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Conventional Chondrosarcoma, Central or Medullary

DEFINITION AND PATHOGENESIS

  • Primarily arising de novo from bone within the IM canal, either low (grade I) or intermediate (grade II)

IMPORTANCE

  • Distinction between enchondroma and low grade IM lesions radiographically and grossly impossible, and difficult with frozen section, so preoperative planning is imperative for appropriate tx
  • 2nd most common sarcoma of bone

CLINICAL FEATURES

  • Rarely seen in children, mean age 46 (5-82)
  • Mean age of 55 (28-93) in hand/foot lesions
  • 11-22% of all primary malignant bone tumors (1/2 as common as osteosarcoma)
  • 31% arise in the pelvis, 21% in the femur, ?6% in the spine (T>L>C)(usually stage IB lesions)
  • Local swelling, pain (81.4%), mass (33.1%), and tenderness; may grow very slowly
  • Pathological fx (8.1%)(15% in spinal lesions)
  • M:F = 1.3:1
  • ± adhesive capsulitis in proximal humeral location
  • Absence of pain does not exlude chondrosarcoma

RADIOLOGIC FEATURES

  • Metaphyseal, diaphyseal, rarely epiphyseal
  • Punctate, flocculent, or rings-and-arcs and popcorn-like calcifications (ossification around cartilage lobules)
  • Regions of the lesion don't retain geographic borders, esp in higher grade lesions
  • Lucencies represent replacement of normal bone by uncalcified cartilage (and without calcifications represent areas of higher grade)
  • Lesion may be "bubbly" in appearance
  • Pathologic fx or stress fx can occur (more commonly in higher grade tumors)
  • Erosion of cortex with breakthrough and a soft tissue mass heralds sarcoma and Grade II status
  • Deep endosteal scalloping (>2/3 of cortical thIickness)
  • 9/12 hand/foot lesions have at least one of the following:
    • Cortical destruction (8/12)
    • Soft tissue extension (7/12)
    • Periosteal reaction (4/12)
  • CT for cortical extent and matrix delineation, and MRI for medullary extent and soft tissue mass or extension
  • T2-weighted images: tumor has bright signal intensity, calcifications have low signal intensity on all se-quences, contrast enhancement in a ring and arc septal pattern; heterogeneity of signal intensity correlates with higher grade, more cellular lesions
  • Bone scan reveals ? uptake, esp along the periphery of the lesion
  • Angiography useful in large pelvic lesions, or thigh lesions for preoperative planning
  • IVP helpful in large pelvic lesions (ureteral stint placement can be helpful prior to resection to palpate for location)
  • When occurring in the sternum, nearly all are malignant
  • When >6-10cm, lesions must be considered most likely malignant

GROSS PATHOLOGY

  • Extension through articular cartilage and through ligaments may occur
  • Soft tissue mass is often surrounded by periosteal new bone or fibrous pseudocapsule

HISTOLOGIC AND MOLECULAR FEATURES

  • If there is malignant osteoid, it is an osteosarcoma
  • Histologic grades "½"-I (60.9%) and II (35.3%), recently "grade 1/2" has been coined; rarely grade III (3.2%)
  • (Older pts tend to have higher grade tumors)
  • ? cellularity and cytological atypia most important in determining grade
  • Hyaline cartilage (may be myxoid) with atypical cells, varibly sized nuclei, and ? cellularity and clumping of cells (cloning), mitotic figures (8%)
  • Myxoid matrix (87%)
  • Trabecular trapping (67%)
  • Collagenase-3 (MMP-13) present in a reported 100% of chondrosarcomas and 25% of benign cartilage tumors by immunohistochemistry
  • von Hippel-Lindau protein significantly reduced in chondrosarcoma tissues
    • Positively correlated with Bax expression
    • Positively correlated with apoptosis index in chondrosarcoma
      • (Reduced expression with decreased apoptosis)
    • (Not independently predictive of survival)
    • von Hippel-Lindau protein a positive regulator of p53
      • (von Hippel-Lindau protein loss of function may lead to malignancy)
    • Impaired von Hippel-Lindau protein levels have increased concentrations of HIF-? and HIF target gene products
      • HIF-? plays a role in evasion of apoptosis by chondrosarcoma cells
        • Associated with elevated levels of anti-apoptotic protein Bcl-xL
  • Endothelin-1 (potent vasoconstrictor) expression
    • Increased migration and expression of MMP-13
      • Reduced by pretreatment with inhibitors:
        • Focal adhesion kinase
        • Phosphatidylinositol 3-kinase
        • AKT
        • Mammalian target of rapamycin (mTOR)
        • NF-?B inhibitor
        • I?B protease inhibitor
    • Endothelin-1 tx induced phosphorylation of:
      • FAK
      • PI3K
      • AKT
      • mTOR
    • Endothelin-1 tx resulted in increased activated FAK/PI3K/AKT/mTOR
      • In turn activated IKK?/? and NF-?B
        • Resulting in crased MMP-13 expression and migration in chondrosarcoma cells

