Sarcoma

SYMPOSIUM ON SOLID TUMORS SARCOMA

Sarcoma KEITH M. SKUBITZ, MD, AND DAVID R. D’ADAMO, MD, PHD Sarcomas comprise a heterogeneous group of mesenchymal neoplasms. They can be grouped into 2 general categories, soft tissue sarcoma and primary bone sarcoma, which have different staging and treatment approaches. This review includes a discussion of both soft tissue sarcomas (malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberans, angiosarcoma, Kaposi sarcoma, gastrointestinal stromal tumor, aggressive fibromatosis or desmoid tumor, rhabdomyosarcoma, and primary alveolar soft-part sarcoma) and primary bone sarcomas (osteosarcoma, Ewing sarcoma, giant cell tumor, and chondrosarcoma). The 3 most important prognostic variables are grade, size, and location of the primary tumor. The approach to a patient with a sarcoma begins with a biopsy that obtains adequate tissue for diagnosis without interfering with subsequent optimal definitive surgery. Subsequent treatment depends on the specific type of sarcoma. Because sarcomas are relatively uncommon yet comprise a wide variety of different entities, evaluation by oncology teams who have expertise in the field is recommended. Treatment and follow-up guidelines have been published by the National Comprehensive Cancer Network (www.nccn.org).

Mayo Clin Proc. 2007;82(11):1409-1432 AF = aggressive fibromatosis; CTAG = cancer/testis antigen; DFS = disease-free survival; DFSP = dermatofibrosarcoma protuberans; DTIC = dacarbazine, EFT = Ewing family of tumors; EOI = European Osteosarcoma Intergroup; EWS = Ewing sarcoma; FAP = familial adenomatous polyposis; FDA = Food and Drug Administration; GCT = giant cell tumor; GIST = gastrointestinal stromal tumor; HIV = human immunodeficiency virus; IESS = Intergroup Ewing Sarcoma Study; IRS = Intergroup Rhabdomyosarcoma Study; KS = Kaposi sarcoma; LMS = leiomyosarcoma; MAID = infusional doxorubicin, ifosfamide, and DTIC; MAP = mitomycin C, doxorubicin, and cisplatin; MFH = malignant fibrous histiocytoma; NF = neurofibromatosis; OS = overall survival; PDGF = platelet-derived growth factor; PET = positron emission tomography; PLD = pegylated liposomal doxorubicin; PVNS = pigmented villonodular synovitis; RANK = receptor activator of nuclear factor κB; RB = retinoblastoma; RMS = rhabdomyosarcoma; STS = soft tissue sarcoma; TLS = translocated in liposarcoma; VAC = vincristine, dactinomycin, and cyclophosphamide

T

he term sarcoma refers to a tumor of connective tissue and derives from the Greek sarkos (flesh) and sarkoma (fleshy substance). Sarcomas comprise a heterogeneous group of mesenchymal neoplasms, including more than 100 distinct diagnostic entities.1,2 This heterogeneity can be identified by light microscopy1,2 and analyses of gene expression.3-8 Marked heterogeneity in biological behavior may exist even within a single histologic category. Because of the large number of subtypes of sarcoma, only the most common or instructive types will be discussed herein. Sarcomas can be grouped into 2 general types, soft tissue sarcoma (STS) and primary bone sarcoma, each of which has different staging and treatment approaches. Soft tissue sarcomas are typically classified on the basis of Mayo Clin Proc.

•

genetic alterations and light-microscopic examination of hematoxylin-eosin–stained tissue, in which recognizable morphological characteristics of normal tissues are identified. Sarcomas are further characterized by histologic grade. The 3 most important prognostic variables are grade, size, and location of the primary tumor.9 The symptoms that call attention to a sarcoma are usually those caused by its presence and growth at its site of origin. If the tumor originates in an easily visible site, the patient may present with an asymptomatic mass. If the tumor distorts normal structures, pain may be the presenting symptom. Therefore, retroperitoneal sarcomas often are large before they are brought to medical attention. In rare instances, paraneoplastic symptoms such as fever may occur. A biopsy (either open or large-gauge core needle) is needed to obtain adequate tissue for diagnosis of sarcoma. Care should be taken to ensure that the biopsy does not interfere with subsequent optimal definitive surgery. Because sarcomas are relatively uncommon, yet comprise a wide variety of different entities, patients should be evaluated by oncologists who have expertise in the field of sarcoma. Several recent reviews of sarcoma have been published.10-12 HISTORY Sarcomas have played an important role in the understanding of the nature of cancer. In 1909, Rous13 was given a Plymouth Rock hen bearing a spindle cell sarcoma. Rous found that he could transfer the tumor from one chicken to another, but not to all types of chickens. In his studies of the nature of the transmissible agent, Rous found that extracts of tumors that passed through a Berkefeld filter (which did not allow passage of particles of the size of known bacteria) could also transfer the sarcoma to other From the Department of Medicine, University of Minnesota Medical School and Masonic Cancer Center, Minneapolis (K.M.S.); and Memorial Sloan Kettering Cancer Center, New York, NY (D.R.D.). Dr Skubitz has received grant support from Amgen, Bristol Myers, Cell Therapeutics, Johnson & Johnson, and Pfizer; is on the speakers’ bureaus of Johnson & Johnson, Novartis, and Pfizer; owns publicly traded stock in Genentech and Johnson & Johnson; and has consulted for Amgen, Johnson & Johnson, Keryx, Novartis, and OSI. Dr D’Adamo is on the speakers’ bureaus of Bayer, Novartis, and Pfizer. Address correspondence to Keith M. Skubitz, MD, MMC 286 University Hospital, Minneapolis, MN 55455 (e-mail: [email protected]). Individual reprints of this article and a bound reprint of the entire Symposium on Solid Tumors will be available for purchase from our Web site www.mayoclinicproceedings.com. © 2007 Mayo Foundation for Medical Education and Research

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1409

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

chickens.14 This work was instrumental in opening the field of tumor virology. Later studies revealed that the transforming region of the Rous sarcoma virus was a gene termed SRC (later V-SRC to distinguish it from the normal cellular homologue CSRC). The first demonstration of protein tyrosine kinase activity was the identification of the tyrosine kinase activity of SRC, and further studies revealed the SRC homology domains known as SH2 and SH3 that regulate certain protein-protein binding reactions. Most recently, tyrosine kinase inhibitors have been studied in gastrointestinal stromal tumor (GIST) as a model of treatment of other solid tumors. CYTOGENETIC CHANGES Cytogenetic changes are common in sarcomas15-28 (Table 1) and can be divided into 2 broad categories. One group has specific characteristic cytogenetic changes and relatively simple karyotypes, such as a fusion gene or point mutation. The other group has nonspecific changes, often with very complex karyotypes.16,29-31 In several cases, the observed genetic changes have been exploited as targets of therapy. A better understanding of the pathophysiology of these tumors may lead to the development of additional therapeutic approaches. ETIOLOGIC AGENTS AND RISK FACTORS Although most sarcomas arise spontaneously, some risk factors have been identified. Exposure to ionizing radiation increases the incidence of sarcomas, typically more than 7 to 10 years after exposure, most commonly in patients treated with radiation therapy for breast and cervical cancer as well as lymphoma.32,33 Patients treated with ionizing radiation for cancer have developed both osteosarcoma and STS, including angiosarcoma.34-38 Other risk factors include chronic lymphedema, which increases the incidence of STS (especially angiosarcoma),38-41 and exposure to some chemicals (eg, vinyl chloride, which increases the risk of hepatic angiosarcoma).42-45 Although the Rous sarcoma virus that causes sarcomas in chickens was the first tumor virus found to cause solid tumors,13,14 the only virus now known to cause sarcoma in humans is human herpesvirus 8, which plays a role in the development of Kaposi sarcoma (KS).46-49 Some genetic syndromes are also associated with the development of sarcoma. Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is an autosomal dominant condition that is typically due to a mutation in the NF1 gene, which encodes the protein neurofibromin. Patients with NF1 have a high incidence of benign schwannomas and neurofibromas as well as an increased risk of develop1410

Mayo Clin Proc.

•

ing malignant peripheral nerve sheath tumors (malignant schwannomas and neurofibrosarcomas). Neurofibromatosis type 2 (NF2), also an autosomal dominant disorder, is associated with the development of meningiomas as well as schwannomas of cranial nerves, especially the vestibular nerve. Gardner syndrome, an autosomal dominant disorder caused by mutation of the APC gene, is associated with desmoid tumors in addition to multiple colonic polyps and colon cancer. The familial form of retinoblastoma (RB) is inherited in an autosomal dominant manner, ie, cells that are heterozygous for a mutation in one RB1 allele develop an acquired mutation in the other allele.50,51 Retinoblastoma typically occurs in young children. Although most children now survive RB in infancy, they may develop osteosarcoma or other STSs later in life.52 Somatic RB1 dysfunction is common in most sporadic STSs.53 A number of other genetic syndromes are also associated with an increased risk of sarcomas, including Li-Fraumeni syndrome, in which mutations interfere with the tumor suppressor function of the TP53 gene. SOFT TISSUE SARCOMAS Soft tissue sarcomas, which represent fewer than 1% of malignancies, may arise in skin or other organs as well as soft tissue. Because the Surveillance, Epidemiology, and End Results data on STS only include those arising in soft tissue, they underestimate their true incidence.54 For example, the 1993 US national estimate increases from approximately 6000 STS cases per year to approximately 11,400 cases after the inclusion of STSs that originated in organs.54,55 Similarly, GIST, which was thought to be an uncommon tumor before the identification of an effective treatment, is now estimated to have an incidence of greater than 5000 per year. STAGING OF STS The staging of STS is based on tumor grade, size, and location. Metastasis of STS to lymph nodes is uncommon and is associated with poor outcome.56 However, some subtypes such as sclerosing epitheloid sarcomas commonly involve lymph nodes without necessarily following the same aggressive course often seen with other STSs that involve lymph nodes.56,57 Both overall and relapse-free survival are influenced by stage (Table 2).58 For example, in some series approximately 85% of patients with stage I disease survive 5 years vs approximately 10% to 20% of those with stage IV disease. Other prognostic factors have been identified,9 and nomograms derived from large numbers of patients may provide more prognostic information.59 Extraskeletal myxoid chondrosarcoma and extraskeletal osteosarcoma are staged as STS. Patients with

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

TABLE 1. Common Cytogenetic Changes in Sarcomas*† Histologic type

Chracteristic cytogenetic events

Alveolar soft-part sarcoma Aggressive fibromatosis (desmoid)

t(X;17)(p11;q25) Trisomies 8 and 20 Deletion of 5q 12q15 rearrangement Ring form of chromosome 12 t(12;16)(q13;p11) t(12;22)(q13;q12) Complex§ Complex§ Ring form of chromosome 12 t(12;14)(q15;q24) or deletion of 7q Deletion of 1p Deletion of 1p t(X;18)(p11;q11)

Lipoma (typical) Well-differentiated liposarcoma Myxoid/round-cell liposarcoma Pleomorphic liposarcoma Malignant fibrous histiocytoma Myxoid malignant fibrous histiocytoma Leiomyoma (uterine) Leiomyoma (extrauterine) Leiomyosarcoma Monophasic synovial sarcoma Biphasic synovial sarcoma Benign schwannoma Malignant, low-grade schwannoma Malignant, high-grade schwannoma (malignant peripheral nerve sheath tumors) EWS and PNET Desmoplastic small round-cell tumor Dermatofibrosarcoma protuberans Endometrial stromal tumor Gastrointestinal stromal tumor Fibrosarcoma, infantile Low-grade osteosarcoma High-grade osteosarcoma Extraskeletal myxoid chondrosarcoma Skeletal chondrosarcoma Alveolar rhabdomyosarcoma Embryonal rhabdomyosarcoma Mesothelioma

Inflammatory myofibroblastic tumor Clear cell sarcoma

t(X;18)(p11;q11) Deletion of chromosome 22 None Complex§ t(11;22)(q24;q12) t(21;22)(q12;q12) t(11;22)(p13;q12) Ring form of chromosomes 17 and 22 t(17;22)(q21;q13) t(7;17)(p15;q21) Monosomies 14 and 22 Deletion of 1p t(12;15)(p13;q26) Ring chromosomes Complex§ t(9;22)(q22;q12) t(9;17)(q22;q11) Complex§ t(2,13)(q35;q14) t(1;13)(p36;q14), double minutes Trisomies 2q, 8 and 20 Deletion of 1p Deletion of 9p Deletion of 22 q Deletions of 3p and 6q 2p23 rearrangement t(12;22)(q13;q12)

Genes involved‡ ASPSCR1-TFE3 (ASPL-TFE3) fusion APC inactivation HMGA2 (HMGIC) rearrangement FUS-DDIT3 (TLS-CHOP) fusion EWSR1-DDIT3 (EWS-CHOP) fusion

HMGA2 (HMGIC) rearrangement

SS18-SSX1 (SYT-SSX1) or SS18-SSX2 (SYT-SSX2) fusion SS18-SSX1 (SYT-SSX1) fusion NF2 inactivation

EWSR1-FLI1 (EWS-FLI1) fusion EWSR1-ERG (EWS-ERG) fusion EWSR1-WT1 (EWS-WT1) fusion COL1A1-PDGFB fusion COL1A1-PDGFB fusion JAZF1- SUZ12 (JAZF1-JJAZ1) KIT of PDGFRA mutation ETV6-NTRK3 fusion RB1 and TP53 (Rb and p53) inactivation EWSR1-NR4A3 (EWS-NR4A3) fusion TAF15-NR4A3 (TAF2N-NR4A3) fusion PAX3-FOXO1 (PAX3-FKHR) fusion PAX7-FOXO1 (PAX7-FKHR) fusion Loss of heterozygosity at 11p15 Possible BCL10 inactivation p15, p16, and p19 inactivation NF2 inactivation ALK fusion genes EWSR1-ATF1 (EWS-ATF1) fusion

*EWS = Ewing sarcoma; PNET = primitive neuroectodermal tumor. †These are common cytogenetic changes observed in these diagnoses but are not the only ones. ‡Gene symbols are those provided in the Human Genome Nomenclature Database (www.genenames.org). Previous names of genes are given in parentheses. §Typically, very complex karyotypes with multiple numerical and structural chromosomal aberrations.

metastatic disease are generally treated with chemotherapy, as described later, although in some cases local issues such as pain or skeletal instability may also require local treatment. Mayo Clin Proc.

•

Grade is one of the most important prognostic factors.60 To determine grading, a pathologist who has expertise in the field of sarcomas should review all biopsy specimens, because reproducibility is not always high among patholo-

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1411

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

TABLE 2. Staging of Soft Tissue Sarcomas* Stage I II III IV

T1a, 1b, 2a, 2b T1a, 1b, 2a T2b Any T

N0 N0 N0 N1

M0 M0 M0 M0

G1-2 G3-4 G3-4 Any G

G1 G2-3 G2-3 Any G

Any T

N0

M1

Any G

Any G

Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 5 cm or less in greatest dimension T1a Superficial tumor† T1b Deep tumor† T2 Tumor more than 5 cm in greatest dimension T2a Superficial tumor† T2b Deep tumor†

Low High High High or low High or low

Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1‡ Regional lymph node metastasis Distant metastases (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastases Histologic grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Poorly differentiated or undifferentiated (4-tiered systems only) *Note that extraskeletal osteosarcoma and extraskeletal chondrosarcoma are staged as soft tissue sarcomas. †Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial to and beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors. ‡Note that presence of positive nodes (N1) is considered stage IV. From AJCC Cancer Staging Manual, sixth edition (2002), published by Springer Science and Business Medical LLC (www.springerlink.com),58 with permission of the American Joint Committee on Cancer (AJCC), Chicago, IL.

gists without such expertise. This problem is exacerbated by the low incidence of the disease. Of the grading systems that have been developed, those of the French Federation of Cancer Centers Sarcoma Group and the National Cancer Institute (both of which are 3-grade systems) are now the most commonly used.60-65 The size of the biopsy specimen may limit the accuracy of the tumor grade.60 In some cases, molecular techniques may greatly complement histologic evaluation. Because of the potential for heterogeneity within sarcomas, directed core biopsies (for example localized to an area of high positron emission tomography [PET] activity66,67) may eventually be useful. APPROACHES TO THE TREATMENT OF STS When the disease appears localized, treatment is based on the prognosis. In general, small low-grade tumors with 1412

Mayo Clin Proc.

