Bethesda Handbook of Clinical Oncology, 2nd Edition

Musculoskeletal

21

Sarcomas and Malignancies of the Bone

Patrick J. Mansky*

Lee Helman^†

*National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland

^†Pediatric Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Malignancies of the soft tissue (6.1%) and bones (4.7%) account for more than 10% of newly diagnosed cancers in children, adolescents, and young adults. Fortunately, benign musculoskeletal neoplasms are 100 times more common than malignant soft-tissue tumors. Median age at diagnosis of rhabdomyosarcoma (RMS) is 5 years, with a male preponderance. Osteosarcomas account for approximately 60% of malignant bone tumors in the first two decades of life. Most of the remaining bone malignancies in children and adolescents are Ewing sarcomas and the histologically similar and genetically identical peripheral primitive neuroectodermal tumors (PNETs). Together, these tumors are often called the Ewing family of tumors (EFT). Chondrosarcomas are seen in older adults. Identification of specific, recurrent genetic alterations in RMS and Ewing sarcoma has improved diagnosis by clarifying pathogenesis. Better supportive care and systematic application of effective multimodality treatment have dramatically improved survival during the last 30 years (see Fig. 21.1 and Table 21.1).

FIG. 21.1. Five-year survival rates among children and adolescents with rhabdomyosarcoma, with osteosarcoma, and with Ewing sarcoma. (From Arndt CAS, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999;342:342–352, with permission.)

TABLE 21.1. Outcome of Therapy for Musculoskeletal Tumors of Childhood and Adolescence

Type of tumor Commonly used agents Duration of therapy (mo) Long-term survival (%) Additional treatment The estimated rates of survival at 3–5 years without the need for re-treatment (progression-free or relapse-free survival) are shown. Rhabdomyosarcoma Low-risk group (those with group I or II embryonal tumors at sites with a favorable outcome or group III orbital tumors) Vincristine, dactinomycin 8–12 90–95 Resection of primary tumor for all tumors except orbital tumors; irradiation of group II or III tumors Intermediate-risk group Vincristine, dactinomycin, cyclophosphamide 8–12 70–80 Irradiation of primary tumor and metastases, if present High-risk group [all those with metastases (group IV) except patients younger than 10 years who have embryonal tumors] Vincristine, dactinomycin, and cyclophosphamide; new agents; high-dose therapy with hematopoietic stem-cell transplantation 8–12 20 Irradiation of primary tumor and all metastatic lesions Osteosarcoma Localized to limb Doxorubicin, high-dose methotrexate, ifosfamide, and cisplatin 8–12 58–76 Surgery for control of tumor Metastatic Doxorubicin, methotrexate, ifosfamide, cisplatin 8–12 14–50 Resection of primary tumor and metastases needed for cure Ewing sarcoma Localized Vincristine, doxorubicin, cyclophosphamide, dactinomycin, etoposide-ifosfamide 8–12 50–70 Surgery, radiation therapy, or both for local control of tumor Metastatic Vincristine, doxorubicin, cyclophosphamide, dactinomycin, etoposide-ifosfamide; high-dose therapy with hematopoietic stem-cell transplantation 8–12 19–30 Surgery, radiation therapy, or both for local control of tumor

RHABDOMYOSARCOMA

Clinical Presentation

RMS has been encountered in almost all anatomic sites. It is associated with development of a mass and signs and symptoms typically related to the anatomic location (see Fig. 21.2):

• Orbit:proptosis
• Nasopharynx:nasal discharge and obstruction
• Basal skull and posterior orbit:cranial nerve palsies and visual loss
• Parameninges:headache and meningism
• Genitourinary tract: vaginal polyp and vaginal discharge (vaginal or uterine tumors)
• Bladder or prostate tumor, pelvis:urinary obstruction
• Genital:paratesticular scrotal mass.

FIG. 21.2. Primary sites of rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma. The numbers of patients with primary tumors at specific sites are shown.

Pathophysiology

RMSs are of mesenchymal origin, characterized by myogenic differentiation. They are histologically distinguished into two main forms, embryonal (80%) and alveolar (15% to 20%)

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subtypes, with characteristic genetic differences (see Table 21.2 and Fig. 21.3). Botryoid RMS and spindle cell sarcoma are both morphologic variants of embryonal RMS.

