Oncology

Bone and Soft Tissue Sarcomas

Sarcomas of soft tissue and bone

What every physician needs to know:

Sarcomas are malignancies of connective tissue, e.g., bone, cartilage, skeletal or smooth muscle, fibroblasts, fat cells, blood vessels. They may occur at any age. Specific sarcomas are characteristic of different age groups, and given the number of different types of tissues involved, it is not surprising that there are at least 70 different histological types of sarcoma.

Sarcomas are far less common than benign connective tissue tumors such as lipomas or fibromas. Just like a palpable mass in the breast requires a biopsy, a growing lump should be biopsied if there is any question as to its nature. There are also connective tissue tumors of intermediate aggressiveness such as desmoid tumors/deep fibromatoses that range from indolent to life threatening.

The treatment of sarcomas is best undertaken at a center with multidisciplinary expertise in pathology, surgery, medical or pediatric oncology and radiation oncology. For example, any biopsy must be performed carefully to insure that the primary resection of the tumor does not require removal of more normal tissue than necessary. The fact that each sarcoma has different biology also underscores the benefit of specialists in this area being involved in management of all patients with these diagnoses.

Are you sure your patient has sarcoma of soft tissue and bone? What should you expect to find?

Sarcomas typically present as growing, painless masses. Lipomas, the most common benign soft tissue tumor, outnumbers sarcomas by 10 to 100 fold, and tend to be soft, mobile and superficial. Sarcomas are typically firmer than fat (even liposarcomas) and grow over the course of weeks to years, depending on the histology and specific patient, whereas lipomas grow even more slowly.

Around half of sarcomas occur in the lower extremity, but any site in the body from the scalp to the toes may be affected.

Radiological studies such as MRI and CT scan will demonstrate the mass, and a biopsy (performed carefully to insure no greater operation is necessary later) confirms the diagnosis. Expert centers may change the diagnosis on as many as 5-10% of samples reviewed, thus if there is a suspicion of a sarcoma that is not borne out in the pathology report, a second opinion at an expert center can be very helpful.

Beware of other conditions that can mimic sarcomas:

Occasional sarcomas are misdiagnosed as melanoma, carcinoma, or even lymphoma. The diagnostic difficulties are especially prevalent with sarcomas that have characteristics of other cancers e.g. synovial sarcoma, epithelioid sarcoma, follicular dendritic cell tumor. An expert pathology review is critical to insure proper therapy.

Which individuals are most at risk for developing sarcoma:

There are no clear causes of most sarcomas. There have been studies of exposure to dioxins and herbicides such as Agent Orange, but these have demonstrated no clear relationship to the development of sarcomas.

However, a significant number of sarcomas are caused by therapeutic radiation, as is used for Hodgkin lymphoma or breast cancer, with a median 9-10 year latency. This risk never disappears, even 30+ years after radiation has been administered.

Rare sarcomas are associated with familial syndromes, such as Li-Fraumeni syndrome, neurofibromatosis type I, familial GIST, Carney-Stratakis syndrome, and familial adenomatous polyposis. Patients with history of other familial cancer syndromes also occasionally develop sarcomas, such as BRCA1, BRCA2 and others.

Patients with Paget's disease of bone have a higher incidence of osteogenic sarcoma than the normal population.

Rare patients with lymphedema will develop (lymph) angiosarcoma, which is known as Stewart-Treves syndrome. There is also a weak link between vinyl chloride exposure and angiosarcoma of the liver, but these are exceedingly rare events.

What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

For soft tissue sarcomas, a biopsy of the mass is essential for diagnosis. The biopsy must be placed with surgery in mind, as the biopsy tract will have to be removed with the tumor. Often, a core needle biopsy is sufficient to make the diagnosis of a soft tissue sarcoma. For tumors in extremity, these biopsies are best performed by orthopaedic surgeons with experience in sarcomas, since they will be the best people to ultimately remove the tumor, at which time both the biopsy tract and a normal tissue around the tumor are usually removed.