•

wide pathologically negative margins can be treated with surgery alone. Larger or higher-grade lesions may benefit from radiotherapy with a reduction in the incidence of local recurrence but with no benefit in overall survival (OS). Chemotherapy may be used before surgery to try to shrink the lesion and after surgery to try to prevent its recurrence. Radiotherapy. In a prospective randomized study of patients with high-grade (n=91) and low-grade (n=50) sarcomas, those with high-grade lesions who received postoperative radiotherapy had a local recurrence rate at 10 years of 0% vs 22% for controls.68 In the same study, those with low-grade lesions who received radiotherapy had local recurrence rates of 4% vs 33% for controls, again with no benefit in OS. No consensus exists on whether preoperative or postoperative radiation therapy is preferable, and the approach that is used depends on the treatment center. Preoperative radiation therapy may potentially allow a smaller field to be treated and a lower radiation dose to be administered; it could also make surgery easier by decreasing tumor size. However, the rationale for using different doses for preoperative vs postoperative radiation is historically based.69 In an early study, radiation therapy (6000 Gy) given postoperatively reduced the local recurrence rate in extremity STS.70 Other studies, which hypothesized that tumor cells would be better oxygenated preoperatively and therefore more responsive to radiation therapy, used 5000 Gy preoperatively with a boost of 1000 Gy postoperatively.71 The postoperative boost of 1000 Gy was later eliminated in patients with negative margins because it was thought unlikely to add much benefit; no changes in patient outcome were discerned.72 Thus, the postoperative radiation therapy dose has never been compared with the current preoperative radiation dose. Preoperative radiation therapy can delay surgery and complicate the pathological evaluation of the resected specimen, problems not present when radiation is delivered postoperatively. Postoperative radiation could also lower the incidence of postoperative wound complications73,74 and, for those patients who received preoperative chemotherapy, could address the difficulty of assessing the response to the chemotherapy when preoperative radiation therapy is also given. Chemotherapy. Preoperative chemotherapy offers a number of advantages. In some cases, it may shrink the tumor, making surgery easier. Administration of preoperative chemotherapy may also show how well a given patient responds to chemotherapy and may aid in decisions about whether postoperative chemotherapy should be considered. The benefit of adjuvant chemotherapy after resection of a primary STS remains a subject of debate. Previous studies of adjuvant chemotherapy have been complicated by the heterogeneity of the biological behavior within and among

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

STS subtypes, the number of patients studied, and the possibility that newer agents and treatment schedules might give better results. A meta-analysis of 14 randomized trials using an anthracycline-based regimen in 1568 patients with STS showed an improvement in disease-free survival (DFS) of approximately 10% (from 45% to 55%) at 10 years, P<.001) but only a statistically insignificant increase in OS (from 50% to 54%).75 Three subsequent studies using an anthracycline and ifosfamide combination76-78 reported a potential increase in OS at 5 years, but the general applicability of these results has been questioned because of concerns about sample size, treatment toxicity, possible high rates of locoregional recurrence, and entry of patients with recurrent disease. A review of 674 patients with stage III STS of the extremity treated with anthracycline-based adjuvant chemotherapy in a nonrandomized manner also s uggested amodest benefit in DFS and disease-specific survival, but potential benefit was not sustained beyond 1 year.79 Better stratification based on both biological risk and probability of response to chemotherapy is desperately needed. It is hoped that stratification by gene expression profiles or other molecular studies of patients in future trials may clarify the role of adjuvant chemotherapy in specific patients with STS.7,80 Chemotherapeutic Agents. Of the chemotherapeutic agents that have been used to treat STS, the 2 most commonly used currently are doxorubicin and ifosfamide. The use of gemcitabine is also increasing. Doxorubicin, one of the first drugs shown to be useful for sarcomas, has been shown to elicit a wide range of response rates (from <10% to >30%) in STS. Response rates are traditionally defined using sums of cross-sectional areas. The variable response rates observed likely reflect, in large part, heterogeneity in the composition of the sample sets treated, as well as possible differences in assessment of response. Doxorubicin causes a well-known form of cardiotoxicity that is dose related and largely irreversible. The original studies that correlated the incidence of heart failure with cumulative doxorubicin dose used bolus administration of the drug. Subsequent studies showed a reduction in cardiotoxicity when the doxorubicin was given by continuous infusion,81-85 and most current sarcoma regimens that contain doxorubicin use some form of infusional administration or split-dosing regimen. Newer liposomal formulations of doxorubicin have been developed to improve its efficacy and reduce its potential toxicity. Pegylated liposomal doxorubicin (PLD) is a formulation in which doxorubicin is contained in liposomes that are coated with methoxypoly-(ethylene glycol). The methoxypoly-(ethylene glycol) confers a decreased uptake by the reticuloendothelial system, a long half-life in blood (approximately 50-60 hours), and a different toxicity Mayo Clin Proc.

•

profile from nonpegylated liposomes.86 In addition, PLD is less cardiotoxic, only infrequently causes alopecia, does not require antiemetics, and is associated with a low incidence of grade 3 to 4 myelosuppression. The limiting toxicities of PLD usually involve the skin or mucosa. Some studies suggest that PLD may concentrate in solid tumors, thus enhancing drug delivery to the tumor.87,88 Pegulated liposomal doxorubicin also has been shown to have clear activity in sarcoma.89-91 It is important to note that the dosing of free doxorubicin differs from that of PLD. In the past, doxorubicin was often combined with dacarbazine (DTIC), an alkylating agent that was also one of the first drugs used for sarcoma and that had a reported response rate in STS of approximately 15%.85,92 Although DTIC is one of the few drugs that has been approved by the Food and Drug Administration (FDA) for STS, its use in first-line therapy is no longer common. Temozolomide, an oral DTIC analogue, has some activity in sarcoma and is being studied further.93 Ifosfamide, a prodrug that is metabolized in the liver to the active alkylating agent, is another of the most active drugs for sarcoma. Its development was limited by the urothelial toxicity of its metabolites until the development of the uroprotective agent mesna. Ifosfamide has been administered in various schedules and is often coupled with other agents in sarcoma regimens.94-98 In some cases, highdose ifosfamide (>10 g/m2) may be useful but can be associated with substantial toxicity.99,100 The nucleoside analogue gemcitabine is active in STS, especially uterine leiomyosarcoma (LMS) and malignant fibrous histiocytoma (MFH).101-105 In a recent trial, the combination of gemcitabine and docetaxel resulted in higher response and survival rates but also greater toxicity than gemcitabine alone.106 Gemcitabine, a deoxycytidine analogue, must be phosphorylated intracellularly if it is to have activity. The diphosphorylated drug inhibits ribonucleotide reductase, thus interfering with DNA synthesis;107 the triphosphorylated form is i ncorporated into DNA and eads l to masked chain termination.108,109 Because the accumulation of intracellular gemcitabine triphosphate is saturable110,111 and tumor cell kill in vitro has been correlated with the duration of exposure to the drug at a concentration of greater than 10 µM,109 recent studies in STS have administered gemcitabine at less than 10 mg/m2 per minute.103,112 Methotrexate, a dihydrofolate reductase inhibitor that is an important component of the treatment of osteosarcoma, has also been used in some STSs, although less commonly. The most common regimens are forms of high-dose methotrexate requiring leucovorin rescue. Cis-diamminedichloroplatinum(II), or cisplatin,113 is another important component of the treatment of osteosarcoma that also has activity in STS. Interestingly, the first

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1413

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

demonstration of the antitumor activity of cisplatin was the original study of the murine sarcoma 180 in Swiss white mice.114,115 Because it maintains activity at low oxygen tensions, mitomycin C was considered an attractive agent to study in solid tumors in which hypoxia is common. Mitomycin C is included in 3 regimens developed at Mayo Clinic: MAP (mitomycin C, doxorubicin, and cisplatin), DMAP (DTIC with MAP), and IMAP (ifosfamide with MAP).94,116,117 Paclitaxel has been found to have limited activity in sarcomas in general; however, its response rate in angiosarcoma is very high.118,119 Ecteinascidin (ET743), an alkaloid derived from the Caribbean sea squirt (Ecteinascidia turbinate) that is still in clinical trials, has shown clear activity in STS.120,121 In these 2 trials, patients with liposarcoma or LMS had response rates of 17% and 8%, respectively; however, the clinical benefits appeared more substantial than these response rates might suggest, justifying further study of its activity in sarcoma. Combination Chemotherapy. The benefits of singleagent vs combination (doxorubicin and ifosfamide) chemotherapy remain a subject of debate. A large randomized trial comparing infusional doxorubicin and DTIC with the MAID regimen (infusional doxorubicin, ifosfamide, and DTIC) in patients with metastatic STS found a higher response rate (approximately 32% vs 17%) and longer time to progression (approximately 6 months vs 4 months) for the MAID regimen.122 However, this same study found that patients 50 years and older died sooner if they were treated with MAID; however, no difference in survival was observed for MAID-treated vs doxorubicin-DTIC–treated patients younger than 50 years. All MAID-treated patients, regardless of age, had a reduced quality of life. Although these results may at first appear discordant, the likely explanation for the findings is that patients in whom first-line therapy failed were allowed to receive subsequent chemotherapy. Another randomized trial also showed a higher response rate to both ifosfamide-doxorubicin and MAP than doxorubicin alone, but with no prolongation in survival.94 Similarly, the addition of other drugs to doxorubicin in the cyclophosphomide, vincristine, doxorubicin, and DTIC regimen did not provide a survival advantage vs doxorubicin alone.123 An important caveat to this discussion is required for patients with rapidly progressive disease, in whom second-line therapy may not be possible if the firstline regimen fails. For these somewhat unusual patients, a combination of agents is preferred. In recent studies of patients with STS, the combination of gemcitabine and taxotere appeared to yield both a higher response rate and a better OS than single-agent gemcitabine, although at a cost of increased toxicity.106 1414

Mayo Clin Proc.

•

TREATMENT OF METASTATIC DISEASE Although with rare exception metastatic sarcoma is incurable, substantial benefit can be derived from the appropriate use of chemotherapy or local control measures including surgery, radiotherapy, and other interventional techniques. Chemotherapy has a role to play in the treatment of most patients with metastatic sarcoma. In general, higher-grade STSs espond r better to chemotherapy than lower-grade tumors.124-126 Some histologic subtypes of sarcomas may be more likely to respond to chemotherapy if they occur in children vs adults.127,128 Gene expression profiles may further the understanding of this observation.129 COMMON TYPES OF STSS The 3 most common subgroups of STSs were previously considered to be MFH, liposarcoma, and LMS. Indeed, after its acceptance as a separate diagnostic entity in the 1970s,130 MFH became the most commonly diagnosed subtype of STSs.131-134 More recently, however, many have questioned whether MFH should be considered a separate diagnostic entity.135-137 Many sarcomas previously identified as MFH appear to share biochemical markers with other subtypes of STS but are not readily recognized as such on the basis of their histologic appearance.4-6,135 Currently, MFH refers to pleomorphic sarcomas without defined differentiation. Liposarcoma and LMS, now considered the 2 most common subgroups, as well as other common or illustrative STS subtypes, are described below. Liposarcoma. Liposarcoma, the most common subtype, represents approximately 20% of STS in the United States.138 Several types of liposarcoma are recognized, including well-differentiated liposarcoma, myxoid liposarcoma, round-cell liposarcoma, dedifferentiated liposarcoma, and pleomorphic liposarcoma.61 Well-differentiated liposarcoma and dedifferentiated liposarcoma occur predominantly in the retroperitoneum; myxoid, round-cell, and pleomorphic liposarcomas, in the extremities. Welldifferentiated liposarcoma and myxoid liposarcoma are classified as low-grade tumors; dedifferentiated liposarcoma and pleomorphic liposarcoma, as high-grade tumors. Well-differentiated liposarcomas, which are unlikely to metastasize, are usually treated solely by surgical resection. Dedifferentiated liposarcoma is thought to be a highgrade sarcoma derived from a well-differentiated liposarcoma. Myxoid liposarcomas contain tumor cells that represent various stages of adipocyte differentiation in a myxoid matrix. Round-cell liposarcomas (with a round-cell component >5%) generally represent a higher-grade form of myxoid liposarcoma and, like dedifferentiated and pleomorphic liposarcomas, are more aggressive tumors.139 Although the grade (which is reflected in the histologic subtype) of liposarcoma has predictive value for local recur-

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

rence and survival and is the single most important prognostic factor, the biological behavior of histologic subtypes can be very heterogeneous.9,27,140-144 A prognostic nomogram specific for liposarcomas has recently been described that may facilitate stratification for clinical trials and aid in the counseling of patients.145 Although the etiology of liposarcoma is unknown, a variety of cytogenetic abnormalities have been described, and gain of 1q and 12q sequences is commonly observed.146,147 The PPAR and CEBP families of transcription factors play important roles in adipocyte differentiation.148,149 The t(12;16) or t(12;22) translocations that result in fusion proteins containing an N-terminus of one of 2 related genes (TLS [translocated in liposarcoma; also known as FUS or TLS/FUS] or EWSR1 [Ewing sarcoma]), coupled with a C-terminus of a C/EBP family member termed CHOP (also known as DDIT3), are found in most myxoid and round-cell liposarcomas.150-153 These fusion proteins are thought to promote tumorigenesis by altering gene expression patterns. 151,154,155 Other cytogenetic changes have been reported in liposarcoma, and TP53, MDM2, and CDK4 have also been implicated as important in the pathophysiology of liposarcoma.22,146,156-159 The overexpression of PPARG in liposarcoma160 and the important role it plays in adipocyte differentiation led to trials of PPARG agonists in the treatment of liposarcoma, but the results of these trials have been mixed.161,162 Recent studies have suggested some efficacy of ecteinascidin743 in liposarcoma. Cancer/testis antigens (CTAGs) are a group of immunogenic proteins that are expressed selectively in some cancers and also by the testis and ovary but not by other normal tissue. Compared with normal tissues, CTAG-1, CTAG-2, and another CTAG known as PRAME have been found to be overexpressed in liposarcoma, suggesting that immunotherapy, including the use of tumor vaccines, may be useful in selected liposarcomas.163,164 Unlike nonmyxoid liposarcomas, myxoid liposarcomas overexpress many ribosomal protein genes.164 Leiomyosarcoma. Leiomyosarcomas are another common subtype of STS. A variety of genetic changes have been observed in LMS, often including changes in TP53 and MDM2 expression, overexpre ssion of cyclin-dependent kinase inhibitor 2A (CDKN2A) (also known as p16), and a loss of gamma-smooth muscle isoactin expression.3,165,166 Frequently, LMS is characterized by a highly aneuploid karyotype.167 Although LMS can occur throughout the body, LMS that originates in the uterus may represent a distinct phenotype; preliminary reports suggest differences in gene expression patterns between uterine and nonuterine LMS.3 In contrast to subcutaneous and deep LMS, cutaneous LMS usually follows a more indolent course with a low risk of metastases.168 A recent analysis of 225 patients with Mayo Clin Proc.

