The Bethesda Handbook of Clinical Oncology

Sarcomas and Malignancies of the Bone 21

Dale R. Shepard

Epidemiology

Sarcomas are tumors of mesenchymal tissues and represent about 1% of adult cancers and about 10% of pediatric cancers. Of these sarcomas, about 80% are in soft tissues and about 20% are in bone.

Soft Tissue Sarcoma

Clinical Presentation

Patients with soft tissue sarcomas rarely have constitutional symptoms, such as weight loss or increased fatigue. They may experience pain, paresthesia, or edema from compression by an enlarging tumor. While soft tissue sarcomas can occur throughout the body, the majority of them are in the extremities. In one series of 4500 sarcomas, 46% were in the groin, thigh, or buttock; 13% in the upper extremity; 18% in the torso, and 13% in the retroperitoneum. Red flags that suggest presence of a soft tissue sarcoma include

Mass greater than 5 cm in size

Rapid growth of the mass

Mass that is deep to the fascia

New pain in a previously painless mass

Recurrence of a mass

Pathology

The World Health Organization classifies soft tissue sarcomas into over 100 subtypes based on histology with designation based on the presumed tissue of origin, such as liposarcoma, synovial sarcoma, fibrosarcoma, peripheral nerve sheath tumors, or angiosarcoma. Pathology should be reviewed by a center that specializes in sarcoma to ensure the proper diagnosis based on morphology, immunohistochemistry, and molecular genetic studies. Soft tissue sarcomas are characterized by the FNCLCC grading system developed by the French Federation of Cancer Centers Sarcoma Group.

Diagnosis

Patients with a suspected sarcoma of the extremity should have an MRI of the primary site. Masses in the abdomen or retroperitoneum can be assessed with CT scans. A CT of the chest should be obtained for staging since this is a frequent site of metastases for soft tissue sarcoma. PET scans may help in some situations, such as distinguishing a neurofibroma from a malignant peripheral nerve sheath tumor, but PET scans should not be obtained as a part of routine staging. Imaging of the CNS is not a part of routine staging and should only be obtained if there is a clinical suspicion for metastasis.

Tumors should be sampled with image-guided core needle biopsies or an incisional biopsy with a preference for a needle biopsy. The biopsy should be along the axis of a planned resection, if possible. A sentinel lymph node biopsy should be obtained in patients with enlarged nodes by palpation or imaging and sarcomas likely to have lymphatic spread (rhabdomyosarcoma, angiosarcoma, clear cell sarcoma, epithelioid sarcoma, or synovial sarcoma). There are no serum or plasma biomarkers that should be used for diagnosis, assessing treatment response, or monitoring for recurrence of disease.

Treatment

Surgery is the treatment of choice for patients with a primary sarcoma of the extremity or the trunk. Negative surgical margins are associated with improved overall survival and surgery is usually done with at least a 1 cm margin with consideration for presence of bone or fascia as a margin. Involvement of the bone or vasculature or the inability to achieve proper margins requires discussion of amputation. Radiation therapy with image-guided external beam radiation should be considered either preoperatively or postoperatively for patients with intermediate or high-grade soft tissue sarcomas. Brachytherapy is an alternative for radiotherapy delivery at the time of surgery either alone or in combination with external beam radiation. Neoadjuvant radiation therapy should also be considered for patients with low-grade tumors if this may improve the likelihood for appropriate surgical margins.

There are conflicting data for the use of neoadjuvant or adjuvant chemotherapy for patients with soft tissue sarcoma of an extremity. A meta-analysis of 1953 patients enrolled in 18 trials failed to show a survival benefit for treatment with adjuvant doxorubicin, but there was a significant hazard ratio for the combination of doxorubicin and ifosfamide. However, a separate pooled analysis of 2 large trials of patients treated with adjuvant doxorubicin and ifosfamide was negative. Trials have not identified the patients most likely to benefit from adjuvant chemotherapy with inconsistent data on the importance of completeness of resection, tumor size, and tumor grade. Ideally, adjuvant chemotherapy would be given in the setting of a clinical trial. Similarly, there is no consensus in the literature on the role of neoadjuvant chemotherapy. Even trials enriched for large- or high-grade tumors or utilizing chemotherapy thought to be more specific, for the tumor histology failed to show a benefit. As with adjuvant chemotherapy, neoadjuvant chemotherapy should only be used on a case-by-case basis or as part of a clinical trial.