For bone tumors, both plain radiographs as well as either CT or MRI images, and biopsy are needed for diagnosis. There are no changes in either imaging or biopsy that are absolutely related to diagnosis, but with the two sets of data combined, the diagnosis can usually be made. This data is best reviewed in a multi-disciplinary setting to get a sense of the possible diagnoses involved.

For primary soft tissue tumors, MRI is generally preferred for imaging of the primary tumor site, but CT scan with new reconstructive techniques can yield equivalent information. Bony primary sarcomas are well imaged by CT or MRI, and plain films provide very useful data, especially in the primary setting.

In screening for metastatic disease, CT scans yield the best anatomical resolution. PET-CT scans can identify occult metastatic disease before surgery is contemplated, but adds little to nothing for routine follow up. There is a very real false positive and false negative rate for PET in sarcoma, and its lack of anatomic resolution makes it an expensive test that generally exposes patients to greater amounts of radioactivity than necessary.

We generally employ CT with contrast for abdomen and pelvis, and CT chest without contrast if there is no primary in the thorax where contrast will be more helpful. After a period of follow-up of 3-5 years we will revert to CXR for follow-up, but will monitor for recurrence of sarcomas for 10 years or more, monitoring for unusual late relapse patients.

Staging

See Table I. The TNM staging of bone sarcomas, Table II. The TNM Staging of soft tissue sarcomas, Table III. The TNM staging of gastrointestinal stromal tumor (GIST).

Table I.

TNM Staging of Bone Sarcomas

Table II.

TNM Staging of Soft Tissue Sarcoma

Table III.

TNM Staging of Gastrointestinal Stromal Tumor (GIST)

What therapies should you initiate immediately ie, emergently?

Surgery is nearly always limb-sparing. Amputation rates for primary tumors is now less than 5% and often involves ray amputation in the hand, forefoot or BKA. Amputations for sarcomas of the foot in which the functional outcome of limb sparing surgery and radiation is inferior to that from the more aggressive operation. Limb perfusion with TNF and chemotherapy (usually melphalan) is approved in Europe but is not available in the United States for local-regionally advanced sarcomas that are otherwise unresectable.

For GIST, the standard of care for easily resectable disease is surgery. 3 years of adjuvant imatinib is the standard of care for high risk disease (gastric GIST > 5 cm with > 5 mit/ 50 hpf; non gastric GIST > 5 cm OR 5 mit/50 hpf, the "rule of fives"). For metastatic disease imatinib is the approved first line therapy, and sunitinib is approved for second line therapy.

For soft tissue sarcomas, other than Ewing sarcoma and rhabdomyosarcoma, the active agents in metastatic disease vary to some degree by subtype, and include doxorubicin, ifosfamide, dacarbazine for leiomyosacomas, gemcitabine-docetaxel for leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS, formerly MFH, malignant fibrous histiocytoma). Dacarbazine (DTIC) and its orally administered cousin temozolomide are active by and large only in leiomyosarcoma and possibly solitary fibrous tumor. Taxanes have specific activity in angiosarcomas.

In addition, in 2015 two drugs were approved for metastatic or unresectable soft tissue sarcoma after treatment with an anthracycline. Trabectedin (a novel DNA alkylator derived from the sea squirt) has specific activity in myxoid-round cell liposarcoma and minor activity in dedifferentiated (but not purely well differentiated) liposarcoma and was approved) for patients with liposarcoma and leiomyosarcoma based on a 2.7-month improvement in progression-free survival compared with dacarbazine. Eribulin mesylate (a microtubule targeting agent derived from the Halicondria sponge) demonstrated an improvement in overall survival from 8.4 to 15.6 months compared to dacarbazine, although the benefit was limited to patients with liposarcoma.

