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Valgus and varus deformity after wide-local excision, brachytherapy and external beam irradiation in two children with lower extremity synovial cell sarcoma: case report
© Fletcher et al; licensee BioMed Central Ltd. 2004
Received: 14 April 2004
Accepted: 27 August 2004
Published: 27 August 2004
Limb-salvage is a primary objective in the management of extremity soft-tissue sarcoma in adults and children. Wide-local excision combined with radiation therapy is effective in achieving local tumor control with acceptable morbidity and good functional outcomes for most patients.
Two cases of deformity after wide-local excision, brachytherapy and external beam irradiation for lower-extremity synovial cell sarcoma are presented and discussed to highlight contributing factors, time course of radiation effects and orthopedic management. In an effort to spare normal tissues from the long-term effects of radiation therapy, more focal irradiation techniques have been applied to patients with musculoskeletal tumors including brachytherapy and conformal radiation therapy. As illustrated in this report, the use of these techniques results in the asymmetric irradiation of growth plates and contributes to the development of valgus or varus deformity and leg-length discrepancies.
Despite good functional outcomes, progressive deformity in both patients required epiphysiodesis more than 3 years after initial management. There is a dearth of information related to the effects of radiation therapy on the musculoskeletal system in children. Because limb-sparing approaches are to be highlighted in the next generation of cooperative group protocols for children with musculoskeletal tumors, documentation of the effects of surgery and radiation therapy will lead to improved decision making in the selection of the best treatment approach and in the follow-up of these patients.
Limb-salvage is an important treatment objective for adults and children with extremity soft tissue sarcoma and often requires the use of limited surgery and irradiation . Limiting the extent of resection balances the need for radical excision with the need to preserve the functional and structural integrity of the limb and tissues adjacent to those involved with tumor. Radiation therapy has been proven to compensate for incomplete resection or limited resections with involved, close or indeterminate margins as long as the dose and volume are adequate [2–5]. Excellent rates of local control have been achieved for adults and children with extremity soft tissue sarcoma using limb sparing approaches [6–11]. Little is known about the long-term morbidity of the combined effects of limited surgery and irradiation on bone and soft tissue in the pediatric population.
Surgery and radiation therapy both have the potential to cause significant morbidity including loss of function and deformity [6, 11–15]. Tumor resection often requires removal of normal tissue compartments and structural elements, even in a limb-sparing approach. This places the patient at risk for complications including destabilization and abnormalities in growth and function. Additive are the effects of high-dose irradiation, which is often required in the treatment of these tumors, and which may compound the effects of resection. The use of chemotherapy, when indicated, may also add to the combined effects of treatment. The timing of surgery and radiation therapy, the operative approach and the selection of the specific radiation treatment modality often depends on a number of important clinical factors including the size and type of tumor, site of involvement, prior surgical manipulation, extent of resection and the potential for as good functional outcome.
Individual cases of valgus and varus deformity after limited surgery and irradiation for extremity soft-tissue sarcoma are presented and discussed to identify factors that may be responsible for these treatment complications. Pre-existing orthopedic problems, multiple attempts at resection, post-operative infection, the use of chemotherapy and the addition of brachytherapy to external beam radiation therapy appear to be contributory. Because limb-sparing approaches will be an important component of the next generation of cooperative group studies for extremity soft tissue sarcoma in children, the incidence and severity of this and other treatment-related complications should be documented as well as efforts to limit the effects of these treatments and identify solutions for established problems.
A decision was made to initiate chemotherapy three weeks into the course of external beam irradiation based on the perceived high-risk nature of his case – longstanding history of symptoms, known residual tumor and size of tumor at presentation. Chemotherapy included vincristine, ifosfamide, and adriamycin was eventually administered for a total of four cycles. There was central dehiscence of the wound prior to the completion of radiation therapy. The wound was colonized with Enterococci sensitive to ampicillin and managed with antibiotics, whirlpool treatment and daily dressing changes. There was a one-week treatment break during the external beam portion of the treatment.
At the completion of chemotherapy (June 1997) the patient underwent excision of scar tissue with rotation flap of gastrocnemius and skin and Z-plasty of the semi-membranous and semi-tendinous tendon for a non-healing ulcer in the operative region. There was also contracture of the knee joint without signs of abscess or cellulitis. One month later, a second procedure was required to debride and irrigate the left popliteal fossa wound at the site of previously irradiated tissue and contracture release with muscle and fasciocutaneous flap closure. One year after the completion of all therapy (June 1998) the patient reported full range of motion and softening of previously fibrotic tissue. He was actively playing baseball and had no imposed limitations.
