Sarcoma – Cancer of the Connective Tissues

Sarcomas are cancers that arise from the cells that hold the body together.  These could be cells related to muscles, nerves, bones, fat, tendons, cartilage, or other forms of "connective tissues". There are hundreds of different kinds of sarcomas, which come from different kinds of cells.

Dr. George D. Demetri, MD
Director, Sarcoma and Bone Oncology Center
Dana-Farber Cancer Institute and Harvard Medical School

There are two categories of sarcomas:

• Soft tissue sarcomas

• Non-soft tissue sarcomas

Sarcomas can invade surrounding tissue and can metastasize (spread) to other organs of the body, forming secondary tumors. The cells of secondary tumors are similar to those of the primary (original) cancer. Secondary tumors are referred to as "metastatic sarcoma" because they are part of the same cancer and are not a new disease.

Sarcoma Subtypes

(click a subtype to toggle extended information)

The Sarcoma Foundation of America has attempted to create location for patients, caregivers, and health care professionals to quickly learn about a particular sub-type of sarcoma.  The number of subtypes of sarcomas is often debated.  We have attempted to create a list that encompasses most of the sarcoma subtypes. 

We hope this list will be a living document, and we will make every attempt to update it as new treatments and therapies become available for each subtype.  Subtypes that cannot be accessed are currently under construction and will have extended information posted shortly.  Please check back soon!

• Alveolar Soft Part Sarcoma (ASPS)

  Alveolar soft part sarcoma is a very rare, slow growing, highly angiogenic (vessel-forming) tumor that can occur in any age group. It is most frequently found in young adults and teenagers and often begins in the lower extremities.
  
  A recent analysis of the MD Anderson Cancer Center’s institutional database, which may overrepresent incidence as a tertiary care center for rare tumors, estimated 90 total new cases of ASPS in the United States in 2004; it predicted that about half of the patients would fall between the ages of 15 and 29 years (Herzog 2005).
  
  Alveolar soft part sarcoma is characterized by a translocation between the ASPL locus on chromosome 17 and the TFE3 locus on the X chromosome (der(17)t(X;17)(p11q25))

  Epidemiology

  Most patients with alveolar soft part sarcoma probably have had the cancer for some time before they come to medical attention. The reason is that the tumor grows so slowly that it at first causes few symptoms and does not form a large mass. By the time the tumor is big enough that the patient feels a lump from the primary lesion and seeks out a physician for help, the tumor has frequently spread, establishing small metastatic colonies throughout the body, frequently found in the lungs and even the brain. It grows even more slowly than clear cell sarcoma, but is definitely a malignant tumor that tends to spread inexorably if not completely removed by surgery. Many patients can live with disease for years and even decades (Pappo, Parham et al. 1996). Although most patients with alveolar soft part sarcoma can never be rid of their cancer completely, many can undergo repeated surgery over the years to keep it somewhat at bay (Weis and Goldblum 2001).

  Distinct Clinical Features

  Alveolar soft part sarcoma gets the “alveolar” part of its name from the arrangement of cells seen under the microscope by the pathologist (Weis and Goldblum 2001). Alveoli are a small air sacks deep within the lung where oxygen is absorbed into the body, and this cancer has an appearance similar to these air sacks. On gross pathological inspection, meaning on visual inspection without the aid of a microscope, of the tumor after it has been cut out, alveolar soft part sarcoma has numerous blood vessels, reflecting its angiogenic nature. The increased blood flow can even cause an audible noise from blood rushing through the tumor – known in medical terms as a bruit (Pappo, Parham et al. 1996). They must be distinguished from vascular malformations (collections of blood vessels that have grown out of control but they are generally not malignant and will not spread like alveolar soft part sarcoma).

  Treatment and Follow-up for Localized Disease

  The prognosis of alveolar soft parts sarcoma is most influenced by its stage. For patients with tumors that are localized at diagnosis, 87% will remain alive five years later; only 20% of those with metastases at diagnosis will live five years. (Portera, 2001) However, even patients with metastases can have indolent courses, and are likely to have a longer life expectancy than a patient with comparable extent of another soft tissue sarcoma.
  
  Most series reported also suggest that alveolar soft part sarcoma does not respond to chemotherapy, and that surgical therapy should be the mainstay of therapy and is associated with a chance for a long term survival(Pappo, Parham et al. 1996; van Ruth, van Coevorden et al. 2002).
  
  Patients treated for alveolar soft part sarcoma should be followed for many years by an experienced oncologist, both for the risk of recurrence and for the risk of side effects from therapy. Even many years out from diagnosis and even in the cases where surgery has rendered the patient apparently “disease free”, these indolent cancers can recur or grow for decades, distinctly longer than the risk period of most other soft tissue sarcomas This is particularly true for alveolar soft part sarcoma. Because late recurrences can occur, and recurrences can be treated with further benefit, long term follow-up including evaluation of the original sites of disease and the lungs is advisable. The individual recommendations for the schedule and type of surveillance scans will vary according to the patient and should consider the small but not negligible risks of repeated exposure to radiation. While there are few treatments that are curative for these tumors if they come back, it is possible that future recurrences will be amenable to surgery and it is also possible that research will uncover new therapies in the future to treat a recurrence.

  Treatment and Follow-up for Metastatic Disease

  Surgical resection of progressive metastases- even scores of lung metastases- should be considered on a case by case basis. Some studies suggest that, particularly in adults, for tumors that cannot be completely resected but do not have evidence of spread beyond the local area where they have occurred, radiation therapy to the tumor bed may be associated with a lower chance for recurrence (Sherman, Vavilala et al. 1994). As children may have a better chance for cure with aggressive surgery and are more likely to suffer from growth disturbance or second malignancies after radiation therapy, the indications for radiation therapy in the child with locally unresectable but non-metastatic disease are not so clear (Pappo, Parham et al. 1996). While there have been no formal studies regarding the use of anti-angiogenic agents in the treatment of patients with alveolar soft part sarcoma, the well characterized ability of this slow growing tumor to both mimic vascular malformations on clinical exam and control blood flow pathologically suggest that blocking the blood supply of this tumor may result in tumor shrinkage.

