Chondrosarcoma

By admin On Oct 16, 2024

Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section
II – Specific Bone Neoplasms and Simulators > 6 – Bone Sarcomas >
6.3 – Chondrosarcoma

6.3

Chondrosarcoma

R. Lor Randall

Kenneth J. Hunt

Chondrosarcomas of bone can be found in any bone in the
human body and include a spectrum of lesions that range from low grade
to dangerously aggressive. Although cartilage bone lesions in general
have a characteristic radiographic appearance, differentiating between
benign and low-grade malignant cartilage lesions often presents a
diagnostic challenge (Table 6.3-1). Since treatment and outcome are based in large part upon an accurate diagnosis, this distinction is important (Fig. 6.3-1).

Pathogenesis

Etiology

Unknown
Current speculation: may arise from monoclonal expansion of single chondrocyte

Epidemiology

Peak age: third to sixth decades (Fig. 6.3-2)
Frequency of chondrosarcomas in the United States
- ~10% to 25% of primary bone tumors are chondrosarcomas.
- Approximately 250 to 625 cases/year in United States
- Second to osteosarcoma among bone sarcomas

Table 6.3-1 Differentiation Between Benign and Low-Grade Malignant Cartilage Lesions

Parameter	Enchondromas	Chondrosarcomas
Definition	Benign cartilage tumors	Malignant cartilage tumors
Metastatic potential	None	Increases with grade
Clinical presentation	Often painless and discovered incidentally	Often painful
Location	Metacarpals and phalanges > long bones Metaphyseal > diaphyseal	Pelvis > femur > ribs > humerus > scapula > tibia
Plain radiographs	Variably mineralized central lesions with arcs, smoke rings, or popcorn patterns No or <50% cortical width endosteal scalloping	Variably mineralized with same patterns or more punctate calcifications Often radiolucencies with sparse mineralization Endosteal scalloping >50% cortical width Cortical breech with soft tissue mass in advanced cases
MRI	Multilobular Dark T1, bright T2	Soft tissue extension and surrounding edema more common Dark T1, bright T2
Histopathology	Hyaline cartilage encased by rim of reactive bone (“enchondroma encasement” pattern) Lobular growth Bland chondrocytes with pyknotic nuclei Variably cellular Lesions of digits and those in Ollier’s disease often more worrisome in appearance (e.g., cytologic atypia and binucleation)	Cartilage permeates around pre-existing bone trabecula (“permeation pattern”) Invasion of haversian canals Lobular growth Cytologic atypia Binucleation more prominent Increased cellularity

Pathophysiology

Histopathology (Fig. 6.3-3)

Macroscopic appearance
- Heterogeneous gross properties, including lobulated areas of chalky calcific admixture
- Regions of firm translucent unmineralized gray cartilage with relatively low vascularity
- Intermixed areas of necrosis and degeneration
Low-grade chondrosarcomas
- Relatively acellular, heavily calcified areas
- Regions of increased activity exhibiting immature cartilage cells with multiple nucleated lacunae
- Permeation pattern of cartilage surrounding pre- existing bony trabeculae

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High-grade chondrosarcomas
- Densely packed, hyperchromatic, malignant-looking cells
- May be difficult to determine that these cells are truly of cartilaginous origin
- Myxomatous changes and highly degenerative areas common

Figure 6.3-1
Degree of differentiation in cartilage tumors. (Adapted from Dorfman
HD, Czerniak B. Malignant cartilage tumors. In: Dorfman HD, Czerniak B,
eds. Bone Tumors. St. Louis: Mosby, 1998.)