Surgical resection is the only potentially curative treatment for retroperitoneal sarcomas. Surgery for these tumors often requires a multidisciplinary team with planned mobilization, resection, or repair of adjacent organs in order to get appropriate margins with an en bloc resection. Preoperative radiation therapy should be given to patients with intermediate- or high-grade soft tissue sarcoma with consideration of intraoperative radiation. Postoperative radiation requires higher doses and increased risk for toxicity to normal tissue. Patients with an unresectable retroperitoneal sarcoma may benefit from systemic chemotherapy to allow for resection in those who respond. In a phase III trial comparing doxorubicin to doxorubicin and ifosfamide in patients with soft-tissue sarcoma, the response rate was 14% and 25%, respectively. Patients should receive the combination of doxorubicin and ifosfamide to optimize the likelihood of subsequent resection. There are no data to support the use of adjuvant chemotherapy for patients with an R0 or R1 resection of a retroperitoneal sarcoma.

There is a lack of histology-specific treatment for most patients with metastatic soft-tissue sarcoma. The initial treatment for most patients is doxorubicin-based therapy. In a trial enrolling patients with numerous subtypes of soft tissue sarcoma, addition of the platelet-derived growth factor receptor (PDGFR) inhibitor olaratumab to doxorubicin resulted in an 18% response rate and improved overall survival (OS) from 14.7 to 26.5 months. Clinical trials should always be considered for patients with metastatic soft tissue sarcoma, but some additional chemotherapy regimens are listed in Table 21.1.

Table 21.1Chemotherapy Regimens for Patients with Metastatic Soft Tissue Sarcoma

Chemotherapy	Indication
Gemcitabine/docetaxel	May have more activity in leiomyosarcoma
Paclitaxel	May be the best initial therapy for angiosarcoma
Pazopanib	Patients with nonlipogenic sarcomas
Trabectedin	Patients with liposarcoma or leiomyosarcoma
Eribulin	Patients with liposarcoma
Sunitinib	Initial therapy for alveolar soft part sarcoma or malignant solitary fibrous tumor
Sirolimus	Initial therapy for perivascular epithelioid cell differentiation (PEComa)

Rhabdomyosarcoma

Clinical Presentation

Rhabdomyosarcoma is the most common soft tissue tumor in children accounting for about half of soft tissue sarcomas in this population; however, these are still rare with an incidence of about 350 new cases in the United States per year. Only 2% to 5% of rhabdomyosarcoma occurs in adults, most often as a head and neck tumor.

As with other soft tissue sarcomas, patients with rhabdomyosarcoma may be asymptomatic or they may have signs and symptoms related to the site of the disease (Table 21.2).

Table 21.2Most Common Sites of Rhabdomyosarcoma, Frequency and Clinical Presentation

Site	Frequency (%)	Presentation/Symptoms
Head and Neck	35–40	Proptosis (orbit), discharge, painless mass
Genitourinary	25	Hematuria, urinary obstruction, vaginal discharge
Extremities	20	Painless mass with erythema of overlying skin

A prognostic stratification has been developed based on stage, clinical group, site of disease, size of tumor, age, histology, presence of metastatic disease, and involvement of lymph nodes. Patients with an excellent prognosis based on this stratification have a >85% event-free survival. Patients with a very good prognosis and good prognosis have a 70% to 85% and 50% to 50% event-free survival, respectively. A poor prognosis is associated with a <30% event-free survival.

Factors associated with poorer prognosis in patients with a relapse of rhabdomyosarcoma include

Metastatic disease

Prior alkylating agents and radiation therapy

Alveolar histology

Shorter time to relapse

Higher stage/clinical group at diagnosis

Pathology

Rhabdomyosarcoma is a tumor of mesenchymal origin that is characterized by myogenic differentiation. Morphologically, rhabdomyosarcoma resembles other tumors, such as lymphoma, mesenchymal chondrosarcoma, and Ewing family sarcomas making it important that the pathology be reviewed at a center with expertise in sarcoma. Rhabdomyosarcoma will usually stain for actin, myosin, desmin, myoglobin, and MyoD. There are pleomorphic and nonpleomorphic rhabdomyosarcomas.

Among nonpleomorphic rhabdomyosarcoma, 80% of patients have an embryonal subtype and about 15% of patients have an alveolar subtype. The embryonal subtype is characterized by 11p15.5 loss of heterogeneity and hyperdiploid DNA. The alveolar subtype is characterized by PAX3/FKHR t(2, 13)(Q35;q14) and PAX3/FKHR t(1:13)(p36;q14) translocations and tetraploid DNA.

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 approach can be determined by a multidisciplinary team responsible for the patient’s subsequent treatment. Patients should have an MRI or CT of the primary site of disease and a PET/CT scan or bone scan to assess for metastatic disease.

