Evaluation of Bone Tumors

Timothy A. Damron

Bone lesions can be difficult to identify specifically, and arriving at a specific diagnosis can elude even the most experienced orthopaedic oncologist. However, by using a systematic approach to the evaluation of these tumors, including consideration of the pathogenesis, often a narrow enough differential diagnosis may be arrived at by clinical and radiological means to allow specific treatment (often observation) or to guide the subsequent evaluation and care. This chapter discusses pathogenesis and an approach to evaluation of bone tumors.

Pathogenesis

Etiology

The vast majority of bone tumors arise de novo with no identifiable predisposing precursor lesion or associated agent. However, well-defined clinical precursor lesions have been established (Box 1-1).
Established etiologic agents for osteosarcoma are given in Box 1-2.
Implicated but unproven causes:
- Chromium, nickel, cobalt, aluminum, titanium, methyl-methacrylate, polyethylene
- Trauma

Epidemiology

Incidence of bone sarcomas
- 0.2% of all cancers
- 0.8 new cases per 100,000 population per year in North America and Europe
Most common bone sarcomas
- #1: Osteosarcoma
- #2: Chondrosarcoma
- #3: Ewing sarcoma
Age distribution is bimodal
- First peak: Second decade of life
  - Osteosarcoma predominates at this age
  - Ewing sarcoma #2
- Second peak: >mt60 years old
  - Chondrosarcoma predominates
  - Secondary osteosarcomas #2
    - Paget’s osteosarcoma
    - Postradiation osteosarcoma

Pathophysiology

Unknown for most bone tumors
Best described for congenital and inherited syndromes (Table 1-1)

Classification

Current classification systems are derived from the type of cell or tissue involved. Hence, bone tumors are divided into osseous, cartilaginous, cystic, myogenic, lipogenic, epithelial, neural, notochordal, fibrous, fibrohistiocytic, giant cell, round cell, and vascular categories as well as those of undefined neoplastic nature. The organization of the subsequent chapters follows this classification scheme.

Box 1-1 Precursor Lesions for Development of Bone Sarcoma

Low Risk

Fibrous dysplasia

Bone infarct

Chronic osteomyelitis

Metallic and polyethylene implants

Osteogenesis imperfecta

Giant cell tumor

Osteoblastoma

Chondroblastoma

Intermediate Risk

Multiple osteochondromas

Polyostotic Paget disease

Radiation osteitis

High Risk

Ollier’s disease (enchondromatosis)

Maffucci syndrome

Familial retinoblastoma syndrome

Rothmund-Thompson syndrome

Adapted from

Fletcher DM, Unni KK, Merlens F, eds. Tumours of Soft Tissue and Bone. World Health Organization Classification of Tumours. Lyon: IARC Press, 2002:228

Diagnosis

For bone lesions, one of the primary goals of the history, physical examination, and radiological evaluation is to at least classify the lesion into one of three categories of biological behavior: latent, active, or aggressive (Table 1-2). The last category includes both aggressive benign lesions and malignancies. In some cases, a specific diagnosis may be attainable, but if not, this classification provides some guide to the need for diagnostic evaluation and treatment.

History and Physical Examination

The patient with a bone lesion in general presents in one of four clinical scenarios: (1) incidentally noted bone lesions, (2) painless bony masses, (3) painful bone lesions, and (4) pathologic fractures. The differential diagnosis and approach are guided by which of these scenarios applies. Hence, the clinical features are divided into those four categories.

Incidentally Noted Bone Lesions

This very frequent scenario in musculoskeletal tumors occurs commonly in a number of ways, such as when a minor injury leads to an x-ray that reveals a bone lesion, shoulder pain from impingement leads to discovery of a proximal humeral bone lesion, or a bone scan done for an entirely different purpose lights up unexpectedly at the site of a previously unrecognized bone lesion not associated with the original problem.

Differential Diagnosis

Common bone lesions discovered incidentally
- Adults: enchondroma
- Pediatrics: nonossifying fibroma

History

Injury leading to discovery
- Did pain precede the injury? Pain preceding the injury may indicate an active or aggressive lesion rather than the typical latent lesion discovered incidentally.
- Is pain resolving since injury? Complete resolution of the injury-related pain supports the incidental nature of the bone lesion.
Pain leading to discovery. The key is to determine whether the pain is more likely to be from a common cause of pain at the affected anatomic site or from the bone lesion itself.
- Shoulder: Elicit exacerbating features such as overhead activity as an indicator of impingement. Consider subacromial injection.
- Knee: Elicit exacerbating features such as going up and down stairs and sitting for long periods with knees flexed as indications of patellar-femoral discomfort. Consider intra-articular injection.
Bone scan leading to discovery
- Has there ever been pain or local tenderness at the site of the bone lesion? Some patients may have had a mild aching pain at the site of a low-grade malignancy that they never sought medical attention for in the past.