•

nonvisceral LMS confirmed the importance of tumor grade, size, and location in LMS.168 Gemcitabine and gemcitabinetaxotere combinations are promising agents for the treatment of metastatic LMS.101,102,106,112 Synovial Sarcoma. Although unrelated to the synovium, synovial sarcoma was originally named because of its histologic resemblance to synovial cells. Its morphology may be reminiscent of that of epithelial cells. Two types of synovial sarcomas are recognized, monophasic and biphasic. Monophasic synovial sarcoma is a pure spindle cell neoplasm, whereas biphasic synovial sarcoma has areas of both spindle cell and epitheloid morphology. More than 90% of synovial sarcomas have a characteristic t(X,18) translocation (p11.2;q11.2), resulting in the fusion of the SS18 (also know as SYT) gene on chromosome 18 with 1 of 3 closely related genes (SSX1, SSX2, and SSX4) on the X chromosome, resulting in aberrant SSX transcription.169-171 This translocation joins the transcriptional activating domain of SS18 and the transcriptional repressor domains of SSX, resulting in a fusion product that is thought to play an important role in the pathogenesis of synovial sarcoma, although the mechanism by which it does so remains unclear. The fusion transcript SS18-SSX1 has been found in both monophasic and biphasic synovial sarcomas; SS18-SSX2, in monophasic synovial sarcomas.172,173 Treatment of synovial sarcoma, which is always considered a high-grade sarcoma, is similar to that of other high-grade STSs. Synovial sarcomas may be especially sensitive to ifosfamide-based regimens.94,174 Synovial sarcomas frequently express CTAGs as well as a unique translocation protein, making them an attractive target for immunotherapy trials.163,175 Angiosarcoma. Angiosarcoma is an uncommon subtype of STS that typically occurs on the scalp or face176,177 and in postradiation fields,36,38 although it may occur at other sites as well.177,178 Angiosarcoma of the scalp commonly occurs in patients who are older or who have undergone irradiation.179 Lymphedema may also predispose to the development of angiosarcoma.38,40,41 Vinyl chloride, an alkylating agent and a gas used in the production of plastic, causes angiosarcoma of the liver in both human and animal models.42,44,45 Surgery followed by radiation therapy has been a standard approach for resectable lesions of the scalp and face. Recent reports indicate that both paclitaxel and PLD are effective in angiosarcomas, both those of the scalp and face and those originating at other sites.118,119,180-187 Although the PLD regimen has activity in many types of sarcoma, taxanes have limited activity in STSs in general. Several of the patients for whom paclitaxel was reported to be effective were treated with continuous infusion paclitaxel,119,180 which offers some advantages over shorter infusions. In a

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1415

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

previously reported case, a patient who had progressive disease of an angiosarcoma when receiving a 3-hour infusion every 3 weeks had a complete response when the regimen was switched to a weekly schedule.118 Newer formulations of paclitaxel such as nanoparticle paclitaxel and polyglutamate paclitaxel may also be effective treatments for angiosarcoma, although they have not been studied in this setting. Kaposi Sarcoma. Although Kaposi’s original description of the tumor that bears his name was that of a disease that was lethal within 2 to 3 years,188,189 KS eventually came to describe a more indolent and less common tumor that usually occurred in older people of Mediterranean or Eastern European descent, often with a family history of the disease.188,190,191 Kaposi sarcoma became much more common with the onset of AIDS; it is the most common malignancy diagnosed in people infected with human immunodeficiency virus (HIV) and is the first manifestation of AIDS in Western countries.192 Human herpesvirus 8, which has been associated with all forms of KS, presumably plays an important role in pathogenesis.46-49 Usually, KS first appears as pink, purple, red, or brownblack nodules or patches on the skin or, less frequently, on the oral mucosa.190,192 In non–HIV-associated KS, the disease is typically limited to the lower extremities, although it may be more widespread. In patients who are immunodeficient, as for example patients with AIDS or those who have undergone solid organ transplant, KS is typically a multifocal systemic disease. In particular, KS may develop in the lungs or gastrointestinal tract, potentially leading to hemorrhage or organ dysfunction. The clinical course of the disease differs among patients, ranging from a single or a few indolent lesions to an aggressive diffuse disease that can rapidly cause severe complications.190-195 In the case of a few localized lesions, local therapy, such as injection of the lesion with vinblastine, topical alitretinoin, or liquid nitrogen cryotherapy, may be adequate.195 With more extensive involvement of the lower legs in classic KS in the absence of immunodeficiency, radiation therapy has been used; however, it may result in lymphedema in some cases, leading many to use systemic treatment for locally advanced disease. For systemic disease or KS with a more aggressive course, liposomal anthracyclines are generally considered the initial treatment of choice. Peyglated liposomal doxorubicin, the most studied formulation,88 was approved by the FDA for the treatment of KS in 1995.196 In 1996 a nonpegylated liposomal formulation of daunorubicin received FDA approval.197 Administration of PLD has been shown to result in a higher doxorubicin concentration in KS lesions than does administration of free doxorubicin.86 Early-phase studies of PLD198 and 2 major randomized trials199,200 have 1416

Mayo Clin Proc.

•

shown the efficacy of PLD in KS. In one trial, in which patients were randomly assigned to either PLD or the combination of bleomycin and vincristine intravenously every 3 weeks for 6 cycles, the overall best response was higher with PLD (58.7% vs 23.3%; P<.001).200 In the other trial, in which patients with no prior chemotherapy were randomly assigned to either PLD or the combination of conventional doxorubicin, bleomycin, and vincristine intravenously every 2 weeks, PLD resulted in a better overall response rate (45.9% vs 24.8%; P<.001) and a shorter time to response (median, 39 days vs 50 days).199 Quality of life was also generally better in the PLD arm.199,201 Three times as many patients discontinued the combination chemotherapy because of an adverse event (37% vs 11%). Although PLD is generally well tolerated in these patients, myelosuppression is more common than in patients with cancer who are immunodeficient, presumably because of the effects of the HIV infection on the bone marrow. In patients with AIDS and KS, neutropenia was the most common dose-limiting adverse effect, with an incidence ranging from approximately 25% to 85% in various studies.190 Less data are available on the use of nonpegylated liposomal daunorubicin, although it clearly has activity in KS.202 Overall, studies have shown that PLD has substantial activity and is well tolerated in the treatment of AIDS-associated KS, and clinical experience has confirmed these same attributes in the treatment of other forms of KS. Phase 3 trials that compared PLD with conventional chemotherapy showed a higher response rate, shorter time to response, lower toxicity, and improvement in several aspects of quality of life in patients treated with PLD, leading to the common use of PLD as a first-line therapy in settings requiring systemic therapy. Paclitaxel has also been shown to have substantial efficacy in treating KS.203-206 Gastrointestinal Stromal Tumors. The most common gastrointestinal sarcomas, GISTs occur equally frequently in men and women and have an annual incidence of approximately 15 per million.207-209 The highest incidence is in those aged 40 to 60 years. Gastrointestinal stromal tumors share several characteristics of the interstitial cells of Cajal, which are c-kit-positive fibroblastlike cells.210-212 These cells, which are located between intramural neurons and smooth muscle cells, generate electrical slow waves and function as pacemaker cells of the gut. Therefore, these tumors usually arise on the outside surface of the gut. Approximately 50% of GISTs occur in the stomach and 25% in the small intestine,213 with the rest arising elsewhere along the gut or in the abdomen or retroperitoneum. Two major pathological subtypes, spindle cell and epitheloid, are recognized.207 Identified in 1998, gain-of-function mutations of KIT, in which c-kit has constitutively active protein tyrosine kinase

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

activity, have been shown to play a critical role in GIST biology.214,215 This observation, coupled with the efficacy of imatinib in chronic myelogenous leukemia and the known ability of imatinib to inhibit c-kit enzymatic activity, led to the first effective nonsurgical treatment of GIST.216 Although most cases of GIST have a mutation of KIT, approximately 5% to 7% have mutations in the platelet-derived growth factor (PDGF) receptor α (PDGFRA) with no KIT mutation.217 The downstream signaling targets of c-kit and PDGFRA are similar and, in general, result in proliferative and antiapoptotic effects. A heritable exon 11 mutation of KIT has been associated with multiple benign and malignant GISTs and diffuse hyperplasia of the interstitial cells of Cajal, suggesting that additional mutations are necessary for the development of GIST.218 Similarly, subsequent mutations of other genes can lead to changes in GIST biology within patients.219,220 In most cases, surgery is the primary treatment of GISTs; however, the rate of recurrence is high221,222 and has been correlated with tumor size and mitotic index; a risk index has been described.207 In general, tumors less than 5 cm in diameter and with fewer than 5 mitoses per 50 highpower fields are considered low risk; those that are greater than 10 cm in diameter or have greater than 10 mitoses per 50 high-power fields, high risk. Standard chemotherapy is rarely effective for GISTs; however, imatinib mesylate has a very high response rate.223-226 In some cases, preoperative imatinib may improve resectability; the potential utility of adjuvant imatinib after surgery is being evaluated. A recent interim analysis of the American College of Surgeons Oncology Group Z9001 trial, a phase 3 randomized trial comparing postoperative imatinib vs placebo in patients with resected GIST, showed improved progression-free survival but not OS after adjuvant therapy with imatinib in high-risk patients. The optimal starting dose of imatinib is still under study, but a starting dosage of 400 mg/d is common.223,226 In some patients, 800 mg/d may control the tumor when 400 mg/d does not. In tumors that progress even with imatinib therapy or in patients who are intolerant of imatinib, sunitinib has substantial activity 227 and is approved by the FDA for this indication. Many other new agents for the treatment of GISTs are in clinical trials.228 Patients should be monitored closely during the early phase of treatment, because spontaneous hemorrhage, often as a result of tumor response, may occur. In general, treatment with imatinib or sunitinib should be continued indefinitely, unless therapy is changed to an alternative regimen. Most GISTs have a mutation in KIT, and the location of the KIT mutation is related to response to imatinib and survival.229,230 Most KIT mutations are in the cytoplasmic juxtamembrane region (exon 11). Some GISTs with mutaMayo Clin Proc.

•

tions in PDGFRA are also sensitive to imatinib.217 Some tumors with no mutation in either KIT or PDGFRA may still respond to imatinib, as may some GISTs that are c-kit negative.231 Consensus has not been reached on how best to assess the response of GISTs to treatment.232-235 One characteristic of a good response is a decrease in tumor density, often accompanied by an increase in overall tumor volume. The activity of most GISTs can be detected by PET; as soon as 24 hours after the initiation of imatinib therapy, such activity may decrease so that it is no longer detectable by PET.232,234 Therefore, PET imaging is often very useful in monitoring this disease. Dermatofibrosarcoma Protuberans. Dermatofibrosarcoma protuberans (DFSP) usually occurs near the body surface and spreads in an infiltrating manner, sometimes making the identification of margins difficult at the time of primary resection. Although DFSP may recur locally, the development of metastases is unusual, and surgery is the primary treatment modality. Dermatofibrosarcoma protuberans is characterized by a translocation of chromosomes 17 and 22 (17q22 and 22q13) in which the collagen, type I, α 1 (COL1A1) promoter is juxtaposed with the β-polypeptide of the PDGF gene (PDGFB), resulting in the constitutive production of PDGFB. Thus, the production of the growth factor PDGFB by the tumor cells can lead to autocrine stimulation of the tumor’s own PDGF receptors, promoting tumor growth and survival. The physiologic relevance of this autocrine loop has been demonstrated by the observation that some patients with metastatic DFSP have had tumor responses when treated with imatinib, which inhibits the PDGF receptor tyrosine kinase as well as c-kit and c-abl.236 Aggressive Fibromatosis or Desmoid Tumor. Aggressive fibromatosis (AF), or desmoid tumor, is a monoclonal proliferation of myofibroblastlike cells with variable collagen deposition that is locally invasive but rarely metastasizes.237-243 However, AF may be multifocal. The term desmoid derives from the Greek work desmos, which means bandlike.244,245 Although AF is uncommon, it occurs 1000-fold more frequently in patients with familial adenomatous polyposis (FAP); approximately 2% of desmoid cases occur in the setting of FAP.245,246 Aggressive fibromatosis has been reported to be the second most common cause of death in patients with FAP.247 Although the association of AF with FAP had been noted earlier, Gardner described a familial syndrome characterized by intestinal polyposis, oeteomas, fibromas, and sebaceous and epidermal cysts.245,248-250 Gardner syndrome is now viewed as a variant of FAP.245,251 The myofibroblastlike cells of AF have histologic similarities to the proliferative phase of wound healing, and AF has been associated with trauma, pregnancy, and the use of oral contraceptives.239

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1417

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

The clinical course of AF varies with the patient. In a series of 12 cases of AF not associated with Garnder syndrome, gene expression studies suggested the existence of at least 2 distinct subsets of AF.252 The beta-catenin (CTNNB1) pathway has been strongly implicated in the pathogenesis of AF and desmoid tumors.239,253-257 In a transgenic mouse model, induction of stabilized beta-catenin leads to the development of AF and hyperplastic cutaneous wounds, suggesting that betacatenin plays a role in these fibroproliferative disorders.254 In a study of sporadic AF, 3 of 12 cases had a mutation in beta-catenin, and the beta-catenin messenger RNA expression was higher in the group carrying the beta-catenin mutation.256 In another study, 16 of 19 cases of AF had a mutation of the WNT pathway (APC or CTNNB1).258 Abnormal growth factor production, which has also been associated with plantar fibromatosis and hereditary gingival fibromatosis, may play a role in the disease in some cases.259-261 Agreement has not been reached on the optimal treatment for AF.262-264 Recurrence after surgery is common.245 Trauma, including surgery, can stimulate AF growth, leading some to discourage surgery as an initial treatment of the disease, especially in the case of FAP-associated AF.239,245,265-267 For others, however, surgery remains the preferred approach. A variety of medical treatments have been reported to be useful in some patients, including chemotherapy (such as methotrexate combined with vinblastine or more aggressive chemotherapy), antiestrogen therapy with tamoxifen, nonsteroidal anti-inflammatory drugs, tamoxifen combined with a nonsteroidal anti-inflammatory drug, radiation therapy, and more recently imatinib.245,258,268-272 One study of 25 patients (17 with FAP and 8 sporadic) with AF used a regimen of tamoxifen (120 mg/d) and sulindac (300 mg/d); although this regimen was not particularly effective in AF that recurred after surgery, the authors recommended it as a primary treatment of patients with FAP-associated AF.245 Given the slow natural history of the disease, a low-toxicity regimen of chemotherapy is preferred; the combination of methotrexate and vinblastine is one of the most studied regimens, although it does have some toxicity.268,272,273 In more aggressive cases, more intensive chemotherapy can be useful.274-276 Vinorelbine has been reported to have activity in a small series of AF cases, with less toxicity than methotrexate-vinblastine.277 Case reports have described meaningful responses to imatinib270,278; in addition, a series of 19 patients with AF showed imatinib to have some activity, with a partial response rate of approximately 16% and 4 additional patients with stable disease.258 Alveolar Soft-Part Sarcoma. Alveolar soft-part sarcoma, usually a slowly growing tumor, is often associated with the late development of metastases. A t(X;17) translo1418

Mayo Clin Proc.

•

cation generates a fusion of ASPSCR (a gene of unknown function) on chromosome 17 to TFE3 (a transcription factor) on the X chromosome, yielding the ASPSCR-TFE3 fusion protein. Alveolar soft-part sarcoma has a low response rate to conventional chemotherapy; however, because of its slow growth rate, surgical resection of metastases may often be of benefit.279 Rhabdomyosarcoma. Rhabdomyosarcoma (RMS), the most common pediatric solid tumor,280 is uncommon in adults. Although RMS is an STS, its treatment is distinct from that of other STSs. As with other pediatric sarcomas, dramatic advances have been made in curing this tumor in the past 4 decades.281 Surgery alone led to cure in fewer than 20% of patients. In contrast, multimodal therapy with surgery, chemotherapy, and radiation has been reported to cure more than 70% of patients. The rapid development of metastatic disease in the absence of systemic therapy again suggests the presence of micrometastatic disease, even in the absence of overt metastases. Histology and Molecular Pathology. Rhabdomyosarcomas arise from primitive cells that are the precursors for striated skeletal muscle. Morphologically, RMSs appear similar to small round blue cell tumors such as Ewing sarcoma (EWS), lymphoma, or desmoplastic small round-cell tumor. Immunohistochemistry, cytogenetics, or electron microscopy may be necessary to establish the diagnosis.282 More than 99% of RMSs stain positive for polyclonal desmin,283 more than 90% contain muscle-specific actin and myogenin, and more than 75% are positive for myoglobin.284 Rhabdomyosarcoma can be divided into embryonal (58%), alveolar (31%), botryoid, pleomorphic, or anaplastic subtypes,285 some with typical cytogenetic changes (Table 2). Embryonal RMS, which is composed of sheets and nests of typical rhabdomyoblasts admixed with occasional fusiform cells, has no distinct architecture. The presence of any alveolar pattern is enough to classify an RMS as an alveolar subtype, which typically appears as fibrovascular septae that are lined with densely packed tumor cells and separated by pseudoalveolar spaces. These spaces vaguely resemble pulmonary alveoli. Embryonal RMS has a more favorable prognosis than alveolar RMS. Most patients with alveolar RMS have 1 of 2 chromosomal translocations.286 In one series, 55% of children with alveolar RMS had a translocation between chromosome 2 and 13, ie, t(2;13)(q35;q14), which fuses the PAX3 gene, a normal transcriptional regulator of early neuromuscular development, with the FOXO1A gene, a member of the forkhead family of transcription factors.287 Approximately 22% of children with alveolar RMS have the less common translocation, t(1;13)(p36;q14), which fuses PAX7 with FOX01A.288 In that same series 23% of patients with alveolar RMS were translocation negative.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

Patients with embryonal RMS do not have any reproducible chromosomal translocations, but most do have loss of heterozygosity at the 11p15 locus, the site of the IGF2 gene. Overproduction of IGF2 by embryonal RMS leads to autocrine growth stimulation of these tumors.289 Alveolar RMS also overexpresses IGF2,290 suggesting that overproduction of IGF2 is important to the growth dysregulation of all RMSs, regardless of histology. Clinical Presentation and Staging. Most children with RMS present with a painless mass, often with overlying erythema. Most patients (75%) have localized disease at diagnosis. The disease most commonly spreads to the lungs or bones.291 Although RMS can occur anywhere, the most common sites of origin are the head and neck (35%-40%), the genitourinary tract (25%), and the extremities (20%). Staging for RMS is based on 2 complementary systems. The older of the two, a system of postsurgical staging, essentially distinguishes those patients who have complete resection of their tumors, those who have gross resection with positive margins, those who have biopsy only and gross residual disease, and those who have metastatic disease.292 The extent of surgical resection influences the chances of cure with this disease.293 In the Third Intergroup Rhabdomyosarcoma Study (IRS), patients with resected stage I disease had a 5-year survival rate of greater than 90%, compared with 80%, 70%, and 30% for those with stage II, III, and IV disease, respectively. The Fourth IRS introduced the second staging system, one for staging tumor node metastasis.294 The T stage is determined by the location of the tumor, its size (ie, whether greater or less than 5 cm in diameter), and its degree of confinement to an anatomic site of origin. Nodal spread to adjacent organs confers stage III disease, and distant metastasis is automatically stage IV. Staging studies should include high-resolution imaging of the primary tumor, computed tomography of the chest, and a radionuclide bone scan. Routine central nervous system imaging is not necessary unless the primary tumor originates in the head and neck region. Local Therapy. Complete resection with negative margins has the best chance of controlling local disease. However, for many locations, such as orbital, parameningeal, or other head and neck locations, complete resection cannot be accomplished without excessive morbidity. Therefore, radiotherapy has a major role in the treatment of RMS, particularly for achieving local control in patients with microscopic or gross residual disease after surgery and chemotherapy (stage II or III disease). For patients with completely resected stage I embryonal RMS with negative margins, IRS I and II showed no benefit for the addition of radiotherapy to postoperative chemotherapy.295 In contrast, patients with RMS, who have a poorer prognosis even after Mayo Clin Proc.