  Targeted Therapies

  There are occasional reports of a response to interferon in alveolar soft part sarcoma patients.  Interferon is a cytokine that may act to inhibit blood vessel formation in tumors but may also act to recruit the immune system to attack the tumor (Kuriyama, Todo et al. 2001; Roozendaal, de Valk et al. 2003).  Another possible approach to therapy for these tumors is to block angiogenesis, or new blood vessel formation.

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• Angiosarcoma

  Angiosarcoma is a rare and clinically highly variable cancer of blood vessels (a form of sarcoma). High grade (aggressive) angiosarcomas can start anywhere in the body. The most common place for angiosarcomas to arise is in the head and neck area, breast (frequently several years after radiation and surgery for breast cancer), bone, or other vital organs such as liver and spleen. Less aggressive forms of angiosarcoma exist as well, such as epithelioid hemangioendothelioma (EHE). There are other rare forms of angiosarcoma, which will not be discussed here. Kaposi sarcoma is also a form of blood vessel sarcoma, but is discussed separately. Kaposi sarcoma is one of the rare forms of cancer caused by a virus, KSHV or HHV-8, which escapes control of the immune system as seen in patients with HIV or in elderly patients, typically living in the areas around the Mediterranean Sea.

  Epidemiology

  Angiosarcomas are relatively rare. They comprise 1-2% of sarcomas in the surgical database from 1982-present from Memorial Hospital. Like other sarcomas, the risk of recurrence depends on the stage of disease. For sarcomas that are localized, low grade sarcomas are stage I, and large, high-grade, deep sarcomas are stage III. If a sarcoma does not have all three features (large, high-grade, and deep), it is stage II. Sarcomas that have traveled to lymph nodes or other sites of the body beyond where they started are considered stage IV, or metastatic, disease. Unlike most sarcomas, which travel via the bloodstream to other organs such as lung or liver, angiosarcomas are one form of sarcoma that travel to lymph nodes more often than most other sarcomas.

  Distinct Clinical Features

  Angiosarcomas tend to have two patterns of growth. In one form they form hard white nodules; in the other, they form blood-filled blebs (looking something like blood blisters) that can be multiple in an area, and grow and spread in an irregular pattern near the surface of the skin, or as masses in soft tissue or other organs. Angiosarcomas have the same proteins within them that are found in blood vessels; they usually contain blood vessel marker proteins CD31 and CD34. As a result they are usually easy to distinguish. It is necessary to distinguish angiosarcomas from hemangiomas, which are non-malignant (benign) collections of blood vessels.

  Treatment and Follow-up for Localized Disease

  Angiosarcomas have a particular ability to recur near the site the tumor first started. As a result, it is more difficult to achieve a clean margin around these tumors at the time of a surgery. For the primary treatment of these tumors, surgery is most often employed, and radiation is often added to try to control the tumor locally. There is no evidence giving chemotherapy after surgical removal of the tumor increases one’s chance for survival. Treatment is also often made more difficult in the breast when the tumor follows a course of radiation; it is often possible to surgically remove the remaining tumor, but it becomes too dangerous to give radiation to the same area twice, the risk being the permanent damage of normal tissue after such radiation. In these situations surgical resection alone is usually recommended.

  Treatment and Follow-up for Metastatic Disease

  In the situation where the tumor is recurrent or metastatic, in some cases radiation or another surgical resection can be offered, but usually treatment consists of intravenous chemotherapy directed against the tumor. The best commercially available chemotherapy drugs for angiosarcomas in our experience at MSKCC have been treatments that contain doxorubicin (including Doxil/Caelyx) or taxanes (docetaxel or paclitaxel). It is possible with careful dose adjustment to be able to treat people with metastatic disease for a year or more with a single type of treatment.

  Targeted Therapies

  Angiosarcomas are an obvious target for anti-angiogenic therapy. Older drugs such as interferon or thalidomide have been examined anecdotally in angiosarcomas, and have not been very effective. In contrast, for very large hemangiomas (benign collections of blood vessels that sometimes cause symptoms), dramatic improvement can be seen with the use of interferon-alfa.
  
  Newer drugs that target blood vessels in principle should target angiosarcomas, but they have not been studied well so far. In 2005-2006, several drugs may be tested that might cause shrinking of angiosarcomas based on targeting the blood vessels growth stimulator VEGF. These drugs include bevacizumab (Avastin®, from Genentech), SU11248 (Pfizer), and BAY43-9006 (Bayer), and AMG706 (Amgen), however, such studies are in the planning stages as of March, 2005. These and other compounds will likely be tested in 2005-2006 against many sarcomas, and there will be particular interest in seeing how people with angiosarcomas respond to this potentially very exciting group of anti-cancer drugs.

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• Chondrosarcoma

• Dermatofibrosarcoma Protuberens

  Dermatofibrosarcoma Protuberans (DFSP) is a tumor of the skin. It is a rare type of sarcoma with low-to-intermediate grade malignancy. It compromises less than 0.1% of all cancers and about 1% of all soft tissue sarcomas.
  
  DFSP tumors occur in the dermis layer of the skin and can invade deeper subcutaneous tissue, such as fat, fascia, and muscle. They are slow growing, and spread laterally or sideways. They may increase in size more rapidly during pregnancy. If left untreated they can come through the skin, ulcerate and become painful. If they are not completely removed they will likely return in the same area. In very rare case or cases left untreated, DFSP can spread to other areas of the body.

  Epidemiology

  DFSP occurs slightly more often in men than women (57% vs 43%) and can occur in all races. It is rare in childhood and affects adults aged 20-50 most often. Approximately 50% of DFSP tumors are found on the trunk, 35% are found on the arms and legs, and 15% are located on the head and neck area. DFSP is locally aggressive and has a high recurrence rate.

  Clinical Features

  Usually, it is first noticed as a skin nodule or lump. They can be quite small (<1 inch) or grow to be several inches in size. They may be bluish, red-brown, or flesh colored. DFSP tumors will appear as a nodule with well-defined edges, however, beneath the skin the tumor spreads with tentacle-like projections, which is why they are locally aggressive and can reoccur.

  Treatment and Follow-up for Metastatic Disease

  DFSP rarely metastasizes.

