropriate surgical management, which may include segmental versus hemicortical resection.

It is thought that complete tumor removal via wide resection results in the best oncologic result. However, resection with wide surgical margins often is difficult to achieve because these tumors tend to be large at presentation because many are asymptomatic until later in their course. Many lesions occur in or near the popliteal fossa, and usually only a small amount of fibroadipose tissue separates the reactive margin and frank tumor from the neurovascular bundle. In most cases in this series the vascular bundle was displaced posteriorly and medially by tumor. The neurologic bundle, consisting of the tibial and peroneal nerves, which travels separately from the vascular bundle, is displaced posteriorly and laterally. In only one case was there apparent violation of the vascular bundle requiring more aggressive surgical treatment to obtain a tumor free margin. In half of the patients in the current series, the soft tissue margin was within 2 mm of tumor, and in two patients the margin contained tumor. Given the extracompartmental nature of this lesion and its frequent location in the axilla and popliteal fossa, it is unreasonable to expect wide margins when all that separates the tumor and its reactive zone from the neurovascular bundle is fibroadipose tissue. The morbidity of doing segmental resections of the neurovascular bundle to achieve wide local margins in all cases is unacceptable, particularly because good local disease control is possible with marginal resections over limited regions of the tumor. For this reason, the authors advocate accepting close, but negative, margins in patients with primary low-grade juxtacortical osteosarcomas.

Parosteal osteosarcoma is a slowly growing tumor, and recurrences can be seen many years after what was thought to be an adequate resection. For this reason, the current study includes a minimum 4-year followup. However, this period is shorter than the median time to failure for patients experiencing recurrence, which was 7.6 years. It may be that with longer followup of this group of patients, an increased incidence of tumor recurrence will be observed. Treatment of multiply recurrent lesions is different because tumor spread may occur beyond the main body of the tumor because seeding may have occurred during previous tumor manipulation and resection, and it is difficult, if not impossible, to differentiate reactive tumor tissue from scar tissue intraoperatively and radiographically.

Difficulties in selecting an acceptable surgical margin before surgery can be compounded by evidence that local recurrences can result, even after wide resection amputations far away from the tumor or the tumor reactive zone. In the current series, only two patients had local recurrence develop, one with positive resection margins and another who underwent primary amputation with a 25-cm margin. In primary lesions, preoperative imaging studies, particularly MRI studies, can be deceiving in interpreting soft tissue planes because reactive edema and tumor have the same appearance on T2-weighted pulse sequences. Because local recurrence was uncommon and did not have the oncologic implications that local recurrence has in high-grade tumors, a rational decision can be made to remove as much normal intervening tissue as possible while preserving neurovascular structures. Such an approach attempts to achieve negative margins and preserve function.

The indication for chemotherapy is unclear for patients with dedifferentiated tumors, but given the higher rate of metastatic spread in patients with these tumors, it seems reasonable to use this treatment. The current study suggests surgical treatment alone is appropriate for patients with low- and intermediate-grade tumors because the risk of local recurrence and metastatic disease is small when negative margins are achieved. The goal in treating low grade juxtacortical or parosteal osteosarcoma is to achieve negative tumor margins. Based on the data presented, histologically negative margins appear to be adequate in preventing local disease recurrence and distant spread. The presence of intramedullary extension of disease is common and is not a negative prognostic indicator for patients with Grade 1 histologic tumor. Although areas of higher tumor grade are seen in almost a third of patients, the presence of dedifferentiation or high-grade histologic changes in primary tumors is rare.

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