•

complete resection, had lower local recurrence rates with the addition of adjuvant radiation. Definitive radiotherapy is indicated for patients with stage III disease and those with gross residual disease after surgery; indeed, in many cases it may be curative. For these patients, IRS IV examined a higher total dose and an accelerated fractionation of radiation, finding that neither improved local control or survival.296,297 Chemotherapy. Before the routine use of chemotherapy, surgery with or without radiation for RMS resulted in survival rates of less than 20%. With the addition of systemic chemotherapy to local treatment, survival rates in patients with localized disease have increased to 60% to 90%. Combination chemotherapy with vincristine, dactinomycin, and cyclophosphamide (VAC) is generally considered the standard treatment of RMS. More or less aggressive combinations have been compared with this regimen. In the IRS trials, the substitution or addition of other active agents (doxorubicin, cisplatin, ifosfamide, and etoposide) did not improve outcomes compared with VAC.293,295,298 However, adverse effects and long-term complications, such as cardiac toxicity with doxorubicin or renal toxicity with ifosfamide, were exacerbated. In contrast, cyclophosphamide can be omitted safely from adjuvant chemotherapy (vincristine and dactinomycin instead of VAC) without compromising outcomes in the subgroup of patients who are classified as low risk. For these patients, adjuvant vincristine and dactinomycin are commonly considered standard treatment. Given the low incidence of and the high degree of specialization required to treat RMS, children with RMS should be referred to specialists with appropriate expertise. Treatment of Metastatic Disease. Patients with metastatic disease clearly have a worse prognosis than those with localized disease. However, for a substantial fraction of patients, durable complete remissions and cures are possible with chemotherapy and often radiotherapy to the primary tumor site and sometimes metastatic sites as well.299 In recent clinical trials, patients (<10 years) with metastatic disease and embryonal histology had a 5-year survival rate of almost 60%. For patients older than 10 years with embryonal RMS and those with alveolar, pleomorphic, or undifferentiated RMS of any age, survival was only half that rate, ie, 30% at 5 years.300 Trials are ongoing, but thus far neither additional chemotherapy nor high-dose therapy with stem cell support301 has proven superior to VAC. Metastasectomy, which has a role in the treatment of other sarcomas, is not usually effective for stage IV RMS. PRIMARY SARCOMAS OF BONE The most common primary bone tumors are osteosarcoma, EWS, and MFH of bone. Management of primary sarco-

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1419

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

mas of bone has improved dramatically in the past 3 decades. Most patients are able to undergo limb-sparing procedures, and survival has improved dramatically. OSTEOSARCOMA Epidemiology and Risk Factors. Although osteosarcoma is the most common primary malignant tumor of bone, it is still rare, accounting for only 5% of childhood cancers. Approximately 400 cases occur each year in the United States, mostly in children and adolescents.302 It is characterized by the production of osteoid or immature bone by the malignant cells. Although most osteosarcomas are sporadic, several risk factors have been associated with their incidence, including prior radiation therapy and prior chemotherapy, particularly with alkylating agents or anthracyclines. Paget disease, a generally benign condition characterized by increased bone turnover, is associated with an increased risk of osteosarcoma.303 Several other benign conditions, including chronic osteomyelitis, osteochondroma, enchondroma, and fibrous dysplasia, have been associated with osteosarcoma. Several rare genetic conditions, namely RB304 and Li-Fraumeni,305 are also associated with an increased incidence of osteosarcoma. Osteosarcomas tend to form in areas of rapid bone growth or turnover, such as in the long bones of a developing adolescent. Unlike EWS, they have not been associated with any specific chromosomal translocation or molecular defect. They tend to have a complex karyotype. Clinical Presentation and Staging. Patients typically present with localized bone pain, often associated with trauma. They typically have symptoms for several months before seeking medical attention. A tender soft tissue mass is often palpable. Unlike EWS, osteosarcoma is rarely associated with “tumor fever” or other “B symptoms” such as anorexia, weight loss, and fatigue. The most common sites of disease are the femur, tibia, and humerus, followed by other bones.306 Laboratory evaluation can show elevations of alkaline phosphatase or lactate dehydrogenase. Elevations in alkaline phosphatase or lactate dehydrogenase can correlate with a poorer prognosis.307 Between 10% and 20% of patients have overt metastatic disease at diagnosis. The most common sites of spread are the lungs or other bones. Long-term survival is possible for 10% to 30% of patients with disease that has spread only to the lungs if they achieve a complete response to chemotherapy or are able to undergo resection of all metastases.308 Long-term survival is significantly worse for patients who present with or subsequently develop bone metastases than for patients in whom the metastatic disease is confined to the lungs.309 Microscopic metastatic disease is presumed to be present in most patients. Historical series and a randomized 1420

Mayo Clin Proc.

•

trial have shown an 80% or higher recurrence rate in the absence of chemotherapy, despite adequate local control. In contrast, current multiagent chemotherapeutic regimens, which are hypothesized to eradicate subclinical disease, are associated with 5-year DFS rates of 50% to 70%.310-313 Staging studies should include plain radiographs of the involved bone as well as high-resolution imaging, usually magnetic resonance imaging or computed tomography, to evaluate the extent of disease, soft tissue involvement, and potential involvement of adjacent neurovascular structures. Computed tomography of the chest and a bone scan should be performed to determine if metastatic disease is present. Local Therapy. Local control is best achieved with surgery with wide margins. Advances in surgery and prosthetic technology have allowed most patients to avoid loss of major limbs. Osteosarcomas are relatively radiation resistant. Patients with unresectable disease of the axial skeleton have a poorer prognosis than those with long bone disease. In these patients, local control is more difficult to achieve314 because of the technical aspects of obtaining a margin-negative resection and because complete pathological responses to chemotherapy and radiation are uncommon. Recent advances in radiation therapy, such as 3dimensional treatment planning and particularly the use of proton beam radiotherapy, promise to improve rates of local control for patients with axial lesions in whom gross total resection of disease is achievable, even in the setting of positive surgical margins.315 Chemotherapy. Osteosarcoma is one of the first solid tumors for which adjuvant chemotherapy proved to be beneficial. Because the historical data were so compelling—recurrence rates of 80% historically vs 30% with adjuvant therapy316—only 1 randomized trial has been completed comparing adjuvant therapy with observation.310 Two-year relapse-free survival was 17% in the observation arm vs 66% in the group who received adjuvant chemotherapy with a multidrug regimen of cyclophosphamide, bleomycin, dactinomycin, high-dose methotrexate with leucovorin rescue, doxorubicin, and cisplatin. A series of subsequent trials have simplified the regimen and identified cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide as the most important components of adjuvant therapy. Some experts believe that optimal adjuvant therapy should include all 4 of these drugs, although no trials have addressed this issue. Bramwell and the European Osteosarcoma Intergroup (EOI)311 conducted a randomized trial of 6 cycles of doxorubicin and cisplatin vs 4 cycles of high-dose methotrexate, doxorubicin, and cisplatin. Although no statistically significant difference in OS was observed (64% vs 50%), 5-year DFS was significantly increased in the doxorubicin-cisplatin arm (57% vs 41%, P=.02).

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

Because osteosarcomas are surrounded by a calcified extracellular matrix, they do not shrink dimensionally as other cancers do in response to neoadjuvant therapy. In contrast, marked histologic response has been documented with induction therapy, and the degree of necrosis correlates with relapse-free survival and OS.307,311,312 Several trials have attempted unsuccessfully to tailor postoperative chemotherapy using histologic response to neoadjuvant treatment. The German Cooperative Osteosarcoma Study Group (COSS) 82 study attempted to omit cisplatin and doxorubicin for patients who achieved good histologic response to high-dose methotrexate, but outcomes were inferior for patients who did not receive those drugs.317 A Sloan-Kettering trial of a more intensive 6-drug T12 regimen showed a modest increase in the proportion of patients with good histologic response but no significant benefit in relapse-free survival over an older T10 protocol.318 In an EOI trial that randomly assigned 407 patients to either 6 cycles (18 weeks) of cisplatin and doxorubicin or a 44-week multidrug (vincristine, high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, and cisplatin) T10 regimen, no benefit in relapse-free survival, OS, or proportion of patients experiencing good histologic response was observed for the longer and more toxic T10 protocol.312 Timing of chemotherapy has been investigated in several trials; no difference in outcome has been found for chemotherapy administered before, after, or half before and half after local resection.319 During the past several years, results have plateaued. In an EOI trial in which patients were randomly assigned to dose-dense doxorubicin and cisplatin at 2-week intervals with growth factor support vs at 3-week intervals with no growth factor support, no difference in clinical outcomes was observed between the experimental and standard treatment arms.313 The Children’s Oncology Group conducted a study using a 2 × 2 factorial design of the addition of ifosfamide and/or muramyl tripeptide to their standard of high-dose methotrexate, alternating with doxorubicin and cisplatin. Unfortunately, the results are difficult to interpret because of the 2 × 2 factorial design and an apparent interaction between the 2 interventions. Treatment of Metastatic Disease. The most effective therapy for select cases of metastases confined to the lung is complete surgical resection with cure possible for up to one-third of patients.320 Adverse prognostic features include synchronous metastases, a large number of metastases, bilateral disease, a short time interval between local therapy and the development of metastatic disease, and a poor response to induction chemotherapy. Patients who do not achieve a complete response to chemotherapy or are not able to be rendered surgically free of disease will eventually die as a result of their sarcoma. Mayo Clin Proc.

•

Patients who are not eligible for metastasectomy are candidates for palliative chemotherapy. Responses to ifosfamide and etoposide have been noted in the salvage setting,321 with higher responses reported for combination than single-agent ifosfamide.322 High-dose methotrexate also has moderate single-agent activity for this disease. Carboplatin, which is frequently substituted for cisplatin in other diseases, appears inferior to cisplatin in osteosarcoma.323 Novel agents such as ecteinascidin 743 (also known as trabectedin) and deforolimus (formerly known as AP23573) have limited single-agent activity; gemcitabine with docetaxel may be useful.324 MFH OF BONE Other high-grade sarcomas of bone include MFH of bone, the most common, and high-grade spindle cell sarcomas of bone.325-331 These tumors do not produce tumor osteoid or cartilage. Because of the rarity of these tumors, well-defined treatment approaches have not been formulated. The best characterized, MFH of bone, is thought to have biological behavior that is similar to that of osteosarcoma and is therefore commonly treated as an osteosarcoma. EWING SARCOMA The Ewing family of tumors (EFT) includes EWS and peripheral neuroectodermal tumors (sometimes referred to as primitive peripheral neuroectodermal tumors). Ewing332 originally described these tumors as primary bone tumors that, unlike osteosarcoma, were responsive to radiation therapy. Ewing sarcoma is a rare sarcoma that develops most commonly in bone in adolescents, but it can also occur in soft tissue and arise at any age. Ewing sarcomas are characterized by a translocation of the EWSR1 gene on chromosome 22 to another chromosome, most typically 11 or 21, generating a fusion protein, usually EWS-FLI1 or EWS-ERG (Table 1). Originally thought to be a separate entity, peripheral neuroectodermal tumor is now known to share with EWS similar immunohistochemical characteristics and the identical chromosomal translocation (Table 1), and it too can arise in soft tissue or bone. The 2 diseases are now treated as 1 entity. Although the incidence is most common in the pediatric population, molecularly confirmed cases have occurred in adults as old as 80 years. An aggressive disease that typically presents as a rapidly growing mass, EFT can spread to lung, bone, and other organs. Most cases (>80%) present as localized disease, but overt metastases are known to develop rapidly after surgery for patients treated with only 1 modality of therapy. Microscopic metastatic disease has been postulated to be present even at the time of presentation, its spread held in check by factors secreted by the primary tumor. When the primary tumor is removed (or irradiated), the loss of these putative

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1421

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

suppressive factors may permit the metastases to grow. The use of chemotherapy in conjunction with surgery (and sometimes radiation) to treat such microscopic disease has substantially improved survival. Surveillance, Epidemiology, and End Results data from the National Cancer Institute showed an increase in 5-year survival rates for patients with EWS from 36% in 1975 to 1984 to 56% in 1985 to 1994.333 Epidemiology and Risk Factors. Ewing sarcoma is the second most common tumor of bone. Of the 600 to 700 bone tumors diagnosed annually, approximately 200 are EWS, with most of the remainder being osteosarcoma.334 The peak incidence is between the ages of 10 and 20 years, with patients younger or older accounting for fewer than 30% of cases.335 For reasons that are not known, EFT are significantly more common in white people than in black people or Asian people.336 No hereditary or congenital syndromes and no environmental factors or known risk factors have been associated with the occurrence of EWS. Histogenesis, Histology, and Molecular Biology. It is not known from which cells EFT originate, but mesenchymal stem cells have been proposed as one possibility. The immunohistochemical profile and ultrastructural features of EFT and their ability to undergo neural differentiation in vitro suggest that they are of neuroectodermal origin. Morphologically, EFT belong to the family of small round blue cell tumors, which includes lymphoma, mesenchymal chondrosarcoma, desmoplastic small round-cell tumor, medulloblastoma, and RMS. These entities can be difficult to distinguish by hematoxylin-eosin staining alone. Immunohistochemistry or molecular techniques are necessary for precise diagnosis.337 Although no routinely used histochemical or immunohistochemical stain can definitively distinguish EFT from other undifferentiated tumors of childhood, most EFT express high levels of CD99.338 Membrane-localized expression of CD99 is a sensitive marker for the EFT but is not specific because other tumors (eg, RMS, astrocytomas, neuroendocrine tumors, and carcinomas) may express this antigen.339 As described earlier, a characteristic reciprocal chromosomal translocation [t(11;22) (q24;q12)] has been identified in 85% to 90% of cases of EFT. The amino terminus of the EWSR1 gene (chromosome 22, band q12) is fused to the DNA-binding domain of the FLI1 transcription factor, a gene on chromosome 11, band q24, to form the EWSFLI1 translocation.340 The FLI1 gene, which was the first translocation partner identified for EWS in the EFT, is a member of the ETS family of DNA-binding transcription factors. These transcription factors are involved in the control of cellular proliferation, development, and tumorigenesis.341 Many other ETS family members have been identified as potential fusion partners for EWS in a minor fraction of EFT. The EWS-ERG translocation [t(21;22) 1422

Mayo Clin Proc.