  Targeted Therapies
  In rare cases, the drug Gleevec (imatinib) is used to treat very large DFSP tumors that cannot safely be removed or the very rare cases of metastases that occur with DFSP.

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• Desmoid Sarcoma

• Ewing’s Sarcoma

  Ewing’s sarcoma, now often referred to as Ewing’s Family of Tumors (EFST), is a small blue round cell sarcoma of bone, but it also can occur exclusively in the soft tissues.  It most commonly occurs in the second decade of life, although it can occur in younger and older patients.  It is a rare tumor, with less than 500 cases diagnosed annually in the United States.  Thus patients should seek treatment at major cancer centers where there is likely to be some experience with the treatment of this disease.  This tumor is most common in Caucasians, and is quite rare among those of African descent.  The tumor most often occurs in the extremities, although 40% occur centrally in the pelvis, vertebrae and chest wall.  Extremity tumors appear to have a better prognosis than do central axis tumors.  The origin of the cell type giving rise to ESFT is thought to be a very primitive mesenchymal cell, perhaps with some neural features.  The tumor is now most clearly identified by the presence of a characteristic chromosomal abnormality and confirmation of the presence of the abnormality should be included in all diagnostic evaluations.

  Epidemiology

  As noted above, ESFT is an exceedingly rare tumor, with annual incidence rates among Caucasian children less than 21 years being in the range of 2-3 cases per million in the U.S.  There are no known predisposition syndromes, although there may be some association with genitourinary developmental abnormalities (undescended testis, replication of the renal collecting system).  The reason underlying the predilection of this tumor for Caucasians remains unknown at the present time.

  Distinct Clinical Features

  Since this tumor is so rare and usually occurs in previously healthy teenagers and young adults, there is often a considerable delay in diagnosis, with one study showing an average of three months from the onset of symptoms until diagnosis.  The most common presenting signs and symptoms are pain and swelling at the site of the primary tumor.  Fevers accompanying these symptoms are also quite common, which reflects the systemic nature of this tumor, even when confined to a single primary tumor site.  Thus the presentation of a young patient with a bony abnormality on x-ray and fever can easily be confused with an infection of the bone, and a biopsy is the only way to establish the diagnosis.  It is important to stress that the biopsy should be done only in close cooperation with an orthopedic oncologist, since position of the biopsy is critical for later surgical resection if the biopsy should turn out to be positive for a malignancy of bone. 

  Treatment and Follow-up for Localized Disease

  ESFT is highly sensitive to chemotherapy and radiation therapy,  and all patients are treated with chemotherapy coupled with surgery and/or radiation therapy to the primary tumor site.  Once the diagnosis is made and prior to initiation of treatment, patients need to be properly staged to search for the extent of the primary tumor and the presence or absence of metastases that will determine the ultimate approach to treatment.  This staging evaluation includes bone scan, CT and MRI exam of the primary tumor and CT of the chest.  In addition, many centers will include a bone marrow evaluation.  Once the staging evaluation is completed, treatment usually begins with chemotherapy given every three weeks for around three months.  Following the three months of “induction chemotherapy,” patients will undergo either surgery or radiation therapy or both to the site of the primary tumor.  If surgery is undertaken, chemotherapy will restart following recovery from the surgery usually within a week or two following surgery.  If radiation alone is used, chemotherapy is usually given together with the radiation, although certain drugs are not given together with the radiation.  The choice of surgery or radiation therapy depends on numerous factors including the resectability of the primary tumor, likely side effects and the local expertise available.   Treatment usually includes 10-14 cycles of chemotherapy.  Once therapy is completed, patients are usually followed closely (every several months) with scans for the first year following completion of treatment, and then less frequently in subsequent years.  Currently, depending on size, location and age, the majority of patients can be cured of localized ESFTs.

  Treatment and Follow-up for Metastatic Disease

  The most common sites of metastases are the lungs, bone and bone marrow.  Although the prognosis for metastatic disease is inferior to localized disease, the site and extent of metastatic disease impacts on prognosis.  Patients with metastases to the lung only generally fare better than those with bone and bone marrow disease.  Treatment of patients with metastatic disease includes similar chemotherapy to those with localized tumors.  Surgery is done less frequently, and most patients receive radiation treatment to their primary tumor site as well as to metastatic sites of disease when feasible.  Patients with lung metastases often receive whole lung radiation at some point during treatment or sometimes it is given at the end of chemotherapy.  The challenge for patients with metastatic disease remains the high rate of recurrence, although most patients respond initially to treatment.  High-dose chemotherapy with peripheral blood stem cell rescue has been used for patients with metastatic disease although results have generally not been superior to standard treatment without high-dose therapy.  Clearly new treatment approaches are necessary to improve on the overall survival of patients with metastatic ESFTs, and ongoing clinical trials are necessary to test such new approaches. 

  Targeted Therapies

  No specific targeted therapies currently exist for the treatment of ESFTs.  However, as noted above, this tumor type is associated with a very specific chromosomal abnormality that we now know leads to the expression of a tumor-specific factor that appears to regulate the expression of a variety of proteins.  Current work is aimed at determining which of these proteins are critical for the malignant behavior of these tumors, with the hope than once identified, these proteins can be the targets for new therapies.

  Related Links

  Lainie's Angels is a website created by the parents of Lainie Afendoulis a twelve year old girl who passed away from Ewing's Sarcoma.

  click here to collapse extended info on Ewing's Sarcoma

• Fibrosarcoma

  Fibrosarcomas are bland appearing firm white tumors and by microscopic examination are composed of sheets of bland appearing spindle shaped cells. It is very important to have such tumors examined by knowledgeable pathologists versed in the diagnosis of sarcomas, given the difficult in discerning them from other important types of sarcomas. In fact, fibrosarcoma is a diagnosis of exclusion, once the possibility of malignant peripheral nerve sheath tumor, myxofibrosarcoma, desmoid tumor, or synovial sarcoma (among others) has been ruled out.

  Epidemiology

  Fibrosarcoma is increasingly rare as a diagnosis compared to other sarcoma subtypes. In older literature, any sarcoma with fibroblasts was termed a fibrosarcoma, and represented two-thirds or more of all sarcomas. In the last 20 years the diagnosis of fibrosarcoma has become much more rare, with better ways of studying tissue such as immunohistochemistry (testing of specific proteins within tumors) and cytogenetics (analysis of chromosomes). Many of these tumors are now termed “MFH” for malignant fibrous histiocytoma, which itself has been renamed “undifferentiated pleomorphic sarcoma” in the latest guide to sarcomas from the World Health Organization (WHO).
  
