Oncology and Pathology

Adam S. Levin

EVALUATION AND STAGING

Staging
- Musculoskeletal Tumor Society (MSTS, Enneking) staging—anatomic, surgical staging system
  - Benign tumors
    - Latent—narrow zone of transition on radiographs
    - Active—may grow but without clear cortical destruction
    - Aggressive—expansile destructive
  - Malignant tumors
    - Low grade (stage I)
      - IA—intracompartmental
      - IB—extracompartmental
    - High grade (stage II)
      - IIA—intracompartmental
      - IIB—extracompartmental
    - Metastatic (stage III)
- American Joint Committee in Cancer (AJCC) staging—prognostic staging system for sarcomas
  - Soft tissue sarcomas
    - Low grade (stage I)
    - High grade (stage II), and either large (>5 cm) or deep to fascia
    - High grade (stage III), large (>5 cm), and deep to fascia
    - Metastatic (stage IV)
  - Bone sarcomas
    - Low grade (stage I)
      - IA: ≤8 cm
      - IB: >8 cm
    - High grade (stage II)
      - IIA: ≤8 cm
      - IIB: >8 cm
    - Skip metastases (stage III)—another discontinuous lesion in the same bone
    - Distant metastasis (stage IV)
Imaging
- Radiography
  - Good detail on aggressiveness of bone tumors
  - Localization gives keys to likely diagnosis.
  - Calcifications of soft tissue lesions can give clue to diagnosis.
- Computed tomography (CT)
  - Improved osseous detail for cortical erosion or scalloping at the primary lesion
  - Chest CT part of standard staging workup for malignant bone or soft tissue tumors
- Magnetic resonance imaging (MRI, Figure 10.1)
  - Excellent soft tissue detail for tumor extent
  - Gadolinium enhancement can determine cystic versus solid masses, degree of vascularity.
  - MRI of the entire compartment or bone to assess for skip metastases
- Positron emission tomography (PET)
  - Fluorodeoxyglucose assesses metabolic activity of lesions
  - Good for detecting lymph node metastases, occult masses, or hematologic malignancy
- Bone scan
  - Technetium-99-methylene diphosphonate
  - Labels site of increased bone turnover
  - 30% of myeloma lesions will be cold on bone scan—improved yield with metastatic skeletal survey.

Biopsy principles

How to perform a biopsy (optimally, by treating surgeon)

Incise along the limb salvage incision

Figure 10.1 A large mass that is deep to the fascia may be concerning for soft tissue sarcoma. Soft tissue sarcoma MRI appearance will often be isointense to muscle on T1-weighted images (A), hyperintense on T2-weighted images (B), and often with heterogeneous enhancement (C).

Figure 10.1 (continued)

Approach with minimal soft tissue flaps/dissection
Avoid contamination of critical structures—neurovascular, joints
Minimize stress risers, protect the limb after biopsy
Practice meticulous hemostasis—avoid postoperative hematoma
Deflate tourniquet before closure
If leaving a drain, in-line with the incision and close to the end

Histopathology principles
- Careful handling of specimen
- Lymphoma very delicate, nondiagnostic biopsy common
- Fresh, sterile collection to allow for immunohistochemical stains, flow cytometry
- Certain tissue types are difficult to assess on frozen section.
  - Lipomatous masses
  - Calcified bone
  - Langerhans cell histiocytosis (LCH)
  - Cartilage

