Sarcomas

Chondrosarcoma

Nancy J. Leahy

DEFINITION

Chondrosarcoma is one type of primary bone cancer that derives its name on the basis of its histologic origin, the cartilage. Primary bone cancers demonstrate wide clinical heterogeneity and are often curable with proper treatment.

INCIDENCE

• Primary bone cancers are extremely rare, accounting for less than 0.2% of all cancers.

• Chondrosarcoma is the second most common form of bone cancer, accounting for 30% of bone cancers in the United States.

• An estimated 4,720 new cases will be diagnosed in 2007 in the United States and 790 people will die from the disease.

• Chondrosarcoma is usually found in middle-aged and older adults.

ETIOLOGY AND RISK FACTORS

Chondrosarcomas characteristically produce cartilage matrix from neoplastic tissue devoid of osteoid. Conventional chondrosarcomas are divided into two groupings: primary or central lesions arising from previously normal-appearing bone preformed from cartilage; secondary or peripheral tumors that arise or develop from preexisting benign cartilage lesions, such as enchondromas, or from the cartilaginous portion of osteochondroma. Malignant transformation has been reported in lesions in patients with Ollier’s disease (enchondromatosis).

SIGNS AND SYMPTOMS

Symptoms of chondrosarcoma are usually mild and depend on tumor size and location. Patients with pelvic or axial lesions are typically diagnosed later in the disease course because the associated pain has a more insidious onset and often occurs when the tumor has reached a significant size.

DIAGNOSTIC WORKUP

Imaging of the primary lesions includes the following:

• X-ray films

˚ Show cortical destruction and loss of medullary bone trabeculations

˚ Evidence of calcification and destruction.

• Magnetic resonance imaging

˚ Shows intramedullary involvement and extraosseous extension of the tumor.

• Serial radiographs

˚ Demonstrate a slow increase in size of the osteochondroma or enchondroma.

• A cartilage “cap” measuring greater than 2 cm on a pre-existing lesion or documented growth after skeletal maturity should raise the suspicion of sarcomatous transformation.

HISTOLOGY

The histologic grade of chondrosarcoma and location are important in treatment decisions. Dedifferentiated chondrosarcomas are high-grade lesions and should be treated as osteosarcoma. Mesenchymal chondrosarcomas are treated as Ewing’s sarcoma as a function of their grade.

GX: Grade cannot be assessed

G1: Well differentiated—low grade

G2: Moderately differentiated—low grade

G3: Poorly differentiated—high grade

G4: Undifferentiated—high grade

Clinical Staging: Chondrosarcoma

CLINICAL STAGING

The American Joint Committee on Cancer TNM Staging System for Bone Sarcomas is used for all bone sarcomas. See the table below for the clinical staging of chondrosarcoma by the AJCC system.

TREATMENT

• Surgery

˚ Patients with resectable low-grade lesions are treated with intralesional excision or wide excision with negative margins.

˚ High-grade lesions (grade II, III or clear cell) surgically treated and obtaining a wide margin.

• Chemotherapy

˚ Some low-grade lesions treated with intralesional excision will receive adjuvant chemo-therapy.

• Radiation

• High-dose photons are used to treat unresectable high and low-grade lesions.

• Proton beam radiation therapy

˚ Also used in unresectable high and low-grade lesions.

• Surveillance

˚ Low-grade lesions

Physical examination

Imaging of the lesion and chest radiograph every 6 to 12 months for 2 years and then yearly as appropriate

˚ High-grade lesions

Physical examination

Primary site or cross-sectional imaging as indicated

Chest imaging every 3 to 6 months for the first 5 years and yearly thereafter for a minimum of 10 years

• Relapse

• Local recurrence or relapse should be treated with wide excision with or without radiation therapy depending on margin status.

• Radiation therapy should be considered after excision with positive surgical margins. Negative surgical margins should be observed.

• Unresectable recurrences are treated with either conventional or proton beam radiation therapy.

• Surgical excision is an option for systemic relapse of a high-grade lesion.

• Patients should also be considered for participation in a clinical trial.

PROGNOSIS

Late metastases and recurrences after 5 years are more common with chondrosarcoma than with other sarcomas.

The higher the grade of chondrosarcoma the worse the prognosis with increased risk for early metastases. Grade I and II tumors five year survival rate is 80-90% with a low potential for metastases. Grade III tumors five year survival rate is reported to be 29% with greater than a 50% potential for metastasis. The Grade IV or undifferentiated tumors have the greatest metastatic potential with a survival rate of less than 10% at one year.

BIBLIOGRAPHY

Bovee J.V., Cleton-Jansen A.M., Taminiau A.H., et al. Emerging pathways in the development of chondrosarcoma of bone and implications for targeted treatment. Lancet Oncology. 2005;6:599–607.

