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A. Introduction

  1. Sarcomas are tumors of the connective (mesenchymal) tissues
  2. Contrast with carcinomas, which are tumors of epidermal tissues
  3. Sarcomas are relatively rare
  4. Divided into Two Groups:
    1. Bone Tumors
    2. Soft Tissue Sarcomas

B. Bone Tumors

  1. Osteogenic, Chondrogenic, Fibrinogenic
  2. Benign
    1. Osteoid Osteoma
    2. Osteochondroma (Exostosis)
    3. Enchondroma
  3. Malignant
    1. Osteosarcoma
    2. Chondrosarcoma
    3. Giant Cell Tumor
    4. Ewing's Sarcoma

C. Types of Soft Tissue Sarcomas (STS)

  1. Over 50 subtypes defined by World Health Organization
  2. Named largely according to tissue they most resemble
  3. Three or 4 step grading systems with staging system (see below)
  4. Overall Distribution
    1. Lower limb and girdle: 40%
    2. Upper limb and girdle: 20%
    3. Retroperitoneal and intraperitoneal (includes GIST): 20%
    4. Trunk: 10%
    5. Head and neck: 10%
  5. Uterus
  6. Visceral Organ Associated
    1. Gastric - such as gastrointestinal stromal tumors (GIST)
    2. Small Intestine
    3. Urinary Bladder
  7. Joint-Associated Sarcomas
    1. Synovial Sarcoma
    2. Chondroscarcoma (rare)
  8. Cell Types
    1. Fibrous tissue - fibrosarcoma, malignant fibrous histiocytoma
    2. Rhabdomyosarcoma (see below)
    3. Leimyosarcoma - smooth muscle tumor
    4. Neural tumors
    5. Angiosarcomas - tumors of blood vessels [5,19]
  9. Lipomas and Liposarcomas - adipose tumors
  10. Increased levels of survivin and telomerase (TERT) messenger RNA associated with high risk of death in patients with soft tissue sarcomas [12] 11 . Gene expression studies will likely lead to new classification scheme for STS [13]
  11. CT and MRI scans are standard requirements for assessment prior to surgical removal

D. Uterine Tumors

  1. Leiomyoma
    1. Benign tumor of smooth muscle origin
    2. Most common tumor arising from female genital tract, with 25% women >30years.
    3. Multiple tumors are often found, but each leiomyoma is clonal
    4. Slow growing, very few or no mitosis
    5. Estrogens enhance growth of these tumors
    6. Firm, pale gray, whorled, pseudo-encapsulated
    7. May cause bleeding, usually due to ulceration
    8. Large tumors may interfere with bowel or bladder function.
    9. Treatment: myomectomy, hysterectomy
  2. Leiomyosarcoma
    1. Very rare tumors, usually occur in older women (>50)
    2. Diagnosis by Mitotic count and nuclear atypia
    3. Aggressive tumor, often fatal
    4. Treatment: total abdominal hysterectomy (TAH) or bilateral salpingoopherectomy (BSO)
  3. Treatment and Prognosis
    1. Local wide surgical resection is critical
    2. Radiation therapy to local area also widely employed
    3. Adjuvant chemotherapy including adriamycin is recommended [18]
    4. Local therpay alone cures ~50% of patients
    5. Adjuvant chemotherapy gave improved recurrence free survivals of 6-10%
    6. Preoperative radiation has slightly better overall survival but greater risk of wound complications than postoperative [14]

