THE TREATMENT AND OUTCOMES OF EXTRASKELETAL OSTEOSARCOMA: INSTITUTIONAL EXPERIENCE AND REVIEW OF THE LITERATURE Lukas M. Nystrom, MD, Nickolas B. Reimer, MD, John D. Reith, MD, Mark T. Scarborough, MD, C. Parker Gibbs Jr., MD ABSTRACT Background: Extraskeletal osteosarcoma is a rare tumor with a poor prognosis. The purpose of this study is to examine the oncologic outcomes of this disease as they relate to surgical treatment and use of adjuvant therapies. Methods: We retrospectively analyzed all patients treated at our institution for high-grade extraskeletal osteosarcoma of the limb or chest wall. We recorded demographic data, presenting stage, surgical margin, use of adjuvant chemotherapy or radiation, incidence of local recurrence, metastases, and death. Overall and event-free sur vival were calculated using Kaplan-Meier sur vival methods. Results: There were 12 patients treated with primar y wide resection or re-excision of a previously operated tumor bed. Four patients presented with metastases. Seven patients received chemotherapy and four patients received radiation therapy. There were two local recurrences, six patients developed new metastases, and nine patients died. There was no difference in overall sur vival in patients who received chemotherapy. There was, however, a trend towards increased length of survival in patients who received chemotherapy compared to those who did not (16.4 months vs. 9.3 months, p=0.16). Conclusions: Despite no difference in overall sur vival, patients treated with adjuvant chemoInvestigation Performed at the University of Florida Corresponding Author: Lukas M. Nystrom, MD Department of Orthopaedic Surgery and Rehabilitation Loyola University Chicago 2160 South First Ave., Maywood, IL 60153 Telephone: (708) 216-1274 Fax: (708) 216-5858 [email protected] One author (CPG) reports disclosures as an editorial board member for both The Journal of Bone and Joint Surgery and Orthopedics, as well as an NIH grant recipient. None of these disclosures are applicable to the current study. Two of the authors (MTS and CPG) report financial disclosures as consultants for Exactech, Inc. which is unrelated to the material presented in this manuscript. The remaining authors (LMN, NBR, JDR) have no financial disclosures. This investigation was reviewed by the Institutional Review Board at the University of Florida and assigned a status of exempt.
98 The Iowa Orthopedic Journal
therapy have a trend towards increased length of sur vival. We suggest that extraskeletal osteosarcoma be treated with standard osteosarcoma chemotherapy regimens in addition to wide resection. INTRODUCTION Extraskeletal osteosarcoma is an extremely rare tumor accounting for approximately 1% of all soft tissue sarcomas and 4% of all osteogenic sarcomas1-4. Unlike conventional osteosarcoma, the extraskeletal variant more commonly affects adults, with most patients being diagnosed after age 405. The lower extremity is the most common location5. The lesion typically demonstrates a central pattern of ossification (Figure 1A) which demonstrates contrast enhancement on magnetic resonance imaging and positron emission tomography (PET) avidity (Figures 1B and 1C) and histologically mimics its bony counterpart (Figure 1D). The prognosis has been demonstrated to be quite poor with a five-year overall survival rate reported as low as 28%5, with more recent series demonstrating five year disease-specific survival of only 45% for patients presenting with localized disease6,7. There is a paucity of literature regarding this disease and few have attempted to address the role of adjuvant therapies on outcomes8. Given the relative rarity of the disease, there is no universally accepted treatment algorithm for extraskeletal osteosarcoma. Unlike its conventional counterpart, the role of chemotherapy in the treatment of extraskeletal osteosarcoma is unclear. Current literature reflects this lack of consensus, with most patient series appearing quite heterogeneous in terms of their treatment algorithms. Recent evidence, however, suggests that outcomes may be improved if extraskeletal osteosarcoma is treated similarly to conventional osteosarcoma with an aggressive chemotherapeutic regimen8,9. A retrospective series of 17 patients published in 2005 found that three year overall survival was 77% when patients were treated with multiagent chemotherapy and surgery; however, this study was limited by short follow-up8. Another report of 20 patients, 15 of which were treated with chemotherapy, noted a 5 year overall survival of 66%9. In contrast, and further strengthening the argument for chemotherapy, a series of 40 patients, in which only two were treated with chemotherapy, reported a 5 year overall survival of 37%10.