FIG. 21.3. Molecular pathogenetic mechanisms in rhabdomyosarcoma and Ewing sarcoma.

TABLE 21.2. Histologically Distinguished Subtypes of Rhabdomyosarcomas

RMS, rhabdomyosarcomas; DNA, deoxyribonucleic acid. Embryonal RMS · Characteristic loss of heterogenicity (LOH) 11p15.5 (IGH-II gene) · Hyperdiploid DNA Alveolar RMS · Characteristic translocations 1. PAX3/FKHR t(2,13)(q35;q14) 2. PAX7/FKHR t(1;13)(p36;q14) · Tetraploid DNA

An increased risk for the development of RMS has been associated with a number of environmental and genetic factors (see Table 21.3).

TABLE 21.3. Associated Risk Factors for Rhabdomyosarcoma

a Link between rhabdomyosarcoma and risk of breast cancer in a female relative plays an important role in cancer surveillance in at-risk families. Genetic Familial cancer risk Germline mutant p53 Congenital abnormalities Neurofibromatosis type I Li-Fraumeni syndrome Risk of breast cancer in female relativesa Environmental parental habits Smoking Recreational drugs Occupational chemical exposure Fetal alcohol syndrome

Diagnosis

Diagnostic Radiology

A comprehensive staging of evaluation of extent of disease includes the following:

1. Tumor localization

• Computerized tomography (CT) and magnetic resonance imaging (MRI).

2. Assessment of metastatic spread

• CT of chest and lungs
• Technetium bone scan for bone or bone marrow involvement.

Biopsy and Pathologic Diagnosis

Open biopsy is the preferred approach for tissue diagnosis and should be undertaken at an oncology center, where diagnostic material can be optimally used and the initial surgical

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approach can be determined by a multidisciplinary team responsible for the patient's subsequent treatment. Needle biopsy may restrict access to fresh and frozen tissue for cytogenetic and molecular genetic investigations.

1. Tumor characterization

• Histopathology
• Immunohistochemistry: desmin and myoD1
• Genetic characterization of tumor
• Reverse transcriptase-polymerase chain reaction (RT-PCR) for presence of PAX/FKHR translocation
• Cytogenetics.

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2. Metastatic spread

• Cerebrospinal fluid polymerase chain reaction (CSF PCR) for PAX/FKHR translocation
• Bone marrow aspirate cytology
• Bone marrow biopsy for histochemistry and PCR.

Treatment Strategies Overview

The diversity of primary sites, the distinctive surgical and radiation therapies for each primary site, the subsequent site-specific rehabilitation, and the potential treatment-related sequelae underscore the importance of treating children and young adults with RMS in the context of a clinical trial at a major medical center with appropriate experience in all therapeutic modalities (see Table 21.4).

TABLE 21.4. Treatment Options, Local Control, and Potential Toxicity in Rhabdomyosarcoma

Treatments Local control Sequelae Sterility Kidneys On growth Esthetics VA, vincristine–actinomycin D; C, cyclophosphamide; V, vincristine; IVA, ifosfamide–vincristine–actinomycin D; VAC, vincristine–actinomycin D–cyclophosphamide; CR, complete remission. ++, Yes; ±, possibly; -, No. 1. Orbit Radical surgery then VA ± C ++ – – ± ± Biopsy then radiation + V ± C ++ ± – ++ ++ Biopsy then IVA/VAC ± ± ± – – No complete remission: Radical surgery — — — ++ ++ or Radiotherapy — — — ++ ++ 2. Paratesticular Surgery + VA ± – – – – Surgery + VAC/IVA ++ ± ± – – 3. Limbs Surgery + VA ± – – – ± Surgery + IVA ++ ± ± – ± 4. Vagina IVA/VAC, complete remission followed by monitoring ± ± ± – – IVA followed by elective surgery or interstitial radiation ++ ± ± ± ± 5. Bladder/prostate Radical surgery then IVA/VAC with or without selective radiotherapy ++ ± ± ± ± IVA/VAC followed by local surgery ± ± ± – ± No complete remission, radiation ± — — — — 6. Thorax, abdomen, pelvis IVA/VAC then selective radiation, then IVA/VAC — ++ ± ± ± IVA/VAC, CR with or without surgery followed by IVA/VAC ± ± ± ± – 7. Parameningeal IVA/VAC followed by extensively early radiation, then IVA/VAC ++ ± ± ++ — IVA/VAC, followed by delayed limited radiation and then by IVA/VAC ± ± ± ± — 8. Nonparameningeal head and neck Radical surgery followed by VA ++ – – – ++ Biopsy then IVA/VAC, followed by CR ± ± ± – – Or non-CR and radiation — — — ++ ± Or non-CR and surgery — — — – ±