Adjuvant treatments
- Chemotherapy
  - Cytotoxic medications target rapidly growing cells.
    - Antiangiogenic agents—vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors
    - Intercalating agents—doxorubicin
    - Alkylating agents—vincristine, ifosfamide
    - Topoisomerase inhibitors—etoposide
    - Antifolate—methotrexate
    - Nucleoside analogs—gemcitabine
  - Targeted chemotherapy options developed for specific pathways
    - Mechanistic target of rapamycin inhibitors—rapamycin, everolimus
- Radiation
  - Deoxyribonucleic acid (DNA) damage induces apoptosis of rapidly dividing cells.
- Local adjuvants
  - Advances cell death locally at the site of tumor excision
  - Often used in benign aggressive tumors (giant cell tumor)
  - Commonly used local adjuvants
    - Cryosurgery
    - Argon beam coagulation
    - Low-intensity pulsed ultrasound
    - Radiofrequency ablation
    - Radiation therapy
    - Polymethyl methacrylate
    - Phenol
Molecular biology of musculoskeletal tumors
- Common translocations
  - t(9;22)—EWS, CHN1—extraskeletal myxoid chondrosarcoma
  - t(11;22)—EWS, FLI1—Ewing family of tumors (also t[21;22])
  - t(12;22)—EWS, ATF1—clear cell sarcoma, angiomatoid fibrous histiocytoma
  - t(17;22)—COL1A1, PDGFB1—dermatofibrosarcoma protuberans
  - t(2;13)—PAX3, FOXO1—alveolar rhabdomyosarcoma
  - t(1;13)—PAX7, FOXO1—alveolar rhabdomyosarcoma
  - t(12;16)—TLS, CHOP—myxoid liposarcoma
  - t(X;18)—SYT, SSX—synovial sarcoma
  - t(X;17)—ASPL, TFE3—alveolar soft-parts sarcoma
- Additional genetic abnormalities
  - Ring chromosome 12
    - Atypical lipomatous tumor/well-differentiated liposarcoma
    - Low-grade osteosarcoma
  - GNAS
    - Fibrous dysplasia
  - Colony-stimulating factor-1 (CSF-1)
    - Pigmented villonodular synovitis/giant cell tumor of tendon sheath
  - EXT1, EXT2, EXT3 genes
    - Multiple hereditary exostoses

BENIGN BONE TUMORS

Bone-forming tumors

Enostosis
- Bone island
- Small, asymptomatic
- Typically cold on bone scan
- No change over time
Osteopoikilosis
- Heritable—autosomal dominant
- Multiple enostoses

Osteoid osteoma (Figure 10.2)

Small (<1.5 or <2 cm) nidus
Osteoid seams with prominent osteoblastic rimming
Typically cortically based
Perilesional sclerosis and perilesional edema

Intensely painful

Figure 10.2 A, Osteoid osteoma may demonstrate a region of marked cortical thickening and benign periosteal new bone formation. B, Computed tomography is typically the best study to demonstrate the radiolucent cortically based nidus. C, A bone scan will typically demonstrate intense activity, similar to a stress reaction. D, Image-guided radiofrequency ablation has become the treatment of choice for most osteoid osteomas occurring in the appendicular skeleton. From Unni KK, Inwards CY. Osteoid osteoma. In: Dahlin’s Bone Tumors: General Aspects and Data on 10,165 Cases. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:102-111.

Figure 10.2 (continued)

Relief with nonsteroidal anti-inflammatory drugs (NSAIDs)
May worsen with ethyl alcohol
In spine, associated with painful scoliosis

Best seen on CT
- One of the few indications when axial CT will be used for diagnosis of a bone mass
Treatment
- NSAIDs (typically resolve after 2-3 years)
- Radiofrequency ablation (standard of care, if location allows)
- Surgical curettage or excision—need to remove entire nidus

Osteoblastoma
- Typically larger than 2 cm
- Histology similar to osteoid osteoma
- Typically more medullary
- Less prominent cortical reaction on imaging than osteoid osteoma
- Pain more variable
- Frequently seen in posterior spine elements

Spine lesions

Posterior elements—typically benign

Osteoid osteoma—painful scoliosis

Osteoblastoma (Figure 10.3A)

Figure 10.3 A, Osteoblastoma of the posterior elements of a 12-year-old girl, causing cord compression. B, Aneurysmal bone cysts (ABCs) demonstrate aneurysmal dilatation of the bone, as demonstrated in the cross-section. The arrow demonstrates a fluid-fluid level. There are typically numerous fluid-fluid levels within an ABC, as demonstrated. B: From Chew FS. Benign lesions. In: Skeletal Radiology: The Bare Bones. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:158-180.