Due to its high propensity for local recurrence and metastasis, aggressive treatment of synovial sarcoma is imperative. While many different methods have been used in the treatment of these high-grade tumors, including mono-bloc soft part resection and amputation, the current standard includes local excision and radiation therapy when feasible . Wide local excision with adjuvant radiation therapy is known to achieve a satisfactory rate of local control and good functional outcome [1–15]. Because these tumors commonly arise near tendon sheaths or joint capsules, treatment plans intending to achieve limb conservation may injury the epiphyseal growth plate affecting normal growth and development. Efforts should continue to improve our ability to delineate the tumor, achieve resection with microscopically negative margins and irradiate the region at risk in a manner that minimizes the effect on normal tissues .
Both patients in our study underwent two surgical procedures and were treated with brachytherapy and external beam irradiation. Brachytherapy was used to confine the highest doses to the region at risk and minimize the dose received by normal tissues. The use of brachytherapy shortens the overall treatment time and increases the rate of local control in the setting of involved margins of resection. CT-based treatment planning was used to define the volume of irradiation and to spare normal tissue structures. By reducing the amount of radiation dose delivered to normal tissues, the probability of growth deformity, radio-chemotherapy interactions, and even the hypothetical risk of second tumor formation may be lowered. No effort was made to symmetrically irradiate the physes, which would hypothetically lead to symmetrically diminished growth without the added effect of angular deformity. Because of concerns about the effects of total joint irradiation and its possible effects on functional outcome, the inhomogeneous and asymmetric approach was taken. Despite the valgus and varus deformity experienced by these children and the need for intervention, both children and parents were completely satisfied with their functional outcome and indicated that they would chose the same course of treatment if presented again with the same options.
The rationale for radiation therapy
The importance of achieving local control with aggressive surgery and high-dose irradiation cannot be overemphasized. Local control is crucial to long-term survival and avoiding the morbidity of local tumor progression. Local control, even in the setting of metastatic disease, is an important endpoint. Radiation therapy is highly successful in achieving local control in soft tissue sarcoma and is standard in the care of children with high-grade tumors such as those reviewed in this report. At our institution high-grade tumors with resection margins of 1 cm has an observed local control rate of 72% (5 of 7 patients) in the absence of radiation therapy and 100% (7 of 7 patients) when radiation therapy was given postoperatively. Among 20 unirradiated high-grade tumors that were completely resected with margins > 1 cm only 15 (75%) were locally controlled for an extended period . Our policy is to use external beam irradiation or brachytherapy alone for high-grade tumors that are completely excised, regardless of age or other considerations including anatomic location. We also recommend brachytherapy combined with external-beam irradiation for high-grade tumors with involved, close or indeterminate margins, regardless of size or anatomic location . Low-grade tumors are treated with external-beam radiation therapy or brachytherapy only when the risk of recurrence and re-resection morbidity is high, or at the time of recurrence. These policies apply even to patients with metastatic disease who are likely to survive for an extended period of time after aggressive multimodality therapy including metastasectomy [19, 20]. Exceptions may be considered for small, superficial tumors in very young patients when resection can be performed with adequate margins, generally < 5 mm although prospective studies demonstrating the appropriateness of this approach are limited .
Bone growth and development and the effects of various conditions and treatments
Despite efforts to achieve local control and minimize the effects of treatment on normal tissues, damage to bone and soft tissues may be unavoidable. Synovial cell sarcoma commonly arises near tendon sheaths and joint capsules of adolescents and young adults and may be in close proximity to an epiphyseal growth plate during a time of rapid growth. The situation is made worse if the tumor is located around the distal femur or proximal tibia. Among the four epiphyseal plates in the lower extremity that contribute to the growth of the limb, those around the knee make the most significant contribution, with the distal femur and proximal tibia accounting for 50–90% and 57% of limb growth, respectively depending on age . In our study, Case 1 was eight years old at the time of diagnosis and had a tumor lateral to the joint capsule of the left knee. Case 2 was nine years old at the time of diagnosis and had a tumor lateral to the left distal femur and in close proximity to the joint space. It was less than one year after diagnosis and definitive management that both patients developed a clinically significant angular deformity and leg length discrepancy.
