Surgical Management of Sarcomas in Skeletally Immature Patients

Joel L. Mayerson, MD, FAAOS, FAOA

Ryan T. Voskuil, MD, FAAOS

Ernest U. Conrad III, MD, FAAOS, FACS

Dr. Mayerson or an immediate family member serves as a paid consultant to or is an employee of ONKOS Surgical and serves as a board member, owner, officer, or committee member of American Academy of Orthopaedic Surgeons and National Comprehensive Cancer Network. Dr. Conrad or an immediate family member serves as a board member, owner, officer, or committee member of Sarcoma Alliance for Research and Collaboration. Neither Dr. Voskuil nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

ABSTRACT

Although limb salvage surgery for pediatric osseous malignancies represents only 20% of all similar procedures in adults, the significance of those procedures is magnified by the longevity and nature of children and their strong desire to be physically active. The different types of resections required to treat primary pediatric bone malignancies are defined by the age and growth potential of the child, the location and size of the tumor, and their response to preoperative chemotherapy. The reconstruction options following resection of pediatric osseous tumors depend on the age and activity goals of the patient as well as the personality of the patient and their parents. The treating surgeon’s responsibility is to offer an accurate description and summary of that patient’s surgical treatment options, the associated surgical risks, and the expected duration of their recovery. Because of the complexity of variables associated with management options for pediatric malignant bone tumors, accurate and appropriate communication about the challenges associated with each care decision is extremely important. Optimal patient and family satisfaction depend on an open and honest discussion about all major surgical treatment options in this challenging patient population.

INTRODUCTION

The immature skeleton adds a unique challenge to oncologic surgical interventions. The resection of pediatric bone sarcomas requires significant accommodations for skeletal growth and consideration of long life expectancy and high activity expectations that clearly exceed the expectations of the typical adult limb salvage patient. Surgeons should also be aware of the expectations that parents have for their children’s treatment, which may vary significantly from family to family. Approximately two-thirds of lower extremity growth occurs at the knee, where most primary bone malignancies occur. The onset of puberty (10 to 18 years of age) is a critical milestone signaling the beginning of the last skeletal growth phase, especially in females
in whom skeletal growth is more predictable and occurs earlier than that with males. Ten-year-old children have significant remaining skeletal growth, especially in the distal femur. The resultant potential leg-length discrepancy affects both girls and boys. Making surgical decisions for pediatric patients younger than 12 years is therefore more challenging than for older patients affected by a diagnosis of osteosarcoma or Ewing sarcoma. Postoperative growth issues make surgical decisions for pediatric patients younger than 12 years with osteosarcoma or Ewing sarcoma more challenging than for older children. In addition, the clinical results for pediatric limb salvage in children younger than 10 to 12 years include a relatively high incidence of failure and revision surgery. Careful surgical decisions regarding this younger pediatric age group are necessary because of the heightened risk of complications. The surgeon must also carefully consider the personality and activity expectations of the child. Children who are highly physically active and participate in sports activities may have a difficult time adhering to the necessary limitations associated with a successful prosthetic reconstruction.

PATTERNS OF GROWTH AND EFFECTS OF CHEMOTHERAPY AND RADIATION THERAPY WITH PEDIATRIC LIMB SALVAGE

The disruptive or harmful effects of current pediatric chemotherapy on a normal physis, as seen with current pediatric bone sarcoma protocols, are typically transient and limited. The same cannot be said for radiation therapy, which typically has a partial or near-complete disruption of normal physeal growth with the current standard doses used for pediatric Ewing sarcoma. The success of current preoperative neoadjuvant chemotherapy in producing tumor necrosis and subsequent improvements in MRI and positron emission tomography (PET) tumor imaging have improved the ability to more accurately assess tumor margins adjacent to the immature physis.¹ Tumor necrosis secondary to preoperative chemotherapy and/or radiation therapy can allow closer surgical margins and the sparing of the adjacent physis, with a minimal increased risk of local recurrence. Guidelines for adequate surgical margins in pediatric osteosarcoma and Ewing sarcoma remain controversial but improved compared with the original surgical margin guidelines published previously.²

Assessing and planning adequate osseous tumor resection margins by reviewing serial preoperative MRI, CT, and PET after neoadjuvant chemotherapy represents the most important and challenging surgical decision that must be made for pediatric patients undergoing limb salvage, especially for younger patients, who are at risk for greater growth disturbances. The limb salvage goals of local tumor control and a good functional and durable limb salvage procedure can be a difficult decision for the surgeon and the patient’s family, given the paucity of published pediatric data for this relatively small cohort of patients representing fewer than 10% to 15% of all limb salvage patients.