Surgery

Local tumor control is the cornerstone of therapy, especially for patients with nonmetastatic disease. Primary tumor resection should be undertaken only if there is no evidence of

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lymph node or metastatic disease and if the tumor can be excised with good margins without functional impairment or mutilation. Surgery has a small role or no role in the primary management of orbital tumors and only a limited role in the local control of head and neck tumors. However, to avoid pelvic irradiation in very young children, the morbidity of radical surgery necessary to achieve local control may be accepted.

Radiation THERAPY

Radiation therapy is recommended for patients with the following characteristics after initial surgical resection or chemotherapy:

1. Completely resected tumor(clinical group I)

• unfavorable histology (alveolar RMS)

2. Microscopic residual disease(clinical group II)

• radiation therapy to 4,100 cGy

3. Gross residual disease(clinical group III)

• radiation therapy to 5,040 cGy.

Treatment volume:

• Volume is determined by the extent of disease at diagnosis prior to resection and chemotherapy.
• Radiation field should extend 2-cm beyond tumor margin.
• Whole-brain irradiation of 2,340 to 3,060 cGy is given for parameningeal disease with intracranial extension.

Chemotherapy

It has long been recognized that neoadjuvant combination, multiagent chemotherapy given for extensive (primarily unresectable) tumors could reduce the extent of subsequent surgery or radiation therapy. Figure 21.4 provides an outline of this multidisciplinary approach for osteosarcoma.

FIG. 21.4. Treatment options schema in osteosarcoma.

OSTEOSARCOMA

Osteosarcoma is a primary bone malignancy with a peak incidence during the pubescent growth spurt (from 15 to 19 years) in the metaphyses of the most rapidly growing bones. Risk factors are listed in Table 21.5.

TABLE 21.5. Risk Factors for Osteosarcoma

Familial cancer Li-Fraumeni syndrome Secondary osteosarcoma Irradiated bones Bilateral retinoblastoma (independent of therapy modality) Loss of tumor-suppressor genes p53 and Rb (retinoblastoma)

Clinical Presentation

• Bone pain
• Swelling
• Most often, mass in area of metaphyseal bones of femur or tibia.

Diagnosis and STAGING

Diagnostic Radiology

1. Assessment of tumor

• Destruction of bone visualized on plain radiograph, with a consequent loss of normal trabeculae and the appearance of radiolucent areas
• New bone formation
• Lytic or sclerotic appearance
• “Sunburst sign”: periosteal elevation by tumor penetrating the cortical bone.

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2. Determination of extent of disease

• MRI to assess primary tumor boundaries of entire long bone area (T1 weighted), including search for skip lesions
• Technetium bone scan.

3. Metastatic spread (15% to 20%)

• Technetium bone scan
• CT chest/lungs.

Biopsy and Laboratory Investigations

Histologic diagnosis depends on the presence of a frankly malignant sarcomatous stroma associated with the production of tumor osteoid. It is highly recommended that if the surgeon suspects a primary malignant bone lesion after a preliminary assessment with history, physical examination, and plain radiographs, all invasive procedures, especially the placement and technique of biopsy, should be done by an experienced orthopedic oncologist.

Generous amounts of fresh and frozen tissue should be available to perform various prognostic assays including measurement of tumor DNA content, molecular genetic evaluations, and P-glycoprotein estimation. Serum lactate dehydrogenase (LDH) levels are also powerful prognostic factors and may be elevated in 30% of patients without metastases.

Treatment Strategies

Almost all patients with osteosarcoma have subclinical micrometastatic disease. Thus, treatment requires surgical ablation of the primary tumor (amputation or limb-sparing resection) and treatment of micrometastatic disease with chemotherapy (see Figs. 21.4, 21.5, 21.6 and21.7).

FIG. 21.5. Treatment options in metastatic osteosarcoma.

FIG. 21.6. Treatment options in postoperative metastatic osteosarcoma.