Physical Examination

Bone tenderness (tumor) versus joint line tenderness (intra-articular pathology) is an important distinguishing feature.
Signs of the possible joint problem causing pain (if any) should be elicited.

Diagnostic Workup

Blood work: No role unless infection suspected (obtain complete blood count >obCBC>cb with differential, erythrocyte sedimentation rate >obESR>cb, C-reactive protein >obCRP>cb)

If suspected cartilage neoplasm, consider computed tomography (CT) or magnetic resonance imaging (MRI)

CT scan: Delineates endosteal scalloping, periosteal reaction best

Table 1.1 Congenital And Inherited Syndromes Predisposing to Bone Sarcomas

Syndrome	Inheritance Pattern	Typical Tumors/Findings	Malignancy	Implicated Genes	Pathophysiology
Ollier’s disease and Maffucci syndrome	Mostly sporadic Some families suggest AD	Multiple enchondromas (hemangiomas in Maffucci syndrome)	Chondro-sarcoma in Ollier’s disease; multiple malignancies in Maffucci syndrome	Unknown	Unknown
McCune-Albright syndrome (MAS), polyostotic fibrous dysplasia, monostotic fibrous dysplasia	Sporadic	Multiple lesions of fibrous dysplasia (endocrine abnormalities and coast of Maine pigmented skin lesions with MAS)		GNAS1 (guanine nucleotide-binding protein, α-stimulating activity polypeptide 1)	Extent of disease dependent upon how large of a cell mass is affected by somatic mutation during embryogenesis
Multiple osteochondromas	50% sporadic 50% AD	Osteochondromas	Chondrosarcoma	EXT1, EXT2 (exostosin)	Mutant exostosin glycoproteins alter heparin sulfate proteoglycans, affecting FGF and Ihh signaling
Retinoblastoma syndrome	60% sporadic 40% AD	Retinoblastoma	Osteosarcoma Other cancers	RB1	Mutant RB1 tumor suppressor gene allows tumor development
Rothmund-Thomson syndrome	AR	Poikiloderma Short stature Sparseness of eyebrows/lashes Juvenile cataracts Sunlight sensitivity Hypogonadism Defective dentition Nail problems	Osteosarcoma Cutaneous epitheliomas Gastric adenocarcinomas Fibrosarcomas	RECQL4	Mutant helicase gene
Bloom syndrome		Telangiectatic erythema resembling SLE Dwarfism Thin, triangular face	Osteosarcoma Other cancers	BME	Mutant RECQ helicase gene
Li-Fraumeni syndrome		<45 with sarcoma and first-degree relative <45 with any cancer and another first- or second-degree relative in same lineage with any cancer at any age	Osteosarcoma Soft tissue sarcoma Breast cancer Brain tumors Acute leukemia Adrenal cortical cancers Gonadal giant cell tumors	TP53 gene (71%)	Mutant p53 tumor suppressor gene

Table 1-2 Classification of Bone Tumors According to Biological Behavior

Classification	Symptoms	Type of Bone Lesion	Radiographic Features	Common Examples
Latent	Asymptomatic No pain preceding fracture	Benign	Narrow zone of transition	Nonossifying fibroma* (fibrous cortical defect) Unicameral bone cyst* Adult osteochondroma*
Active	Painful Pain preceding fracture	Benign	Intermediate zone of transition Expansion	Fibrous dysplasia Osteoid osteoma Osteochondroma
Aggressive or malignant	Painful Pain preceding fracture	Benign or malignant	Broad zone of transition Cortical destruction Soft tissue extension	Benign Aneurysmal bone cyst# Chondroblastoma# Giant cell tumor# Osteoblastoma# Malignant Sarcoma Metastatic carcinoma Lymphoma
*Classic latent lesions such as these may be active during childhood. #Some tumors, such as aneurysmal bone cyst, chondroblastoma, and giant cell tumor, may have a spectrum of clinical behavior patterns.