The Treatment and Outcomes of Extraskeletal Osteosarcoma Table I. Patient and tumor characteristics, treatment and outcomes for the entire patient cohort. Patient
Gender
Age (yrs)
Location
Size (cm)
Volume (cc)
MSTS stage
Prior unplanned excision
Final Margins
Limb Salvage
Chemo-therapy
Radiation
Status
Follow-up (mos)
1
F
72
distal thigh
19x7x7
931
IIB
Y
wide
N
N
N
DOD
2
2
M
76
chest wall
unknown
unknown
IIA
Y
wide
Y
N
Y
DOD
9
proximal thigh
1.5x2.4x1.4
5
IIA
Y
wide
Y
N
Y
NED
64
3
M
83
4
F
64
buttock
8x5x1.5
60
III
Y
wide
Y
Y
N
DOD
1
F
32
proximal thigh
7x6.5x3
137
IIB
N
radical
N
Y
N
DOD
18
6
F
52
buttock
14x14.9x14.8
3087
IIIA
N
wide
Y
Y
N
DOD
28
7
M
58
chest wall
15x17x10
2550
IIIB
N
wide
Y
Y
Y
DOD
12
13x10x7
910
IIB
N
wide
N
N
N
DOD
9
IIB
Y
wide
N
N
N
DOD
17
5
8
F
71
proximal thigh
9
M
57
proximal thigh
10x10x8
800
10
F
40
buttock
4.3x5.3x5.1
116
III
N
wide
Y
Y
N
NED
12
11
M
69
calf
7x5x3.5
123
IIA
N
wide
Y
Y
N
DOD
23
12
M
43
thigh
4x3.8x2.5
38
IIB
Y
wide
Y
Y
Y
AWD
12
The objective of the current study is to evaluate the experience of a large referral institution and add to the current literature regarding the multidisciplinary treatment of extraskeletal osteosarcoma. METHODS We performed a retrospective analysis of our orthopedic oncology database to identify all patients with extraskeletal osteosarcoma treated at our institution. The database contains prospectively collected data on all surgically treated patients treated from 1960 through 2012. The study protocol was approved for a waiver of informed consent by our Institutional Review Board prior to the beginning of data collection. We included all patients treated for high-grade extraskeletal osteosarcoma of the limb or chest wall. All diagnoses were made by a pathologist specializing in musculoskeletal oncology. Surgical notes, radiology reports and actual images, when available, and pathology reports were reviewed to confirm that the mass occurred exclusively in the soft tissues. Exclusion criteria were patients with incomplete charts, those with low-grade tumors, those with periosteal or juxtacortical locations, those who were treated surgically at other institutions, those with unclear survival outcome, or those documented as living but with less than 12 months of clinical follow-up. We recorded patient demographic data, tumor size and presenting stage, surgical interventions prior to referral to our institution, final surgical margin status
after surgery at our institution, use of chemotherapy or radiation, presence of metastatic disease on presentation, development of new metastatic disease during follow-up, development of local recurrence, and death. Statistical analysis was performed utilizing SPSS software (IBM Corporation, Armonk, NY, USA). Overall survival (OS) and event-free survival (EFS) was assessed using Kaplan-Meier survivorship methods. Survival was defined from the date of surgery to the date of last followup. Univariate analysis was utilized to assess differences in OS based upon tumor size, prior unplanned excision, type of adjuvant therapy, and presence of local recurrence or metastatic disease. Variables were compared utilizing the Mann-Whitney U test and p-values less than 0.05 were considered statistically significant. RESULTS We identified 18 patients in our database with extraskeletal osteosarcoma. Three patients were excluded due to having all of their treatment exclusively at outside institutions; three additional cases were excluded, including one case that refused further treatment, a second case that transferred care to another institution prior to treatment, and a third case that did not have clinical follow-up or outcome data beyond one month postoperatively. Twelve patients were available for analysis, with an average age of 60 years ± 16 years. The demographic, treatment, and final outcome data for the 12 patients comprising our case series are summarized in Table I. Volume 36 99
L. M. Nystrom, N. B. Reimer, J. D. Reith, M. T. Scarborough, C. P. Gibbs Jr.
Figure 1. (a) Plain radiographic image demonstrating an ossific mass in the region of the right hip. (b) Axial T1 post-contrast MRI demonstrating the mass arising from the right gluteal musculature with a thin peripheral rim of enhancement. (c) Positron emission tomography scan demonstrating the mass with ver y high standardized uptake value. (d) Hematoxylin and eosin slide demonstrating immature osteoid formation by malignant appearing spindle cells.
