Liposarcoma

DEFINITION AND PATHOGENESIS

• Takes origin from primitive mesenchymal cells rather than mature adipose cells

IMPORTANCE

• A fairly common malignancy of fat most common in the thigh, retroperitoneum, and inguinal regions
• Most common in occurrence rates for soft-tissue sarcomas (20%)
• Retroperitoneal lesions may occur simultaneously or sequentially to extremity lesions

CLINICAL FEATURES

• 8 months to 87 years, mean 57 years, M:F = 3:2
• Rare in subcutaneous fat and GI subserosa
  • Submucosal mass in small bowel mesenteric location
• Most common sites are thigh (25-30%) and retroperitoneum (?20%)
• Unusual locations
  • Oral and maxillofacial regions
  • Rare in the hands or feet
• Insidiously growing, deep-seated, ill-defined mass
• Pain, tenderness only in 10-15%
• Hemodynamic deteriorationin cardiac and abdominal locations reported
  • Synchronous cardiac and abdominal metastases 13 yrs after a thigh liposarcoma reported
• Preexisting lipoma is extremely rare
• Liposarcoma associated with multiple intramuscular lipomas reported in a 71-year-old
• Has been reported in NF1
  • Dedifferentiated liposarcoma

RADIOLOGIC FEATURES

• Depend largely on histological type
• Well-delineated radiolucency to dense mass
• May have foci of calcification and ossification (esp well differentiated)
• Vascularity often seen on bone scan
• CT may show a low density mass with an area of higher density
  • Myxoid liposarcoma may show a homogenous density between -40 to +30 Hounsfield units
• MRI shows inhomogeneic regions, some isointense with fat
  • Intermediate T1 signal, bright on T2
• A liposarcoma of the pectoral muscle has been reported initially detected at mammography (heterogeneous without discrete margins) in a 76 yr-old man with painless gynecomastia

GROSS PATHOLOGY

• Usually well encapsulated and distinctly lobulated (lobules can become separated)
• Can be the largest of neoplasms, esp in the retroperitoneal location

HISTOLOGIC/MOLECULAR FEATURES

• Histological classification of liposarcoma
• AFIP
  • Well-differentiated liposarcoma (atypical lipoma)
  • Lipoma-like: scattered lipoblasts
  • Sclerosing: inguinal prevalence
  • Inflammatory: prominent inflammatory component
  • Dedifferentiated: well and poorly differentiated together
  • Myxoid liposarcoma (40-50%):lipoblasts, capillaries, myxoid matrix
  • Round cell liposarcoma: tends more to metastasize
  • Pleomorphic liposarcoma: bizarre cells
• Evans
  • Myxoid
  • Well-differentiated
  • Dedifferentiated
  • Pleomorphic
  • Well-differentiated with a pleomorphic component
• Lipoblasts the characteristic cell
• Vacuolated tumor cell with single vacuole and eccentric nucleus or multiple vacuoles and a central nucleus; "signet ring" cell
• Vacuoles within the cell contain fat (+ oil red O)
• Cytogenetic studies
  • t(12;16),(q13;p11) (in tumor lipoblasts)
  • Other abnormalities reported include trisomy 8
• Molecular
  • Chromosome 12 amplificationin well-differentiated and dedifferentiated liposarcomas
    • MDM2 gene
    • CDK4 gene
      • ~10% do not amplify CDK4
      • Alteration in CDKN2A/CDKN2B/CDK4/CCND1 pathwaydemonstrable
        • Array-CGH
        • Real-time genomic PCR
        • Gene expression array
        • Real-time RT-PCR
      • Chromosome 1q21-1q23 is preferential partner of chromosome 12 amplicon in tumors with amplification/overexpression CDK4
  • Over 40 microRNA expression alterations reporteddysregulated in dedifferentiated liposarcomas
    • Upregulated microRNAs
      • miR-21
      • miR-26a
    • Downregulated microRNAs
      • miR-143
        • Restoring miR-143 expression:
          • Inhibited proliferation
          • Induced apoptosis
          • Decreased expression of BCL2
          • Decreased expression of topoisomerase 2A
          • Decreased expression of protein regulator of cytokinesis (PRC1)
          • Decreased expression of polo-like kinase 1 (PLK1)
            • Tx with a PLK1 inhibitor potently induced G(2)-M growth arrest and apoptosis
      • miR-145