E. Rhabdomyosarcoma [4,16]

  1. Tumors derived from striated muscle, can occur at any site
  2. More than 50% of all soft tissue sarcomas in children (most common type)
  3. Incidence ~5 per million children under age 15 annually
  4. Whites are more commonly affected than blacks or Asians
  5. Most are spontaneous, but can occur with Li-Fraumeni Syndrome (germline p53 mutations)
  6. Clinical Presentation
    1. Symptoms are site-dependent
    2. About 35% of patients have readily resectable tumors
    3. About 15% of patients have metastatic disease at presentation
  7. Common Sites of Primary Tumors
    1. Genitourinary: 24%
    2. Limbs: 19%
    3. Parameningeal: 16%
    4. Head and Neck: 10%
    5. Orbits: 9%
    6. Other areas: 22%
  8. Histopathology
    1. Embryonal Rhabdomyosarcoma: 80% of cases
    2. Alveolar Rhabdomyosarcoma: 20% of cases
    3. Positive stains for muscle specific proteins
    4. Actin/myosin filaments and Z bands on electron micrographs
  9. Genetics of Alveolar Rhabdomyosarcomas
    1. Chromsomal translocations common: t(2;13)(q35;q14) and t(1;13)(p36;q14)
    2. PAX3 gene on chr 2 encodes a developmentally regulated transcription factor
    3. FKHR gene on chr 13 encodes a widely expressed transcription factor
    4. PAX7 gene on chr 1 also encodes a developmentally regulated transcription factor
  10. Genetics of Embryonal Tumors
    1. Loss of heterozygosity of 11p15.5 is common (unknown locus)
    2. Mutations or loss of p53, N-ras, K-ras and N-myc are common
  11. Treatment
    1. Surgical resection - may be done after initial chemotherapy for unresectable tumors
    2. Low risk group - chemotherapy with dactinomycin and vincristine for 8-12 months
    3. Intermediate risk group - dactinomycin, vincristine and cyclophosphamide for 1 year
    4. High risk group (metastatic, other) - multiagent chemotherapy ± stem cell support
    5. Irradiation of primary tumors and metastases for majority of tumors
    6. Proton beam irradiation spares normal tissues and should be considered in children [16]
  12. Disease Free Survival at 3-5 Years
    1. Low risk: >90%
    2. Intermediate risk: ~75%
    3. High risk: 20%

F. Angiosarcomas

  1. Tumors of blood vessels
  2. Certain atrial myxomas are angiosarcomas
  3. Kaposi sarcoma (KS) is a tumor of blood vessels, associated with a herpes virus
  4. KS risk is highly elevated (>300 fold) in patients with HIV infection
  5. Non-KS angiosarcomas are increased >35 fold in patients with HIV and AIDS

G. Synovial Sarcomas [6,7]

  1. Account for ~8% of all soft tissue sarcomas
  2. Usually age 16-25 years, ~65% in legs
  3. Slightly more common in males
  4. Usually found near joints, but only ~10% are intraarticular or continuous with synovial lining
  5. Typically present with palpable soft tissue mass (metastatic in ~25%)
  6. Histology Types
    1. Biphasic - spindle and epithelial cells
    2. Monophasic - spindle cells only
  7. Genetics [2]
    1. Over 90% of these tumors have chromosomal translocation t(X;18)(p11;q11)
    2. Involves fusion of novel genes SYT (18q11) and SSX (Xp11)
    3. SSX breakpoint occurs at any of 2 ornithine aminotransferase (OATL)-like pseudogenes
    4. The abnormal fusion genes produce nuclear proteins, transcriptional activators
    5. SYT-SSX2 translocation was exclusively associated with monophasic tumors
    6. SYT-SSX1 translocation was equally found in monophasic and biphasic tumors
  8. Overall, SSX2 fusions had 48% 5 year survival versus 24% for SSX1 fusions
  9. Metastasis or local recurrence in 80% of patients
  10. Standard radiographs may be normal in ~50% of cases; MRI is diagnostic modality of choice
  11. Radiation therapy is nearly always given, often preoperatively
  12. Chemotherapy [7]
    1. Usually given with radiation therapy for tumors 8 cm or larger
    2. Also for metastatic disease
    3. Response rates to adriamycin with ifosfamide in ~50% of patients