Figure 2. Kaplan-Meier sur vival plot of overall sur vival (OS) for the twelve patients in this series.
There were six males and six females. Ten tumors were in the lower extremity (6 thigh, 3 buttock, 1 lower leg), and the remaining two tumors were in the chest wall. All were high-grade osteosarcoma at presentation. Two cases are believed to be radiation-associated secondary osteosarcomas in patients who had radiation treatment for unrelated malignancies greater than 15 years prior to extraskeletal osteosarcoma being diagnosed at the margin of their radiation field. The average tumor volume was 796 cc ± 1070 cc (range 5 – 3087 cc). All of the remaining 12 patients were managed surgically. Surgical intervention at our institution consisted of A a wide or radical resection of the mass or wide or either radical re-excision of a previously operated tumor bed. Limb-sparing surgery was performed in eight patients, and four patients were treated with amputation. Seven patients received chemotherapy and four received radiation therapy. Two patients were treated with both chemotherapy and radiation. Three patients were managed with surgery alone. Of those who received chemotherapy, one of the regimens was unknown as that patient was treated at an outside institution with no available records regarding the specifics of their treatment. The other six patients all had doxorubicinbased chemotherapy regimens. Four patients received therapy only in the adjuvant setting and two received both neo-adjuvant and adjuvant chemotherapy. Of the four patients who were treated with radiation therapy, one was treated pre-operatively with the remaining three
being treated post-operatively. All patients treated with adjuvant radiation therapy were treated with a minimum dose of 5040 centigrey (cGy). There were six unplanned resections prior to referral to our institution. The average tumor volume in patients with an unplanned resection was 367cc, compared to 1154cc in those with no prior unplanned resection (p=0.24). Of the twelve patients, four (33.3%) had metastatic disease on presentation. Five patients without metastases at diagnosis subsequently developed metastatic disease. There were two local recurrences, at an average of 6 months post-operatively. At the time of final analysis, there were three patients living at an average follow up of 29.3 months (range 12 – 64 months). Two of the three living patients received chemotherapy as part of their treatment. All three patients treated with surgery alone died of disease at 2, 9, and 17 months after surgery. In total, nine patients died of disease at an average of 13 months post-operatively. Kaplan-Meier survival analysis demonstrated a median survival of 17 months and a 5-year OS of 11.7% (Figure 2). When evaluating OS stratified by patients who received chemotherapy compared to those who did not, there was no significant difference in survival (Figure 3). 5-year EFS was 10.4% (Figure 4). Among the patients who died, there was a trend towards increased length of survival in patients who received chemotherapy compared to those who did not receive chemotherapy (16.4 months vs. 9.3 months,
100 The Iowa Orthopedic Journal
The Treatment and Outcomes of Extraskeletal Osteosarcoma Table II. Univariate analysis of individual tumor and treatment factors on overall sur vival. Mean Sur vival (mos)
95% CI
p-value
>500cc
13.6
(-4.2, 31.4)
0.47
98 The Iowa Orthopedic Journal
therapy have a trend towards increased length of sur vival. We suggest that extraskeletal osteosarcoma be treated with standard osteosarcoma chemotherapy regimens in addition to wide resection. INTRODUCTION Extraskeletal osteosarcoma is an extremely rare tumor accounting for approximately 1% of all soft tissue sarcomas and 4% of all osteogenic sarcomas1-4. Unlike conventional osteosarcoma, the extraskeletal variant more commonly affects adults, with most patients being diagnosed after age 405. The lower extremity is the most common location5. The lesion typically demonstrates a central pattern of ossification (Figure 1A) which demonstrates contrast enhancement on magnetic resonance imaging and positron emission tomography (PET) avidity (Figures 1B and 1C) and histologically mimics its bony counterpart (Figure 1D). The prognosis has been demonstrated to be quite poor with a five-year overall survival rate reported as low as 28%5, with more recent series demonstrating five year disease-specific survival of only 45% for patients presenting with localized disease6,7. There is a paucity of literature regarding this disease and few have attempted to address the role of adjuvant therapies on outcomes8. Given the relative rarity of the disease, there is no universally accepted treatment algorithm for extraskeletal osteosarcoma. Unlike its conventional counterpart, the role of chemotherapy in the treatment of extraskeletal osteosarcoma is unclear. Current literature reflects this lack of consensus, with most patient series appearing quite heterogeneous in terms of their treatment algorithms. Recent evidence, however, suggests that outcomes may be improved if extraskeletal osteosarcoma is treated similarly to conventional osteosarcoma with an aggressive chemotherapeutic regimen8,9. A retrospective series of 17 patients published in 2005 found that three year overall survival was 77% when patients were treated with multiagent chemotherapy and surgery; however, this study was limited by short follow-up8. Another report of 20 patients, 15 of which were treated with chemotherapy, noted a 5 year overall survival of 66%9. In contrast, and further strengthening the argument for chemotherapy, a series of 40 patients, in which only two were treated with chemotherapy, reported a 5 year overall survival of 37%10.