Olaratumab, a recombinant human IgG1 monoclonal antibody that binds the platelet-derived growth factor receptor alpha (PDGFRα), preventing PDGF binding and receptor activation, is approved for first-line therapy in combination with doxorubicin for metastatic or unresectable soft tissue sarcoma types where an anthracycline would be an appropriate drug. This was based on a phase II trial demonstrating an almost 14-month improvement in overall survival (26.5 vs. 14.7 months) compared to doxorubicin monotherapy.

Clinical trials, where available, are always a reasonable option for sarcoma patients, given the relatively limited number of therapeutic options among standard cytotoxic agents.

What should the initial definitive therapy for the cancer be?

Only patients with metastatic disease causing life-threatening or morbid conditions e.g. spinal cord compression, require immediate attention. An accurate diagnosis is usually more important than starting therapy. If anything, surgery can be considered the primary approach, if all else is equal, as chemotherapy or radiation can be given post-operatively. However, for larger tumors that would cause a great deal of surgical morbidity, chemotherapy or radiation can be considered pre-operatively.

For soft tissue sarcomas, accurate diagnosis is important to generate an appropriate treatment plan. Surgery is generally the mainstay of therapy, but radiation is often given for tumors over 5cm in greatest dimension; therapy can be given preoperatively or postoperatively, depending on the risk to the patient and concerns of the surgeon and radiation oncologist. For a small number of tumors, chemotherapy will be given first. Intra-arterial chemotherapy is used at some specialist centers, but is not generally used in the community given technical challenges when patients develop complications.

The treatment is depended upon the specific diagnosis. For most larger soft tissue sarcomas the primary treatment is surgery followed by adjuvant radiation, or neoadjuvant radiation followed by surgery. The use of doxorubicin-ifosfamide-[mesna] (AIM) chemotherapy remains controversial, since the benefit, if any, is a small one.

For diagnoses of sarcomas more common in children i.e. osteogenic sarcoma, rhabdomyosarcoma and Ewing sarcoma, chemotherapy is generally given first, followed by surgery and/or radiation therapy.

For desmoid tumors/deep fibromatosis, given the morbidity of surgery in many patients, systemic therapy is often utilized (antiestrogens, liposomal doxorubicin (Caelyx(R), Doxil(R)), or sorafenib). Such tumors do not have metastatic potential and are often overtreated, resulting in greater patient morbidity than necessary.

Selected chemotherapy regimens for soft tissue and bone sarcomas are listed below. Bone sarcoma regimens have been studied principally in the pediatric setting.

Soft Tissue Sarcomas

AIM (Doxorubicin, Ifosfamide, Mesna):

  • Doxorubicin total dose 75 mg/m2 per cycle IV (25 mg/m2/day IV push daily for 3 days).

  • Ifosfamide 2500-3000 mg/m2 IV over 2-3 hours daily for 4 days.

  • Mesna to give 60-100% of the ifosfamide dose IV in split doses before and 3-4 and 6-8 hours after each dose of ifosfamide. Mesna may also be given orally at twice the IV dose.

Repeat cycle every 21 days. Prophylactic myeloid growth factors (e.g., G-CSF, pegfilgrastim) are recommended.

Olaratumab-Doxorubicin:

  • Doxorubicin 75 mg/m2 per cycle IV on Day 1

  • Olaratumab 15 mg/kg IV on Day 1 and 8

Repeat cycle every 21 days. After 8 cycles doxorubicin is stopped but olaratumab may be continued until progression or unacceptable toxicity.

Gemcitabine-Docetaxel:

  • Gemcitabine 900 mg/m² IV over 90 min on days 1 and 8.

  • Docetaxel 75 mg/m² on day 8. The previously published dose of 100 mg/m² is generally too high for use outside a study.

Repeat cycle every 21 days. Prophylactic myeloid growth factors (e.g., G-CSF, pegfilgrastim) are recommended. Reduce doses 25% if extensive prior chemotherapy or pelvic radiation therapy.

Trabectedin:

  • 1.5 mg/m2 continuous IV infusion over 24 hours on day 1.

Repeat cycle every 21 days. 20 mg dexamethasone premedication recommended prior to each administration. Approved for metastatic or unresectable disease following treatment with an anthracycline.