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

• If lipoblasts are seen, the dx is made
• Lipid stains are positive in mesenchymal or epithelial neoplasms
• Myxoid chondrosarcoma and chordoma
• Vacuolated forms of lymphoma ("signet-ring" lymphoma)
• Rarely meningioma, malignant melanoma
• Intramuscular myxoma, myxoid MFH

DISEASE COURSE AND TREATMENT

• Wide resection, long course in some low grade lesions
• Lung metastases (most common) as well as viscera; check retroperitoneum (extrapulmonary metastases, esp with myxoid variant)
• +/- XRT; preoperative + postoperative boost in higher grade lesions
  • XRT effective in preventing LR but not reported to impact survival
• Mediastinal and bone metastases have been reported
• Prognosis
  • 5-yr survivals (with appropriate tx)
  • 74% overall 5-yr survival, all subtypes
  • 80% myxoid liposarcoma, LR <10% with resection and XRT
  • Oral and maxillofacial region
    • Tumor size > 3.6 cm
    • Histopathologic subtype
• Chemotx trials for lesions >8cm in diameter

 SPECIAL CONSIDERATIONS

• MYXOID LIPOSARCOMA

• • Most common subtype in the pediatric population
  • t(12; 16)(q13; p11)
    • Leads to the formation of FUS-CHOP fusion transcript
  • Lung resistance major vault protein gene on 16p11.2 reported with low or absent expression
  • 5- and 10-yr metastatic-free survivals 84 and 77% with surgical resection and XRT
  • Trabectedin infusion for advanced disease reported in a Phase II clinical trial with 3/23 with CR

• ROUND-CELL LIPOSARCOMA

• • 5- and 10-yr metastatic-free survivals 69 and 46% reported for surgical resection and XRT

• WELL-DIFFERENTIATED LIPOSARCOMA

• • Characterized by the presence of ring or giant rod chomosomescontaining several amplified genes
    • MDM2
    • TSPAN31
    • CDK4
    • AKT activationin 27%
      • Robust AKT phosphorylation
        • BEZ235 (small molecule inhibitor of P13K and mammalian target of Rapamycin)
          • Effectively inhibits AKT activation in culture
    • Others derived from chromosome bands 12q13-15
      • Fibroblast growth factor receptor substrate 2 gene
    • Characterized by chromosome 12q13-15 amplification
    • Poorly responsive to XRT or chemotherapy
  • ANIMAL MODEL
    • Zebrafishexpressing constitutively active AKT2 in mesenchymal progenitors develop well-differentiated liposarcoma similar to the human counterpart
      • p53 pathogenesis
        • 8% in p53 wild-type zebrafish
        • 6% in p53 heterozygotes
        • 29% in p53-homozygous mutant zebrafis

• DEDIFFERENTIATED LIPOSARCOMA

  • Consists of both well-differentiated liposarcoma and a transformed nonlipogenic sarcomatous component
  • Histologic subtypes
    • Undifferentiated pleomorphic sarcoma
    • Osteosarcoma
    • Rhabdomyosarcoma
      • Extensive necrosis reported
    • Leiomyosarcoma
    • MPNST
  • Cytogenetics
    • Characterized by chromosome 12q13-15 amplification
    • Amplified genes
      • MDM2
      • CDK4
      • Fibroblast growth factor receptor substrate 2
  • Extremely large tumors have been reported
    • 46 kg tumor reported in the retroperitoneum
  • 3/18 with lung metastasis at initial presentation reported
  • 61.1% 5YS reported
  • Poor prognostic findings
    • > 8 cm dedifferentiated area
    • High MIB-1-labeling index (>30%)
    • Lung metastasis at presentation
  • Cell line
    • NDDLS-1
      • Produces IL-6 and G-CSF

• RETROPERITONEAL LIPOSARCOMA  

  •  Any grade or histological type may be found in this location
  • Giant (50 cm and 52 kg) liposarcoma of the retroperitoneal spermatic cord reported 
  • Tumors in this location may become huge and simulate pregnancy

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