•

(q22;q12)], which is present in 5% to 10% of EFT, is the second most common.342 Although EWS-ETS family translocations are specific for EFT, the EWSR1 gene can be fused to other partners in other tumors. For example, EWS-ATF1 is characteristic of clear cell sarcoma,343 EWSR1-WT1 of desmoplastic small round-cell tumor,344 and EWSR1-TEC of extraskeletal mesenchymal chondrosarcoma.345 Clinical Presentation and Staging. The most common presenting symptom of patients with EFT is bone pain, followed by soft tissue swelling and fever, which is present in one-fourth of patients with EFT.346 Tumors arise most frequently in long bones and are several-fold more likely to occur in lower vs upper extremities. The time from initial symptoms to actual diagnosis can average from 4 to 6 months, largely because cancer is seldom in the differential diagnosis for a healthy active adolescent with bone pain. Staging studies should include high-resolution imaging of the primary tumor site, standard radiography to evaluate bone involvement, computed tomography of the chest, and a bone scan to evaluate potential sites of metastases. Although bone marrow biopsies are performed in many pediatric protocols, bone marrow disease is seldom present in the absence of clinical symptoms or a positive bone scan. When available, PET can be a useful tool for staging the disease347 and for arriving at a prognosis by measuring metabolic response to neoadjuvant therapy.348 Local Therapy. Local control is achieved either through surgery or high-dose radiotherapy. Although EFT are relatively sensitive to radiotherapy, retrospective studies show better control with surgical resection than radiotherapy,346 perhaps because of selection bias.349,350 For patients with soft tissue lesions or with long bone tumors that are amenable to limb salvage procedures, surgery is the preferred method of local therapy. For patients with axial skeleton lesions or pelvic primary tumors, wide surgical excision typically is not feasible, and definitive radiotherapy must be relied on for local control. In fact, death is far more often the result of metastatic disease than of local recurrence. However, primary EFT in the pelvis are associated with a poorer outcome than those located in the extremities. They are also associated with higher rates of local recurrence,351 likely because of the difficulty of achieving negative-margin resection of such tumors. Chemotherapy. Historical series show that few (10%20%) patients with EFT survive when treated with local therapy alone. With combination therapy cure rates increased to 25%.352 The first advances came in the late 1960s and early 1970s with the use of dactinomycin, cyclophosphamide, and vincristine.353 The next advance was the advent of doxorubicin. At the same time, US and European cooperative groups formed to address clinical questions via randomized trial.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

In the first Intergroup Ewing Sarcoma Study (IESS) the addition of doxorubicin to the VAC backbone was associated with a significantly better 5-year relapse-free survival (60%) than VAC alone (24%) or VAC plus adjuvant bilateral pulmonary irradiation (44%).354 In IESS-II, only patients with nonpelvic primary tumors were studied. The upfront use of high-dose doxorubicin and high-dose cyclophosphamide increased the 5-year survival rate to 77% vs 63% for patients who received lower-dose weekly cyclophosphamide and lower doses of doxorubicin later in their treatment course.355 More recently, the IESS-III study, which examined the addition of ifosfamide and etoposide to the VACA (vincristine, doxorubicin [Adriamycin], cyclophosphomide, and dactinomycin [actinomycin D]) backbone, showed an increase in 5-year survival from 61% to 72% for patients in the experimental arm.356 Other nonrandomized trials also suggest a benefit for the addition of ifosfamide and etoposide to standard therapy.357 The standard of care today is therefore a 5-drug regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. The continued use of dactinomycin in treatment protocols for localized disease is controversial. Typically, patients receive 4 to 6 cycles of neoadjuvant chemotherapy, followed by definitive local therapy (surgery, radiation, or both) with additional adjuvant chemotherapy. Even patients with localized disease are typically treated for up to 1 year after diagnosis. Treatment of Metastatic Disease. Patients who present with metastatic disease or who develop metastases within 2 years of their diagnosis have a much poorer prognosis than those with localized disease. Although longterm cure has been reported for up to 20% of patients who present with metastatic disease,356 more intensive therapies with additional agents have failed to appreciably increase that percentage. Patients whose metastatic disease is confined to the lung may have a more favorable prognosis than those with skeletal or visceral metastases.358 The use of whole-lung radiotherapy has been investigated and may be of some benefit for patients whose metastatic disease is confined to the lung.359 Because EFT are relatively sensitive to chemotherapy, high-dose therapy with stem cell rescue has been investigated in several nonrandomized phase 2 trials, resulting in outcomes that were better than expected based on historical controls.360,361 However, investigators have since questioned the general applicability of such results.306,362 Two ongoing randomized trials, one in the United States and one in Europe, should provide definitive data on the utility of high-dose chemotherapy. For patients with progression of disease after standard therapy, prognosis is grim. Partial responses have been reported to single-agent irinotecan or the combinations of Mayo Clin Proc.

•

cyclophosphamide and topotecan,363 or temozolomide and irinotecan364; however, such responses tend to be short and patients typically survive less than a year. GIANT CELL TUMOR Giant cell tumors (GCTs) of bone, also known as osteoclastomas, are primary bone neoplasms. They are usually benign but locally aggressive and most commonly occur in the epiphyses of long bones. Rarely, GCTs can originate at extraosseous sites.365 Treatment of GCT of bone is usually surgical curettage with application of bone cement. Radiation therapy is sometimes used after surgery when the tumor has recurred locally. Metastases from GCT of bone are unusual. Pulmonary metastases of GCT of bone usually grow slowly and are often treated by surgery; however, in some cases chemotherapy with various agents or radiation therapy has been used.365 Even more rarely, GCT may exhibit a much more aggressive phenotype. Although the role of chemotherapy in metastatic GCT is not well defined, it has been reported to be useful in some cases.365,366 In the early 1970s, Walker367,368 observed that osteoclasts are derived from monocytic progenitors found in the blood. This work provided the first demonstration of the existence of stem cells in blood for nonhematopoietic tissue and also paved the way for a better understanding of the biology of GCT. The origin of GCT is unknown; however, GCT cells have been reported to produce chemoattractants for osteoclasts and tartrate-resistant acid phosphatase–positive monocytic osteoclast precursors.369,370 One growth factor of potential importance in GCT is the receptor activator of nuclear factor κB (RANK) ligand.365,369-374 Thus, GCT is a primary osteolytic bone neoplasm in which monocytic macrophage/osteoclast precursor cells and multinucleated osteoclastlike giant cells infiltrate the tumor because of the production of trophic factors produced by the tumor cells.369,372,374 In particular, the RANK ligand appears to play a critical role in GCT. It binds specific hematopoietic progenitor cells, induces osteoclast differentiation, activates osteoclasts, and is necessary and sufficient for the induction of osteoclastogenesis from precursor cells.375 The messenger RNA of the RANK ligand has been reported to be overexpressed in the stromal-like tumor cells of GCT, but its receptor, RANK, was expressed only in the macrophagelike mononuclear cells and multinucleated giant cells.372,376,377 It is unknown whether tumor cell–osteoclast interaction/codependence (eg, a paracrine loop between the stromal tumor cells and the osteoclastlike cells) has a role to play in GCT, but the possibility is intriguing.365,371 For example, given that osteoclasts produce a number of cytokines, new agents that may inhibit osteoclastogenesis

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1423

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

via the RANK/RANK ligand pathway could be useful in the treatment of GCT. A trial of the efficacy of one such agent, denosumab, a monoclonal antibody that binds the RANK ligand, in the treatment of GCT is ongoing. Reports have also shown that bisphosphonates may induce apoptosis in both osteoclastlike giant cells and stromal tumor cells in vivo and in vitro in GCT, 378,379 possibly by interfering with an autocrine and/or paracrine loop between stromal tumor cells and osteoclastlike giant cells in the tumor. Osteoclastlike giant cells are present in many reactive conditions as well as benign and malignant tumors, and care must be taken to distinguish these from true GCT. Among the other tumors with a giant cell component is giant cell tumor of the tendon sheath, the most common tumor of the synovium and tendon sheath.380 Also known as localized nodular tenosynovitis, it is the same as or similar to pigmented villonodular synovitis (PVNS). It is an entity unrelated to GCT that usually occurs in the tendon sheath of the hands but also may occur in the feet. The term PVNS is typically used when a joint is involved by the process. It is mentioned here to distinguish it from GCT of bone. The name PVNS derives from the presence of hemosiderin in multinucleated giant cells in the tumor. Proliferation may lead to bone destruction and the development of cysts. Diffuse PVNS, a benign proliferation of synovium-lined joints, usually occurs in the hips, ankles, and knees. Although karyotype abnormalities have been reported, it is thought to be a polyclonal proliferation.381-383 Although PVNS can recur after excision, it rarely undergoes malignant transformation. The etiology is unknown, but complete excision is the optimal treatment. CHONDROSARCOMAS Chondrosarcomas, which are characterized by the production of a cartilage mix, comprise a heterogeneous group of bone and soft tissue tumors. They most commonly arise in a benign cartilage abnormality such as an osteochondroma or enchondroma, and patients with Olier disease (multiple enchondromatosis) or Maffucci syndrome (multiple enchondromas and hemangiomas) are at much higher risk. Patients with low-grade chondrosarcomas, which grow more slowly, generally have a better prognosis than those with high-grade chondrosarcomas. Less common subtypes of chondrosarcoma include mesenchymal chondrosarcomas, which contain both low-grade cartilaginous tumor cells and a high-grade component that resembles EWS cells; clear cell chondrosarcomas, which are low-grade tumors; and dedifferentiated chondrosarcomas. Extraskeletal myxoid chondrosarcomas are defined by the presence of a fusion gene between the orphan nuclear receptor CHN1/NR4A3 and one of several partners, most commonly EWSR1. 1424

Mayo Clin Proc.

•

The primary treatment of chondrosarcoma is surgery. The conventional chondrosarcoma is typically resistant to chemotherapy; however, chemotherapy may be of benefit in some cases of dedifferentiated chondrosarcoma. SURGICAL RESECTION OF METASTASES Given the heterogeneity in the biological behavior of sarcoma, resection of metastatic disease, which often occurs with osteosarcoma but may occur with any sarcoma, is a reasonable option. The most commonly resected metastases are those of the lung. Factors that are weighed when deciding whether to resect metastases include the length of the disease-free interval, the number of metastases, and the growth rate of the metastases. Clearly, a short disease-free interval, the presence of a large number of metastases, and the rapid growth of metastases argue against metastasectomy. Although randomized trial data do not exist, some patients with metastatic disease clearly benefit from surgery. Patients who have been disease free for more than 2 years and who had only a single lesion are the ideal candidates for surgery; however, surgery may be of benefit in many other scenarios as well. Patients should be approached on a case-by-case basis by physicians experienced with the disease. In some patients with slowly growing sarcomas (such as alveolar soft-part sarcoma), prolonged DFS has been achieved after the removal of as many as 20 metastatic lesions; however, such cases are rare. More typically, 3 or 4 metastases would be considered a reasonable number for surgical removal; again, however, the number depends on the overall scenario.384-389 In select cases, resection of metastatic disease at other sites is also reasonable, with the same considerations as described above. A good example would be localized GIST metastases that are not responding to tyrosine kinase inhibitors. For selected sites that are not amenable to surgery, radiation therapy may be appropriate, even in the absence of symptoms from the tumor. FUTURE DEVELOPMENTS The development of optimal treatment strategies for sarcoma has been greatly complicated by the large number of subtypes, the heterogeneity in their biological behavior, and the small number of patients with particular subtypes enrolled in trials. Molecular techniques such as microarraybased gene expression profiles promise to improve our ability to predict both the probability of metastasis and overall clinical course and the probability of response to a particular treatment.7,8,80 Recent studies have found gene expression patterns that predict the probability of metastasis in high-grade pleomorphic STS,390 as well as poor out-

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

come in EWS86 and LMS.19,391 It is essential that future trials archive pretreatment biopsy material in a manner that allows molecular analysis in later studies. The information gained in clinical trials may also be increased by stratification based on currently available parameters.390 Such stratification would be particularly helpful in adjuvant chemotherapy trials, in which the ability to predict recurrence would be invaluable. CONCLUSION Sarcomas comprise a heterogeneous group of neoplasms that can be grouped into 2 general categories, STSs and primary bone sarcomas, each with different staging and treatment approaches. The approach to a patient with a sarcoma begins with a biopsy that obtains adequate tissue for diagnosis without interfering with subsequent optimal definitive surgery. Subsequent treatment depends on the specific type of sarcoma. Because sarcomas are relatively uncommon and yet comprise a wide variety of different entities, evaluation by oncology teams who have expertise in the field is recommended. General treatment and followup guidelines have been published by the National Comprehensive Cancer Network (www.nccn.org). REFERENCES 1. Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors. St. Louis, MO: Mosby; 2001. 2. Brennan M, Alektiar KM, Maki R. Sarcomas of soft tissue and bone: soft tissue sarcoma, in Cancer: Principles and Practice of Oncology. Philadelphia, PA: Williams and Wilkins; 2001:1841-1891. 3. Skubitz KM, Skubitz AP. Differential gene expression in leiomyosarcoma. Cancer. 2003;98:1029-1038. 4. Skubitz KM, Skubitz AP. Characterization of sarcomas by means of gene expression. J Lab Clin Med. 2004;144:78-91. 5. Segal NH, Pavlidis P, Antonescu CR, et al. Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am J Pathol. 2003;163:691-700. 6. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 2002;359:1301-1307. 7. West RB, van de Rijn M. The role of microarray technologies in the study of soft tissue tumours. Histopathology. 2006;48:22-31. 8. Baird K, Davis S, Antonescu CR, et al. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005;65:92269235. 9. Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14:1679-1689. 10. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res. 2003;9:1941-1956. 11. Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005;353:701-711. 12. Dileo P, Demetri GD. Update on new diagnostic and therapeutic approaches for sarcomas. Clin Adv Hematol Oncol. 2005;3:781-791. 13. Rous P. Sarcoma of the common fowl. J Exp Med. 1910;12:696–705. 14. Rous P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J Exp Med. 1911;13:397-411. 15. Tomescu O, Barr FG. Chromosomal translocations in sarcomas: prospects for therapy. Trends Mol Med. 2001;7:554-559. 16. van de Rijn M, Fletcher JA. Genetics of soft tissue tumors. Annu Rev Pathol Mech Dis. 2006;1:435-466. 17. Turc-Carel C, Limon J, Dal Cin P, Rao U, Karakousis C, Sandberg AA. Cytogenetic studies of adipose tissue tumors, II: recurrent reciprocal transloca-

Mayo Clin Proc.

•

tion t(12;16)(q13;p11) in myxoid liposarcomas. Cancer Genet Cytogenet. 1986;23:291-299. 18. Sreekantaiah C, Ladanyi M, Rodriguez E, Chaganti RS. Chromosomal aberrations in soft tissue tumors: relevance to diagnosis, classification, and molecular mechanisms. Am J Pathol. 1994;144:1121-1134. 19. Ren B, Yu YP, Jing L, et al. Gene expression analysis of human soft tissue leiomyosarcomas. Hum Pathol. 2003;34:549-558. 20. Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004;40:97-108. 21. Pedeutour F, Forus A, Coindre JM, et al. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes Chromosomes Cancer. 1999;24:30-41. 22. Pedeutour F, Suijkerbuijk RF, Forus A, et al. Complex composition and co-amplification of SAS and MDM2 in ring and giant rod marker chromosomes in well-differentiated liposarcoma. Genes Chromosomes Cancer. 1994; 10:85-94. 23. Mugneret F, Lizard S, Aurias A, Turc-Carel C. Chromosomes in Ewing’s sarcoma, II: nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet. 1988;32:239-245. 24. Lee YF, John M, Edwards S, et al. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J Cancer. 2003;88:510-515. 25. Jeon IS, Davis JN, Braun BS, et al. A variant Ewing’s sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995;10:1229-1234. 26. Fletcher JA, Kozakewich HP, Hoffer FA, et al. Diagnostic relevance of clonal cytogenetic aberrations in malignant soft-tissue tumors. N Engl J Med. 1991;324:436-442. 27. Fletcher CD, Akerman M, Dal Cin P, et al. Correlation between clinicopathological features and karyotype in lipomatous tumors: a report of 178 cases from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. Am J Pathol. 1996;148:623-630. 28. Aman P, Ron D, Mandahl N, et al. Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer. 1992;5:278-285. 29. Bennicelli JL, Barr FG. Chromosomal translocations and sarcomas. Curr Opin Oncol. 2002;14:412-419. 30. Ladanyi M, Bridge JA. Contribution of molecular genetic data to the classification of sarcomas. Hum Pathol. 2000;31:532-538. 31. Mitelman F. Recurrent chromosome aberrations in cancer. Mutat Res. 2000;462:247-253. 32. Amendola BE, Amendola MA, McClatchey KD, Miller CH Jr. Radiation-associated sarcoma: a review of 23 patients with postradiation sarcoma over a 50-year period. Am J Clin Oncol. 1989;12:411-415. 33. Cahan WG. Radiation-induced sarcoma—50 years later [editorial]. Cancer. 1998;82:6-7. 34. Arlen M, Higinbotham NL, Huvos AG, Marcove RC, Miller T, Shah IC. Radiation-induced sarcoma of bone. Cancer. 1971;28:1087-1099. 35. Brenin CM, Small W Jr, Talamonti MS, Gradisher WJ. Radiationinduced sarcoma following treatment of breast cancer. Cancer Control. 1998;5:425-432. 36. Nanus DM, Kelsen D, Clark DG. Radiation-induced angiosarcoma. Cancer. 1987;60:777-779. 37. Souba WW, McKenna RJ Jr, Meis J, Benjamin R, Raymond AK, Mountain CF. Radiation-induced sarcomas of the chest wall. Cancer. 1986;57:610-615. 38. Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the breast. Cancer. 2005;104:2682-2688. 39. Ruocco V, Schwartz RA, Ruocco E. Lymphedema: an immunologically vulnerable site for development of neoplasms. J Am Acad Dermatol. 2002;47: 124-127. 40. Requena L, Sangueza OP. Cutaneous vascular proliferations, part III: malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol. 1998;38(2, pt 1):143-175. 41. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphoedematous extremities. Cancer. 1972;30:562-572. 42. Pirastu R, Baccini M, Biggeri A, Comba P. Epidemiologic study of workers exposed to vinyl chloride in Porto Marghera: mortality update. Epidemiol Prev. 2003;27:161-172. 43. Mikoczy Z, Schutz A, Stromberg U, Hagmar L. Cancer incidence and specific occupational exposures in the Swedish leather tanning industry: a cohort based case-control study. Occup Environ Med. 1996;53:463-467. 44. Block JB. Angiosarcoma of the liver following vinyl chloride exposure. JAMA. 1974;229:53-54.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1425