H. Gastrointestinal (GI) Stromal Tumors (GIST) [8,9,10]

  1. Mesenchymal Neoplasm
    1. Derived from connective tissue of GI tract
    2. Related to or derived from interstitial cells of Cajal
    3. These are innervated automatic pacemaker cells associated with Auerbach's plexus
  2. Median age 58 years with 75% in >50 year olds
  3. Gastric 50%, ~25% small intestine, ~10% colorectal, elsewhere in GI tract
  4. Molecular Pathogenesis
    1. c-kit (CD117) is a tyrosine kinase (growth factor receptor)
    2. c-kit expression is most specific diagnostic criterion for this tumor (95% of cases)
    3. Normally, stem cell factor (c-kit ligand, steel factor) binds to c-kit
    4. Mutations in c-kit cause constitutive activation of this receptor in these tumors
    5. ~10% of GIST have PDGF-alpha receptor mutations
    6. Either of these mutations lead to uncontrolled proliferation of these cells
    7. Cells then accumulate a number of additional chromosomal abnormalities
    8. Metastatic lesions commonly have chromosomal delations and/or trisomy
  5. Presentation usually nonspecific symptoms: early satiety, fatigue, GI bleeding
  6. Evaluation
    1. CT scan and PET scan are standard to evaluate for metastatic disease
    2. Pathological specimen for evaluation of mitotic figures (rate)
    3. Size and mitotic rate are best for determining metastatic potential and prognosis
    4. Quantitive fluorodeoxyglucose-PET scanning is best modality for monitoring responses
    5. Tumors can respond to therapy and appear to stabilize or increase in size on CT
  7. Treatment Overview
    1. Surgical resection for localized disease
    2. Imatinib is standard first line therapy for metastatic disease
    3. Adjuvant imatinib therapy is being evaluated following surgical resection
    4. Sunitinib is approved following recurrence or intolerance of imatinib
    5. Typically highly resistant to usual chemotherapy
  8. Imatinib (Gleevec®) [9,15,17]
    1. Orally active selective tyrosine kinase inhibitor
    2. Competitive inhibitor of bcr-abl, PDGF-R, and c-kit tyrosine kinases
    3. Effective and well tolerated for treatment of chronic myeloid leukemia (CML)
    4. Partial response (>50% shrinkage) rates ~55% in patients with metastatic GIST [15]
    5. 5% complete response, 47% partial response, 32% stable with metastatic GIST [17]
    6. Dose 400mg bid for GIST induces more rapid remissions than 400mg qd
    7. Progression free survival 2-2.5 years with metastatic GIST
    8. Recommended dose 400mg qd or bid indefinitely
    9. Early discontinuation of imatinib usually leads to rapid recurrence
  9. Sunitinib (Sutent®) [20]
    1. Oral multikinase inhibitor which inhibits VEGF and PDGF receptor kinases, other kinases
    2. Blocks both tumor cell and angiogenic targets
    3. Progression free and overall survival improved versus placebo in gastrointestinal stromal tumors (GIST) after disease progression or intolerance to imatinib
    4. Also approved for renal cell (clear cell) carcinoma based on objective response rates
    5. Cycles of 50mg po qd x 4 weeks, then 2 weeks off; maximum 87.5mg qd
    6. Fatigue, nausea, mucositis, stomatitis, skin discoloration, hypothyroidism, hepatitis
    7. Frequent screening for hypothyoridism with TSH testing is recommended [21]

I. Lipomas [11]

  1. Slow growing adipose tumors
  2. Nearly always benign
    1. Solitary lipomas more common in women
    2. Multiple lipomas more common in men
  3. Location
    1. Most often found in subcutaneous tissues
    2. Intermuscular septa
    3. Abdominal organs
    4. Oral cavity
    5. Cerebellopontine angle
    6. Torax
  4. Usually appear between ages 40-60
    1. May occur as benign symmetric lipomatosis (Madelung's Disease)
    2. Congenital lipomas uncommon but found in children
  5. Presentation
    1. Usually nonpainful, round, mobile masses
    2. Soft, doughy feel
    3. Overlying skin normal
    4. Adiposis Dolorosa (Dercum's Disease): rare clinical condition with painful lipomas
  6. Differential Diagnosis
    1. Epidermoid Cyst
    2. Subcutaneous Tumors and Metastatic Disease
    3. Nodular Fasciitis
    4. Liposarcoma
    5. Erythema nodosum
    6. Nodular subcutaneous fat necrosis
    7. Systemic Inflammatory (Weber-Christian) Panniculitis
    8. Vasculitic Nodules
    9. Rheumatoid Nodules
    10. Sarcoidosis
    11. Hematoma
    12. Onchocerciasis, Ioiasis
  7. Pathology
    1. Mature adipocytes arranged in lobules
    2. Occasionally are nonencapsulated with infiltration into muscle (infiltrating lipoma)
    3. Angiolipomas: variant from with coexisting vascular proliferation (may be painful)
    4. Pleomorphic lipomas: bizarre, multinucleated giant cells mixed with normal adipocytes
    5. Spindle cell lipoma: slender, spindle cells admixed with regular adipocytes
    6. Adenolipoma: eccrine sweat glands admixed into fatty tumor
  8. Treatment Overview
    1. Nonexcisional: glucocorticoid injection or liposuction
    2. Surgical excision: enucleation of 3-4mm tumors or actual excision

