Sarcoma


A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues.
Sarcomas are one of five different types of cancer, classified by the cell type from which they originate. While there are five types under this category, sarcomas are most frequently contrasted with carcinomas which are much more common. Sarcomas are quite rare, making up about 1% of all adult cancer diagnoses and 15% of childhood cancer diagnoses.
There are many subtypes of sarcoma, which are classified based on the specific tissue and type of cell from which the tumor originates. Common examples of sarcoma include liposarcoma, leiomyosarcoma, and osteosarcoma. Sarcomas are primary connective tissue tumors, meaning that they arise in connective tissues. This is in contrast to secondary connective tissue tumors, which occur when a cancer from elsewhere in the body spreads to the connective tissue.
The word sarcoma is derived from the Greek σάρκωμα sarkōma 'fleshy excrescence or substance', itself from σάρξ sarx meaning 'flesh'.

Classification

Sarcomas are typically divided into two major groups: bone sarcomas and soft-tissue sarcomas, each of which has multiple subtypes. In the United States, the American Joint Committee on Cancer publishes guidelines that classify the subtypes of sarcoma. These subtypes are as follows:

Subtypes of bone sarcoma

Symptoms of bone sarcomas typically include bone pain, especially at night, and swelling around the site of the tumor.
Symptoms of soft-tissue sarcomas vary, but they often present as firm, oftentimes painless lumps or nodules. Gastrointestinal stromal tumors often are asymptomatic, but can be associated with vague complaints of abdominal pain, bleeding into the intestines, a feeling of fullness, or other signs of intestinal obstruction.

Cause

Causes and risk factors

The cause of most bone sarcomas is not known, but several factors are associated with an increased risk of developing bone sarcoma. Previous exposure to ionizing radiation is one such risk factor. Therapeutic radiation is associated with sarcoma after 10 to 20 years. Exposure to alkylating agents, such as those found in certain cancer chemotherapeutic medicines, also increases the risk of bone sarcoma. Certain inherited genetic syndromes, including Li-Fraumeni syndrome, inherited RB1 gene mutations, and Paget's disease of bone are associated with an increased risk of developing bone sarcomas.
Most soft-tissue sarcomas arise from what doctors call "sporadic" genetic mutations within an affected person's cells. Nevertheless, there are certain risk factors associated with an increased risk of developing soft-tissue sarcoma. Previous exposure to ionizing radiation is one such risk factor. Exposure to vinyl chloride, arsenic and Thorotrast all are associated with an increased risk of angiosarcoma. Lymphedema, such as that resulting from certain types of breast cancer treatment, also is a risk factor for development of angiosarcoma. As with bone sarcomas, certain inherited genetic syndromes also are associated with an increased risk of developing soft-tissue sarcoma, including Li-Fraumeni syndrome, familial adenomatous polyposis, neurofibromatosis type 1, and heritable RB1 gene mutations. Kaposi sarcoma is caused by Kaposi sarcoma-associated herpesvirus.

Mechanisms

The mechanisms by which healthy cells transform into cancer cells are described in detail elsewhere. The precise molecular changes that result in sarcoma are not always known, but certain types of sarcomas are associated with particular genetic mutations. Examples include:
  • Most cases of Ewing sarcoma are associated with a chromosomal translocation in which part of chromosome 11 fuses with part of chromosome 22. This results in the EWSR1 gene becoming fused to other genes, including the FLI1 gene in 90% of Ewing cases and ERG gene in 5-10% of cases. These fusions result in the production of abnormal proteins, although how these abnormal proteins result in cancer is not fully known.
  • Dermatofibrosarcoma protuberans often is associated with a chromosomal translocation in which the COL1A1 gene becomes fused to the PDGFRB gene. This results in over-active PDGF signaling, which is thought to promote cell division and ultimately lead to tumor development.
  • Inflammatory myofibroblastic tumor often is associated with rearrangements of the ALK gene, and occasionally with rearrangements of the HMGA2 gene.
  • Tenosynovial giant cell tumor frequently is associated with a chromosomal translocation between chromosome 1 and chromosome 2, in which the CSF1 gene becomes fused with the COL6A3 gene. This results in increased CSF1 protein production, which is thought to play a role in cancer development.
  • Many liposarcomas are associated with amplification of part of chromosome 12, which results in extra copies of known cancer-promoting genes such as the CDK4 gene, the MDM2 gene and the HMGA2 gene.

    Diagnosis

Bone sarcomas

Diagnosis of bone sarcomas begins with a thorough history and physical examination which may reveal characteristic signs and symptoms. Laboratory studies are not particularly useful in diagnosis, although some bone sarcomas may be associated with elevated alkaline phosphatase levels, while others can be associated with elevated erythrocyte sedimentation rate. Importantly, however, none of these laboratory findings are specific to bone sarcomas, meaning that elevations in these lab values are associated with many other conditions as well as sarcoma, and thus cannot be relied upon to conclusively diagnose sarcoma.
Imaging studies are critically important in diagnosis, and most clinicians will order a plain radiograph initially. Other imaging studies commonly used in diagnosis include magnetic resonance imaging studies and radioisotope bone scans. A CT scan is typically not used in diagnosis of most types of bone sarcoma, although it is an important tool for staging. Definitive diagnosis requires biopsy of the tumor and careful review of the biopsy specimen by an experienced pathologist.

Soft-tissue sarcomas

Diagnosis of soft-tissue sarcomas also begins with a thorough history and physical examination. Imaging studies can include either CT or MRI, although CT tends to be preferred for soft-tissue sarcomas located in the thorax, abdomen, or retroperitoneum. Positron emission tomography also may be useful in diagnosis, although its most common use is for staging. As with bone sarcomas, definitive diagnosis requires biopsy of the tumor with evaluation of histology by a trained pathologist.

Staging

In general, cancer staging refers to how advanced a cancer is, and usually it is based upon factors such as tumor size and whether it has spread to other parts of the body. Staging is important because the stage affects the prognosis, as well as the types of treatments that are likely to be effective against the cancer. With sarcomas, staging requires a determination of whether the tumor has grown into surrounding tissues, as well as imaging to determine whether it has spread to lymph nodes or to other tissues or organs in the body.
The most common imaging tools used for staging bone sarcomas are MRI or CT to evaluate the primary tumor, contrast-enhanced CT of the chest to evaluate whether the cancer has spread to the lungs, and radioisotope bone scan to evaluate whether the cancer has spread to other bones. Staging for soft-tissue sarcomas typically includes imaging of the primary tumor by MRI or CT to determine tumor size, as well as contrast-enhanced CT of the chest to evaluate for metastatic tumors in the lungs.

Grade

Like some other cancers, sarcomas are assigned a grade based on the appearance of the tumor cells under a microscope. In general, grade refers to how aggressive the cancer is and how likely it is to spread to other parts of the body. Low-grade sarcomas have a better prognosis than higher-grade sarcomas, and are usually treated surgically, although sometimes radiation therapy or chemotherapy are used. Intermediate- and high-grade sarcomas are more frequently treated with a combination of surgery, chemotherapy, or radiation therapy. Since high-grade tumors are more likely to undergo metastasis, they are treated more aggressively. The recognition that many sarcomas are sensitive to chemotherapy has dramatically improved the survival of patients. For example, in the era before chemotherapy, long-term survival for pediatric patients with localized osteosarcoma was only about 20%, but now has risen to 60–70%.