Treatment

Pleomorphic rhabdomyosarcoma should be treated as a soft-tissue sarcoma. The diversity of primary sites, distinctive surgical approaches and radiotherapy regimens for each primary site, subsequent site-specific rehabilitation, and potential treatment-related sequelae underscore the importance of patients with nonpleomorphic rhabdomyosarcoma consulting with or being treated at a medical center that has appropriate experience in surgery, radiation therapy, and medical oncology. Tumors should only be resected if there is no evidence of adenopathy or metastatic disease and the surgery would not lead to excessive morbidity. Due to poor survival with surgery alone, rhabdomyosarcoma is usually treated with a combination of surgery, radiation therapy, and chemotherapy. This combination therapy is determined by the estimated risk of recurrence.

Patients with rhabdomyosarcoma usually have a very long course of treatment. Those with low-risk, intermediate-risk, or high-risk disease receive chemotherapy for 24 to 45 weeks with radiation therapy starting at week 13 (Table 21.3). Most patients also receive radiation therapy starting at week 13 of their therapy, so consultation with radiation oncology as part of a multidisciplinary team is important.

Table 21.3Chemotherapy Regimens for Patients with Newly Diagnosed Rhabdomyosarcoma

Prognosis Group	Regimen
Low risk (excellent prognosis)	VA for 15 cycles OR VAC/VA for 8 cycles
Low risk (very good prognosis)	VAC for 15 cycles
Intermediate risk (good prognosis)	VAC for 14 cycles OR VAC/VI for 14 cycles
High risk (poor prognosis)	VAC for 14 cycles

VA (vincristine and dactinomycin); VAC (vincristine, dactinomycin, cyclophosphamide); VI (vincristine and irinotecan).

Osteosarcoma

Osteosarcoma, a primary malignancy of the bone, represents 1% of all cases of cancer diagnosed in the United States annually. This cancer primarily affects adolescents with a peak incidence between ages 13 and 16 and adults over 65 years of age. It is the most common primary cancer of the bone in children and young adults. While a primary cancer in children and young adults, osteosarcoma in adults is often secondary to prior radiation or the presence of Paget’s disease.

Clinical Presentation

In children, osteosarcoma is most common in the metaphysis of long bones. In adults, osteosarcoma is more common in the axial skeleton or at sites of either prior radiation or abnormalities of the bone. Most patients present with localized pain, often with a long period of pain with intermittent severity. Fever, weight loss, and fatigue are rare. Patients generally develop a soft tissue mass that is painful to palpation. Fifteen to twenty percent of patients have metastatic disease at the time of diagnosis.

Diagnosis

The primary differential diagnosis for patients with osteosarcoma is Ewing sarcoma, lymphoma, and metastatic disease. Plain radiographs may show either a lytic or sclerotic appearance or periosteal elevation from tumor penetration of the cortical bone. Workup should include an MRI of the involved bone, a CT of the lungs, and a bone scan or PET/CT to assess for metastatic disease. A biopsy is required to confirm the diagnosis. The biopsy should be done carefully with consideration of how it may impact subsequent definitive surgery and either be a surgical or core biopsy. Patients of reproductive age should have a discussion about fertility.

Pathology

Osteosarcomas are of mesenchymal origin and can differentiate to fibrous tissue, cartilage, or bone. Histologically, osteosarcomas have a sarcomatous stroma with tumor osteoid and bone. There are no translocations or molecular abnormalities that define osteosarcoma. Osteosarcoma can be defined as low grade with intramedullary and surface involvement, periosteal, high-grade intramedullary, and surface or extraskeletal osteosarcoma. Extraskeletal osteosarcomas are soft-tissue sarcomas that don’t involve the bone or periosteum, but produce bone, osteoid, or chondroid material.

Treatment

Amputation and limb-sparing resection incorporate wide en bloc excision of the tumor with the biopsy site through normal tissue planes, leaving a cuff of normal tissue around the periphery of the tumor. Wide excision with negative margins improves local tumor control. Limb-sparing surgery is now the preferred approach for 70% to 90% of patients with osteosarcoma due to improved functional outcome. Reconstruction may involve allografts or customized prosthetic devices.

Patients with low-grade osteosarcoma of the intramedullary or surface of the bone or with periosteal osteosarcoma should undergo wide excision of the tumor with consideration of adjuvant chemotherapy for those with periosteal osteosarcoma (Table 21.4). If these patients have a high-grade tumor on excision, they should receive chemotherapy.

Patients with a high-grade osteosarcoma involving the intramedullary or surface of the bone should receive neoadjuvant chemotherapy. Those with an unresectable tumor after neoadjuvant chemotherapy should receive radiation therapy or additional chemotherapy. Patients with a resectable tumor after the neoadjuvant chemotherapy should have a wide excision. Further therapy is based on the surgical margins and response to therapy with poor response defined as >10% viable tumor in the resected tumor. Treatment options for patients with positive margins include additional surgery, radiation therapy, and adjuvant chemotherapy. Patients with negative surgical margins should receive adjuvant chemotherapy with either the initial neoadjuvant regimen or a different regimen based on the treatment response.