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

45. Dogliotti E. Molecular mechanisms of carcinogenesis by vinyl chloride. Ann Ist Super Sanita. 2006;42:163-169. 46. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266:18651869. 47. Hengge UR, Ruzicka T, Tyring SK, et al. Update on Kaposi’s sarcoma and other HHV8 associated diseases, part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis. 2002;2:281-292. 48. Memar OM, Rady PL, Tyring SK. Human herpesvirus-8: detection of novel herpesvirus-like DNA sequences in Kaposi’s sarcoma and other lesions. J Mol Med. 1995;73:603-609. 49. Whitby D, Howard MR, Tenant-Flowers M, et al. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi’s sarcoma. Lancet. 1995;346:799-802. 50. Hethcote HW, Knudson AG Jr. Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci U S A. 1978;75:24532457. 51. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820-823. 52. Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer. 1987;56:339-347. 53. Polsky D, Mastorides S, Kim D, et al. Altered patterns of RB expression define groups of soft tissue sarcoma patients with distinct biological and clinical behavior. Histol Histopathol. 2006;21:743-752. 54. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922-2930. 55. Ross JA, Severson RK, Davis S, Brooks JJ. Trends in the incidence of soft tissue sarcomas in the United States from 1973 through 1987. Cancer. 1993;72:486-490. 56. Fong Y, Coit DG, Woodruff JM, Brennan MF. Lymph node metastasis from soft tissue sarcoma in adults: analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg. 1993;217:72-77. 57. Antonescu CR, Rosenblum MK, Pereira P, Nascimento AG, Woodruff JM. Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor. Am J Surg Pathol. 2001;25:699-709. 58. Greene FL, Page D, Fleming I, eds. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002. 59. Kattan MW, Leung DH, Brennan MF. Postoperative nomogram for 12year sarcoma-specific death. J Clin Oncol. 2002;20:791-796. 60. Coindre JM. Grading of soft tissue sarcomas: review and update. Arch Pathol Lab Med. 2006;130:1448-1453. 61. Fletcher CD, Unni KK, Mertens F, eds. World Health Organization Classification of Tumors. Vol 5. Lyon, France: IARC Press; 2002. 62. Costa J, Wesley RA, Glatstein E, Rosenberg SA. The grading of soft tissue sarcomas: results of a clinicohistopathologic correlation in a series of 163 cases. Cancer. 1984;53:530-541. 63. Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol. 1997;15:350-362. 64. Oliveira AM, Nascimento AG. Grading in soft tissue tumors: principles and problems. Skeletal Radiol. 2001;30:543-559. 65. Trojani M, Contesso G, Coindre JM, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984;33:37-42. 66. Schuetze SM. Imaging and response in soft tissue sarcomas. Hematol Oncol Clin North Am. 2005;19:471-487. 67. Hicks RJ. Functional imaging techniques for evaluation of sarcomas. Cancer Imaging. 2005;5:58-65. 68. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998;16:197-203. 69. Dusenbery K. Extremity soft tissue sarcoma in adults. In: Levitt SH, Kahn FM, Potish RA, eds. The Technological Basis of Radiation Therapy: Practical Clinical Applications. 2nd ed. Phiadelphia, PA: Lea & Febiger; 1992. 70. Rosenberg SA, Tepper J, Glatstein E, et al. Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities. Cancer. 1983;52:424-434. 71. Suit HD, Proppe KH, Mankin HJ, Wood WC. Preoperative radiation therapy for sarcoma of soft tissue. Cancer. 1981;47:2269-2274. 72. Sadoski C, Suit HD, Rosenberg A, Mankin H, Efird J. Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol. 1993;52:223-230.

1426

Mayo Clin Proc.

•

73. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235-2241. 74. Davis AM, O’Sullivan B, Bell RS, et al. Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol. 2002;20:4472-4477. 75. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350:1647-1654. 76. Sarcoma Meta-analysis Collaboration (SMAC). Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Cochrane Database Syst Rev. 2000:CD001419. 77. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19:1238-1247. 78. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25:468473. 79. Cormier JN, Huang X, Xing Y, et al. Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol. 2004;22:4567-4574. 80. Skubitz KM, Skubitz AP. Role of gene expression arrays in sarcomas. Curr Oncol Rep. 2004;6:309-314. 81. Bielack SS, Erttmann R, Winkler K, Landbeck G. Doxorubicin: effect of different schedules on toxicity and anti-tumor efficacy. Eur J Cancer Clin Oncol. 1989;25:873-882. 82. Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med. 1982;96:133-139. 83. Samuels BL, Vogelzang NJ, Ruane M, Simon MA. Continuous venous infusion of doxorubicin in advanced sarcomas. Cancer Treat Rep. 1987;71:971972. 84. Shapira J, Gotfried M, Lishner M, Ravid M. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen: a prospective randomized evaluation. Cancer. 1990;65:870-873. 85. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. 1991;83:926-932. 86. Northfelt DW, Martin FJ, Working P, et al. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol. 1996;36:55-63. 87. Northfelt DW. Stealth liposomal doxorubicin (SLD) delivers more doxorubicin (DOX) to AIDS-related Kaposi’s sarcoma (AIDS-KS) lesions than to normal skin [abstract 5]. Proc Am Soc Clin Oncol. 1994;13:51. 88. Alberts DS, Muggia FM, Carmichael J, et al. Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials. Semin Oncol. 2004;31:5390. 89. Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37:870877. 90. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Invest. 2003;21:167-176. 91. Toma S, Tucci A, Villani G, Carteni G, Spadini N, Palumbo R. Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG). Anticancer Res. 2000;20:485-491. 92. Gottlieb JA, Baker LH, Quagliana JM, et al. Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide. Cancer. 1972;30:1632-1638. 93. Awada A, Gil T, Sales F, et al. Prolonged schedule of temozolomide (Temodal) plus liposomal doxorubicin (Caelyx) in advanced solid cancers. Anticancer Drugs. 2004;15:499-502. 94. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11:1269-1275. 95. Patel SR, Vadhan-Raj S, Burgess MA, et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998;21:317-321. 96. Palumbo R, Palmeri S, Antimi M, et al. Phase II study of continuousinfusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas. Ann Oncol. 1997;8:1159-1162.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

97. Skubitz KM, Hamdan H, Thompson RC Jr. Ambulatory continuous infusion ifosfamide with oral etoposide in advanced sarcomas. Cancer. 1993; 72:2963-2969. 98. Blair SC, Zalupski MM, Baker LH. Ifosfamide and etoposide in the treatment of advanced soft tissue sarcomas. Am J Clin Oncol. 1994;17:480484. 99. Nielsen OS, Judson I, van Hoesel Q, et al. Effect of high-dose ifosfamide in advanced soft tissue sarcomas: a multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2000;36:61-67. 100. Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies—doseresponse and schedule dependence. J Clin Oncol. 1997;15:2378-2384. 101. Okuno S, Edmonson J, Mahoney M, Buckner JC, Frytak S, Galanis E. Phase II trial of gemcitabine in advanced sarcomas. Cancer. 2002;94:32253229. 102. Okuno S, Ryan LM, Edmonson JH, Priebat DA, Blum RH. Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer. 2003;97:1969-1973. 103. Patel SR, Gandhi V, Jenkins J, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol. 2001;19:34833489. 104. Look KY, Sandler A, Blessing JA, Lucci JA III, Rose PG. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study. Gynecol Oncol. 2004;92:644647. 105. Svancarova L, Blay JY, Judson IR, et al. Gemcitabine in advanced adult soft-tissue sarcomas: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2002;38:556-559. 106. Maki RG, Hensley ML, Wathen JK, et al, SARC: Sarcoma Alliance for Research. A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS) [abstract 9514]. J Clin Oncol. 2006;24(suppl):18S. 107. Heinemann V, Xu YZ, Chubb S, et al. Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. Mol Pharmacol. 1990;38:567-572. 108. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2′,2′difluorodeoxycytidine on DNA synthesis. Cancer Res. 1991;51:6110-6117. 109. Plunkett W, Huang P, Searcy CE, Gandhi V. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol. 1996;23(5, suppl 10):3-15. 110. Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W. Saturation of 2′,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol. 1991;27: 258-262. 111. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991; 9:491-498. 112. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824-2831. 113. Alderden RA, Hall MD, Hambley TW. The discovery and development of cisplatin. J Chem Educ. 2006;83:728. 114. Rosenberg B, VanCamp L. The successful regression of large solid sarcoma 180 tumors by platinum compounds. Cancer Res. 1970;30:17991802. 115. Rosenberg B, VanCamp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumour agents. Nature. 1969;222:385-386. 116. Edmonson JH, Long HJ, Richardson RL, Creagan ET, Green SJ. Phase II study of a combination of mitomycin, doxorubicin and cisplatin in advanced sarcomas. Cancer Chemother Pharmacol. 1985;15:181-182. 117. Edmonson JH, Petersen IA, Shives TC, et al. Chemotherapy, irradiation, and surgery for function-preserving therapy of primary extremity soft tissue sarcomas: initial treatment with ifosfamide, mitomycin, doxorubicin, and cisplatin plus granulocyte macrophage-colony-stimulating factor. Cancer. 2002;94:786-792. 118. Fata F, O’Reilly E, Ilson D, et al. Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer. 1999;86:2034-2037. 119. Skubitz KM, Haddad PA. Paclitaxel and pegylated-liposomal doxorubicin are both active in angiosarcoma. Cancer. 2005;104:361-366. 120. Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial [published correction appears in J Clin Oncol. 2005;23:5276]. J Clin Oncol. 2005; 23:576-584.

Mayo Clin Proc.

•

121. Garcia-Carbonero R, Supko JG, Maki RG, et al. Ecteinascidin-743 (ET743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol. 2005;23:54845492. 122. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276-1285. 123. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995;13:1537-1545. 124. Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989;7:12081216. 125. Schmidt RA, Conrad EU III, Collins C, Rabinovitch P, Finney A. Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer. 1993;72:2593-2601. 126. van Haelst-Pisani CM, Buckner JC, Reiman HM, Schaid DJ, Edmonson JH, Hahn RG. Does histologic grade in soft tissue sarcoma influence response rate to systemic chemotherapy? Cancer. 1991;68:2354-2358. 127. Scurr M, Judson I. How to treat the Ewing’s family of sarcomas in adult patients. Oncologist. 2006;11:65-72. 128. Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 1999;341:342-352. 129. Ohali A, Avigad S, Zaizov R, et al. Prediction of high risk Ewing’s sarcoma by gene expression profiling. Oncogene. 2004;23:8997-9006. 130. Kempson RL, Kyriakos M. Fibroxanthosarcoma of the soft tissues: a type of malignant fibrous histiocytoma. Cancer. 1972;29:961-976. 131. Le Doussal V, Coindre JM, Leroux A, et al. Prognostic factors for patients with localized primary malignant fibrous histiocytoma: a multicenter study of 216 patients with multivariate analysis. Cancer. 1996;77:18231830. 132. Pezzi CM, Rawlings MS Jr, Esgro JJ, Pollock RE, Romsdahl MM. Prognostic factors in 227 patients with malignant fibrous histiocytoma. Cancer. 1992;69:2098-2103. 133. Rooser B, Willen H, Gustafson P, Alvegard TA, Rydholm A. Malignant fibrous histiocytoma of soft tissue: a population-based epidemiologic and prognostic study of 137 patients. Cancer. 1991;67:499-505. 134. Weiss SW. Malignant fibrous histiocytoma: a reaffirmation. Am J Surg Pathol. 1982;6:773-784. 135. Fletcher CD, Gustafson P, Rydholm A, Willen H, Akerman M. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol. 2001;19:3045-3050. 136. Fletcher CD. Pleomorphic malignant fibrous histiocytoma: fact or fiction? a critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg Pathol. 1992;16:213-228. 137. Dehner LP. Malignant fibrous histiocytoma: nonspecific morphologic pattern, specific pathologic entity, or both? Arch Pathol Lab Med. 1988;112:236237. 138. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106-130. 139. Antonescu CR, Tschernyavsky SJ, Decuseara R, et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin Cancer Res. 2001;7:3977-3987. 140. Chang HR, Hajdu SI, Collin C, Brennan MF. The prognostic value of histologic subtypes in primary extremity liposarcoma. Cancer. 1989;64:15141520. 141. Lewis JJ, Brennan MF. The management of retroperitoneal soft tissue sarcoma. Adv Surg. 1999;33:329-344. 142. Lewis JJ, Leung D, Casper ES, Woodruff J, Hajdu SI, Brennan MF. Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma. Arch Surg. 1999;134:190-194. 143. Gebhard S, Coindre JM, Michels JJ, et al. Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol. 2002;26:601-616. 144. Mentzel T, Fletcher CD. Lipomatous tumours of soft tissues: an update. Virchows Arch. 1995;427:353-363. 145. Dalal KM, Kattan MW, Antonescu CR, Brennan MF, Singer S. Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk. Ann Surg. 2006;244:381-391.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1427

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

146. Szymanska J, Virolainen M, Tarkkanen M, et al. Overrepresentation of 1q21-23 and 12q13-21 in lipoma-like liposarcomas but not in benign lipomas: a comparative genomic hybridization study. Cancer Genet Cytogenet. 1997;99: 14-18. 147. Wanschura S, Belge G, Stenman G, et al. Mapping of the translocation breakpoints of primary pleomorphic adenomas and lipomas within a common region of chromosome 12. Cancer Genet Cytogenet. 1996;86:39-45. 148. Cornelius P, MacDougald OA, Lane MD. Regulation of adipocyte development. Annu Rev Nutr. 1994;14:99-129. 149. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006;7:885-896. 150. Matsui Y, Ueda T, Kubo T, et al. A novel type of EWS-CHOP fusion gene in myxoid liposarcoma. Biochem Biophys Res Commun. 2006 Sep 22; 348:437-440. Epub 2006 Jul 28. 151. Kuroda M, Wang X, Sok J, et al. Induction of a secreted protein by the myxoid liposarcoma oncogene. Proc Natl Acad Sci U S A. 1999;96:5025-5030. 152. Gibas Z, Miettinen M, Limon J, et al. Cytogenetic and immunohistochemical profile of myxoid liposarcoma. Am J Clin Pathol. 1995;103:20-26. 153. Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNAbinding protein in human myxoid liposarcoma. Nature. 1993;363:640-644. 154. Adelmant G, Gilbert JD, Freytag SO. Human translocation liposarcoma-CCAAT/enhancer binding protein (C/EBP) homologous protein (TLSCHOP) oncoprotein prevents adipocyte differentiation by directly interfering with C/EBPbeta function. J Biol Chem. 1998;273:15574-15581. 155. Uranishi H, Tetsuka T, Yamashita M, et al. Involvement of the prooncoprotein TLS (translocated in liposarcoma) in nuclear factor-kappa B p65mediated transcription as a coactivator. J Biol Chem. 2001 Apr 20;276:1339513401. Epub 2001 Jan 24. 156. Nilbert M, Rydholm A, Willen H, Mitelman F, Mandahl N. MDM2 gene amplification correlates with ring chromosome in soft tissue tumors. Genes Chromosomes Cancer. 1994;9:261-265. 157. Latres E, Drobnjak M, Pollack D, et al. Chromosome 17 abnormalities and TP53 mutations in adult soft tissue sarcomas. Am J Pathol. 1994;145:345355. 158. Pilotti S, Della Torre G, Lavarino C, et al. Distinct mdm2/p53 expression patterns in liposarcoma subgroups: implications for different pathogenetic mechanisms. J Pathol. 1997;181:14-24. 159. Pilotti S, Della Torre G, Lavarino C, et al. Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22. J Pathol. 1998;185:188-190. 160. Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferatoractivated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A. 1997;94:237-241. 161. Demetri GD, Fletcher CD, Mueller E, et al. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci U S A. 1999;96:3951-3956. 162. Debrock G, Vanhentenrijk V, Sciot R, Debiec-Rychter M, Oyen R, Van Oosterom A. A phase II trial with rosiglitazone in liposarcoma patients. Br J Cancer. 2003;89:1409-1412. 163. Maki RG. Future directions for immunotherapeutic intervention against sarcomas. Curr Opin Oncol. 2006;18:363-368. 164. Skubitz KM, Cheng EY, Clohisy DR, Thompson RC, Skubitz AP. Differential gene expression in liposarcoma, lipoma, and adipose tissue. Cancer Invest. 2005;23:105-118. 165. Trzyna W, McHugh M, McCue P, McHugh KM. Molecular determination of the malignant potential of smooth muscle neoplasms. Cancer. 1997;80:211-217. 166. Miyajima K, Tamiya S, Oda Y, et al. Relative quantitation of p53 and MDM2 gene expression in leiomyosarcoma; real-time semi-quantitative reverse transcription-polymerase chain reaction. Cancer Lett. 2001;164:177188. 167. Fletcher CD, Dal Cin P, de Wever I, et al. Correlation between clinicopathological features and karyotype in spindle cell sarcomas: a report of 130 cases from the CHAMP study group. Am J Pathol. 1999;154:1841-1847. 168. Svarvar C, Bohling T, Berlin O, et al. Clinical course of nonvisceral soft tissue leiomyosarcoma in 225 patients from the Scandinavian Sarcoma Group. Cancer. 2007;109:282-291. 169. Clark J, Rocques PJ, Crew AJ, et al. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet. 1994;7:502-508. 170. Crew AJ, Clark J, Fisher C, et al. Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma. EMBO J. 1995;14:2333-2340.