  Based on data from Memorial Hospital from a database from 1982 to present of patients operated on at that hospital, these tumors comprise approximately 10% of all sarcomas. Their prognosis may be better than that of other sarcomas, perhaps because they are found to be lower grade (less aggressive) than other sarcomas of comparable size, and tend to occur at a slightly younger age than other sarcomas, with a peak incidence between ages 30 and 40.

  Distinct Clinical Features

  Some forms of fibrosarcoma are unique in terms of their biology. For example, Evans’ tumor is a form of fibrosarcoma (low grade fibromyxoid sarcoma), which looks to be a non-aggressive form of sarcoma under the microscope, but behaves badly and frequently travels elsewhere in the body in the form of metastases. Sclerosing epithelioid fibrosarcoma has some features of more common cancers (carcinomas) in terms of the cells seen within the fibrous background of the tumor, which can make ruling out another diagnosis very difficult.

  Treatment and Follow-up for Localized Disease

  Treatment for fibrosarcoma remains focused on treatment of the primary tumor. Surgery is the only curative treatment for these tumors available, and radiation is often used when the tumor measures at least 5 cm (2 inches) in size. The use of chemotherapy after surgical removal of the original tumor to try and destroy microscopic undetected metastatic disease to other parts of the body (adjuvant chemotherapy) remains controversial.
  
  Like all sarcomas, the risk of recurrence after surgical treatment depends on the stage of disease. For sarcomas that are localized, low grade sarcomas are stage I, and large, high-grade, deep sarcomas are stage III. If a sarcoma does not have all three features (large, high-grade, and deep), it is stage II. Sarcomas that have traveled to lymph nodes or other sites of the body beyond where they started are considered stage IV, or metastatic, disease.

  Treatment and Follow-up for Metastatic Disease

  If fibrosarcoma forms metastases, such metastases are usually located in the lungs. If the tumors cannot be easily removed from the lungs surgically (typically when there are multiple tumors or if they are found in difficult locations in the lungs) then chemotherapy is used in an attempt to control the tumor. A standard chemotherapy drug, such as doxorubicin (in its regular form, or in an encapsulated form called Doxil or Caelyx) is frequently used for metastatic disease, and ifosfamide chemotherapy with the bladder protectant mesna is often used as well. Dacarbazine (DTIC) can be considered for treatment of these tumors, as can other commercially available drugs not specifically approved for sarcomas, such as the combination of gemcitabine and docetaxel. In this setting, when available, new medications under study can be used either before or after use of standard chemotherapy drugs in clinical studies, available from an increasing number of institutions.

  Targeted Therapies

  There is presently no specific “targeted” therapy against fibrosarcoma because we have not identified proteins unique to fibrosarcomas that could be used as targets for such treatment. However, it is expected that new drugs available for other soft tissue sarcomas will be used for fibrosarcomas as well.

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• Gastrointerstinal Stromal Tumor (GIST)

  Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. The tumor can originate anywhere from the esophagus to the rectum, but most often comes from the stomach or small intestine. Uncommonly, GIST arises elsewhere in the abdomen outside of the gastrointestinal tract. GIST is a distinct entity from gastrointestinal leiomyosarcoma.

  Epidemiology

  The exact incidence of GIST in the United States is unknown. Previously, the diagnosis was often missed because GIST was not widely recognized and the average pathologist had little to no experience with the tumor. Within the last 10 years, pathologists began using a certain test (CD117 or KIT staining) on tumors suspected to be GIST and this has made it easier to identify GIST. Currently, it is estimated that 3,000 patients in the United States are found to have GIST each year.
  
  GIST affects slightly more males than females. Most patients are between 40 and 80 years of age at diagnosis. In nearly all patients, there is no apparent reason why GIST has developed. GIST has been found to run in only a dozen or so families in the world.
  
  Historically, the 5 year survival of patients after removal of a primary GIST is approximately 50-60%. However, survival has now been markedly improved by the development of targeted chemotherapy (see below). In fact, patients with metastatic GIST treated with imatinib mesylate now have a 2 year survival of about 80% from the time of metastasis.
  
  The prognosis of a patient with primary GIST depends on tumor size, location, and cellular division. Generally, patients with tumors that are 10 cm or greater in size have a high chance of developing tumor recurrence. Meanwhile, those with tumors less than 2 cm are more likely to be cured by surgical resection. Patients with tumors between 2 and 10 cm have an intermediate risk of having the tumor come back after surgery. The location of a primary GIST is also thought to influence outcome. Patients with stomach GIST fare better than those with small intestine GIST. The rate of cellular division (known as mitotic rate) of GIST is determined by examining the tumor under a microscope. Patients with a mitotic rate of 5 or greater per 50 high power microscopic fields have a higher chance of tumor recurrence after removal of a primary GIST. Another important factor in predicting outcome is the presence of tumor spread (metastasis) at the time of diagnosis of a primary GIST; these patients have a worse prognosis.

  Clinical Features

  A primary GIST may be discovered in a variety of ways. Some patients lack symptoms and the tumor is detected during a radiologic examination, abdominal operation, or endoscopy performed for another reason. Other patients have abdominal discomfort or pain, or feel a mass. About 20% of patients will have slow bleeding in their gastrointestinal tract which they will not notice. Others have obvious gastrointestinal bleeding. Occasionally, a patient will develop intense abdominal pain and bleeding due to rupture of a GIST.
  
  Like many sarcomas, GIST tends to push, and not invade, nearby structures. GIST also tends to be very vascular; in other words, it has many blood vessels supplying it. Nevertheless, GIST is often not diagnosed before it is removed. Under microscopic examination, the cells have a characteristic appearance and about 95% of tumors have stain for the KIT protein. It must be emphasized that an expert pathologist should be consulted whenever there is a possibility that a tumor may be a GIST but the diagnosis is uncertain. In particular, it is difficult to recognize the 5% of GIST that do not demonstrate KIT staining.