The Treatment and Outcomes of Extraskeletal Osteosarcoma Table I. Patient and tumor characteristics, treatment and outcomes for the entire patient cohort. Patient
Gender
Age (yrs)
Location
Size (cm)
Volume (cc)
MSTS stage
Prior unplanned excision
Final Margins
Limb Salvage
Chemo-therapy
Radiation
Status
Follow-up (mos)
1
F
72
distal thigh
19x7x7
931
IIB
Y
wide
N
N
N
DOD
2
2
M
76
chest wall
unknown
unknown
IIA
Y
wide
Y
N
Y
DOD
9
proximal thigh
1.5x2.4x1.4
5
IIA
Y
wide
Y
N
Y
NED
64
3
M
83
4
F
64
buttock
8x5x1.5
60
III
Y
wide
Y
Y
N
DOD
1
F
32
proximal thigh
7x6.5x3
137
IIB
N
radical
N
Y
N
DOD
18
6
F
52
buttock
14x14.9x14.8
3087
IIIA
N
wide
Y
Y
N
DOD
28
7
M
58
chest wall
15x17x10
2550
IIIB
N
wide
Y
Y
Y
DOD
12
13x10x7
910
IIB
N
wide
N
N
N
DOD
9
IIB
Y
wide
N
N
N
DOD
17
5
8
F
71
proximal thigh
9
M
57
proximal thigh
10x10x8
800
10
F
40
buttock
4.3x5.3x5.1
116
III
N
wide
Y
Y
N
NED
12
11
M
69
calf
7x5x3.5
123
IIA
N
wide
Y
Y
N
DOD
23
12
M
43
thigh
4x3.8x2.5
38
IIB
Y
wide
Y
Y
Y
AWD
12
The objective of the current study is to evaluate the experience of a large referral institution and add to the current literature regarding the multidisciplinary treatment of extraskeletal osteosarcoma. METHODS We performed a retrospective analysis of our orthopedic oncology database to identify all patients with extraskeletal osteosarcoma treated at our institution. The database contains prospectively collected data on all surgically treated patients treated from 1960 through 2012. The study protocol was approved for a waiver of informed consent by our Institutional Review Board prior to the beginning of data collection. We included all patients treated for high-grade extraskeletal osteosarcoma of the limb or chest wall. All diagnoses were made by a pathologist specializing in musculoskeletal oncology. Surgical notes, radiology reports and actual images, when available, and pathology reports were reviewed to confirm that the mass occurred exclusively in the soft tissues. Exclusion criteria were patients with incomplete charts, those with low-grade tumors, those with periosteal or juxtacortical locations, those who were treated surgically at other institutions, those with unclear survival outcome, or those documented as living but with less than 12 months of clinical follow-up. We recorded patient demographic data, tumor size and presenting stage, surgical interventions prior to referral to our institution, final surgical margin status
after surgery at our institution, use of chemotherapy or radiation, presence of metastatic disease on presentation, development of new metastatic disease during follow-up, development of local recurrence, and death. Statistical analysis was performed utilizing SPSS software (IBM Corporation, Armonk, NY, USA). Overall survival (OS) and event-free survival (EFS) was assessed using Kaplan-Meier survivorship methods. Survival was defined from the date of surgery to the date of last followup. Univariate analysis was utilized to assess differences in OS based upon tumor size, prior unplanned excision, type of adjuvant therapy, and presence of local recurrence or metastatic disease. Variables were compared utilizing the Mann-Whitney U test and p-values less than 0.05 were considered statistically significant. RESULTS We identified 18 patients in our database with extraskeletal osteosarcoma. Three patients were excluded due to having all of their treatment exclusively at outside institutions; three additional cases were excluded, including one case that refused further treatment, a second case that transferred care to another institution prior to treatment, and a third case that did not have clinical follow-up or outcome data beyond one month postoperatively. Twelve patients were available for analysis, with an average age of 60 years ± 16 years. The demographic, treatment, and final outcome data for the 12 patients comprising our case series are summarized in Table I. Volume 36 99