1428

Mayo Clin Proc.

•

171. Skytting B, Nilsson G, Brodin B, et al. A novel fusion gene, SYT-SSX4, in synovial sarcoma. J Natl Cancer Inst. 1999;91:974-975. 172. Mancuso T, Mezzelani A, Riva C, et al. Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma. Lab Invest. 2000;80:805-813. 173. Mezzelani A, Mariani L, Tamborini E, et al. SYT-SSX fusion genes and prognosis in synovial sarcoma. Br J Cancer. 2001;85:1535-1539. 174. Rosen G, Forscher C, Lowenbraun S, et al. Synovial sarcoma: uniform response of metastases to high dose ifosfamide. Cancer. 1994;73:2506-2511. 175. Lee SY, Obata Y, Yoshida M, et al. Immunomic analysis of human sarcoma. Proc Natl Acad Sci U S A. 2003 Mar 4;100:2651-2656. Epub 2004 Feb 24. 176. Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face and scalp, prognosis and treatment. Cancer. 1987;59:1046-1057. 177. Vonderheide RH, Fleming MD, Carter G, Singer S, Demetri G. Angiosarcoma. J Clin Oncol. 1997;15:1708-1709. 178. Mark RJ, Poen JC, Tran LM, Fu YS, Juillard GF. Angiosarcoma: a report of 67 patients and a review of the literature. Cancer. 1996;77:24002406. 179. Stone NM, Holden CA. Postirradiation angiosarcoma. Clin Exp Dermatol. 1997;22:46-47. 180. Skubitz KM. A phase I study of ambulatory continuous infusion paclitaxel. Anticancer Drugs. 1997;8:823-828. 181. Wollina U, Fuller J, Graefe T, Kaatz M, Lopatta E. Angiosarcoma of the scalp: treatment with liposomal doxorubicin and radiotherapy. J Cancer Res Clin Oncol. 2001;127:396-399. 182. Ockenfels HM, Brockmeyer NH, Hengge U, Goos M. Cutaneous angiosarcoma: a novel therapy with liposomal doxorubicin? J Eur Acad Dermatol Venereol. 1996;6:71-75. 183. Lankester KJ, Brown RS, Spittle MF. Complete resolution of angiosarcoma of the scalp with liposomal daunorubicin and radiotherapy. Clin Oncol (R Coll Radiol). 1999;11:208-210. 184. Jackel A, Deichmann M, Waldmann V, Bock M, Naher H. Regression of metastatic angiosarcoma of the skin after systemic treatment with liposomeencapsulated doxorubicin and interferon-alpha. Br J Dermatol. 1999;140:11871188. 185. Fury MG, Antonescu CR, Van Zee KJ, Brennan MF, Maki RG. A 14year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy [published correction appears in Cancer J .2005;11:354]. Cancer J. 2005;11:241-247. 186. Eiling S, Lischner S, Busch JO, Rothaupt D, Christophers E, Hauschild A. Complete remission of a radio-resistant cutaneous angiosarcoma of the scalp by systemic treatment with liposomal doxorubicin. Br J Dermatol. 2002;147: 150-153. 187. Casper ES, Waltzman RJ, Schwartz GK, et al. Phase II trial of paclitaxel in patients with soft-tissue sarcoma. Cancer Invest. 1998;16:442-446. 188. Breimer L. Original description of Kaposi’s sarcoma [letter]. BMJ. 1994; 308:1303-1304. 189. Kaposi M. Idiopathisches multiples pigmentsarkom der Haut. Arch Dermatol Syph. 1872;4:265-273. 190. Udhrain A, Skubitz KM, Northfelt DW. Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma. Int J Nanomed. 2007; 2(3):345-352. 191. Mitsuyasu RT. AIDS-related Kaposi’s sarcoma: current treatment options, future trends. Oncology (Williston Park). 2000;14:867-878. 192. Wang CY, Schroeter AL, Su WP. Acquired immunodeficiency syndrome-related Kaposi’s sarcoma. Mayo Clin Proc. 1995;70:869-879. 193. Peters BS, Beck EJ, Coleman DG, et al. Changing disease patterns in patients with AIDS in a referral centre in the United Kingdom: the changing face of AIDS. BMJ. 1991;302:203-207. 194. Krown SE, Northfelt DW, Osoba D, Stewart JS. Use of liposomal anthracyclines in Kaposi’s sarcoma. Semin Oncol. 2004;31:36-52. 195. Krown SE. Highly active antiretroviral therapy in AIDS-associated Kaposi’s sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi’s sarcoma. J Clin Oncol. 2004;22:399402. 196. Doxil (doxorubicin HCI liposome injection) [prescribing information]. Bridgewater, NJ: Ortho Biotech Products, LP; 2001. 197. DaunoXome (daunorubicin citrate liposome injection) [prescribing information]. San Dimas, CA: Gilead Sciences, Inc; 1996. 198. Northfelt DW, Dezube BJ, Thommes JA, et al. Efficacy of pegylatedliposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma after failure of standard chemotherapy. J Clin Oncol. 1997;15:653-659. 199. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998;16:2445-2451. 200. Stewart S, Jablonowski H, Goebel FD, et al, International Pegylated Liposomal Doxorubicin Study Group. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. J Clin Oncol. 1998;16:683-691. 201. Osoba D, Northfelt DW, Budd DW, Himmelberger D. Effect of treatment on health-related quality of life in acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma: a randomized trial of pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine. Cancer Invest. 2001;19:573-580. 202. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J Clin Oncol. 1996;14:2353-2364. 203. Gill PS, Tulpule A, Espina BM, et al. Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol. 1999;17:1876-1883. 204. Fardet L, Stoebner PE, Bachelez H, et al. Treatment with taxanes of refractory or life-threatening Kaposi sarcoma not associated with human immunodeficiency virus infection. Cancer. 2006;106:1785-1789. 205. Saville MW, Lietzau J, Pluda JM, et al. Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet. 1995;346:26-28. 206. Welles L, Saville MW, Lietzau J, et al. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol. 1998;16:1112-1121. 207. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459-465. 208. Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours. Lancet Oncol. 2002;3:655-664. 209. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol. 2003;54:3-24. 210. Sircar K, Hewlett BR, Huizinga JD, Chorneyko K, Berezin I, Riddell RH. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol. 1999;23:377-389. 211. Takayama I, Horiguchi K, Daigo Y, Mine T, Fujino MA, Ohno S. The interstitial cells of Cajal and a gastroenteric pacemaker system. Arch Histol Cytol. 2002;65:1-26. 212. Wang L, Vargas H, French SW. Cellular origin of gastrointestinal stromal tumors: a study of 27 cases. Arch Pathol Lab Med. 2000;124:14711475. 213. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol. 1999;23:82-87. 214. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580. 215. Sommer G, Agosti V, Ehlers I, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci U S A. 2003 May 27;100:6706-6711. Epub 2003 May 16. 216. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052-1056. 217. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710. 218. Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet. 1998;19:323324. 219. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33:484-495. 220. Chen Y, Tzeng CC, Liou CP, Chang MY, Li CF, Lin CN. Biological significance of chromosomal imbalance aberrations in gastrointestinal stromal tumors. J Biomed Sci. 2004;11:65-71. 221. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51-58. 222. Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol. 2006;24:2325-2331. 223. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480. 224. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813-3825.

Mayo Clin Proc.

•

225. Blanke CD, Corless CL. State-of-the art therapy for gastrointestinal stromal tumors. Cancer Invest. 2005;23:274-280. 226. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127-1134. 227. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329-1338. 228. Trent JC, Benjamin RS. New developments in gastrointestinal stromal tumor. Curr Opin Oncol. 2006;18:386-395. 229. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24: 4764-4774. 230. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. 231. Bauer S, Corless CL, Heinrich MC, et al. Response to imatinib mesylate of a gastrointestinal stromal tumor with very low expression of KIT. Cancer Chemother Pharmacol. 2003 Mar;51:261-265. Epub 2003 Feb 26. 232. Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and dualmodality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med. 2004;45:357-365. 233. Choi H, Charnsangavej C, de Castro Faria S, et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol. 2004;183:1619-1628. 234. Stroobants S, Goeminne J, Seegers M, et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:20122020. 235. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer. 2006 May;42:10311039. Epub 2006 Apr 17. 236. Maki RG, Awan RA, Dixon RH, Jhanwar S, Antonescu CR. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer. 2002;100:623-626. 237. Alman BA, Pajerski ME, Diaz-Cano S, Corboy K, Wolfe HJ. Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder. Diagn Mol Pathol. 1997;6:98-101. 238. Alman BA, Goldberg MJ, Naber SP, Galanopoulous T, Antoniades HN, Wolfe HJ. Aggressive fibromatosis. J Pediatr Orthop. 1992;12:1-10. 239. Bertario L, Russo A, Sala P, et al. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer. 2001;95:102-107. 240. Hoos A, Lewis JJ, Antonescu CR, et al. Characterization of molecular abnormalities in human fibroblastic neoplasms: a model for genotype-phenotype association in soft tissue tumors. Cancer Res. 2001;61:3171-3175. 241. Li M, Cordon-Cardo C, Gerald WL, Rosai J. Desmoid fibromatosis is a clonal process. Hum Pathol. 1996;27:939-943. 242. Lucas DR, Shroyer KR, McCarthy PJ, Markham NE, Fujita M, Enomoto TE. Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation. Am J Surg Pathol. 1997;21:306-311. 243. Middleton SB, Frayling IM, Phillips RK. Desmoids in familial adenomatous polyposis are monoclonal proliferations. Br J Cancer. 2000;82: 827-832. 244. Muller J. About the fine structure and types of pathological tumors [in German]. Erste Lieferung. 1838:60. 245. Hansmann A, Adolph C, Vogel T, Unger A, Moeslein G. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer. 2004;100:612-620. 246. Farmer KC, Hawley PR, Phillips RK. Desmoid disease. In: Phillips RK, Spigelman AD, Thompson JP, eds. Familial Adenomatous Polyposis and Other Polyposis Syndromes. London, England: Edward Arnold; 1994:128142. 247. Klemmer S, Pascoe L, DeCosse J. Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet. 1987;28: 385-392. 248. Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet. 1951;3:167-176. 249. Nichols RW. Desmoid tumors: a report of 31 cases. Arch Surg. 1923;7: 227-236. 250. Smith WG. Multiple polyposis, Gardner’s syndrome and desmoid tumors. Dis Colon Rectum. 1958;1:323-332.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1429

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

251. Rodriguez-Bigas MA, Mahoney MC, Karakousis CP, Petrelli NJ. Desmoid tumors in patients with familial adenomatous polyposis. Cancer. 1994;74:1270-1274. 252. Skubitz KM, Skubitz AP. Gene expression in aggressive fibromatosis. J Lab Clin Med. 2004;143:89-98. 253. Alman BA, Li C, Pajerski ME, Diaz-Cano S, Wolfe HJ. Increased betacatenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol. 1997;151:329-334. 254. Cheon SS, Cheah AY, Turley S, et al. beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc Natl Acad Sci U S A. 2002;99:6973-6978. 255. Couture J, Mitri A, Lagace R, et al. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000;57:205-212. 256. Saito T, Oda Y, Kawaguchi K, et al. Possible association between higher beta-catenin mRNA expression and mutated beta-catenin in sporadic desmoid tumors: real-time semiquantitative assay by TaqMan polymerase chain reaction. Lab Invest. 2002;82:97-103. 257. Tejpar S, Nollet F, Li C, et al. Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene. 1999;18:6615-6620. 258. Heinrich MC, McArthur GA, Demetri GD, et al. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol. 2006;24:1195-1203. 259. de Andrade CR, Cotrin P, Graner E, Almeida OP, Sauk JJ, Coletta RD. Transforming growth factor-beta1 autocrine stimulation regulates fibroblast proliferation in hereditary gingival fibromatosis. J Periodontol. 2001;72:1726-1733. 260. Alman BA, Greel DA, Ruby LK, Goldberg MJ, Wolfe HJ. Regulation of proliferation and platelet-derived growth factor expression in palmar fibromatosis (Dupuytren contracture) by mechanical strain. J Orthop Res. 1996;14:722728. 261. Magro G, Lanteri E, Micali G, Paravizzini G, Travali S, Lanzafame S. Myofibroblasts of palmar fibromatosis co-express transforming growth factoralpha and epidermal growth factor receptor. J Pathol. 1997;181:213-217. 262. Smith AJ, Lewis JJ, Merchant NB, Leung DH, Woodruff JM, Brennan MF. Surgical management of intra-abdominal desmoid tumours. Br J Surg. 2000;87:608-613. 263. Lewis JJ, Boland PJ, Leung DH, Woodruff JM, Brennan MF. The enigma of desmoid tumors. Ann Surg. 1999;229:866-872. 264. Bus PJ, Verspaget HW, van Krieken JH, et al. Treatment of mesenteric desmoid tumours with the anti-oestrogenic agent toremifene: case histories and an overview of the literature. Eur J Gastroenterol Hepatol. 1999;11:1179-1183. 265. Harvey JC, Quan SH, Fortner JG. Gardner’s syndrome complicated by mesenteric desmoid tumors. Surgery. 1979;85:475-477. 266. Jones IT, Jagelman DG, Fazio VW, Lavery IC, Weakley FL, McGannon E. Desmoid tumors in familial polyposis coli. Ann Surg. 1986; 204:94-97. 267. Friedl W, Caspari R, Sengteller M, et al. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut. 2001;48:515-521. 268. Azzarelli A, Gronchi A, Bertulli R, et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer. 2001;92:1259-1264. 269. Ballo MT, Zagars GK, Pollack A. Radiation therapy in the management of desmoid tumors. Int J Radiat Oncol Biol Phys. 1998;42:1007-1014. 270. Mace J, Sybil Biermann J, Sondak V, et al. Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer. 2002;95:23732379. 271. Schnitzler M, Cohen Z, Blackstein M, et al. Chemotherapy for desmoid tumors in association with familial adenomatous polyposis. Dis Colon Rectum. 1997;40:798-801. 272. Weiss AJ, Lackman RD. Low-dose chemotherapy of desmoid tumors. Cancer. 1989;64:1192-1194. 273. Skapek SX, Hawk BJ, Hoffer FA, et al. Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children. J Clin Oncol. 1998;16:3021-3027. 274. Gega M, Yanagi H, Yoshikawa R, et al. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol. 2006;24:102105. 275. Patel SR, Benjamin RS. Desmoid tumors respond to chemotherapy: defying the dogma in oncology. [editorial]. J Clin Oncol. 2006 Jan 1;24:11-12. Epub 2005 Dec 5.

1430

Mayo Clin Proc.