Physeal Biology and Predicting Physeal Growth

Pressure epiphyses, or normal epiphyseal plate physes, account for vertical extremity height in most instances and are found near major joints. Traction epiphyses, such as the greater trochanter and the tibial apophysis, do not involve the joint and serve as major muscle insertion points. The epiphyseal plate is composed of chondrocytes in various stages of differentiation with the result of skeletal growth by enchondral ossification.³ This region is composed of three zones: the resting, proliferative, and hypertrophic zones. In the resting or reserve zone, chondrocytes rarely divide, and nutrients are stored. In the proliferative zone, chondrocytes rapidly divide and arrange themselves vertically in columns. In the hypertrophic zone, chondrocytes enlarge and proceed to proliferate. Because of its increased cellular division, the proliferative zone is at a greater risk of being affected by adjuvant chemotherapy and radiation therapy.⁴^,⁵ Regulation via feedback loops of parathyroid hormone-related protein, which in turn regulates Indian hedgehog (IHH), is responsible for chondrocyte proliferation and maturation and the rate at which this process occurs.⁶ Vascular endothelial growth factor is found in hypertrophic chondrocytes and assists with chondrocyte apoptosis, angiogenesis, and subsequent ossification. Chondrocytes undergoing apoptosis express transforming growth factor beta, which regulates the hypertrophic zone and maintains physis height during growth. Researchers have suggested that following an epiphyseal plate injury, an inflammatory phase is initiated, and epiphyseal plate cells differentiate toward hypertrophy. If disruption of the epiphyseal plate circulation or bone bridge formation occurs via trauma or surgical intervention, angular growth deformities or limb-length discrepancies can result.⁷ Multiple methods of predicting limb-length discrepancy at skeletal maturity have been developed for use in pediatric orthopaedics and include the arithmetic method, the growth-remaining method, the Paley multiplier method, and the straight-line graph method.

Arithmetic Method

The arithmetic method is the simplest method for calculation of limb-length discrepancy because it does not require any special charts or graphs. It uses the child’s chronologic age and assumes that boys reach skeletal maturity at the age of 16 years and girls reach skeletal maturity at the age of 14 years. The method also operates on the assumption that the distal femoral physis grows
at a rate of 10 mm/yr, the proximal tibia at 6 mm/yr, and the proximal femur and distal tibia at 4 mm/yr.⁸^,⁹ The arithmetic method is the preferred method of most oncologic surgeons because of its simplicity, but it is less accurate for children who are not in their last few years of growth.¹⁰

Growth-Remaining Method

The growth-remaining method relies on extensive longitudinal data collected in the earlier half of the 20th century. Benefits of this method include the use of skeletal (as opposed to chronologic) age and the ability to factor growth percentile into the prediction, but it does require the use of specific charts.⁹^,¹¹

Paley Multiplier Method

The Paley multiplier method was developed using the data from the charts used for the growth-remaining method, but rather than requiring the use of the actual charts, it is based on a table of multipliers and can use as few as one data point to predict discrepancy. For example, a 4-year-old boy has reached 50% of adult leg length; therefore, the multiplier would be 2.¹² The Paley multiplier method is recommended for limb salvage patients younger than 10 years because of the need for more accurate future growth predictions.

Straight-Line Graph Method

The straight-line graph method uses the data from the growth-remaining method in a complex system of graphs and charts. Benefits of the system include the use of skeletal age and growth percentiles, but the accuracy of the system is reliant on multiple data points.¹³ Incorporation of this method into computer programs has greatly improved the method’s ease of use.

Limitations of the Limb-Length Discrepancy Prediction Methods

Applying any of the four main limb-length discrepancy prediction methods is challenging for patients undergoing limb salvage surgery for sarcoma. None of the four methods account for the effects of chemotherapy, radiation therapy, or decreased nutrition, all of which can affect children undergoing sarcoma treatment. Each of these factors can affect not only the rate of growth in the physes but also the age of skeletal maturity. Furthermore, three of the four methods are largely based on data collected from children in the Boston area in the 1940s and may not accurately reflect current growth rates of children in various parts of the world³^,⁹ (Tables 1 and 2).