Patients with metastatic disease at the time of diagnosis should have consideration of resection or stereotactic radiation for pulmonary, visceral, or skeletal metastases followed by chemotherapy. Patients with unresectable disease should receive chemotherapy or radiation therapy with reassessment for resectability of the metastatic disease.

Patients with an extraosseous osteosarcoma should have their tumor treated as a soft-tissue sarcoma.

Table 21.4Chemotherapy Options for Patients with Osteosarcoma

First-line chemotherapy (neoadjuvant or adjuvant therapy or metastatic disease)

Doxorubicin and cisplatin

Doxorubicin, cisplatin, high-dose methotrexate

Doxorubicin, cisplatin, high-dose methotrexate, ifosfamide

Second-line/Subsequent therapy

Docetaxel and gemcitabine

Etoposide and cyclophosphamide

Etoposide and high-dose ifosfamide

Gemcitabine

Radium-223

Sorafenib

Ewing Family of Tumors (EFT)

The EFT comprises Ewing sarcoma of the bone, peripheral primitive neuroectodermal tumors (PNET), and extraosseous Ewing sarcoma. These tumors have similar immunohistochemical and histologic features and chromosomal translocations suggesting they are derived from a common cell of origin. The EFT is the second most common primary bone tumor in children and adolescents.

Clinical Presentation

EFT are most common in the long bones of the extremities and the bones of the pelvis. In a review of nearly 1000 patients with EFT, 54% of patients had disease in the axial skeleton with 42% in the appendicular skeleton. Typical symptoms of EFT is localized pain or swelling that may be present for weeks to months with an increase in intensity over time. Pain may be worse with exercise or at night. Patients may have a mass that is tender to palpation with some localized erythema. Fatigue, weight loss, and fever can occur, but are rare. Approximately 20% of patients with EFT have overt metastases at diagnosis with metastatic disease more common in patients with tumors in the pelvis. Of the patients with metastatic disease, about 50% have lung metastases and about 40% have multiple bone lesions and diffuse bone marrow involvement. The peak incidence is in those between 10 and 15 years of age with 30% of cases in those greater than 20 years of age.

Diagnosis

Patients with EFT should have a history and physical, an MRI with contrast of the primary site, a CT of the chest, and a PET/CT or a bone scan to determine the presence of metastatic disease. Patients preferably have an open biopsy for the tissue diagnosis, ideally at an oncology center where the diagnostic material can be optimally assessed 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 that are necessary to diagnose an EFT. Patients should have a consultation about fertility, unless past the age of reproductive potential.

Pathology

Morphologically, EFT are similar to other small, round, blue cell tumors including lymphoma, small cell osteosarcoma, undifferentiated neuroblastoma, desmoplastic small round cell tumors, and rhabdomyosarcoma. EFT can be diagnosed by the presence of EWSR1 translocations, the most common being t(11;22)(q24;q12) leading to the EWSR1-FLI1 gene fusion.

Treatment

Many patients with EFT with apparently localized disease at the time of diagnosis have subclinical micrometastases. Patients with EFT should be treated with a multidisciplinary approach including systemic chemotherapy, surgery, and radiation therapy.

Patients with localized or metastatic EFT should be treated initially with combination chemotherapy for at least 12 weeks (Table 21.5). Patients should be restaged with MRI and/or CT of the primary site, a CT of the chest and possibly PET/CT or bone scan to determine treatment response.

Patients with stable disease or a treatment response following the initial chemotherapy should undergo wide excision, continue with definitive radiation and chemotherapy or, in some cases, amputation. Patients with positive margins after wide resection should have adjuvant chemotherapy and radiation therapy with adjuvant chemotherapy alone in patients with negative margins. Patients requiring amputation as local therapy should receive adjuvant chemotherapy with radiation therapy for positive margins.

Patients with progressive disease after their initial chemotherapy should consider radiation therapy or surgery to the primary site of disease for palliation followed by additional chemotherapy.

Table 21.5Chemotherapy Options for Patients with EFT

First-line therapy for neoadjuvant or adjuvant therapy

VAC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide

VAI (vincristine, doxorubicin, and ifosfamide)

VIDE (vincristine, ifosfamide, doxorubicin, and etoposide)

First-line therapy for metastatic disease at diagnosis

VAC

VAC/IE

VAI

VIDE

Second-line therapy for relapsed/refractory or metastatic disease

Cyclophosphamide and topotecan

Irinotecan and temozolomide

Etoposide and high-dose ifosfamide

Gemcitabine and docetaxel