Aneurysmal bone cyst (ABC, Figure 10.3B)
Osteochondroma

Anterior elements—often malignant
- Metastatic carcinoma
- Plasmacytoma/multiple myeloma
- Chordoma—classically clivus or sacrum but can be anywhere along the spine
- Hemangioma—most common
- LCH—vertebra plana in a child (Figure 10.4)

Cartilage-forming tumors
- Enchondroma
  - Benign, intramedullary cartilage lesion
  - Often metaphyseal
  - “Ring and arc” or popcorn-like calcifications
    - Hand/foot imaging may look more aggressive but remain benign.
    - Radiographic differential diagnosis includes:
      - Osteonecrosis—“smoke up a chimney” calcification
      - Chondrosarcoma
  - MRI
    - Dark T1
    - Bright T2
    - Variable gadolinium enhancement in a lobular pattern
  - Most common in the short tubular bones of the hands/feet (50%-60%)
    - Other common sites
      - Proximal humerus
      - Distal femur
      - Proximal tibia
    - Commonly asymptomatic and found incidentally while imaging for other nearby joint pathology
      
      Figure 10.4 Langerhans cell histiocytosis may present with vertebra plana (arrow) in a young patient.
  - Treatment
    - Observation
    - Avoidance with adjacent joint surgery
    - Curettage and local adjuvant treatment if necessary
  - Malignant degeneration
    - Reports suggest approximately 1% lifetime risk for a solitary enchondroma
    - Increased concern for malignancy if:
      - >90% medullary fill by the tumor
      - Size > 5 cm
      - Pain related to the tumor rather than adjacent joint
      - Endosteal scalloping, cortical breach
      - Endosteal buttressing
      - Periosteal reaction
      - Measurable growth over time
      - Decreased mineralization over time—an indication of dedifferentiated chondrosarcoma
- Ollier disease
  - Multiple enchondromas
  - Often involves one limb or half of body
  - Risk of malignancy (chondrosarcoma) approximately 30%
- Maffucci syndrome
  - Multiple enchondromas with associated angiomas
  - Risk of malignancy (chondrosarcoma, angiosarcoma)—almost 100%
- Osteochondroma
  - Metaphyseal location
  - Points away from physis
  - Thought to represent physeal growth in an altered direction
  - May be sessile or pedunculated
  - Imaging with medullary and cortical continuity of bone with a cartilage cap
  - Cartilage cap mimics physeal cartilage in children
    - Cartilage cap more than 1.5 to 2 cm concerning for malignancy in adults
    - Cartilage cap growth after skeletal maturity concerning for malignancy
    - No limit to cartilage cap thickness in children
    - Reports suggest up to 1% lifetime risk of malignancy (chondrosarcoma) in solitary osteochondroma
    - Treatment
      - Observation
      - Excision at the base of the osteochondroma if symptomatic
      - Removal of entire cartilage cap and perichondrium necessary to prevent recurrence
- Multiple hereditary exostoses/multiple hereditary osteochondromas (Figure 10.5)
  - Heritable, autosomal dominant
    - EXT1, EXT2, EXT3 genes
  - Multiple osteochondromas with variable severity
    - Often includes most long bones
  - May present with substantial deformity of the extremity and decreased range of motion
  - Up to 10% lifetime risk of malignancy (chondrosarcoma)
- Trevor disease (dysplasia epiphysealis hemimelica)
  - Similar to osteochondroma but found in the epiphysis
  - Typically noted in growing children
- Chondroblastoma
  - Typically in the epiphysis of skeletally immature adolescents
  - Often painful with large inflammatory response on imaging
    