Classification

Several classification schemes
- Histologic grade (I, II, III, dedifferentiated)
  - The most important factor in the
    malignant potential of a chondrosarcoma is its histologic grade. Most
    (~85%) chondrosarcomas are low-grade lesions.
- Location within the bone and body
  - Peripheral (periosteal or juxtacortical
    chondrosarcoma and secondary chondrosarcoma arising from
    osteochondroma) versus central (intramedullary)
  - Axial versus appendicular skeleton
- Primary versus secondary
  - Primary: arises de novo
  - Secondary central: arises from enchondroma
  - Secondary peripheral: arises from osteochondroma
- Specific histologic subtype
  - Conventional
  - Clear cell chondrosarcoma
  - Mesenchymal chondrosarcoma
  - Dedifferentiated chondrosarcoma

Histologic grades of conventional chondrosarcomas (Table 6.3-2)

Grade I (“low-grade”) tumors

Slow-growing and locally aggressive

Figure 6.3-2
Age-specific frequency and distribution of chondrosarcoma, based on
SEER 1973–1987 data. (After Dorfman HD, Czerniak B. Bone cancers. Cancer 1995;75:223–227.)

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Figure 6.3-3 Representative histopathology specimens from typical chondrosarcomas. (A) Grade I chondrosarcoma demonstrates increased cellularity, perhaps some hyperchromatism but not necessarily atypia. (B) Grade II chondrosarcoma demonstrates increased cellularity and atypia. (C) Grade III chondrosarcoma demonstrates markedly increased cellularity and pleomorphism. (D)
Dedifferentiated chondrosarcoma demonstrates area of low-grade
chondrosarcoma with abrupt transitions into a spindle cell sarcoma. (E)
Clear cell chondrosarcoma demonstrates bony trabeculae-intertwined
tumor cells containing clear cytoplasm with central atypical nuclei
admixed with benign giant cells. (F) Myxoid chondrosarcoma demonstrates round cells with myxoid features. (G)
Mesenchymal chondrosarcoma demonstrates nodules of chondroid tissue
surrounding vascular spaces, resembling a hemangiopericytoma.

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Table 6.3-2 Clinicopathologic Features of Cartilaginous Tumors

Lesion	Clinical	Radiology	Histopathology	Treatment
Enchondroma	Mostly asymptomatic and incidentally recognized	9% have endosteal scalloping	Enchondroma encasement pattern	Surveillance, intralesional excision if symptomatic
Chondrosarcoma
Grade I	60% are painful	Endosteal scalloping, calcifications in rings or spicules, uniform calcifications, eccentric lobular growth	Chondrosarcomatous permeative pattern	Controversial: Extended intralesional excision versus wide resection
Grade II	Up to 80% painful	Endosteal scalloping, potentially more aggressive and adaptive changes	Mixture of grade I and grade III characteristics	Wide resection
Grade III	Up to 80% painful	Endosteal scalloping, faint amorphous calcifications, large lucent areas, growing soft tissue mass	Densely packed hyperchromatic malignant-looking cells, cells of questionable cartilaginous origin, myxomatous changes, highly degenerative areas	Wide resection Possible adjunct radiation therapy and chemotherapy in selected cases

Recurrence common, but very low metastatic potential
Histologically resemble normal hyaline
cartilage, may surround or permeate through areas of lamellar bone (a
feature not seen in benign lesions, which are more typically encased by
bone)
Radiographically may show bone expansion, cortical thinning, endosteal scalloping, periosteal reaction, lytic areas

Grade II (“intermediate-grade”) tumors
- Locally aggressive with higher potential for recurrence
- ~10% to 15% metastasize (lung > bone)
- Histologically show increased cellularity
  and cytological atypia (enlarged nuclei and often multinucleated cells)
  with foci of myxoid changes
- Radiographically, grade II lesions show endosteal scalloping.
Grade III (“high-grade”) tumors
- Highly aggressive and rapidly growing, with significant metastatic potential
- More than 50% will metastasize.
- Grade II lesions may recur as grade III.
- Histologically: high cellularity, marked pleomorphism, and necrosis
- Radiographically, these lesions show aggressive cortical destruction and a destructive pattern of growth.