Table 1 Comparative Femoral Growth by Sex and Age

	Girls						Boys
Age (yr)	6	8	10	12	14	16	6	8	10	12	14	16
Femoral length (cm)	28.5	32.7	36.7	40.7	43.1	43.6	28.1	32.3	36.3	40.1	44.2	46.7
Growth (cm)^a	15.1	10.9	6.9	2.9	0.5	—	19.2	15.0	11.0	7.2	3.1	0.6
Growth (%)^a	34.6	25.0	15.8	6.7	1.2	—	40.6	38.7	23.3	15.2	6.6	1.3
^aCompares difference with femoral length at 16 years of age for girls and 18 years of age for boys.

Table 2 Predicted Leg-Length Discrepancy—Arithmetic Method^a

	Girls							Boys
Age (yr)	6	8	10	12	14	16	18	6	8	10	12	14	16	18
Distal femur growth remaining (cm)	8.0	6.0	4.0	2.0	0.5	—	—	10.0	8.0	6.0	4.0	2.0	—	—
Proximal tibia growth remaining (cm)	4.0	3.0	2.0	1.0	—	—	—	5.0	4.0	3.0	2.0	1.0	—	—
Total growth remaining (cm)	12.0	9.0	6.0	3.0	0.5	—	—	15.0	12.0	9.0	6.0	3.0	—	—
Femur length (cm)	28.5	32.7	36.7	40.7	43.1	43.6	43.6	28.1	32.3	36.3	40.1	44.2	46.7	47.3
^aAssumes distal femur growth of 1.0 cm/yr and proximal tibia growth of 0.5 cm/yr; assumes growth ends at 14 years of age for girls and 16 years of age for boys.

Effects of Chemotherapy on the Pediatric Physis

The effects of chemotherapy on the growing immature physis have been well documented in multiple studies demonstrating the negative transient effect of doxorubicin, methotrexate, and most of the other agents associated with current neoadjuvant protocols for sarcoma therapy in children. These agents typically affect chondrocytic proliferation in the proliferative zone. Although the effects may be transient, they are relatively immediate and are associated with decreased bone formation and an increased risk of fracture and other significant secondary bone effects.⁵^,¹⁴ Epiphyseal plate proliferation is affected by the direct effect of chemotherapy agents on the chondrocyte proliferation and by the depressive effects of chemotherapy and malnutrition on different regulatory pathways involving growth hormone-releasing hormone, insulinlike growth factor 1, vitamin D, and alkaline phosphatase.¹⁴ The authors of one study¹⁵ examined distal femur epiphyseal plates of patients treated for osteosarcoma with neoadjuvant chemotherapy. They found histologic evidence to support the presence of partial growth arrest but confirmed that bone growth can resume after chemotherapy has ceased. Because current chemotherapy protocols for osteosarcoma and Ewing sarcoma involve chemotherapy agents that inhibit proliferating chondrocytes and reduce growth, better studies to assess the effects of chemotherapy and specific regimens are advised.¹⁶^,¹⁷

Effects of Radiation Therapy on the Physis

The effects of radiation therapy at dosages given for osseous sarcoma may lead to a partial, if not complete, physeal compromise. These effects can occur even after moderate irradiation doses (20 Gy) in younger children and require longer follow-up and continuing assessments.¹⁸ Radiation therapy is much more commonly used for pediatric Ewing sarcoma and soft-tissue sarcomas than for osteosarcoma. The effects of radiation therapy on the epiphyseal plate have been well studied and include rapid and significant effects on the physis that are likely to be permanent, especially in younger children. Decreased skeletal growth is more evident when irradiation is used on patients younger than 10 years and is dose dependent.¹⁸^,¹⁹ Radiation therapy causes hypovascularity and cytotoxic effects in the chondrocyte population through downregulation. Cellular apoptosis increases, leading to decreased skeletal growth.¹⁸^,¹⁹ Radiation therapy to the axial skeleton appears to have an even greater effect on the spine and cranial axis growth. Postoperative wound healing is delayed by preoperative radiation therapy, which has a well-established risk of wound complications in 20% to 30% of adolescent and adult patients.²⁰ The positive results from limiting radiation dosimetry, field size, and using alternative radiation modalities has succeeded in minimizing the damaging effects of radiation therapy for many adults and children over the past decade.²¹

Studies of radioprotectors involve mostly animal models, with limited preclinical work on patients. Amifostine and other radioprotectors (selenium, misoprostol) have shown protective effects on chondrocytic proliferation and subsequent longitudinal growth in animal models but are not currently in clinical use for pediatric sarcoma therapy.