L. M. Nystrom, N. B. Reimer, J. D. Reith, M. T. Scarborough, C. P. Gibbs Jr.
Figure 1. (a) Plain radiographic image demonstrating an ossific mass in the region of the right hip. (b) Axial T1 post-contrast MRI demonstrating the mass arising from the right gluteal musculature with a thin peripheral rim of enhancement. (c) Positron emission tomography scan demonstrating the mass with ver y high standardized uptake value. (d) Hematoxylin and eosin slide demonstrating immature osteoid formation by malignant appearing spindle cells.
Figure 2. Kaplan-Meier sur vival plot of overall sur vival (OS) for the twelve patients in this series.
There were six males and six females. Ten tumors were in the lower extremity (6 thigh, 3 buttock, 1 lower leg), and the remaining two tumors were in the chest wall. All were high-grade osteosarcoma at presentation. Two cases are believed to be radiation-associated secondary osteosarcomas in patients who had radiation treatment for unrelated malignancies greater than 15 years prior to extraskeletal osteosarcoma being diagnosed at the margin of their radiation field. The average tumor volume was 796 cc ± 1070 cc (range 5 – 3087 cc). All of the remaining 12 patients were managed surgically. Surgical intervention at our institution consisted of A a wide or radical resection of the mass or wide or either radical re-excision of a previously operated tumor bed. Limb-sparing surgery was performed in eight patients, and four patients were treated with amputation. Seven patients received chemotherapy and four received radiation therapy. Two patients were treated with both chemotherapy and radiation. Three patients were managed with surgery alone. Of those who received chemotherapy, one of the regimens was unknown as that patient was treated at an outside institution with no available records regarding the specifics of their treatment. The other six patients all had doxorubicinbased chemotherapy regimens. Four patients received therapy only in the adjuvant setting and two received both neo-adjuvant and adjuvant chemotherapy. Of the four patients who were treated with radiation therapy, one was treated pre-operatively with the remaining three
being treated post-operatively. All patients treated with adjuvant radiation therapy were treated with a minimum dose of 5040 centigrey (cGy). There were six unplanned resections prior to referral to our institution. The average tumor volume in patients with an unplanned resection was 367cc, compared to 1154cc in those with no prior unplanned resection (p=0.24). Of the twelve patients, four (33.3%) had metastatic disease on presentation. Five patients without metastases at diagnosis subsequently developed metastatic disease. There were two local recurrences, at an average of 6 months post-operatively. At the time of final analysis, there were three patients living at an average follow up of 29.3 months (range 12 – 64 months). Two of the three living patients received chemotherapy as part of their treatment. All three patients treated with surgery alone died of disease at 2, 9, and 17 months after surgery. In total, nine patients died of disease at an average of 13 months post-operatively. Kaplan-Meier survival analysis demonstrated a median survival of 17 months and a 5-year OS of 11.7% (Figure 2). When evaluating OS stratified by patients who received chemotherapy compared to those who did not, there was no significant difference in survival (Figure 3). 5-year EFS was 10.4% (Figure 4). Among the patients who died, there was a trend towards increased length of survival in patients who received chemotherapy compared to those who did not receive chemotherapy (16.4 months vs. 9.3 months,
100 The Iowa Orthopedic Journal
The Treatment and Outcomes of Extraskeletal Osteosarcoma Table II. Univariate analysis of individual tumor and treatment factors on overall sur vival. Mean Sur vival (mos)
95% CI
p-value
>500cc
13.6
(-4.2, 31.4)
0.47
