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Periosteal Margin in Soft-Tissue Sarcoma Patrick P. Lin, MD1 Eduardo Diaz Pino, MD1 Anne N. Normand, MD1 Michael T. Deavers, MD2 Christopher P. Cannon, MD1 Matthew T. Ballo, MD3 Peter W. T. Pisters, MD4 Raphael E. Pollock, MD, PhD4 Valerae O. Lewis, MD1 Gunar K. Zagars, MD3 Alan W. Yasko, MBA, MD1
a single institution between 1990 and 2004. All patients had high-grade, T2
1
Section of Orthopaedic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
50 cases (6%). Local recurrence in the soft tissues developed in 8 of 50 (16%)
2
bone contact in 1 of 8 cases. There was no statistically significant difference in local recurrence between patients who had composite bone resection and
BACKGROUND. Soft-tissue sarcomas frequently rest in contact with bone. The purpose of the study was to evaluate the risk of local recurrence for sarcomas adjacent to bone and to determine whether the periosteum provides an adequate margin of resection.
METHODS. Fifty patients with soft-tissue sarcomas abutting bone were treated at (>5 cm), nonmetastatic disease in the lower extremity. Bone contact was verified by preoperative magnetic resonance imaging (MRI) and/or computed tomography (CT) scans. Forty-three of 50 patients received preoperative radiation with a mean dose of 50 Gy. In 11 cases a composite resection of bone and soft tissue was performed. In 39 cases the excision involved only soft tissue.
RESULTS. True bone invasion was verified by histopathologic examination in 3 of
Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas. 3 Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas. 4 Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
patients. In no case did the recurrence involve destruction of cortical bone or erosion into bone. The recurrent tumor resided against the region of previous
patients who had soft-tissue resection only (P ¼ .87).
CONCLUSIONS. Relatively few sarcomas are able to penetrate cortical bone. Composite bone and soft-tissue resections are indicated primarily for frank bone invasion. In the absence of this, the periosteum is an adequate surgical margin for sarcomas treated with wide excision and radiation. Cancer 2007;109:598–602. 2006 American Cancer Society.
KEYWORDS: sarcoma, bone, periosteum, surgical margins.
I
Address for reprints: Patrick P. Lin, MD, University of Texas M. D. Anderson Cancer Center, Department of Orthopaedic Oncology, Unit 408, PO Box 301402, Houston, TX 77230; Fax: (713) 792-8448; E-mail:
[email protected] Received September 19, 2006; revision received October 30, 2006; accepted October 31, 2006.
ª 2006 American Cancer Society
t is a well-accepted tenet that wide surgical margins are necessary for the treatment of soft-tissue sarcomas.1,2 Despite advances in radiotherapy, surgery, and chemotherapy, the risk of local recurrence remains an important problem, particularly for large T2 (>5 cm), high-grade, deep tumors.3–5 It is still true that the rate of recurrence depends on the adequacy of the surgical margins.6 Sarcomas that rest directly against bone pose a dilemma for the surgeon.7 A wide margin is not possible in the literal sense without excision of the bone. Whereas reconstruction of skeletal defects is possible, it adds to the complexity of the surgery and increases potential complications. The function of limbs may be worse when major reconstructive surgery for large bone defects is attempted in the setting of high-dose radiation. These considerations lead one to ask whether excision of bone is necessary from an oncological standpoint. Relatively little attention has been paid to the periosteal margin in soft-tissue sarcomas. Whereas many surgeons consider the periosteum to be a resistant barrier to the growth of sarcomas, few studies have tried to quantify the rate of recurrence in bone and soft
DOI 10.1002/cncr.22429 Published online 20 December 2006 in Wiley InterScience (www.interscience.wiley.com).
Periosteal Margin in Soft-Tissue Sarcoma/Lin et al.
tissue after subperiosteal stripping of tumors. Recent work has shown that the prevalence of bone invasion is less than 10%.8 Tumors that invade bone may be associated with a worse prognosis.8,9 It is not clear, however, from these data what the exact indications are for combined bone and soft-tissue resection. The purpose of this study was to determine the risk of local recurrence for soft-tissue sarcomas adjacent to bone and to determine whether the periosteum forms an acceptable margin of resection.
MATERIALS AND METHODS Between 1990 and 2004, 50 patients were treated at 1 institution for a high-grade, soft-tissue sarcoma that resided directly against bone. In 11 cases a composite resection of bone and soft tissue was performed. In the remaining 39 cases the surgical excision involved only soft tissue. All patients had localized, nonmetastatic disease at the time of diagnosis. The primary tumors were all greater than 5 cm in largest dimension, and all were located in the thigh or calf. All patients were treated with limb-sparing surgery. A retrospective review was performed after approval of the study by the Institutional Review Board. Patients were identified by querying and cross-referencing several institutional databases, including the Sarcoma Database, the Orthopaedic Oncology Database, and the Radiation Oncology Database. Information regarding patient demographics, tumor size, location, treatment, recurrence, and survival were obtained from review of medical records and imaging studies. All patients had sarcomas that were in contact with bone. This was verified by review of transaxial images from computed tomography (CT) and/or magnetic resonance imaging (MRI) scans. Bone contact was defined as the absence of normal tissue between the tumor and bone. The site of bone contact was categorized as diaphyseal, metaphyseal, epiphyseal, or a combination of these areas. The length of contact was measured. The percent contact of the overall circumference was also measured at the site of greatest contact. Histologic subtypes included malignant fibrous histiocytoma (15 cases), myxoid liposarcoma (12), synovial sarcoma (8), unclassified sarcoma (6), pleomorphic liposarcoma (2), dedifferentiated liposarcoma (2), fibrosarcoma (2), primitive neuroectodermal tumor (1), extraskeletal osteosarcoma (1), and epithelioid sarcoma (1). Tumors were designated as unclassified if they did not fulfill the strict histopathologic criteria for more specific subtypes of soft-tissue sarcomas.