  Treatment and Follow up for Local Disease

  The treatment for primary GIST is surgical resection whenever possible. The goal of the surgeon is to remove the entire tumor without rupturing it. This may require removing parts of adjacent organs if the tumor adheres to them. During the operation, the surgeon should look carefully throughout the abdomen for the presence of tumor spread to other sites. It is unclear whether any other therapy should be given after successful removal of a primary GIST (see below). Outside of a clinical trial, the current recommendation is that patients should undergo surveillance for tumor recurrence by having a CT scan of the abdomen and pelvis with oral and intravenous contrast every 3-6 months for several years.
  
  In some patients with primary GIST, the tumor may be too large to remove or may require extensive resection of other organs. In this setting, imatinib mesylate may be given for a few months to shrink the tumor and make surgery possible or to reduce the extent of the operation.

  Treatment and Follow-up for Metastatic Disease

  GIST tends to spread (metastasize) initially to the liver or to the lining of the abdomen (called the peritoneum). The initial treatment for metastatic GIST is currently imatinib mesylate (see below). Within 1-2 months, the tumors will shrink or stabilize in size in over 80% of patients. Other agents are available for patients who do not respond to imatinib. In patients who respond to imatinib, consideration should be given to removing their residual tumors whenever possible. Unlike targeted therapy, traditional chemotherapy has almost no effect on GIST and has mostly been abandoned.

  Targeted therapies for GISTs

  Imatinib mesylate (also known as Gleevec or STI571) was developed by Novartis Pharmaceuticals (Basel, Switzerland). Imatinib is a selective inhibitor of KIT and PDGFRA. These 2 proteins are involved in cell growth. Over 80% of patients with GIST have a mutation in the KIT gene, and about 5% have a mutation in the PDGFRA gene. Imatinib also inhibits another protein that is involved in a type of leukemia. The first patient with metastatic GIST was treated with imatinib in the year 2000. Imatinib is a pill that is taken daily. Unlike traditional chemotherapy, it is generally well-tolerated. The most common side effects are swelling around the eyes or in the legs, a skin rash, and minor stomach discomfort or diarrhea. Remarkably, imatinib provides benefit to over 80% of patients with metastatic GIST. George Demetri from the Dana Farber Cancer Institute and colleagues have shown that about 30% will have their tumor stop growing and another 50% will have their tumor shrink to less than half the original size. Rarely, imatinib may cause a small tumor to disappear completely. Imatinib has dramatically affected the outcome of patients with metastatic GIST. As stated above, the 2 year survival in metastatic GIST from the time of imatinib therapy is about 80%. In contrast, other chemotherapy agents used in the past provided almost no benefit.
  
  The best dose of imatinib for metastatic GIST is currently being evaluated in 2 large studies. The initial data from the United States study show that the doses of 400 mg per day and 800 mg per day appear to be equivalent. It is generally recommended that imatinib be continued in patients with metastatic GIST unless the tumor becomes resistant to it. About half of the patients treated with imatinib will have their tumor start to grow again by 2 years. For this reason, we recommend that patients who respond to imatinib should be considered for complete surgical resection of their metastatic disease whenever possible. Postoperatively, imatinib should be resumed due to the likelihood of residual microscopic disease.
  
  While it is clear that imatinib is useful for metastatic GIST, it is uncertain whether it should be used in patients following the complete resection of primary GIST. This is called adjuvant therapy. Adjuvant therapy is performed to reduce or eliminate the chance of a tumor coming back after its removal. Adjuvant imatinib is being studied in 2 clinical trials in this country and Canada. One trial (American College of Surgeons Oncology Group (ACOSOG) Z9000) of 106 patients with high risk primary GIST has completed accrual and the other trial (ACOSOG Z9001) in patients with a GIST 3 cm or greater in size has accrued over 300 patients so far. In both trials, 1 year of imatinib at a dose of 400 mg per day is given. In ACOSOG Z9001, half the patients receive a placebo. Because GIST is a relatively uncommon disease, both trials have required the participation of multiple cooperative groups of physicians. Data should become available in the next few years as to whether adjuvant imatinib is beneficial.
  
  There are other targeted agents that are currently being tested for GIST. The most developed drug is SU11248, which was originally made by SUGEN, Inc. and is now owned by Pfizer, Inc. It inhibits KIT and PDGFRA as well as 2 other proteins called VEGFR and Flt3. So far, it has only been used in patients who have failed imatinib therapy and the agent will likely be approved shortly for use outside of a clinical trial.

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• Non-Uterine Leiomyosarcoma

• Uterine Leiomyosarcoma

Uterine leiomyosarcoma (LMS) is a smooth muscle tumor that arises from the muscular part of the uterus. Leiomyoma, or fibroid, is a very common benign smooth muscle tumor of the uterus. A LMS may develop in approximately one to five out of every 1,000 women with fibroids. Uterine LMS appears to behave in a slightly different way from LMS in other organs.

Epidemiology

Uterine LMS is a rare tumor. Only about 6 out of one million women will be diagnosed with this rare cancer in the U.S. annually. The average age of diagnosis is 51 years. Uterine LMS is most often discovered by chance when a woman has a hysterectomy performed for fibroids. It is difficult to accurately diagnose LMS before surgery because most women with LMS will have multiple fibroids making it difficult to know which ones should be biopsied. Magnetic resonance imaging (MRI) might offer some information but is not entirely accurate. A special MRI exam in combination with a blood test for serum lactic dehydrogenase (LDH) level has been reported to be accurate in diagnosing uterine LMS. MRI-guided biopsy of suspected LMS has also been reported. These things appear to be promising approaches. However, they should not be routinely performed until we can further test their value.

Surgery is the primary therapy for patients when they are first diagnosed with uterine LMS. The cancer has not spread beyond the body of the uterus (stage I and II) in approximately 70-75% of patients. This tumor tends to be aggressive. The 5-year survival rate is only 50% with patients whose tumor is confined to the uterus. The 5-year survival rate for most other gynecologic cancers can be more than 90% if the tumor has not spread outside the organ of origin. Women with uterine LMS that has spread beyond the uterus and cervix have an extremely poor prognosis.