There are two non-congenital mechanisms that are known to interfere with growth of the physis: direct trauma and environmental change around the plate. Trauma includes acute injury to the growth plate in manner that affects all or partial growth and results in premature closure or the formation of a physeal bar. Even if the region has retained its ability to grow it is hampered by solid bone formation across the plate . Environmental change is less common and poorly understood. Roberts  discussed the disturbance of epiphyseal growth in the knee of infants with osteomyelitis and suggested that damage to the epiphysis might be due to an abscess or ischemia following occlusion of the blood supply. Infection is known to produce more severe leg length discrepancy problems than trauma, because the patients are typically younger at onset . Tumors can contribute to leg length discrepancy either by direct invasion or by originating from the cartilage cells of the physis, thereby stealing growth potential from the plate . Vascular malformations adjacent to the physis have been known to both inhibit and stimulate growth [26, 27].
Paralysis is also known to cause of growth inhibition, although the mechanism is poorly understood. Proposed contributors include reduced muscle activity, which indirectly alters the blood supply, and abnormal vasomotor control . Avascular necrosis of the epiphysis can involve the growth plate, which obtains its blood supply from epiphyseal circulation, causing growth inhibition. Peterson described a case in which premature closure of the distal tibial physis occurred in an infant after a temporary but significant episode of vascular insufficiency during surgery to correct developmental dislocation of the right hip .
Rogalski et al.  observed that the proximity of vascular abnormalities to the epiphyseal growth plate was associated with growth disturbance. In his series, 11 out of 41 patients with extremity angiodysplastic lesions developed either hypertrophy or leg length discrepancy. Although vascular malformations have been associated with both undergrowth and overgrowth, all of the patients in this study with leg length discrepancies had overgrowth of the involved limb. These same authors postulated that increased oxygen uptake and increased flow often associated with such vascular malformation contributed to the alteration in growth.
It is also conceivable that repeated surgeries to the lateral aspect of the knee in both patients played a contributive role. A change in the environment surrounding the physis, such as muscle atrophy following prolonged bed rest, paralysis, or limb-sparing surgery with muscle loss, is known to cause a significant slowing of growth . Although efforts were made to keep scarring from surgery to a minimum, re-resection of tumor combined with the damaging effects of radiation to soft tissues would inevitably cause a decrease in tissue vascularity potentially leading to subclinical or clinical necrosis, causing a continual mechanical compression of the physis and retarding growth. Such damage has been documented in heat-related injuries to extremities in which circumferential eschar causes a prolonged ischemia to the physis and subsequent growth inhibition .
The patients included in this report had many of the above noted contributions to abnormal growth and development including a pre-existing condition, vascular compromise due to multiple surgeries, loss of muscle mass, limited use of the extremity for a defined period of time, infection and chemotherapy. Chemotherapy may temporarily reduce bone growth through systemic effects that include the direct effects of specific agents or the indirect effects resulting from systemic infections and abnormalities in metabolism and nutrition.
The effects of irradiation on bone growth
It has been known for almost a century that radiation therapy at sufficient levels can affect growing bone. Several factors contributing to the severity of effect including the total dose, dose per fraction, dosimetry (asymmetry and inhomogeneity) and age at the time of irradiation [24, 30, 31]. Probert and Parker  studied the standing and sitting height of 44 children who underwent total spinal irradiation for Hodgkin's disease, medulloblastoma or acute lymphoblastic leukemia. Among the patients receiving more than 3,500 rads of spinal irradiation, 8 out of 29 (28%) had a sitting height more than 2 standard deviations below the mean for age. Among those receiving less than 2,500 rads, 6 out of 15 (40%) had a sitting height more than 2 standard deviations below the mean for age. They concluded that doses in excess of 2,000 rads affect vertebral body growth in children. They further noted that children less than six years of age or those undergoing puberty experienced the most significant damage, suggesting that there is an increased sensitivity of bone to irradiation during specific developmental periods.
The conclusions of Gonzalez and Breur  were slightly different. In their study, that included 22 patients who experienced growth retardation of long bones as the result of radiotherapy in childhood, definitive limb shortening was strongly dependent on the age of the patient when the irradiation treatment began. When the growth remaining after irradiation was taken into account, no differences in radioresponsiveness were apparent. Their results suggested that despite, a temporary decrease in growth rate, irradiated bone will eventually grow at a similar rate to unirradiated bone. The total dose administered had a major influence on limb shortening as higher doses produced a greater effect. The authors noted that a "saturation dose" was apparent at 40 Gy because higher doses did not appear to produce further considerable increase in shortening.