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In general, the unclassified tumors were high-grade, poorly differentiated tumors. The mean size of the tumor was 13.4 cm (range, 5.5–34 cm). The bone affected included the femur (30 cases), the tibia (10), the fibula (4), and both the tibia and fibula (6). The mean dose of radiation was 51 Gy. In all, 43 patients received preoperative external beam radiation and 3 patients received postoperative external beam radiation. One patient received brachytherapy. One patient did not receive postoperative radiation because of major wound complications. Two patients refused radiation. Thirty-four patients were treated with chemotherapy before surgery. The chemotherapy consisted of doxorubicin and ifosfamide, generally for 6 cycles before preoperative radiation and surgery. Statistical analysis was performed with the aid of the SPSS 11.0 (Chicago, IL) program. Local recurrence-free survival (LRFS) and overall survival (OS) were determined by Kaplan-Meier survivorship analysis. The effect of categorical variables on LRFS and OS was determined by the log-rank test. The relation between the means of continuous variables and local recurrence rate was assessed by analysis of variance (ANOVA). Statistical significance was defined as P < .05.
RESULTS The study included 21 females and 29 males. The mean age was 56 years (range, 15–90 years). The minimum follow-up was 2 years unless the patient died as a result of the disease before 2 years. The mean follow-up was 41 months (range, 7–157 months). The differences in patient demographics between patients who underwent resection of bone and patients who did not have resection of bone are shown in Table 1. There were 3 (6%) cases of true bone invasion, as verified pathologically on review of the resection specimen. The histological diagnoses were synovial sarcoma (1 case) and unclassified poorly differentiated sarcoma (2 cases). In 2 cases of bone invasion the preoperative MRI scan correctly demonstrated frank invasion into the cortex and medullary canal. In 1 case the bone invasion was equivocal on MRI scan and subsequently proven on microscopic examination of the decalcified cortical bone. In 8 cases where a composite resection of bone and soft tissue was performed, no invasion into bone was identified by the pathologist. Eight (16%) patients developed local recurrence. The effect of categorical variables on local recurrence was assessed by Kaplan-Meier survivorship and the log-rank test for LRFS (Table 2). There was no statistical
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TABLE 1 Demographics Variable
Bone resection
No bone resection
N Sex Men Women Age, y Mean Range Size of tumor, cm Mean Range Follow-up, mo Mean Range Histology Liposarcoma, myxoid MFH Synovial sarcoma Liposarcoma, other Other
11
39
5 6
24 15
51 23–90
54 15–81
12 6–34
14 6–25
52 7–157
44 6–145
1 5 3 0 2
11 10 5 3 10
MFH indicates malignant fibrous histiocytoma.
FIGURE 1. Kaplan-Meier analysis of local recurrence-free survival (LRFS) showed no significant difference between patients who underwent bone resec-
TABLE 2 Univariate Analysis of LRFS
tion and patients who had excision of soft tissue only. For bone resection, the LRFS at 1 and 5 years was 82% and 82%, respectively. For no bone resection,
Variable
Group
LRFS at 5 y
P
Site of bone contact
Diaphyseal only Diaphyseal þ metaphyseal Women Men Positive Negative Yes No Yes No
0.86 0.65 0.90 0.69 0.61 0.86 0.83 0.72 0.82 0.77
.004
Sex Margin Chemotherapy Bone resected
the LRFS at 1 and 5 years was 92% and 76%, respectively (P ¼ .85).
.24
TABLE 3 Effect of Continuous Variables on Local Recurrence
.35
Variable
Group
Mean value
P
.61
Size of tumor Length bone contact
16.1 cm 13.4 cm 9.4 cm 9.8 cm 36% 37% 48 y 54 y
.24
.85
Recurrent Nonrecurrent Recurrent Nonrecurrent Recurrent Nonrecurrent Recurrent Nonrecurrent
Circumference bone contact LRFS indicates local recurrence-free survival.
