Bone Tumor

Describe Bone Tumors

• Primary =?

• MC Types?

• Dx?

• Primary = Rare

  • Metastatic tumors + hematopoietic tumors > primary 

• MC primary malignant bone tumors:

  1. Osteosarcoma

  2. Chondrosarcoma

  3. Ewing Sarcoma

• Dx:

  • Radiographic = important role

  • Bx = necessary 

Epi of Bone Tumors

• Epi:

  • Most develop during first several decades

  • Propensity for long bones of extremities

  • Lethal in 50% of cases

  • ≈ 2400 new cases of bone sarcoma are diagnosed annually in the US

  • AGE

    • M/F 1.6:1

    • Bimodal age distribution

      • 10 – 14 yrs

      • > 65 yrs

Describe OSTEOSARCOMA

• What is it?

• Location

• Presentation

• Associations?

• Genetics?

• Morphology

• Prognosis

• Tx

OSTEOSARCOMA

• What is it?

  • Malignant tumor which forms bone

    • MC primary malignant tumor of bone

• Location:

  • Usually arise in metaphyseal region of long bones

    • 50% occur near knee

• Presentation:

  • Painful, progressively enlarging mass

  • Sometimes has pathologic fracture

• Associations (older):

  • Paget disease, 

  • bone infarcts 

  • prior radiation

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Genetics:

• Involves Tumor Suppressor or Oncogenes:

  • RB

  • TP53

  • CDKN2A

    • Encodes 2 tumor suppressors

      • P16: a cyclin dependent kinase inhibitor

      • P14: inhibits MDM2

  • Overexpression of CDK4 & MDM2

    • Amplification of 12q13–q15

      • Seen in many low-grade osteosarcomas

---

Morphology

• Bulky, gritty tumors + hemorrhage and cystic degeneration

• Frequently invade cortex

• Spread extensively along medullary canal Pleomorphic nuclei, bizarre tumor giant cells & numerous mitoses, including atypical mitoses

• Necrosis and vascular invasion common

• Dx requires presence of malignant tumor cells producing osteoid or bone

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Prognosis

• All Pt = assumed to have occult metastases @ time of Dx

  • Pt w/o: 74% 5yrs survival rate 

• Metastasizes to:

  • lungs, bone, brain & other sites

  • @ Dx time; 10-20% = pulmonary metastases

  • w/ distant metastases: 27% 5yr survival rate

---

Tx:

• neoadjuvant chemoRx, 

• Limb- sparing surgery, 

• adjuvant chemoRx

X-ray of an osteosarcoma arising in the distal femur. The tumor has invaded through the cortex with resultant neoplastic bone formation in the surrounding soft tissue. The arrow is pointing to an area where the periosteum has been lifted from the cortical surface by the tumor, and has laid down a triangular-shaped mass of reactive bone known as a “Codman triangle.”

The image is a gross photo of an osteosarcoma, which has arisen in the proximal tibia. The tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and resulted in formation of soft tissue masses on both sides of the bone.

Histologic section from an osteosarcoma exhibiting pleomorphic malignant tumor cells, which have produced a fine, lacelike pattern of neoplastic bone. The blue arrow is pointing at a multinucleated tumor giant cell. The black arrow is pointing at two abnormal (atypical) mitotic figures. .

Epi of Chondrosarcoma

Epi:

• M/F 2:1

• Usually occur in individuals in their 40s or older

1. Describe Chondrosarcoma

   • What is it

   • Sites

   • Subclassified histologically as:

   • Clinical Features

2. Describe the patho:

   • Of Multiple hereditary exostosis syndrome

   • What are the other 2 genetic mutation associated

3. Morphology

4. Prog.

5. Tx

Chondrosarcoma

• What is it?

  • Malignant tumors that produce cartilage

    • 2nd most common primary malignant bone tumor

• Sites:

  • axial skeleton

    • pelvis, shoulder & ribs

• Subclassified histologically as:

  • Conventional

    • 15% = secondary (enchondroma or osteochondroma)

  • Clear cell

    • (in teens-20s)

  • Dedifferentiated (2nd high grade component)

  • Mesenchymal (2nd component resembling Ewing sarcoma)

    • (in teens - 20s)

• Clinical Features

  • Painful, progressively enlarging masses

  • Location:

    • pelvis, shoulder & ribs

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Multiple hereditary exostosis syndrome

• Loss of function: EXT1 or EXT2 genes

  • Loss of Heparin Sulfate -> impaired IHH Diffusion -> impaired dif + inc. prolif. Of Chondrocytes -> multiple osteochondromas