Various characteristics of uterine LMS have been suggested to affect the prognosis of a patient with this cancer. Features such as tumor size, DNA content, hormone receptor status, cellular division (i.e. mitotic rate), and tumor grade have all been reported by different investigators to be related to prognosis. However, none of these things can reliably predict what will happen. In addition, none of these features should influence a physician’s treatment recommendations.

Despite complete surgical removal and best available treatments, approximately 70% of patients will develop a recurrence within an average of 8 to 16 months after the initial diagnosis. Recurrent uterine LMS is difficult to manage. Options include surgery, chemotherapy, and radiation therapy.

Clinical Features

There are no reliable methods to diagnose a uterine LMS before surgery. It is almost always found by chance at the time of a hysterectomy for what was thought to be benign fibroids. There are no specific signs or symptoms, especially in young women. Rapidly changing, or enlarging, fibroids in premenopausal women should be investigated. The vast majority of the time these are not malignant fibroids that are growing in a menopausal woman are concerning and should always be surgical removed.

This cancer can grow to be very large and often recur. Nearly 70% of women with stage I and II uterine LMS will develop a recurrence. Tumor size and mitotic rate do not appear to be associated with prognosis unlike LMS from other sites. Uterine LMS tends to metastasize to the liver and lung frequently. Surgical removal, if possible, is the best treatment. Chemotherapy and radiation therapy have limited roles in the treatment of these tumors.

Treatment and Follow-up for Local Disease (stages I and II)

Surgery is the primary therapy. All patients with stage I and II LMS should have a total abdominal hysterectomy (TAH) performed. Removal of both fallopian tubes and ovaries (known as a bilateral salpingo-oophorectomy or BSO) is recommended for women who are menopausal or have metastatic disease. The value of performing a BSO in younger women with normal appearing ovaries is unclear. Microscopic metastases to the ovary occur in only 3% of women with uterine LMS. Many physicians have recommended BSO in all women with uterine LMS because of the fear that these tumors are stimulated by hormone (estrogen and progesterone) production from the ovaries. It is also feared that the chances of the cancer coming back (known as recurrence) are worse if the ovaries are not removed. This is a valid theoretical concern. However, there was no difference in recurrence or survival in a recent small report comparing women with uterine LMS who had a BSO and those who did not have a BSO. In addition, the receptors for estrogen and progesterone are found less often in LMS than in fibroids.

Removal of the ovaries will make you menopausal immediately. Menopause, especially one that is induced so quickly, can create significant symptoms, such as hot flashes and mood changes. These can often be controlled somewhat with medications. Menopause also increases the risk of bone loss or osteoporosis, which makes the bones weak. This makes it easier for bones to break or fracture. Complications from osteoporosis-related fractures are one of the leading causes of sickness and death in menopausal women. All of this must be carefully considered when deciding whether to have your ovaries removed. It is a very difficult and personal decision. The information that we have to help guide us is based on experiences with very small numbers of women.

It has also been controversial as to whether “staging” procedures, in which lymph nodes are assessed, are necessary. The rate of lymph node involvement is less than 3%. It is not beneficial to perform another surgical procedure to sample lymph nodes in patients whose diagnosis has been confirmed after hysterectomy and in whom there was no obvious evidence of cancer spread outside the uterus. Such procedures have associated risks and will not change the management of this cancer.

Currently, there has been no proven overall benefit of using any further chemotherapy or radiation therapy after complete surgical removal of all visible uterine LMS. Chemotherapy and/or radiation therapy given after complete surgical removal of all tumor is known as “adjuvant” therapy. Adjuvant radiation to the pelvis has been shown to decrease the chance that the cancer will come back in the pelvis. It does not change the chance of the cancer returning in other areas, such as the lung or liver; this happens nearly 80% of the time when a recurrence develops. Pelvic radiation to all patients who have all the cancer removed should not be routinely offered. However, some physicians and patients do elect to try radiation therapy to reduce the chance that the tumor returns in the pelvis. This is done with an understanding that the chances of surviving are no different than for those who do not get radiation therapy.

The use of adjuvant chemotherapy has also not yet been proven beneficial. The largest trial of adjuvant chemotherapy in patients with all types of uterine sarcomas, using one of the most active drugs, doxorubicin, showed the chances of recurrence and survival were the same in patients who either received or did not receive doxorubicin. Currently, the use of routine adjuvant chemotherapy is not recommended, except in the context of a clinical trial. Recently, a combination of two other drugs, gemcitabine and docetaxel, produced a dramatic response in patients with recurrent or advanced uterine LMS. This combination is being investigated in the adjuvant setting. Patients on this trial are given gemcitabine and docetaxel in the adjuvant setting to hopefully decrease the possibility of recurrence and improve the chances of survival.

Patients should be followed very closely after surgery. Many physicians will recommend that patients are examined every 3 months for the first 3 years after diagnosis, every 6 months for 2 years after that, and then annually. A computed tomography (CT) scan is often done every 6 months to one year. It might be useful to have a CT scan done soon after surgery or completion of therapy in order to have a starting point for future comparisons. Any unusual symptoms should be evaluated by a physician.

Surgery is the primary therapy. All patients with stage I and II LMS should have a total abdominal hysterectomy (TAH) performed. Removal of both fallopian tubes and ovaries (known as a bilateral salpingo-oophorectomy or BSO) is recommended for women who are menopausal or have metastatic disease. The value of performing a BSO in younger women with normal app

Treatment and Follow-up for Metastatic (stages III and IV) and/or Recurrent Disease

The treatment of patients with metastatic and/or recurrent disease needs to be determined on case-to-case basis. The best possible treatment is surgery to completely remove any and all tumor. However, this is not always possible. Radiation therapy to try and shrink the tumors and help improve the chances of surgical removal may be considered but is not always successful. Responses to radiation therapy and chemotherapy alone are limited. The most active drugs in the past, doxorubicin and ifosfamide, provided a 30% response rate when used in combination. A recent trial using the combination of gemcitabine and docetaxel found a 55% response in patients with advanced, primary, or recurrent and surgically unresectable uterine LMS. Other drugs, such as vincristine, cyclophosphamide, dacarbazine, topotecan, paclitaxel, etoposide, and hydroxyurea have been used, either alone or in combinations with disappointing results. In addition, the average time until the tumor progresses or recurs after using any of these drugs, including the most active ones, is less than 1 year.