FIG. 21.7. Treatment options in postoperative localized osteosarcoma.

Chemotherapy

Most patients receive neoadjuvant and adjuvant therapy.

1. Neoadjuvant chemotherapy

• Evaluation of bone marrow, cardiac liver, and renal function
• Initiation early after completion of biopsy and staging studies
• Duration: 9 to 12 weeks.

2. Adjuvant chemotherapy

• Evaluation of extent of tumor necrosis in surgical specimen for prognostic purposes (predictor of disease-free and overall survival)
• Initiation early after definitive surgery of primary tumor
• Duration: 35 to 40 weeks.

Surgery

Both amputation and limb-salvage operations incorporate the basic principle of wide en bloc excision of the tumor and biopsy site through normal tissue planes, leaving a cuff of normal tissue around the periphery of the tumor. Limb-sparing surgery is now the preferred approach

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for most (70% to 90%) patients with osteosarcoma because it achieves a better functional outcome. Reconstruction uses allografts, customized endoprosthetic devices, modular endoprosthetic devices, or combinations of these methods. This requires a multidisciplinary team and close cooperation between the chemotherapist and orthopedic oncologist.

Follow-up

Patients with osteosarcomas should be monitored frequently for metastases with radiographic studies for at least 5 years after completion of therapy. Most first recurrences appear asymptomatically in the lungs. All patients with recurrent disease should be approached with curative intent because durable salvage has been reported in 10% to 20% of such patients.

EWING FAMILY OF TUMORS

The EFT include Ewing sarcoma of the bone, PNETs, Askin–Rosai tumor (PNET of the chest wall), and extraosseous Ewing (EOE) sarcoma. Studies using immunohistochemical markers, cytogenetics, and tissue culture indicate that these tumors are all derived from the same primordial stem cell and are distinguished only by the degree of neural differentiation. Epidemiologically, it is remarkable that there is a low incidence in black and Chinese populations. Nearly 12% of patients with Ewing sarcoma also have associated urogenital anomalies such as cryptorchidism, hypospadias, and ureteral duplication. Ewing sarcoma accounts for 10% to 15% of all malignant bone tumors; peak incidence is between 10 and 15 years of age.

Clinical Presentation

• Persistent and increasing pain, local swelling, and functional impairment of affected area (see Table 21.6)
• Fever
• Associated neurologic symptoms include paraplegia and peripheral nerve abnormalities

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• Uncommon symptoms include

1. lymph node involvement
2. meningeal spread
3. central nervous system (CNS) disease.

TABLE 21.6. Clinical Presentation of Osteosarcoma and Ewing Family of Tumors

Osteosarcoma EFT EFT, Ewing family of tumors. Tumor localization Metaphyseal bone Diaphyseal/flat bones Radiographic characteristics Periosteal elevation with new bone formation: “sun burst” Patchy bone destruction: “moth eaten” Periosteal lamellation: “onion skin” Associated signs Soft-tissue swelling Soft-tissue swelling, pleural effusion

Diagnosis and STAGING

Diagnostic Radiology

1. Evaluation of primary tumor

• CT and MRI of primary lesion

2. Metastatic spread(20%)

• CT scan of the chest and lungs
• Technetium bone scan for tumor extent and bone marrow involvement.

Approximately 20% of patients have visible metastases at diagnosis. Of these patients, about 50% have lung metastases and about 40% have multiple-bone involvement and diffuse bone marrow involvement.

Biopsy and Laboratory Investigations

Open biopsy is the preferred approach for tissue diagnosis and should be undertaken at an oncology center, where the diagnostic material can be optimally used and the initial surgical approach can be determined by a multidisciplinary team responsible for the patient's subsequent treatment. Needle biopsy may restrict access to fresh and frozen tissue for cytogenetic and molecular genetic investigations.

1. Serology

• LDH: prognostic indicator reflecting disease burden

2. Histopathologic evaluation

• “Small blue round cell tumor”
• Immunohistochemistry: NSE, vimentin, S-100, HBA-71

3. Cytogenetics/molecular genetics

• t(11;22)(q24;q12) in 85% of tumors
• RT PCR of EWS/FLI transcripts.