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

  • Enchondroma, atypical enchondroma
  • Chondroblastic osteosarcoma (or other histiocytic types)
  • Sheets of spindle cells, chondroid lobules and lace-like osteoid
  • Osteoblastoma
  • IM infarcts, osteonecrosis
  • Intraosseous (ossifying) lipoma
  • MFH
  • Fibrosarcoma
  • Metastatic disease or multiple myeloma

DISEASE COURSE AND TREATMENT

  • Wide resection in ³ grade II lesions (contaminated margins will allow local recurrence, low oxygen tension in hematoma will sustain malignant cartilage growth in surrounding soft tissue)
  • Uncontaminated, clear margins the goal in pelvic resections
  • Ray resection (or limited amputation in phalangeal location) in hand/foot lesions
  • Biopsy the soft tissue mass (to R/O a higher grade lesion), otherwise low grade lesions best treated without bx, but with careful preoperative planning because of characteristic radiographical findings and problems with misdiagnoses associated with sampling errors
  • Cryosurgery after curettage and burring for low grade ("1/2" to 1) lesions (without soft tissue mass)
  • Metastases occur in <15% of low grade lesions and 15-50% of intermediate (grade II) lesions (tumor grade most important prognostic factor)
  • Poorer prognosis in axial lesions (including pelvic location), and incompletely curetted or resected lesions
  • Aggressively resecting pelvic chondrosarcomas results in long term survival (the outcome is determined by the adequacy of the resection)
  • 94% 1 yr, 82% 5 yr, 80% 10 yr, 77% 15 yr survival for pelvic chondrosarcomas
  • Re-resection of pelvic LR may result in cure
  • 5-year survival of pts with condrosarcoma of the spine is 55%, median survival 6 yrs
  • Relatively avascular tumor allows mechanical transplantabiltiy from one site to another (esp with < wide resec-tions)
  • Complications
  • Recurrences usually herald a stepup in grade and ? metastases (and possibly under tx in the first place)(may not occur for >10 years after initial tx)
  • Progression may occur via intravenous extension or to adjacent vital structures
  • Chemotherapy or XRT not helpful in controlling local disease or metastases
  • XRT should be considered in vertebral lesions when surgical ablation is not obtainable
  • Fluoroquinolone toxic to immature chondrocytes and their use in chondrosarcoma under investigation (induces oxidative metabolism?impairment of proteoglycan and procollagen synthesis; interacts with topoisomerase II?? inhibits DNA replication?DNA strand breaks and apoptosis)
  • ? incidence of LR and metastases when p53 overexpression or alteration is present (38% of conventional chondrosarcomas), mitoses, a myxoid tumor matrix, necrosis, high-grade tumor, size >100cc, and a ploidic abnormality (aneuploidy/high mean DNA index)
  • MIB-1 expression associated with recurrence and death (more predictive than histologic grade)
    Low ratio of mRNA expression of matrix metalloproteinase-1 to the tissue inhibitor of metalloproteinase-1 low histological grade, and F gender predictors of better prognosis

SPECIAL CONSIDERATION

  • INTRACORTICAL CHONDROSARCOMA
    • Lucent lesion within the cortex
    • Intermediate grade chondrosarcoma which requires en bloc resection
  • MULTICENTRIC CHONDROSARCOMAS
    • May be monomelic (± skip lesions) or disseminated
    • Can be synchronous, metachronous, occasionally with Ollier's disease

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