Eribulin:

  • 1.4 mg/m2 IV on days 1 and 8.

Repeat cycle every 21 days. Approved for metastatic or unresectable disease following treatment with an anthracycline. Only patients with liposarcoma benefit and approval is limited to this histologic subtype.

Gastrointestinal Stromal Tumors (GIST):

  • Imatinib 400 mg PO daily (can be increased up to 800 mg PO daily).

For progressing (2nd-line) disease:

  • Sunitinib 50 mg PO daily for 4 weeks on/2 weeks off every 6 weeks. An alternative schedule is 37.5 mg oral daily. Frequently, the dose is started at 25 mg oral daily and increased as tolerated.

For post-sunitinib progressing (3rd-line) disease:

  • Regorafenib 160 mg PO daily for 3 weeks on/1 week off every 4 weeks.

Bone Sarcomas

Ewing Sarcoma

High-dose VAI (Vincristine, Adriamycin, Ifosfamide):

  • Vincristine 1.4 mg/m2, 2mg maximum dose, IV on day 1.

  • Doxorubicin total dose 75 mg/m2 per cycle IV (25 mg/m2/day IV push daily for 3 days).

  • Ifosfamide 2500-3000 mg/m2 IV over 2-3 hours daily for 4 days.

  • Mesna to give 60-100% of the ifosfamide dose IV in split doses before and 3-4 and 6-8 hours after each dose of ifosfamide. Mesna may also be given orally at twice the IV dose.

Repeat cycle every 21 days. Prophylactic myeloid growth factors (e.g., G-CSF, pegfilgrastim) are recommended.

IE/CAV (Ifosfamide, Etoposide/Cyclophosphamide, Doxorubicin, Vincristine)- pediatric regimen:

  • Ifosfamide 1800 mg/m² IV daily x 5 days (with mesna).

  • Etoposide 100 mg/m² IV daily x 5 days.

2-3 weeks later

  • Vincristine 1.5 mg/m² IV day 1, cap dose at 2 mg.

  • Doxorubicin 75 mg/m² IV day 1, (in pediatric populations, often given with dexrazoxane for all doses.

  • Cyclophosphamide 1200 mg/m² IV day 1.

Return to first regimen 2-3 weeks later.

Osteosarcoma

Doxorubicin-Cisplatin:

  • Doxorubicin 75 mg/m² IV in split doses IV push over 2-3 days.

  • Cisplatin 75-120 mg/m² IV in split doses day 1-2, or as bolus day 1 only.

Repeat cycle every 21 days for 3-4 courses preoperatively.

If more than 90% tumor necrosis at surgery, administer 3-6 postoperative courses. If less than 90% tumor necrosis at surgery, switch to alternate Methotrexate-Ifosfamide regimen below.

High-dose Methotrexate with Ifosfamide-Doxorubicin:

  • High-dose Methotrexate 8-12g/m² IV with urine alkalinization and leucovorin rescue every 1-2 weeks for 4 doses

3 weeks later, administer:

  • Ifosfamide 2000 mg/m² IV over 2-4 hours daily for 5 days with mesna plus

  • Doxorubicin 75 mg/m² IVP in split doses over 2-3 days

Repeat 3 weeks later.

3 weeks later, repeat entire cycle of MTX x 4 and Ifosfamide-Doxorubicin x 2.

What other therapies are helpful for reducing complications?

For high dose cytotoxic therapy such as doxorubicin-ifosfamide, the use of filgrastim or pegfilgrastim can minimize the risk of febrile neutropenia. ASCO guidelines indicate a standard means to employ the cardiac protectant dexrazoxane for patients receiving anthracycline based chemotherapy.

Dexrazoxane decreases the rate of congestive heart failure due to myocardial weakening by doxorubicin by serving as an iron scavenger in the cardiomyocyte. The use of dexrazoxane is suggested once the cumulative lifetime dose of doxorubicin exceeds 300 mg/m2. Other anthracylines require different scaling of cumulative doses. The use of growth factors for anemia is controversial in sarcoma patients, since there is no direct data indicating association to increased mortality rates (as has been shown in head and neck cancers, and other carcinomas).