The t(11;22)(q24;q12) translocation results in the formation of a chimeric gene between EWS (Ewing sarcoma gene), a novel putative RNA-binding gene located on chromosome 22q12, and FLI1, a member of the erythroblastosis virus–transforming sequence (ETS) family

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of transcription factors located on chromosome 11q24, and has been fully characterized at the molecular genetic level. RT PCR of the fusion transcripts from the tumor can identify patients with favorable prognosis with localized primary tumors.

Treatment Strategies

Almost all patients with apparently localized disease at diagnosis have subclinical micrometastatic disease. Hence, a multidisciplinary approach including local disease control with surgery and/or radiation as well as systemic chemotherapy is indicated (see Fig. 21.8).

FIG. 21.8. Dose-intensive chemotherapy for children with Ewing family of tumors. (From Marina NM, Pappo AS, Parham DM, et al. Chemotherapy dose-intensification for pediatric patients with Ewing family of tumors and desmoplastic small round cell tumors: a feasibility study at St. Jude Children's Research Hospital. J Clin Oncol 1999;17:180–190, with permission.)

Surgery

Generally, surgery is the preferred approach if the lesion is resectable. Radiation therapy is used for patients who do not have a surgical option that preserves function and for patients whose tumors have been excised but with inadequate margins.

Radiation therapy

The Intergroup Ewing's Sarcoma Study (IESS) recommendations include the following:

• For gross residual disease: 4,500 cGy plus a 1,080-cGy boost to tumor site.
• For microscopic residual disease: 4,500 cGy plus 5,400-cGy boost.
• For pulmonary metastasis: whole-lung radiation of 1,200 to 1,500 cGy even if complete resolution of pulmonary metastatic disease is possible with chemotherapy.
• For metastatic sites of disease in bone and soft tissues: 4,500 to 5,600 cGy.

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of EFT.

Chemotherapy

The two most effective agents are cyclophosphamide and doxorubicin, but vincristine and dactinomycin are also active. Recently, dose-intensification studies using ifosfamide and etoposide have shown significant promise. Prognosis was poor before the advent of effective multiagent chemotherapy (5-year survival of 10% to 20%, despite good local control) and continues to be dismal in patients with metastatic disease (one recent study reported a 3-year event-free survival of only 26.7% ± 13.2%).

FUTURE DIRECTIONS

Better understanding of the molecular pathogenesis of these tumors by characterization of chromosomal translocations associated with RMS and Ewing sarcoma can lead to novel therapeutic strategies. Some current investigational approaches include biologic response modifiers; cell cycle signaling pathway inhibitors; vaccines designed to elicit T-cell immunity, with specificity for tumor-specific fusion peptides; and antibody targeting of immunotoxins to tumor cells.

SUGGESTED READINGS

Arndt CAS, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999;342:342–352.

Ginsberg JP, Woo S, Johnson ME. Ewing's sarcoma family of tumors. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. Philadelphia, PA: Lippincott–Raven Publishers, 2002:973–1016.

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Link PM, Gebhardt MC, Meyers PA. Osteosarcoma. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. Philadelphia, PA: Lippincott–Raven Publishers, 2002:1051–1089.

Marina NM, Pappo AS, Parham DM, et al. Chemotherapy dose-intensification for pediatric patients with Ewing's family of tumors and desmoplastic small round cell tumors: a feasibility study at St. Jude Children's Research Hospital. J Clin Oncol 1999;17:180–190.

NCNN. Pediatric osteosarcoma practice guidelines. Oncology 1996;10:1799–1806.

PDQR Cancer Information Summaries. http://www.cancernet.nci.nih.gov/pdq/pdq_treatment.shtml 2005.

Philip T, Blay JY, Brunat-Mentigny M, et al. Standards, options and recommendations (SOR) for diagnosis, treatment and follow-up of osteosarcoma [French]. Bull Cancer 1999;86:159–176.

Pinkerton CR. Clinical challenges in pediatric oncology. Oxford: ISIS Medical Media, 1999:117–134, 143–156.

Sommelet D, Pinkerton R, Brunat-Mentigny M, et al. Standards, options and recommendations (SOR) for clinical care of rhabdomyosarcoma (RMS) and other soft tissue sarcoma in children [French]. Bull Cancer 1998;85:1015–1042.

Wexler LH, Christ WM, Helman LJ. Rhabdomyosarcoma and undifferentiated sarcomas. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. Philadelphia, PA: Lippincott–Raven Publishers, 2002:939–971.