Follow-up is based on case-to-case basis and should be discussed with your physician.

Targeted Therapies

There are no known effective targeted therapies for uterine LMS. Clinical trials are investigating new treatments. All patients with this disease should strongly consider participating in clinical trials.

Uterine LMS is a rare cancer that requires specialized care. All patients should seek the opinion of physicians who are trained to treat this disease, such as gynecologic oncologists or specialized surgical oncologists. They will be able to help guide you in making the difficult decisions to treat this disease.

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• Liposarcoma

• Malignant Fibro Histiocytoma (MFH)

• Malignant Peripheral Nerve Sheath Tumor (MPNST)

• Osteosarcoma

  Osteosarcoma, the most common primary malignant bone tumor, is composed of spindle cells that produce osteoid. Osteosarcoma is a disease primarily of adolescents and young adults, although it can occur in older individuals. In older individuals it can frequently be linked to Paget’s disease, fibrous dysplasia or radiation exposure. In younger individuals it is virtually always high grade and is a highly aggressive tumor. In older individuals, osteosarcoma can be a low grade tumor which is locally invasive but has a much lower tendency to metastasize.
  
  The most common clinical presentation of osteosarcoma is pain in the involved region of bone, with or without an associated soft tissue mass. Pain is often attributed to trauma or vigorous physical exercise, both of which are common in the patient population at risk. Symptoms are usually present for several months before the diagnosis is made. Osteosarcoma can occur in any bone of the body. Approximately half of all osteosarcomas originate in the region around the knee. The upper arm is the next most common location but it can present in any bone.
  
  Osteosarcoma metastasizes very early in its evolution. Approximately 20% of patients present with radiographically detectable metastatic disease, but virtually all patients have subclinical, microscopic metastasis. The most frequent site for metastatic disease is the lung. Much less frequently, metastases at initial diagnosis occur in other bones and soft tissues. Systemic symptoms, such as fever and weight loss, occur rarely in the absence of very advanced disease.

  Epidemiology

  Osteosarcoma has a bimodal age distribution with the first peak in the second decade of life and the second among older adults. In older patients osteosarcoma arises frequently in abnormal bone, such as those affected by long standing Paget’s disease. Estimates of the frequency of osteosarcoma vary. It is extremely rare before the age of 5. The peak incidence occurs in the second decade of life during the adolescent growth spurt. The modal age of incidence is 16 years for girls and 18 for boys. It is estimated that approximately 400 children and adolescents younger than 20 years of age are diagnosed with osteosarcoma each year in the United States. Boys are affected more frequently in most series and the incidence in African American children is slightly higher than in caucasians.

  Treatment and Follow-up for Localized Disease

  Almost all patients with osteosarcoma have microscopic metastatic disease at the time of diagnosis. The successful treatment requires systemic chemotherapy. Despite the effectiveness of chemotherapy against microscopic disease it cannot control clinically detectable disease. Tumors that can be clinically detected by conventional techniques, both at the primary site and all sites of metastatic disease require local control. Osteosarcoma is extremely resistant to radiation therapy, and therefore local control is usually surgery. Advances made in surgery have significantly improved the clinical practice and options available.
  The last national North American based randomized Phase III pediatric cooperative group study jointly administered by the Children’s Cancer Group and the Pediatric Oncology Group addressed two study questions. The study tested whether the addition of ifosfamide and/or muramyl tripeptide – phosphatidyl ethanolamine (MTP-PE) to the three other agents used in the standard treatment of osteosarcoma (doxorubicin, cisplatin, high dose methotrexate) would improve the probability of disease free survival. The preliminary results of this trial did not demonstrate a benefit for the patients who were treated with the addition of ifosfamide or muramyl tripeptide – phosphatidyl ethanolamine alone. Standard chemotherapy at present is therefore still comprised of cisplatin, doxorubicin and high dose methotrexate.
  
  Surgical treatment needs to be a complete resection of the tumor with a margin of normal tissue. As most tumors occur in an extremity this can be achieved in virtually all patients. Historically this surgery was an amputation. Now the vast majority are treated with limb salvage procedures. A variety of options for limb salvage exist dependent upon the size, location of the tumor and age of the patient among many other factors.

  Treatment and Follow-up for Metastatic Disease

  The standard management of patients with metastatic disease follows the same general principles as those who present with localized disease. Patients undergo surgery to remove all evidence of bulk disease. This includes the primary tumor as well as all sites of detectable metastatic disease. Several chemotherapy and surgical timing approaches have been reported for the treatment of these patients. Survival has clearly been enhanced by aggressive treatment designed with a curative intent.

  Targeted Therapies

  New therapies are clearly needed for the treatment of osteosarcoma patients. Patients who present with metastatic disease or develop recurrent disease have a poor prognosis and are appropriate for consideration for clinical trials of novel agents. Clinical trials are being performed at a number of institutions throughout the United States. Monoclonal antibodies against osteosarcoma may prove useful as treatments or for delivering drugs or radiopharmaceuticals directly to tumor. Therapies such as trastuzumab, which targets the epidermal growth factor receptor type-2, are being tested in osteosarcoma. Other biologic approaches such as the use of inhaled granulocyte macrophage colony stimulating factor are being tested and the use of others such as the interleukins and interferons are being tested at some sites. Bone seeking isotopes such as samarium may allow the delivery of extremely high dose local radiation therapy, perhaps providing an appropriate treatment approach for sites of mineralized disease. Studies of new drugs such as trimetrexate are underway as are studies of conventional agents administered via inhalation to treat pulmonary metastases.

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• Rhabdomyosarcoma

Rhabdomyosarcoma is the most common malignant soft tissue tumor of children and young adults. It is an uncommon tumor in adults over the age of 30. There are approximately 250 cases per year in the United States. Males are affected slightly more than females. More than half the cases occur below the age of 10 years.

The malignant cells of this tumor have features characteristic of developing skeletal muscle. Although rhabdomyosarcoma can appear in the extremities, it is more frequently seen in other areas: the head and neck region, the vaginal area in females, the testicular area in males, or the bladder and prostate. Most commonly the disease presents as a painless mass. It can also be diagnosed secondary to bleeding or pain at the site. Sometimes the tumor will present as a grape-like mass, somewhat unique among the soft tissue tumors.