Age
difference in LRFS between patients who underwent bone resection and patients who did not have bone resection (Fig. 1; P ¼ .85). Gender, positive inked margin, and chemotherapy also did not affect LRFS. The site of bone contact did demonstrate a statistical effect on LRFS. Location of the tumor on metaphyseal bone was more likely to be associated with local recurrence (P ¼ .004). The effect of continuous variables on local recurrence was determined by ANOVA (Table 3). The mean values for size of tumor, length of bone contact, percent circumference of bone contact, and age were not statistically different for cases that
.80 .87 .68
developed recurrence and cases that did not develop recurrence. The area of local recurrence was examined to determine whether the site of bone contact may have had some relation to the recurrence. In no case did the recurrence involve destruction of cortical bone or erosion into bone. The recurrent tumor resided against bone in the vicinity of previous bone contact in 1 of 8 recurrent cases. The OS for the entire cohort was 71% at 5 years and 59% at 10 years by Kaplan-Meier survivorship (Fig. 2). There was no statistical difference in OS between
Periosteal Margin in Soft-Tissue Sarcoma/Lin et al.
FIGURE 2. Kaplan-Meier analysis demonstrated overall survival of 91% and 74% at 1 and 5 years, respectively, for the entire cohort of 50 patients.
patients who underwent bone resection and patients who did not undergo bone resection (P ¼ .62). Patients who developed local recurrence had statistically worse OS (P ¼ .009).
DISCUSSION The results of this study confirm the clinical impression that the periosteal margin is an adequate margin for high-grade, soft-tissue sarcomas in contact with bone. Although the margin may be very thin or even focally positive, the risk of recurrence at the bone interface does not appear to be substantial. There were no recurrences in dense cortical bone, which appears to be an unfavorable environment for the growth of soft-tissue sarcomas. The lack of correlation between a positive margin at the periosteal margin and local recurrence is consistent with the results reported by Gerrand et al.10 The sample size in this study (50) is relatively small, and this limits the statistical power of the study. However, it is emphasized that the cases were selected from a much larger group of sarcomas treated at this institution. We deliberately chose to include only high-grade tumors greater than 5 cm in size. The inclusion of low-grade lesions and small T1 lesions would be likely to decrease the perceived risk
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of local recurrence, and we did not want to underestimate the rate of local recurrence for high-grade tumors with substantial areas of bone contact. The possibility does exist that local recurrence in the soft tissue may arise from microscopic residual disease on cortical bone. At most this would have accounted for 1 local recurrence (2%) in this series. It is impossible to prove or disprove whether this actually occurred. Even assuming it to be true, it would not justify resecting the bone on a routine basis. Reconstruction of a major skeletal defect in an irradiated wound may incur significant added risks of wound dehiscence, osteomyelitis, implant failure, compromised function, and loss of limb. The selection of cases for composite bone and soft-tissue resection merits careful consideration and thought. When the tumor invades bone on preoperative MRI scans and other imaging studies, a combined resection of bone and soft tissue is clearly indicated. Our results suggest that this occurs in fewer than 10% of cases where the tumor abuts bone. In the remaining cases, the tumor may be applied directly against bone, but does not penetrate the cortical bone. Such cases are generally amenable to resection of soft tissue only with the periosteum as the deep margin. Both MRI and CT scans are useful for assessing the invasion of bone by sarcomas.11,12 The metaphyseal bone poses a more difficult area to interpret on MRI and CT scans than the diaphyseal bone, which has a thicker and better-defined cortex. The thin cortex of the metaphysis may make it very difficult to determine whether the tumor has eroded into the medullary canal. Other areas that have been noted to be difficult to interpret include tendinous insertions in bone and the linea aspera of the femur.13 When there is equivocal penetration into bone, especially in the metaphyseal region, surgeons have sometimes elected to resect a portion of the bone with the tumor. Whereas this seems reasonable, the results of the present study suggest that the rate at which the tumor actually invaded bone was low (1 of 9 cases without obvious cortical penetration). Histologic examination of composite resections showed that in most cases the tumor respected the bone boundary. The results of recent studies suggest that there may be a worse prognosis for patients whose tumors invade bone.8,14 The number of patients in the current study with bone invasion does not permit a critical analysis of the hypothesis. Of the 3 patients with bone invasion, 1 patient is continuously free of disease at 5 years, 1 patient is alive with metastatic disease, and 1 patient died of unrelated causes. It should be
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stressed that the current study involves only patients with nonmetastatic disease at the time of presentation. We have observed a greater proportion of cases with bone invasion in patients who present with metastatic disease (unpubl. data). It therefore seems quite plausible that tumors that have acquired increased invasiveness may be more aggressive and apt to spread. A statistically higher rate of local recurrence was observed for tumors adjacent to metaphyseal bone as opposed to diaphyseal bone. The cause for this is not altogether certain. It is possible that the soft-tissue margins are generally thinner in the metaphyseal region, particularly around the knee, where the muscle mass is thinner, and the tumors are more likely to reside adjacent to nerves or major vessels. In conclusion, invasion of bone by soft-tissue sarcomas is an uncommon phenomenon. In most cases the preoperative MRI or CT scan is capable of demonstrating the erosion into bone. Composite bone and soft-tissue resections are indicated primarily for frank bone invasion by tumor. In the absence of overt bone invasion, the periosteum is an adequate surgical margin for high-grade, nonmetastatic soft-tissue sarcomas that are treated with wide surgical excision and radiation.
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