    Figure 10.5 Multiple hereditary exostoses is associated with EXT mutations. This is characterized by osteochondromas in numerous bones, with characteristic deformities of the metaphyses.
  - MRI
    - Appears lobular with similar characteristics to cartilage
    - Large surrounding edema pattern
    - May have a secondary ABC
    - On a short differential diagnosis list for “end-of-bone” or epiphyseal osseous lesions—same list as for apophyses
    - Chondroblastoma—often skeletally immature, chondroid
    - Clear cell chondrosarcoma—typically skeletally mature, chondroid
    - Giant cell tumor of bone
  - Histopathology
    - Round chondroblasts with central nuclei—“fried egg” cells
    - Occasionally have some honeycombed mineralization—“chicken wire” calcifications
  - Treatment
    - Curettage and local adjuvant
  - Despite benign etiology, is capable of “benign metastasis” to the lung (like giant cell tumor of bone)
- Chondromyxoid fibroma
  - Most commonly in tibia of young adults
  - Lobulated, “soap bubble” appearance on imaging
  - Histopathology
    - Areas of low and high cellularity on low power
    - Higher power imaging with abundant myxoid background and stellate cells that look like helicopter propellers or “Mercedes-Benz” symbols
Cystic lesions
- Unicameral bone cyst (simple bone cyst)
  - Common pediatric condition (typically school-age at diagnosis)
  - Typically in the proximal humerus
  - Largely self-limiting
  - May present with pain or pathologic fracture
  - Pathologic fracture does not necessitate treatment if alignment can be maintained
  - Radiographs
    - Radiolucent lesion with thinned cortex
      - May have some mild expansion of the bone
      - Narrow zone of transition on imaging
    - Active—adjacent to the physis
    - Inactive—away from the physis
    - Can often have septations or with “fallen leaf” sign, representing a shelf of bone that has fallen within the cyst
  - Histopathology
    - Thin cyst wall lined by a fibrocellular membrane
  - Treatment
    - Observation
    - Aspiration and injection of corticosteroids
    - Aspiration and injection of marrow with demineralized bone matrix
    - Curettage and bone graft
- ABC
  - Typically seen in children and adolescents
  - May be expansile and may act aggressively locally
  - Often presents with pain
  - Typically in the long bones, although may be seen in the pelvis or posterior elements of the spine
  - Radiographs
    - Radiolucent, expansile lesion
    - Often lobulated
    - Typically wider than the physis
  - MRI
    - Typically with multiple septations
    - Multiple fluid-fluid levels on axial and sagittal imaging, representing blood products
  - Pathology
    - Multiloculated cyst wall with red blood cell within the cyst cavities
    - Multinucleated giant cells within the solid components
      - Note: Multiple etiologies demonstrate multinucleated giant cells, not just giant cell tumors.
  - Radiologic differential diagnosis includes telangiectatic osteosarcoma.
  - Treatment
    - Curettage and local adjuvant treatment
    - Wide excision if expendable bone
    - High local recurrence rate
- Intraosseous ganglion (geode)
  - Often related to nearby joint degeneration
  - Well-defined lytic lesion on imaging
  - Typically subchondral location
  - Clear, synovial or serous fluid

Fibrous tumors

Nonossifying fibroma (NOF, Figure 10.6)

The most common benign bone tumor
Also known as xanthoma of bone; fibrous cortical defect
Typically noted in children, although may not be recognized until adulthood
Often asymptomatic, found incidentally for adjacent trauma

Radiographs

Figure 10.6 A nonossifying fibroma will typically be localized eccentrically in the metaphysis and demonstrates a thin cortical rim, as demonstrated by the arrows. AP (A) and lateral (B) radiographs of a distal tibial nonossifying fibroma in a skeletally immature patient. From Monu JU, Pope TL Jr. Diaphysis. In: Pope TL Jr, Harris JH Jr, eds. Harris & Harris’: The Radiology of Emergency Medicine. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:973-988.

Cortical or eccentric
Well-defined borders with a narrow cortical rim
No periosteal elevation or reaction

Histopathology
- Bland, spindle cell proliferation in a fibrous stroma
- Multinucleated giant cells and foamy histiocytes more common in adults
Typically self-limiting, although may persist into adulthood
- Often partially calcified over time
Treatment
- Observation
- Curettage and bone graft if concern for risk of pathologic fracture

Avulsive cortical irregularity
- Similar to NOF
- Thought to represent repetitive avulsive microtrauma at the medial gastrocnemius insertion

Jaffe-Campanacci syndrome

Multiple NOFs

Café-au-lait spots (Figure 10.7)

Café-au-lait spots can be seen in multiple conditions

Jaffe-Campanacci syndrome
Neurofibromatosis type 1 (NF1)—“coast of California”
McCune-Albright syndrome
Tuberous sclerosis

Fanconi anemia

Figure 10.7 Café-au-lait spots may be seen in a number of conditions. This patient’s spots have a rugged border, similar to the coast of Maine, in the setting of McCune-Albright syndrome. From Aronsson DD, Lisle JW. The pediatric orthopaedic examination. In: Weinstein SL, Flynn JM, eds. Lovell and Winter’s Pediatric Orthopaedics. Vol 1. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:87-128.

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