Epidemiology

Prognosis for most of those diagnosed with rhabdomyosarcoma has improved significantly in the last 30 years. Overall survival rates have improved from 25% to more than 70% in recent reports. Prognosis is influenced by the primary site of disease, the extent of disease and the histologic subtype. Favorable primary sites include the orbit, the head and neck region (except the areas near the lining of the nervous system), the vagina and the area near the testis. The extent of the disease, particularly after surgery, is also important. Those who have surgery which completely or almost completely removes all tumors have a better outlook than those who have significant disease remaining after surgery.

Most rhabdomyosarcomas occur without predisposing risk factors. In some cases these tumors are associated with a genetic predisposition to cancer such as the Li-Fraumeni syndrome.

Rhabdomyosarcoma can involve regional lymph nodes at a higher rate than other soft tissue sarcomas, and this can impact on prognosis as well. Children who present with metastatic disease at diagnosis (approximately 20% of cases) fare less well, but those with limited metastatic sites (two or fewer) and favorable histology can have survival rates approaching 40%. With regard to histology, embryonal rhabdomyosarcoma has a more favorable prognosis than the alveolar subtype.

Treatment and Follow-up for Localized Disease

Treatment for local disease includes a combination of chemotherapy and surgery. Radiation may also be employed when complete tumor resection has not been possible. Chemotherapy is indicated for all patients with rhabdomyosarcoma, but the amount of chemotherapy and the duration of treatment can vary depending on risk factors. The drugs which have demonstrated activity in rhabdomyosarcoma include vincristine, actinomycin, cyclophosphamide, ifosfamide, doxorubicin, carboplatin, etoposide, irinotecan and topotecan. These drugs are given in various combinations dependent on disease evaluation. The two drug regimen, vincristine and actinomycin, is employed for those with a favorable prognosis, and alternate two or three drug combinations are used in other settings.

Treatment and Follow-up for Metastatic Disease

Metastatic disease most commonly occurs in the lungs, lymph nodes or bone marrow but many other locations are possible. Metastatic disease developing after initial treatment or locally recurrent disease is still treatable, but the outcome is generally less favorable and particularly for those with metastatic disease the overall prognosis is guarded. The role of intensive regimens utilizing bone marrow or peripheral blood stem cells is unproven at this time.

When rhabdomyosarcoma occurs in adults, it is generally the pleiomorphic subtype which portends a less favorable prognosis. Treatment can be given in a manner similar to the regimens used in children, although actinomycin is less commonly used in the adult population.

Targeted Therapies

No specific targeted therapies exist for rhabdomyosarcoma at present. Specific chromosomal translocations which give rise to different fusion proteins have been delineated for alveolar rhabdomyosarcoma and these are potential targets for future therapies. In addition, these fusion proteins identify patients with differing risks (PAX7-FKHR more favorable than PAX3-FKHR).

Stage 1: Favorable localized disease completely resected
Stage 2: Localized disease at an unfavorable primary site, less than 5 cm in size and without lymph node involvement
Stage 3: Localized disease at an unfavorable primary site and either greater than 5 cm in size or with lymph node involvement.
Stage 4: Metastatic disease at diagnosis

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• Synovial Sarcoma

  Synovial sarcoma most commonly affects adolescents and young adults in age 15-40. It originates from mesenchymal cells, but not from the synovium as the name implies. More than 90% of synovial sarcomas demonstrate t(X:18) translocation involving SYT and SSX genes, resulting in abnormal fusion (chimeric) protein (SYT-SSX). The fusion protein has altered function and represents the initiating molecular event leading to tumor formation. Synovial sarcoma can spread to other part of body mainly through blood circulation, sometimes through lymph node. Metastasis occurs in half of all cases, months to years after the initial diagnosis, or presents at the time of diagnosis.

  Epidemiology

  Synovial sarcoma is the fourth most commonly occurring sarcoma, accounting for 8-10 % of all sarcoma. The incidence is estimated to be 900 new cases a year in US. There is 2-4 fold predilection of development of synovial sarcoma for males over females. People with Li-Fraumeni syndrome (loss of p53 gene function) and neurofibromatosis (altered function of NF1 gene) are associated with higher risk. The poor prognostic factors include (1) distant metastasis, (2) age older than 25 years, (3) tumor size of greater than 5 cm, (4) poorly differentiated area seen in histology.

  Clinical Features

  Synovial sarcoma most commonly presents in lower extremities, but can also present in upper extremities and represents one of the three most common sarcomas in upper extremities. It can present in trunk, head & neck, infrequently in lungs. Synovial sarcoma usually presents with a mass, often deep-seated, rapidly growing with or without pain. Other presentations depend on the specific anatomical location(s), i.e. pneumothorax (punctured lung) or hemoptysis (coughing blood) or cough due to lung metastasis, bone pain or pathological fracture due to bone metastasis, G.I. symptoms due to metastasis to liver, abdomen or pelvis. The 5-, 10-, and 20-year overall survival rates for the non-metastatic adult group are approximately 66%, 48%, and 38%. The Pediatric multi-center study show the estimated 5-year overall survival and event-free survival rates for the entire group were 80% and 72%, respectively.

  Treatment and Follow-up for Localized Disease

  For tumor size of 5 cm or less, limb-saving surgical resection with generous margin with or without radiation therapy is recommended. For tumor greater than 5 cm, multi-disciplinary approach using pre-operative (neoadjuvant) chemotherapy, plus pre-operative radiation treatment, followed by surgery is recommended, although the role of chemotherapy continues to be debated.

  Treatment and Follow-up for Metastatic Disease

  Multi-disciplinary approach utilizing chemotherapy, radiation treatment and limb-sparing surgery is recommended. The goals are to control disease as well as preserve quality of life.

  Targeted Therapies

  Currently, there is no targeted therapy yet. More than 90% of synovial sarcoma show specific translocation t(X:18) involving SYT and SSX genes. SYT and SSX and the abnormal fusion (chimeric) protein (SYT-SSX) represent tumor-specific abnormal molecules and are ideal targets for drug therapy and vaccine/immunotherapy.

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