Special histologic subtypes of chondrosarcoma
- Clear cell chondrosarcoma
  - <5% of all chondrosarcomas
  - Low-grade malignant tumor with significant amounts of glycogen
  - Produces lytic defects in epiphysis that imitate chondroblastoma
  - Frequently extends to joint surface
  - Typically involves proximal portion of femur, tibia, or humerus
  - Histologically, displays tumor cells with
    abundant clear cytoplasm embedded in a loose cartilaginous matrix and
    infiltrative growth pattern
  - Radiographically, produces lytic defect at end of long bones that is sharply demarcated with sclerotic margins
  - Peak age range 20 to 40
- Mesenchymal chondrosarcoma
  - 2% of all chondrosarcomas
  - Highly aggressive tumor that is
    radiographically and histologically distinct from conventional and
    dedifferentiated chondrosarcoma
  - Noncartilaginous elements usually predominate.
  - Eccentrically located in bone
  - Prominent extension into soft tissues is common.
  - Usually affects young adults and teenagers
  - Usually affects axial skeleton; maxilla and mandible are frequent sites
  - Surgical excision is mainstay of treatment.
  - Ten-year survival rate ~28%
- Dedifferentiated chondrosarcomas
  - ~10% of all chondrosarcomas
  - Thought to represent the transformation of a
    
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    low-grade (I or II) chondrosarcoma into a high-grade malignant sarcoma
  - Distribution in femur > pelvis > humerus > ribs > scapula
  - Two components on histologic analysis with clear demarcation
    - The dedifferentiated component likely arises from one of the other three histologic subtypes or from a benign precursor.
    - High-grade sarcoma with or without heterologous elements
- Low-grade cartilaginous lesion
  - Radiographically, displays area of
    punctuate opacities surrounded by lytic area with complete cortical
    disruption and extension into the soft tissues

Genetics

There is considerable complexity and heterogeneity in
the histopathology and clinical behavior of chondrosarcomas. This is
reflected in the diversity of cytogenetic and molecular genetic
characteristics that have been described in these tumors.
Chondrosarcoma karyotypes may range from a few simple numerical changes
to complex numerical and structural abnormalities. A number of genes
have been investigated in chondrosarcoma. Table 6.3-3 offers a basic summary of current research on the genetics of chondrosarcoma.

The genetic changes specific to chondrosarcoma continue
to be investigated extensively. The understanding of these genetic
alterations will have profound implications on prognosis and may serve
as a foundation for the development of therapy unique to these tumors.

Staging

Chondrosarcomas are staged using either the method of the American Joint Committee on Cancer (AJCC) or Enneking (see Chapter 1, Evaluation of Bone Tumors).

Diagnosis

Physical Examination and History

Clinical Features

Distribution

Pelvis > femur > ribs > humerus > scapula > tibia (Fig. 6.3-4)
Metaphysis > diaphysis

Pain

Most patients with a chondrosarcoma will have dull, aching pain.
Benign cartilage tumors less frequently produce pain.
Grade II or III chondrosarcomas present with pain in up to 80% of cases.
Rest pain and night pain are common in chondrosarcomas.

Table 6.3-3 Tumor Suppressor Genes and Oncogenes in Chondrosarcoma

Gene	Significance
TP53	Altered patterns of p53 expression and mutations in TP53 have been detected in high-grade chondrosarcoma tumors.
HRAS	Mutations in HRAS occur during the course of dedifferentiation and may affect malignant potential.
ABL	Expression of the ABL gene has been detected in grade I and II chondrosacoma and is likely associated with inhibition of apoptosis.
MET	MET (hepatocyte growth factor receptor) expression has been detected in benign and malignant cartilage tumors.
MMPs	Increased expression of several MMPs (1, 2, 9, 13) and decreased expression of others (3, 8) has corresponded with malignancy in chondrosarcoma.
MDR1	Multiple drug resistance gene 1 (MDR1) has been seen in chondrosarcoma and may be related to chemotherapy response.
EXT1,2	Germline mutations and functional loss of EXT1 or EXT2 are often found in multiple osteochondromas and predispose to the development of chondrosarcoma (about 2% to 3%).
Sox9	The transcription factor Sox9, which plays an essential role in the early phases of chondrocyte differentiation and is a key regulator of chondrogenesis, has been shown to be expressed almost exclusively in the small cell component of mesenchymal chondrosarcoma.
PDGF-α	High expression of PDGF-α has been shown in aggressive chondrosarcoma. This may have a role in therapeutic strategies.