What should you tell the patient and the family about prognosis?

For primary disease, the goal is cure, which usually involves surgery and radiation therapy. For some people, chemotherapy is needed to improve the chance of cure, for others, it is not. For people with metastatic disease, cure is uncommon, but is usually predicated on good results with both surgery and chemotherapy.

What if scenarios.

Biopsies must be performed with final resection in mind. An incorrect horizontal incision across the thigh means a much larger area must be removed compared to people who have a core needle biopsy.

A piecemeal resection is generally unacceptable. In most anatomic sites, surgery must be done en bloc, completely encompassing the tumor and surrounding normal tissues.

In contrast to treatment of sarcomas, in which surgery is often curative, desmoid tumors, which often recur locally despite surgery and/or radiation, do not metastasize, so the thinking behind local therapy should be much more conservative, keeping local function in mind.

Follow-up surveillance and therapy/management of recurrences.

As with follow-up breast exams following mastectomy, the primary site should be followed by the patient for changes between physician visits. Frequency of imaging is based on risk of recurrence for a specific sarcoma subtype, or the need to follow metastatic disease on toxic systemic therapy.

In general, fusion PET-CT scans are over-utilized and actually provide less anatomic detail than conventional contrast enhanced CT scans. They may be helpful in the specific situation that patients cannot tolerate IV contrast for CT scans or MRI.

Pathophysiology

With 13,000 cases per year in the U.S. (approximate incidence of 3-4 per million), sarcomas represent under 1% of all cancers. There are over 70 different types of sarcomas, each with its own molecular biology, behooving diagnosis by pathologists who look at them every day, and management by physicians in multidisciplinary groups familiar with their diagnosis.

In general, there are GISTs with KIT or PDGFRA mutations, soft tissue and bone sarcomas with translocations (like hematological malignancies), and sarcomas with aneuploid karyotypes and three major classes of sarcomas.

The most common sarcomas that have translocations include myxoid-round cell liposarcoma with t(12;16) FUS-DDIT3, synovial sarcoma with t(X;18) SS18-SSX(1, 2, or 4). Ewing sarcoma contains a characteristic t(11;22) EWSR1-FLI1 in most cases.

Of note, many different translocations can generate the same sarcoma. It is worth noting that presence of a EWSR1 translocation by FISH does not automatically mean a Ewing sarcoma is involved, or that drugs used in Ewing sarcoma will work in that diagnosis. For example, clear cell sarcoma contains t(12;22) EWSR1-ATF1 and is essentially impervious to standard doxorubicin based chemotherapy.

What other clinical manifestations may help me to diagnose sarcomas?

Sarcomas usually present as painless masses. Those most frequently causing pain in the author's practice have been synovial sarcomas. Rare patients will present with paraneoplastic syndromes such as hypoglycemia with Doege Potter syndrome (IGF2 secretion by large solitary fibrous tumors/hemangiopericytomas).

Patients with nerve sheath tumors in the setting of neurofibromatosis type I will have the stigmata of NF, such as cafe au lait spots, neurofibromas, and Lisch nodules of the iris. Patients with familial adenomatous polyposis and desmoid tumors may have polyps, colon cancer, congenital hypertrophy of pigmented retinal epithelium (CHRPE), and osteomas of the jaw.

What other additional laboratory studies may be ordered?

Molecular testing will discern specific sarcoma subtypes when there is difficulty with the differential diagnosis. For example, small round blue cell tumors could represent a wide spectrum of tumors, from small cell carcinoma to lymphoma, rhabdomyosarcoma, Ewing sarcoma, poorly differentiated synovial sarcoma or round cell liposarcoma. Molecular tests such as immunohistochemistry and assessment for translocations by FISH and other techniques will help make an irrefutable diagnosis.

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