J. Liposarcoma

  1. Malignant adipose tissue tumors
  2. Mdm2 amplification and increased levels are common
  3. Types
    1. Well-Differentiated Liposarcoma
    2. Pleomorphic liposarcoma.
    3. Dedifferentiated Liposarcoma
  4. Well-Differentiated Liposarcoma (~40%)
    1. Retroperitoneum and limbs most common
    2. Also occurs in paratesticular area and mediastinum
    3. Peak incidence age 40-70
    4. Nonmetastasizing (similar to atypical lipoma)
    5. Histology: adipocytic, sclerosing, inflammatory, spindle (fibroblastic) cell, myxoid
    6. Adipocytic liposcarcoma composed of mainly mature cells, nuclear atypia
    7. Myxoid liposarcoma most common type
    8. Characteristic ring as well as giant marker chromosomes
    9. 12q13-14 chromosome region makes up giant marker chromosomes
  5. Pleomorphic Liposarcoma
    1. High-grade pleomorphic sarcoma with frequent metastases
    2. Contains multivacuolated lipoblasts
    3. Occurs frequently in the extremities of older individuals
    4. Lung metastases
    5. Prognosis parallels that of many other high-grade sarcomas
    6. 5-year overall survival rate 40% (median survival, 48 months)
    7. Radiation and chemotherapy may follow surgery
  6. Dedifferentiated Liposarcoma.
    1. High-grade nonlipogenic sarcoma
    2. Occurs most frequently in adults beyond the 6th decade of life
    3. Similar chromosomal abnormality as well differentiated form
    4. Surgery is main treatment
    5. Local recurrence rate ~45% with 15% distant metastases
    6. 30% disease-related mortality rate
  7. Treatment
    1. Multimodality usually required
    2. Preoperative radiation has slightly better overall survival but greater risk of wound complications than postoperative [14]
    3. Localized tumors can be resected with wide margins
    4. Chemotherapy for palliation of disease
    5. PPARg agonists being evaluated to induce differentiation

K. Staging, Grading and Prognosis [1]

  1. TNM Staging
    1. T1: tumor not more than 5.0 cm in largest dimension
    2. T1a: superficial to deep fascia
    3. T1b: deep to deep fascia
    4. T2: tumor >5.0 cm in any dimension
    5. T2a and 2b defined as for T1
    6. N0: no lymph node involvement; N1 with regional nodal metastasis
    7. M1: distant metastasis
  2. Grade
    1. G1: well differentiated
    2. G2: moderately differentiated
    3. G3: poorly differentiated
    4. G4: undifferentiated
  3. Staging
    1. Stage 1A: T1(a or b) N0 M0, Grade 1 or 2
    2. Stage 1B: T2a N0 M0, Grade 1 or 2
    3. Stage 2A: T2b N0 M0, Grade 1 or 2
    4. Stage 2B: T1(a or b) N0 M0, Grade 3 or 4
    5. Stage 2C: T2a N0 M0, Grade 3 or 4
    6. Stage 3: T2b N0 M0, Grade 3 or 4
    7. Stage 4: T any, N1 or M1
  4. Prognosis: 5 Year Survival
    1. Stage 1: 85%
    2. Stage 2: 70%
    3. Stage 3: 50%
    4. Stage 4: ~15%

References

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  3. Goedert JJ, Cote TR, Virgo P, et al. 1998. Lancet. 351(9119):1833 abstract
  4. Arndt CAS and Crist WM. 1999. NEJM. 341(5):343
  5. Mandel J and Mark EJ. 2000. NEJM. 343(7):493 (Case Record)
  6. Einhorn TA and Nielsen GP. 2001. NEJM. 344(2):124
  7. Spillane AJ, A'Hern R, Judson IR, et al. 2000. J Clin Oncol. 18(22):3794 abstract
  8. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. 2001. NEJM. 344(14):1052 abstract
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  10. Rubin BP, Heinrich MC, Corless CI. 2007. Lancet. 369(9574):1731 abstract
  11. Salam GA. 2002. Am Fam Phys. 65(5):901 abstract
  12. Wurl P, Kappler M, Meye A, et al. 2002. Lancet. 359(9310):943 abstract
  13. Nielsen TO, West RB, Linn SC, et al. 2002. Lancet. 359(9314):1301 abstract
  14. O'Sullivan B, Davis AM, Turcotte R, et al. 2002. Lancet. 359(9325):2235 abstract
  15. Demetri GD, von Nehren M, Blanke CD, et al. 2002. NEJM. 347(7):472 abstract
  16. Friedmann Am, Tarbell NJ, Schaefer PW, Hoch BL. 2004. NEJM. 350(5):494 (Case Record) abstract
  17. Verweij J, Casali PG, Zalcberg J, et al. 2004. Lancet. 364(9440):1127 abstract
  18. Sarcoma Meta-Analysis Collaboration. 1997. Lancet. 350(9091):1647
  19. Pinto DS, Blair BM, Schwartzstein RM, Smith CC. 2005. NEJM. 35399):934 (Case Record)
  20. Demetri GD, van Oosterom AT, Garrett CR, et al. 2006. Lancet. 368(9544):1329 abstract
  21. Desai J, Yassa L, Marquesee E, et al. 2006. Ann Intern Med. 145(9):660 abstract