Bruns J., Elbracht M., Niggemeyer O. Chondrosarcoma of bone: an oncological and functional follow-up study. Annals of Oncology. 2001;84:93–99.

Fiorenza F., Abudu A., Grimer R.J., et al. Risk factors for survival and local control in chondrosarcoma of bone. Journal of Bone and Joint Surgery British. 2002;84:93–99.

Hug E.B., Slater J.D. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. Neurosurgery Clinics of North America. 2000;11:627–638.

Lee F.Y., Mank H.J., Fondren G., et al. Chondrosarcomas of bone: an assessment of outcome. Journal of Bone and Joint Surgery American. 1999;81:326–338.

Mankin H.J., Cantley K.D., Lipielo L., et al. The biology of human chondrosarcoma, I: description of cases, grading, and biochemical analyses. Journal of Bone and Joint Surgery American. 1980;62:160–176.

Mankin H.J., Cantley K.D., Schiller A.L., et al. The biology of human chondrosarcoma, II: variation in chemical composite among types and subtypes of benign and malignant cartilage tumors. Journal of Bone and Joint Surgery American. 1980;62:176–188.

Terek R.M. Recent advances in basic science of chondrosarcoma. Orthopedic Clinics of North America. 2006;37:9–14.

Ewing’s Sarcoma

Nancy J. Leahy

DEFINITION

Ewing’s sarcoma is one type of primary bone cancer that has an unknown histologic origin. Primary bone cancers demonstrate wide clinical heterogeneity and are often curable with proper treatment. Ewing’s sarcoma family of tumors (ESFT) includes Ewing’s sarcoma, primitive neuroectodermal tumor (PNET), Askin’s tumor, PNET of bone, and extraosseous Ewing’s sarcoma.

INCIDENCE

Ewing’s sarcoma is the third most common form of bone cancer and accounts for 16% of all bone cancer cases. Ewing’s sarcoma develops mainly in adolescents and young adults.

ETIOLOGY AND RISK FACTORS

Ewing’s sarcoma and PNET are small round cell neoplasms developing in bone and soft tissue. They exhibit chromosomal translocation, t(11;22) (q24;q12), and closely related variants. Ewing’s sarcoma is poorly differentiated and is also characterized by strong expression of cell-surface glycoprotein CD99. The most common sites of primary Ewing’s sarcoma are the femur, pelvic bones, and the bones of chest wall, although any bone may be affected. Presentation in a long bone most frequently involves the diaphysis. The bone has been described as mottled on imaging. Periosteal reaction is classic and is referred to as “onion skin” by radiologists.

SIGNS AND SYMPTOMS

• Localized pain or swelling.

• Constitutional symptoms such as fever, weight loss, and fatigue are occasionally noted on presentation.

• Nearly 25% of patients have metastatic disease on diagnosis.

DIAGNOSTIC WORKUP

If ESFT is suspected as a diagnosis, the patient should undergo a complete staging before biopsy.

• Imaging of the primary lesions

˚ Plain radiographs of primary site

˚ Computed tomography (CT) or magnetic resonance imaging (MRI) of the entire involved bone or area

˚ CT of the chest

˚ Bone scan

˚ Positron emission tomographic scan can also be considered; it is still considered experimental by most insurance companies.

˚ MRI of spine and pelvis should be considered.

• Laboratory values most often elevated in Ewing’s sarcoma:

˚ Lactate dehydrogenase (a prognostic value as a tumor marker)

˚ Leukocytosis

• Cytogenetic analysis of the biopsy specimen to evaluate the t(11;22) translocation

• Bone marrow biopsy should be considered to complete the workup.

HISTOLOGY

GX: Grade cannot be assessed

G1: Well differentiated—low grade

G2: Moderately differentiated—low grade

G3: Poorly differentiated—high grade

G4: Undifferentiated—high grade

Note: Ewing’s sarcoma is classified as G4.

CLINICAL STAGING

The American Joint Committee on Cancer (AJCC) TNM Staging System for Bone Sarcomas is used for all bone sarcomas. See the table on page 122 for stages of Ewing’s sarcoma according to the AJCC system.

TREATMENT

• Surgery

˚ For local control; includes wide excision

˚ Amputation may be required in some cases.

• Chemotherapy

˚ A combination of at least three of the following agents:

Ifosfamide and/or cyclophosphamide

Etoposide

Doxorubicin

Vincristine

˚ If patient responds, he or she is treated with further adjuvant chemotherapy after surgery or radiation.

˚ Chemotherapy should be given for a total of 36 weeks, including chemotherapy received before local therapy.