MRI scan: Helps differentiate features of hyaline cartilage
- Lobular organization pattern, bright with T2 weighting, dark with T1 weighting
If fibrous dysplasia or enchondroma considered, consider total body bone scan to establish solitary or polyostotic process
- Enchondroma versus Ollier’s disease/enchondromatosis
- Monostotic versus polyostotic fibrous dysplasia or McCune-Albright syndrome
If presumptive diagnosis of latent lesion is established on plain radiographs, key is serial clinical and radiographic follow-up.
- Common serial follow-up plan: 3 months, 6 months, 1 year, and 2 years after discovery
- If lesion behaves more aggressively than expected, biopsy and appropriate surgical treatment may be necessary.
- In most cases, the lesion will remain unchanged (e.g., enchondroma) or go on to heal (e.g., nonossifying fibroma), and after 2 years of follow-up, most asymptomatic lesions may be considered stable.
Biopsy is usually unnecessary.

Painless Bony Masses

Differential Diagnosis

Osteochondroma (most common by far)
Low-grade malignancies with associated soft tissue mass
- Parosteal osteosarcoma
- Periosteal chondrosarcoma
- Secondary chondrosarcoma arising in osteochondroma

History

Age
- Pediatric patient: Osteochondroma grows during skeletal immaturity
- Adult patients: Osteochondromas should not grow once growth has ceased. Consider other diagnoses.
Pain
- Osteochondroma typically painless unless pressure on other structures
- Pain may be associated with low-grade malignancies.
Family history of osteochondromatosis
- Half of cases are spontaneous mutations, so many patients will have negative family history despite autosomal-dominant (AD) mode of transmission.

Physical Examination

Bone versus soft tissue origin
- Soft tissue masses close to bone may mimic surface bone lesions (myositis ossificans).
Signs of multiple osteochondromatosis
- Other bony masses
- Short stature
Findings that might warrant surgical excision of osteochondroma
- Local tenderness, limited motion, nerve compression

Diagnostic Workup

Blood work: No role unless infection suspected (obtain CBC with differential, ESR, CRP)
Total body bone scan: establish monostotic versus polyostotic process
- Solitary osteochondroma versus osteochondromatosis
If distinction between benign and malignant lesions necessary, consider CT scan.
- Myositis ossificans shows peripherally mature mineralization.
- Osteochondroma shows continuity of cortical and medullary bone from stalk to adjacent bone.
- Parosteal osteosarcoma gives a “stuck-on” appearance, often with a very thin radiolucency between the lesion and the underlying bone.
If osteochondroma or parosteal osteosarcoma suspected, MRI scan should be obtained.
- For osteochondroma: assess thickness of cartilage cap, especially in adults, to differentiate from peripheral chondrosarcoma.
  - Cap thickness >mt2 cm is consistent with a chondrosarcoma.
  - Cap thickness 1 to 2 cm in adults is concerning for chondrosarcoma.
- For parosteal osteosarcoma, MRI determines both soft tissue extent and involvement of underlying medullary cavity.
If parosteal osteosarcoma is a diagnostic consideration or if the diagnosis cannot be established with imaging studies, a biopsy is needed.

Painful Bone Lesions

Differential Diagnosis

Pediatric patients (<20)
- Painful active lesions
  - Osteoid osteoma
- Painful aggressive benign lesions
  - Osteoblastoma
  - Aneurysmal bone cyst
  - Langerhans cell histiocytosis
- Painful malignant lesions
  - Osteosarcoma
  - Ewing sarcoma
Young adult patients (20 to 40)
- Giant cell tumor of bone
- Lymphoma
- Ewing sarcoma (5 to 30 years)
Adult patients (>mt40)
- Metastatic carcinoma
- Myeloma
- Lymphoma
- Chondrosarcoma and other sarcomas

History

If osteoid osteoma suggested, seek typical pain pattern (worse at night, relieved by nonsteroidal anti-inflammatory agents >obNSAIDs>cb).
Pain at rest in addition to mechanical pain suggests tumor-related pain.
- Tumor-related causes of rest pain
  - Bone destruction
  - Intraosseous pressure
  - Proteinases
  - Inflammatory cytokine response
- Tumor-related causes of activity-related pain
  - Advanced bone destruction
  - Extra-osseous soft tissue pressure
If malignancy suspected, check for systemic symptoms, more common with disseminated malignancies.
- Fevers, chills, unintentional weight loss, anorexia, fatigue
In adults, elicit risk factors for and signs of systemic malignancies:
- Family history of breast cancer
- Prostate symptoms for prostate cancer
- Smoking history for lung cancer
- Hematuria for renal cancer
- Thyroid masses/symptoms for thyroid cancer
- Complete review of systems

Physical Examination

Adults (also see section on metastatic disease)
- Potential sources of primary carcinoma (especially breast, prostate, lung, kidney, thyroid)
- Other evidence of metastatic disease (lymph nodes, soft tissues)
All: Site of primary symptoms