Pathologic Fracture

Occurs in a relatively small number of cases (3% to 8%) of low-grade chondrosarcoma
Incidence much higher in high-grade tumors (36% of dedifferentiated chondrosarcomas in one series)

Physical Examination Findings

Local swelling and tenderness
Antalgic gait for lower extremity tumors (variable)
Decreased range of motion at adjacent joints (variable)
Palpable mass in tumors with associated soft tissue extension

Radiologic Features

It is frequently a challenge to differentiate between enchondromas and grade I chondrosarcomas based on radiographic

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features. Both can demonstrate the classic discrete stippled calcified
opacities indicative of hyaline cartilage matrix within the
intramedullary region(s) of typical long bones.

Figure 6.3-4 Distribution of chondrosarcoma by site of lesion (numbers represent percentage frequency).

Plain Radiography (Fig. 6.3-5)

Radiolucent area with varying numbers of punctate opacities
Endosteal scalloping can indicate malignant potential but is not confirmatory (Box 6.3-1).
Adaptive changes include cortical expansion or thickening.
Aggressive features include cortical disruption and soft tissue expansion.
Change in radiographic appearance with
time. Radiographs taken at different points in time (usually 3 months
apart) illustrating increases in endosteal scalloping and cortical
destruction or fewer intralesional calcifications suggest a malignant
lesion.

Figure 6.3-5 Plain radiographs of a low-grade cartilage lesion.

Computed Tomography (Fig. 6.3-6)

Axial computed tomography (CT) can assist in determining extent of endosteal scalloping and bony destruction.
Change in the nature of calcifications with sequential scanning can suggest malignancy.

Box 6.3-1 Indicators Favoring Malignancy in Cartilage Tumors

Clinical Features
Age >40
Pain
   Insidious onset
   At night, waking from sleep
   At rest, unrelated to activity
   Persistent over 6 months
Mass
   Firm and fixed
   Nodular surface
   Enlargement after skeletal maturity
Radiographic Findings
>6 cm in greatest diameter
Calcifications
   Faint, hazy windblown densities
   Overall intramedullary radiolucency
   High ratio of lucent to calcified matrix
   Discrete densities beyond outer bone margin
Cortex
   Endosteal erosions
   Expansion, thickening, destruction
   Periosteal new bone formation

Adapted from Weis L. Common malignant bone tumors: osteosarcoma. In: Simon MA, Springfield D, eds. Surgery for Bone and Soft Tissue Tumors. Philadelphia: Lippincott-Raven, 1998.

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Magnetic Resonance Imaging (Fig. 6.3-7)

Degree of medullary fill
- Involvement of >90% of the medullary canal suggests chondrosarcoma.
- <90% medullary involvement and noncontiguous foci of cartilage suggest a benign cartilage tumor.
Low-signal T1-weighted images, high-signal T2-weighted images
Septal enhancements on magnetic resonance
imaging (MRI) suggest intralesional fibrotic bands, a histologic
finding associated with grade I and II chondrosarcomas.
Gadolinium enhancement delineates extent of tumor and proximity to neurovascular structures.

Technetium-99m Diphosphonate Bone Scan (Fig. 6.3-8)

Identifies multifocal disease of multiple enchondromatosis (Ollier’s disease, Maffucci’s syndrome)
Lesions with radioisotope uptake are more likely to be chondrosarcoma than enchondroma, especially in long bones.
Bone scan may play a role in screening
malignant transformation of enchondroma into chondrosarcoma if serial
examinations are available.
Some enchondromas can exhibit uptake of radioisotope.

Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography (FDG PET)

May have a role in tumor grading in chondrosarcoma

Figure 6.3-6 Axial CT of chondrosarcoma of vertebral elements (left) and distal femur (right).

Treatment

Surgical Indications and Contraindications

Surgical resection remains the primary and most
successful means of treating chondrosarcomas. The decision regarding
the extent of surgical resection and adjuvant therapy depends on the
clinical and histologic characteristics of the lesion. This remains
somewhat controversial. To date, studies have not shown adjuvant
treatments such as chemotherapy or radiation to have any significant
impact on patient

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morbidity
or mortality in most isolated primary lesions. Possible exceptions are
younger patients with a dedifferentiated subtype and those with
metastatic disease. As these adjunctive modalities are of no proven
benefit, the burden of a cure falls upon adequate initial surgical
resection.

Figure 6.3-7 MRI images of distal femoral chondrosarcoma.

Figure 6.3-8 Bone scan of patient with left distal femoral chondrosarcoma.

Surgical and Nonoperative Options

Historically, wide resection was considered the method
of choice for all chondrosarcomas. Unfortunately, these tumors are
frequently found in regions such as the pelvis or proximal long bones,
where aggressive surgical management may endanger adjacent vital organs
and structures or compromise limb function. For low-grade tumors with
minimal metastatic potential, less aggressive approaches such as
marginal excision and extended intralesional excision with margin
expansion using adjuncts such as phenol or cryotherapy have received
increasing attention. While rigorous evidence-based criteria are
lacking at present, individual centers may have their own criteria and
algorithms for surgical decision making (see Algorithm 6.3-1).
In general, benign lesions should be treated conservatively, while
high-grade malignancies should be treated aggressively with complete
resection. Optimal treatment for low-grade chondrosarcoma remains a
diagnostic and therapeutic dilemma.

Primary indications for surgical treatment of cartilaginous tumors are for:
- Symptomatic lesions
- Aggressive appearance on radiographic studies
- Change over time in radiographic appearance of lesion without initial aggressive appearance
Specific treatments
- Low-grade lesions: wide resection versus extended intralesional curettage
  - Phenol and liquid nitrogen are commonly used adjuvants for extended intralesional curettage.
- Intermediate grade: wide resection necessary
- High-grade, aggressive tumors: wide resection necessary

Algorithm 6.3-1. Diagnostic work-up of chondrosarcoma.

Results and Outcome

In general, the prognosis for
chondrosarcoma depends on the histologic grade of the lesion and the
attainment of complete excision of the tumor (Table 6.3-4). There is a limited role for adjuvant therapies (i.e., chemotherapy and irradiation).

Conventional Chondrosarcoma

Prognosis is excellent for low-grade tumors after adequate excision.
Low incidence of pulmonary metastasis in low- and intermediate-grade tumors if the primary lesion is widely resected
Recurrences can occur, even up to 15 years after treatment.

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Secondary and peripheral chondrosarcomas have better prognosis than primary/central.

Table 6.3-4 Survival Features of Chondrosarcoma

Type	5-Year Survival	Metastatic Potential	Recurrence Rate
Grade I	90%	0%	Low
Grade II	81%	10% to 15%	Intermediate
Grade III	29%	>50%	High
Dedifferentiated	<10% (1-year)	Most	High

Dedifferentiated Chondrosarcoma

Uniformly poor prognosis

Clear Cell Chondrosarcoma

Fair prognosis with wide resection and reconstruction
Overall recurrence rate 16%
Poor prognosis if treated with simple curettage and allografting
Often mistaken for chondroblastoma

Mesenchymal Chondrosarcoma

Prognosis very poor despite aggressive treatment
High incidence of pulmonary metastatic disease
High mortality

Postoperative Management

Patients should be followed for serial
surveillance radiographic and clinical examinations to assess for
recurrence and/or metastatic disease.