LIMB SALVAGE SURGERY

Surgical Indications, Complications, Preoperative Assessment, and Obtaining Consent

Understanding limb salvage in children requires an understanding of the different types of resections and reconstructions and the different pediatric age groups. Significant growth potential affects decision making in young children. For example, 10-year-old children have 10% to 20% of their overall skeletal growth and 15% to 25% of their femoral growth remaining (Figure 1). The decision to perform osseous limb salvage in a child typically involves two different types of resections and four different types of reconstructions in three different patient age groups. One type of resection is an osteoarticular (or osteochondral) resection, which involves the resection of a tumor near the joint and may or may not require sacrificing the adjacent physis or the adjacent joint, sometimes referred to as a physeal-sparing or condyle-sparing resection (Figure 2). The second type of pediatric resection is a diaphyseal (or intercalary) resection and involves resecting a portion of the femoral or tibial shaft or diaphysis without involvement of the joint or physis. Intercalary or diaphyseal resections should have a lower incidence of significant physeal growth disturbances. The type of resection is dictated by the location of the tumor and its responsiveness to neoadjuvant therapy.

FIGURE 1 Illustration showing physeal growth and maturation.

(Adapted with permission from Conrad EU: Orthopaedic Oncology: Diagnosis and Treatment. Thieme, 2009. Data from Rathjen KE, Birch JG: Physeal injuries and growth disturbances, in Beaty JH, Kasser JR, eds: Rockwood and Wilkins’ Fractures in Children, ed 6. Lippincott Williams & Wilkins, 2006, pp 99-104 and Anderson M, Messner MB, Green WT: Distribution of lengths of the normal femur and tibia in children from one to eighteen years. J Bone Joint Surg Am 1964;46:1197-1202.)

FIGURE 2 Illustration showing pediatric femoral resection and reconstructive limb salvage options.

(Courtesy of Ernest U. Conrad III, MD, FAAOS, FACS and Ryan J. Warth, MD.)

Resections that sacrifice the physis in children younger than 10 years can be managed with an amputation, a rotationplasty, or a more challenging expandable implant that typically involves a total knee arthroplasty and multiple surgical or nonsurgical lengthening procedures. The higher risk and more challenging reconstructions involve expandable pediatric oncologic total knee implants that are typically lengthened at 3- to 4-month postoperative intervals with either surgical or nonsurgical methods. Achieving skeletal growth with growing implants has been unsatisfactory, with a high incidence of revision surgery (40% to 50%) and limited success with lengthening and function.²²^,²³ Rotationplasty (Figure 3) is an excellent surgical alternative for younger patients, which has gained widespread popularity because of its good function and durability. It is a procedure that can be used in any age group but requires careful patient selection especially in older adolescent patients. A procedure initially described in one study²⁴ for pediatric orthopaedic deformities was later adapted for femoral and tibial tumors and subsequently used for failed limb salvage in patients of any age.²⁵

FIGURE 3 Illustration displaying fundamental biomechanics of rotationplasty.

(Courtesy of R. Lor Randa ll, MD, FAAOS, FACS.)

For patients younger than 10 years, the surgical decisions are more difficult because of a greater potential growth loss, and surgical choices and decisions depend on a patient’s age and sex and the tumor size and location (Figure 2). Remaining growth in the lower extremity for this age group ranges from 2.9 to 6.9 cm for girls and from 7.2 to 11.0 cm for boys.⁸^,⁹ Patients older than 12 years have a lower extremity growth potential of approximately 3.0 cm (5.0%) for girls and approximately 6.0 cm (9.2%) for boys. Girls older than 12 years have a smaller problem with leg-length discrepancy (3 cm) because of their relative skeletal maturity. Older adolescent pediatric patients (older than 12 years) are better candidates for oncologic total knee arthroplasties or occasionally for expandable, growing implants when treatment alternatives such as rotationplasty are refused for cosmetic, body image, or psychosocial concerns. The durability and function of rotationplasty is a positive factor for children who want to play sports, which is contraindicated with many alternative limb salvage procedures.²⁵^,²⁶

Most importantly, pediatric limb salvage patients and their families must understand fully the associated surgical risks, complications, required rehabilitation, and functional expectations of their different surgical treatment options. Important surgical details for families include rehabilitation restrictions and the length of postoperative recovery for full weight bearing to be achieved (ie, walking without crutches), which typically requires 6 to 12 months with allografts and vascularized fibulas, 3 to 4 months for oncologic implants, and 3 to 6 months for a rotationplasty. Two studies,²²^,²³ including one from 2020,²³ reported that the final functional results and durability associated with an oncologic implant, or an allograft reconstruction vary significantly, depending on the type of resection and the type of reconstruction. This detailed surgical information and meeting patient and family expectations is critical to a good long-term clinical result and a happy patient and their family.