• Radiation therapy with or without surgery followed by chemotherapy or best supportive care is recommended for unresponsive or progressive disease.

• Investigational approaches should be considered in patients with recurrent and metastatic disease.

• Surveillance

˚ Every 2 to 3 months

˚ Physician examination

˚ Chest x-ray film

˚ Local imaging

˚ Increase interval after 2 years

˚ Long-term surveillance should be completed annually after 5 years.

PROGNOSIS

In the past, Ewing’s sarcoma was associated with a poor prognosis. The development of multiagent chemotherapy regimens for both neoadjuvant and adjuvant treatment has improved the prognosis greatly for patients with Ewing’s sarcoma: 60% to 75% progression-free survival has been observed in patients with localized Ewing’s sarcoma. Even patients diagnosed with metastatic disease at presentation are able to achieve a cure.

BIBLIOGRAPHY

Avigad S., Cohen I.J., Zilberstein J., et al. The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors. Cancer. 2004;100:1053–1058.

Bernstein M., Cover H., Paulsen M., et al. Ewing’s sarcoma family of tumors: current management. Oncologist. 2006;11:503–519.

Cotterill S.O., Ahrens S., Paulussen M., et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients form the European Intergroup Cooperative Ewing’s sarcoma study group. Journal of Clinical Oncology. 2000;18:3108–3114.

De Alva E., Gerald W.L. Molecular biology of the Ewing’s sarcoma/PNET. Journal of Clinical Oncology. 2000;18:204–213.

DeAlva E., Kawai A., Healy J.H., et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. Journal of Clinical Oncology. 1998;16:1248–1255.

Denny C.T. Gene rearrangements in Ewing’s sarcoma. Cancer Investigation. 1996;14:83–88.

Hawking D.S., Schuetze S.M., Butrynski J.E., et al. 18F-fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. Journal of Clinical Oncology. 2005;23:8828–8834.

Zoubeck, A., Codkhonr-Dworniczak, B., Delattre, O., et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing’s tumor patients? Journal of Clinical Oncology 12, 1245-1251.

Kaposi’s Sarcoma

Nancy J. Leahy

DEFINITION

Kaposi’s sarcoma (KS) is a tumor caused by Kaposi’s sarcoma–associated herpes virus (KSHV), also known as human herpes virus 8. Despite its name, it is generally not considered a true sarcoma, which is a tumor arising from connective tissue. KS actually arises as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance.

INCIDENCE

KS was historically very rare and found mainly in older men of Mediterranean, Jewish, or African origin (classic KS) or in patients with severely weakened immune systems, such as after an organ transplant (immunosuppressive treatment– related KS). In the early 1980s KS began to be seen in patients with acquired immunodeficiency syndrome (AIDS). This led to the belief that AIDS weakened the immune system. KSHV is responsible for all forms of KS. The percentage of people in the United States infected with this virus is unknown. Studies suggest an infection rate of 3.5% to 25% varied by geography.

ETIOLOGY AND RISK FACTORS

• Sex

˚ Men are much more likely than women to have this disease.

˚ White men are the most likely group to be affected.

• Sexual activity

˚ Men who have sex with men

˚ Women who have sex with these men

• Immune deficiency

˚ A defect in the immune system increases the risk of KS in those with human immunodeficiency virus (HIV) infection.

˚ There have been reports of some drugs used to block immunity leading to KS.

• Patient whose immune system is suppressed due to AIDS or after organ transplant.

SIGNS AND SYMPTOMS

• Red to brown to purple growth on the skin—found mostly on the legs and face

• Mouth and throat lesions, mainly on the roof of the mouth

• The throat may be tender and sore and may bleed. Eating, breathing, or swallowing may be uncomfortable.

• Lesions can contribute to dental problems, including tooth loss.

• Possible abdominal discomfort

˚ Intestinal tract common site for disease at diagnosis

˚ Lesions in the gastrointestinal tract do not usually cause symptoms.

˚ Bleeding and pain are sometimes seen.

˚ Gastrointestinal lesions may interfere with digestion and absorption of nutrients from food, which may lead to diarrhea.

• Lymphedema is seen in some people; it may appear with or without skin lesions.

• May develop in the lung and produce cough, shortness of breath, and fever

DIAGNOSTIC WORKUP

• Complete medical history

˚ Sexual history

˚ Exposure to KSHV

˚ Exposure to HIV

• Physical examination

˚ Thorough skin assessment

˚ Rectal examination

• Biopsy of lesion(s)

˚ Punch biopsy

˚ Excisional biopsy

• Chest x-ray film

• Endoscopy with biopsy of lesions

• Bronchoscopy, especially if bloody sputum is present

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