•

276. Patel SR, Evans HL, Benjamin RS. Combination chemotherapy in adult desmoid tumors. Cancer. 1993;72:3244-3247. 277. Weiss AJ, Horowitz S, Lackman RD. Therapy of desmoid tumors and fibromatosis using vinorelbine. Am J Clin Oncol. 1999;22:193-195. 278. Wcislo G, Szarlej-Wcislo K, Szczylik C. Control of aggressive fibromatosis by treatment with imatinib mesylate: a case report and review of the literature. J Cancer Res Clin Oncol. 2007 Aug;133:533-538. Epub 2007 Apr 24. 279. Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and update. J Clin Pathol. 2006;59:1127-1132. 280. Ries LAG, Smith MA, Gurney JG, et al, eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 19751995. Bethesda, MD: National Cancer Institute, SEER Program; 1999. NIH Pub No. 99-4649. Available at: http://seer.cancer.gov/publications/childhood/. Accessed September 25, 2007. 281. Pastore G, Peris-Bonet R, Carli M, Martinez-Garcia C, Sanchez de Toledo J, Steliarova-Foucher E. Childhood soft tissue sarcomas incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42:2136-2149. 282. Qualman SJ, Bowen J, Parham DM, Branton PA, Meyer WH. Protocol for the examination of specimens from patients (children and young adults) with rhabdomyosarcoma. Arch Pathol Lab Med. 2003;127:1290-1297. 283. Dias P, Parham DM, Shapiro DN, Webber BL, Houghton PJ. Myogenic regulatory protein (MyoD1) expression in childhood solid tumors: diagnostic utility in rhabdomyosarcoma. Am J Pathol. 1990;137:1283-1291. 284. Hicks J, Flaitz C. Rhabdomyosarcoma of the head and neck in children. Oral Oncol. 2002;38:450-459. 285. Qualman SJ, Coffin CM, Newton WA, et al. Intergroup Rhabdomyosarcoma Study: update for pathologists. Pediatr Dev Pathol. 1998;1:550-561. 286. Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol. 2002;20:2672-2679. 287. Shapiro DN, Sublett JE, Li B, Downing JR, Naeve CW. Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res. 1993;53:5108-5112. 288. Davis RJ, D’Cruz CM, Lovell MA, Biegel JA, Barr FG. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res. 1994;54:2869-2872. 289. El-Badry OM, Minniti C, Kohn EC, Houghton PJ, Daughaday WH, Helman LJ. Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differ. 1990;1:325-331. 290. Khan J, Bittner ML, Saal LH, et al. cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. Proc Natl Acad Sci U S A. 1999;96:13264-13269. 291. Raney RB Jr, Tefft M, Maurer HM, et al. Disease patterns and survival rate in children with metastatic soft-tissue sarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer. 1988;62:1257-1266. 292. Crist WM, Garnsey L, Beltangady MS, et al, Intergroup Rhabdomyosarcoma Committee. Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. J Clin Oncol. 1990;8:443-452. 293. Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol. 1995;13:610-630. 294. Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001;19:3091-3102. 295. Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomyosarcoma Study-I: a final report. Cancer. 1988;61:209-220. 296. Baker KS, Anderson JR, Link MP, et al. Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol. 2000;18:24272434. 297. Donaldson SS, Meza J, Breneman JC, et al. Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma—a report from the IRSG. Int J Radiat Oncol Biol Phys. 2001;51:718-728. 298. Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup Rhabdomyosarcoma Study-II. Cancer. 1993;71:1904-1922. 299. Breneman JC, Lyden E, Pappo AS, et al. Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma—a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol. 2003;21:78-84. 300. Raney RB, Anderson JR, Barr FG, et al. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol. 2001;23:215-220.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

301. Weigel BJ, Breitfeld PP, Hawkins D, Crist WM, Baker KS. Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol. 2001;23:272-276. 302. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in children in the United States: sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995;75:2186-2195. 303. Hadjipavlou A, Lander P, Srolovitz H, Enker IP. Malignant transformation in Paget disease of bone. Cancer. 1992;70:2802-2808. 304. Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. JAMA. 1997;278:12621267. 305. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358-5362. 306. Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am. 1997; 44:973-989. 307. Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer. 2006;106:1154-1161. 308. Mialou V, Philip T, Kalifa C, et al. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome—the French pediatric experience. Cancer. 2005;104:1100-1109. 309. Bacci G, Longhi A, Bertoni F, et al. Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy: the Rizzoli experience in 52 patients. Acta Orthop. 2006;77:938-943. 310. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314:1600-1606. 311. Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992;10:1579-1591. 312. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997;350:911-917. 313. Lewis IJ, Nooij MA, Whelan J, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007;99:112-128. 314. Bielack SS, Wulff B, Delling G, et al. Osteosarcoma of the trunk treated by multimodal therapy: experience of the Cooperative Osteosarcoma Study Group (COSS). Med Pediatr Oncol. 1995;24:6-12. 315. DeLaney TF, Park L, Goldberg SI, et al. Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys. 2005;61:492-498. 316. Sutow WW, Sullivan MP, Fernbach DJ, Cangir A, George SL. Adjuvant chemotherapy in primary treatment of osteogenic sarcoma: a Southwest Oncology Group study. Cancer. 1975;36:1598-1602. 317. Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988;6:329-337. 318. Meyers PA, Gorlick R, Heller G, et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial SloanKettering (T12) protocol. J Clin Oncol. 1998;16:2452-2458. 319. Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol. 2003;21:1574-1580. 320. Giritsky AS, Etcubanas E, Mark JB. Pulmonary resection in children with metastatic osteogenic sarcoma: improved survival with surgery, chemotherapy, and irradiation. J Thorac Cardiovasc Surg. 1978;75:354-362. 321. Chou AJ, Merola PR, Wexler LH, et al. Treatment of osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering Cancer Center experience. Cancer. 2005;104:2214-2221. 322. Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol. 2002;20:426-433. 323. Ferguson WS, Harris MB, Goorin AM, et al. Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial. J Pediatr Hematol Oncol. 2001;23:340-348. 324. Bay JO, Ray-Coquard I, Fayette J, et al. Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer. 2006;119:706-711.

Mayo Clin Proc.

•

325. Bacci G, Avella M, Picci P, et al. The effectiveness of chemotherapy in localized malignant fibrous histiocytoma (MFH) of bone: the Rizzoli Institute experience with 66 patients treated with surgery alone or surgery + adjuvant or neoadjuvant chemotherapy. Chemioterapia. 1988;7:406-413. 326. Bramwell VH, Steward WP, Nooij M, et al. Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: a European Osteosarcoma Intergroup study. J Clin Oncol. 1999;17:3260-3269. 327. Ham SJ, Hoekstra HJ, van der Graaf WT, Kamps WA, Molenaar WM, Schraffordt Koops H. The value of high-dose methotrexate-based neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone. J Clin Oncol. 1996;14:490-496. 328. Nishida J, Sim FH, Wenger DE, Unni KK. Malignant fibrous histiocytoma of bone: a clinicopathologic study of 81 patients. Cancer. 1997;79:482493. 329. Nooij MA, Whelan J, Bramwell VH, et al. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study. Eur J Cancer. 2005;41:225-230. 330. Picci P, Bacci G, Ferrari S, Mercuri M. Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol. 1997;8:1107-1115. 331. Spanier SS, Enneking WF, Enriquez P. Primary malignant fibrous histiocytoma of bone. Cancer. 1975;36:2084-2098. 332. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc. 1921;12:17-24. 333. Smith MA, Ungerleider RS, Horowitz ME, Simon R. Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing’s sarcoma. J Natl Cancer Inst. 1991;83:1460-1470. 334. Smith MA, Gurney JG, Ries LAG. Cancer among adolescents 15-19 years old. In: Ries LAG, Smith MA, Gurney JG, et al, eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD: National Cancer Institute, SEER Program; 1999:157-164. NIH Pub No. 99-4649. 335. Stiller CA, Bielack SS, Jundt G, Steliarova-Foucher E. Bone tumours in European children and adolescents, 1978-1997: report from the Automated Childhood Cancer Information System Project. Eur J Cancer. 2006;42:21242135. 336. Parkin DM, Stiller CA, Nectoux J. International variations in the incidence of childhood bone tumours. Int J Cancer. 1993;53:371-376. 337. de Alava E, Gerald WL. Molecular biology of the Ewing’s sarcoma/ primitive neuroectodermal tumor family. J Clin Oncol. 2000;18:204-213. 338. Ambros IM, Ambros PF, Strehl S, Kovar H, Gadner H, SalzerKuntschik M. MIC2 is a specific marker for Ewing’s sarcoma and peripheral primitive neuroectodermal tumors: evidence for a common histogenesis of Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer. 1991;67:1886-1893. 339. Fellinger EJ, Garin-Chesa P, Triche TJ, Huvos AG, Rettig WJ. Immunohistochemical analysis of Ewing’s sarcoma cell surface antigen p30/ 32MIC2. Am J Pathol. 1991;139:317-325. 340. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359:162-165. 341. Hromas R, Klemsz M. The ETS oncogene family in development, proliferation and neoplasia. Int J Hematol. 1994;59:257-265. 342. Desmaze C, Brizard F, Turc-Carel C, et al. Multiple chromosomal mechanisms generate an EWS/FLI1 or an EWS/ERG fusion gene in Ewing tumors. Cancer Genet Cytogenet. 1997;97:12-19. 343. Zucman J, Delattre O, Desmaze C, et al. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993;4:341-345. 344. Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 1994;54:2837-2840. 345. Gill S, McManus AP, Crew AJ, et al. Fusion of the EWS gene to a DNA segment from 9q22-31 in a human myxoid chondrosarcoma. Genes Chromosomes Cancer. 1995;12:307-310. 346. Bacci G, Ferrari S, Rosito P, et al. Ewing’s sarcoma of the bone: anatomoclinical study of 424 cases [in Italian]. Minerva Pediatr. 1992;44:345359. 347. Gyorke T, Zajic T, Lange A, et al. Impact of FDG PET for staging of Ewing sarcomas and primitive neuroectodermal tumours. Nucl Med Commun. 2006;27:17-24. 348. Hawkins DS, Schuetze SM, Butrynski JE, et al. [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol. 2005;23:8828-8834.

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

1431

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

SARCOMA

349. Paulino AC, Nguyen TX, Mai WY. An analysis of primary site control and late effects according to local control modality in non-metastatic Ewing sarcoma. Pediatr Blood Cancer. 2007;48:423-429. 350. Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2003;55:168-177. 351. Yock TI, Krailo M, Fryer CJ, et al. Local control in pelvic Ewing sarcoma: analysis from INT-0091—a report from the Children’s Oncology Group. J Clin Oncol. 2006;24:3838-3843. 352. Marsa GW, Johnson RE. Altered pattern of metastasis following treatment of Ewing’s sarcoma with radiotherapy and adjuvant chemotherapy. Cancer. 1971;27:1051-1054. 353. Jaffe N, Paed D, Traggis D, Salian S, Cassady JR. Improved outlook for Ewing’s sarcoma with combination chemotherapy (vincristine, actinomycin D and cyclophosphamide) and radiation therapy. Cancer. 1976;38:1925-1930. 354. Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma of bone: a longterm follow-up of the First Intergroup study. J Clin Oncol. 1990;8:16641674. 355. Burgert EO Jr, Nesbit ME, Garnsey LA, et al. Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup study IESS-II. J Clin Oncol. 1990;8:1514-1524. 356. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694-701. 357. Ferrari S, Mercuri M, Rosito P, et al. Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing’s sarcoma of the extremity. J Chemother. 1998;10:484-491. 358. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol. 2000;18:3108-3114. 359. Paulussen M, Ahrens S, Craft AW, et al. Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s Sarcoma Studies patients. J Clin Oncol. 1998;16:3044-3052. 360. Marcus RB Jr, Graham-Pole JR, Springfield DS, et al. High-risk Ewing’s sarcoma: end-intensification using autologous bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1988;15:53-59. 361. Burdach S, Peters C, Paulussen M, et al. Improved relapse free survival in patients with poor prognosis Ewing’s sarcoma after consolidation with hyperfractionated total body irradiation and fractionated high dose melphalan followed by high dose etoposide and hematopoietic rescue. Bone Marrow Transplant. 1991;7(suppl 2):95. 362. Frohlich B, Ahrens S, Burdach S, et al. High-dosage chemotherapy in primary metastasized and relapsed Ewing’s sarcoma: (EI)CESS [in German]. Klin Padiatr. 1999;211:284-290. 363. Cosetti M, Wexler LH, Calleja E, et al. Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol. 2002;24:101-105. 364. Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007;48:132-139. 365. Skubitz KM, Manivel JC. Giant cell tumor of the uterus: case report and response to chemotherapy. BMC Cancer. 2007;7:46. 366. Dickerman JD. Interferon and giant cell tumors. Pediatrics. 1999;103: 1282-1283. 367. Walker DG. Congenital osteopetrosis in mice cured by parabiotic union with normal siblings. Endocrinology. 1972;91:916-920. 368. Walker DG. Spleen cells transmit osteopetrosis in mice. Science. 1975;190:785-787. 369. Zheng MH, Fan Y, Smith A, Wysocki S, Papadimitriou JM, Wood DJ. Gene expression of monocyte chemoattractant protein-1 in giant cell tumors of

bone osteoclastoma: possible involvement in CD68+ macrophage-like cell migration. J Cell Biochem. 1998;70:121-129. 370. Morgan T, Atkins GJ, Trivett MK, et al. Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kappaB. Am J Pathol. 2005;167:117-128. 371. Skubitz KM, Cheng EY, Clohisy DR, Thompson RC, Skubitz AP. Gene expression in giant-cell tumors. J Lab Clin Med. 2004;144:193-200. 372. Roux S, Amazit L, Meduri G, Guiochon-Mantel A, Milgrom E, Mariette X. RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone. Am J Clin Pathol. 2002; 117:210-216. 373. Goldring SR, Roelke MS, Petrison KK, Bhan AK. Human giant cell tumors of bone identification and characterization of cell types. J Clin Invest. 1987;79:483-491. 374. Athanasou NA, Bliss E, Gatter KC, Heryet A, Woods CG, McGee JO. An immunohistological study of giant-cell tumour of bone: evidence for an osteoclast origin of the giant cells. J Pathol. 1985;147:153-158. 375. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-176. 376. Huang L, Xu J, Wood DJ, Zheng MH. Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation. Am J Pathol. 2000;156:761-767. 377. Atkins GJ, Haynes DR, Graves SE, et al. Expression of osteoclast differentiation signals by stromal elements of giant cell tumors. J Bone Miner Res. 2000;15:640-649. 378. Chang SS, Suratwala SJ, Jung KM, et al. Bisphosphonates may reduce recurrence in giant cell tumor by inducing apoptosis. Clin Orthop Relat Res. 2004:103-109. 379. Cheng YY, Huang L, Lee KM, Xu JK, Zheng MH, Kumta SM. Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone. Calcif Tissue Int. 2004;75:71-77. 380. Reid R, Banerjee SS, Sciot R. Giant cell tumor. In: Fletcher CDM, Unni KK, Mertens F, eds. WHO Classification of Tumors, Pathology and Genetics, Tumors of Soft Tissue and Bone. Lyons, France: IARC Press; 2002:310-312. 381. Walsh EF, Mechrefe A, Akelman E, Schiller AL. Giant cell tumor of tendon sheath. Am J Orthop. 2005;34:116-121. 382. Vogrincic GS, O’Connell JX, Gilks CB. Giant cell tumor of tendon sheath is a polyclonal cellular proliferation. Hum Pathol. 1997;28:815-819. 383. Nilsson M, Hoglund M, Panagopoulos I, et al. Molecular cytogenetic mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors. Virchows Arch. 2002;441:475-480. 384. Casson AG, Putnam JB, Natarajan G, et al. Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer. 1992;69:662-668. 385. Belal A, Salah E, Hajjar W, et al. Pulmonary metastasectomy for soft tissue sarcomas: is it valuable? J Cardiovasc Surg (Torino). 2001;42:835-840. 386. Billingsley KG, Burt ME, Jara E, et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival. Ann Surg. 1999;229:602-610. 387. Pastorino U, Valente M, Santoro A, et al. Results of salvage surgery for metastatic sarcomas. Ann Oncol. 1990;1:269-273. 388. Saltzman DA, Snyder CL, Ferrell KL, Thompson RC, Leonard AS. Aggressive metastasectomy for pulmonic sarcomatous metastases: a follow-up study. Am J Surg. 1993;166:543-547. 389. Temple LK, Brennan MF. The role of pulmonary metastasectomy in soft tissue sarcoma. Semin Thorac Cardiovasc Surg. 2002;14:35-44. 390. Francis P, Namlos HM, Muller C, et al. Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics. 2007;8:73. 391. Lee YF, John M, Falconer A, et al. A gene expression signature associated with metastatic outcome in human leiomyosarcomas. Cancer Res. 2004;64:7201-7204.

The Symposium on Solid Tumors will continue in the December issue. 1432

Mayo Clin Proc.

•

November 2007;82(11):1409-1432

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.