Contraindications to limb salvage surgery most commonly include large tumors with excessive soft-tissue involvement with or without diagnostic delay and/or subsequent involvement of the adjacent major neurovascular structures, soft tissue, and skin. For cases in which limb salvage surgery is not possible, amputation should be considered as the preferred treatment option especially for large tumors. Amputations typically avoid the complications of limb salvage and, most significantly, should provide superior local tumor control.²⁷ This was also reported on in 2023.²⁸ Currently, pediatric patients being considered for conventional amputation receive consideration for a rotationplasty amputation. Childhood amputations in patients younger than 12 years may present challenges such as bony overgrowth at the bony residuum, especially in younger children, and may require subsequent revision surgeries or difficult prosthetic fittings. Autogenous epiphyseal metatarsal transplants harvested from the amputated limb, or osteochondral or synthetic caps placed over the residual limb’s medullary canal, have reduced bone overgrowth complications.²⁹

The preoperative consent process for limb salvage in children is more demanding because parents have appropriate high expectations for their children’s health. The consent process involves reviewing every possible complication in detail (Table 3) regarding the length of postoperative recovery and the expectations for growth and physical activity. Parents of limb salvage patients should sign a surgical consent document that lists all surgical complications. In addition, the details of expected leg-length discrepancies and alignment deformity should be carefully reviewed and documented. Evaluation of the child’s parental and social support must be used to help determine whether limb salvage, amputation, or rotationplasty are all appropriate options in the individual circumstance. Embarking on
rotationplasty or extensive limb salvage surgery is fraught with multiple additional challenges without appropriate family support for the child.

Table 3 Limb Salvage Complications

General Complications

Massive surgical blood loss (5%)

Occurs mostly with pelvic, sacral, and proximal femoral resections and can involve life-threatening blood loss in the pelvis in addition to possible bladder, bowel, ureteral, neurovascular, and spinal injuries

Neurovascular injury (5% to 10%)

May be diagnosed intraoperatively versus postoperatively with either immediate repair or delayed repair depending on location and severity

Wound complications (5% to 10%)

Requires incision and drainage, or washout and antibiotics and possible wound/flap revision if skin necrosis is present

Deep wound infection (10%)

Requires washout and/or possible graft or implant removal or spacer and long-term (6 to 12 wk) intravenous antibiotics

Contaminated tumor margins (5% to 10%)

Resection pathology report should be reviewed within 2 to 4 wk postoperatively and discussed with the patient and family and recorded in the medical record regarding pathology final margins, and plan for reresection or amputation versus observation

Tumor local recurrence (5% to 10%)

Typically occurs at 1 to 2 yr postoperatively with patients who have experienced a poor histologic response to preoperative chemotherapy

Arthrofibrosis or joint stiffness (10% to 15%)

May require surgical manipulation, open release of intensive physical therapy, and so on

Chronic pain (5% to 10%)

Variable incidence usually related to poor range of motion, neurovascular injury, or patient tolerance of pain

Leg-length discrepancy or deformity (5% to 10%)

Dependent on patient age and tumor location and type of reconstruction. Correction depends on severity and timing of treatment

Second/revision surgery (20% to 30%)

Dependent on reconstruction type—allograft versus autograft versus oncologic implant versus rotationplasty

Allograft-, Autograft-, and Oncologic Implant-Specific Complications

Allograft/implant late infections (10% to 15%)

May occur with either allograft or implants at 5 to 10 yr requiring major revision/removal with long-term antibiotics and revision surgery

Allograft/autograft nonunion, delayed union, or fracture (10% to 20%)

Requires graft fixation revision, autografting, vascularized fibula, or revision to an oncologic arthroplasty, amputation, or rotationplasty

Oncologic arthroplasty or growing arthroplasty (20% to 30%)

Surgical revisions required for oncologic implant/arthroplasties; revisions for failure to lengthen, aseptic loosening of cemented stems, rotational alignment, stiffness, and other complications

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