The epiphyseal growth plate is the area of the developing skeleton most sensitive to the effect of radiation due in part to its rapidly proliferating stem cell population. Even low doses of radiation have been shown to cause histologic changes including temporary swelling, fragmentation, and degeneration of chondrocytes . When higher doses are given, permanent changes including necrosis and premature closure of the physis become evident. Such was the case in our study, as both patients received a total radiation dose of over 50 Gy regionally and nearly 75 Gy focally, which undoubtedly contributed to the observed leg length discrepancies. Furthermore, the angular deformity can be attributed to the unequal dose distribution across the physis as depicted in Figures 3 and 9.
Orthopedic intervention for valgus deformity
Creating a treatment plan for patients with leg deformities who have undergone radiation therapy with or without chemotherapy can pose a difficult challenge. Because the osteocytes of neighboring bone are also destroyed, it may take years for the bone to revascularize and repopulate with healthy osteocytes . The absence of healthy osteoblasts and precursors make lengthening procedures difficult due to unpredictable healing. Radiation damage to regional soft tissues is also an important consideration when planning a lengthening procedure. For these reasons, we decided to delay intervention to correct both the angular deformity and leg length discrepancy, and try to minimize further progression of leg deformity. At the time of surgery, Case 1 had a leg length discrepancy measuring 6 cm clinically. It was felt that epiphysiodesis of the growth plates in the healthy right knee should be the initial treatment, as it would halt progression of discrepancy and allow for some degree of correction, albeit unpredictable because of radiation damage to the growth plates of the left knee. Because of significant angular deformity, case 2 required an osteotomy to correct the defect. Future procedures are planned to address the anticipated leg length inequalities.
Historically, there have been two primary treatments for patients with angular limb deformities: epiphysiodesis and stapling. Both methods seek to achieve the same result while offering different sets of advantages and disadvantages. Partial epiphysiodesis of the knee to correct angular deformity was first described by Phemister in 1933 . It has been used for the correction of idiopathic genu valgum or varum in the adolescent patient. Bowen  described a common surgical technique in which a bone block, centered on the physeal line, was removed through a 2 cm incision, rotated 90 degrees, and reset. This procedure causes growth arrest on the treated side and allows for continued growth and self-correction on the opposite side. Advantages to partial epiphysiodesis include a good assessment of further growth using the Green and Anderson technique , small surgical scar and high predictability of self-correction due to permanent physeal ablation. Disadvantages involve its confinement for use in adolescents due to the irreversibility of the physeal ablation. Also, estimation of skeletal maturity is difficult and unreliable. Physeal stapling, an alternative method, was first reported by Blount and Clark in 1949. They used stainless steel staples to produce reversible growth retardation and it remains the only reversible means of manipulating growth. This procedure has traditionally been used for adolescents .
Newer radiation delivery techniques including high-dose rate brachytherapy, intraoperative radiation therapy [39, 40] and the spectrum of conformal external beam radiation therapy planning and delivery techniques  seek to confine the prescription dose to the region at risk and minimize the dose received by normal tissues. Computerized treatment planning technology and the use of 3-dimensional imaging permits the delineation of both target and normal tissue structures to the extent that the dosimetry for a defined normal tissue structure, such as bone or soft tissue, may be known with a high degree of precision. This information can be used relatively to compare different treatment plans for a given patient. Prospectively assessed, this information may be used as a clinical variable to correlate treatment dosimetry to abnormalities in growth and development including their time to onset and severity . Until more complete knowledge is available regarding the effects of 3-dimensional dosimetry on bone and soft tissue, the full benefit of these newer treatment techniques will not be realized. We are concerned about the effects of newer treatment technology and the use of more focal irradiation. More focal treatment is likely to result in inhomogeneity and asymmetric irradiation of growth elements in bone. Prospective assessment of the use of these techniques is required.
Limited surgery and irradiation may result in growth abnormalities and deformity. These effects may have minimal or significant impact depending on functional outcome and the value attached to limb preservation for a particular patient. As mentioned in this report, both patients and families were queried about their decisions regarding treatment and both reported satisfaction with outcome recognizing that side effects were anticipated. Both families attached a high value to limb preservation.
Supported in part the American Lebanese Syrian Associated Charities (ALSAC)
The authors would like to thank Ms. Barbara Outlaw for secretarial assistance in the manuscript preparation.
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