  • Multiple osteochondromas -> chondrosarcoma

    • B/c abnormal proliferating cartilage can acquire additional mutations over time

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Other Genetic Pathogenesis

• IDH1 or IDH2 Mutations:

  • Encodes isocitrate dehydrogenase isoforms 

    • isocitrate -> alpha ketoglutarate

  • Mutation =

    •  Isocitrate -> 2- hydroxyglutarate

  • 2- hydroxyglutarate inhibits demethylases

    • -> Histone hypermethylation 

  • Ult. Leads to enchondromatosis-related and sporadic chondrosarcomas

• Silencing of the CDKN2A gene by hypermethylation

---

• Morphology

  • Conventionally: Large Buly Tumors

    • Invades through cortex into surrounding soft tissue

  • Graded histologically from 1-3

    • Correlates w/ biological behavior 

• Prognosis:

  • Most = grade 1 tumors

    • 5-year survival rates of 80% to 90%

  • Grade 3 = 43% (5 yr)

• Tx:

  • Conventional: surgical excision

  • Mesenchymal & dedifferentiated: surgical excision + adjuvant chemoRx

Right: Gross photo of a chondrosarcoma. A gelatinous-appearing tumor can be seen to be permeating throughout the medullary cavity, invading through the cortex, and forming a relatively well-circumscribed soft tissue mass (arrow).

Upper Left: Conventional chondrosarcoma, grade 1. Malignant chondrocytes exhibiting mild anaplasia are embedded in a hyaline cartilage matrix.

Lower Right: Conventional chondrosarcoma, grade 3. Malignant chondrocytes exhibiting marked anaplasia are once again embedded in a hyaline cartilage matrix.

Epi for Ewing Sarcoma

Epi:

• Second most common bone sarcoma in children

  • ≈ 80% of patients are younger than 20 years of age

• Striking predilection for Caucasians

Describe Ewing Sarcoma

• What is it?

• Location?

• Patho

• Clinical Features

• Morphology

• Tx

• Prog

Ewing Sarcoma

• What is it?

  • Malignant bone tumor composed of primitive small round cells without obvious differentiation

• Location:

  • diaphysis of long tubular bones,

    •  Femur + Flat bone of pelvis 

---

Pathogenesis

• Reciprocal translocation of t(11;22)(q24;q12)

  • EWSR1/FLI1 fusion gene

    • EWSR1 = EWS 

      • Has Trxn act. + RNA binding domain

    • FLI1 = FLI1

      • ETS transcription factor

• Resulting chimeric protein = aberrant Trnx. Factor = uncontroll growth/dif

  • Cell of Origin:

    • mesenchymal stem cells & primitive neuroectodermal cells

    • This is just a theory

---

Clinical Features

• painful enlarging mass

  • frequently tender, warm & swollen

• Some = Systemic:

  • fever, leukocytosis, inc.  sed. rate

---

Morphology

• Arise in medullary cavity  -> Cortext, periosteum & soft tissue

• Soft, tan-white & frequently contains areas of hemorrhage and necrosis

• Very cellular with little stroma

• Composed of sheets of uniform, small, round cells

• Have scant cytoplasm, which may appear clear due to abundant glycogen

• Some exhibit Homer-Wright rosettes

---

• Tx:

  • neoadjuvant chemoRx, surgical excision & adjuvant chemoRx, with or without irradiation

• Prog.

  • 5-year survival rate is 75%

  • Long-term cure rate is 50%

Upper left: Ewing sarcoma exhibiting sheets of uniform small, round, blue cells with small amounts of clear cytoplasm, which is rich in glycogen.

Lower Right: Ewing sarcoma exhibiting Homer-Wright rosettes. The tumor cells are surrounding a central area exhibiting a dense network of cytoplasmic processes from the tumor cells. Homer-Wright rosettes are indicative of neuroectodermal differentiation.

Epi for Giant Cell Tumor

Usually arises in the third through fifth decades of life

Describe Giant Cell Tumor (osteoclastoma)

• What is it?

• Benign or Malignant?

• Location?

• Patho

• Clinical Features

• Morpho?

• Prog.

• Tx

Giant Cell Tumor (osteoclastoma)

• What is it?

  • Tumor characterized by the presence of numerous multinucleated osteoclast-type giant cells

• Benign or Malignant?

  • Benign but:

    • Locally aggressive

    • Frequently recur after curettage

    • Small percentage can metastasize

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• Location:

  • w/in epiphysis and can extend -> metaphysis

    • >50% in Knee

    • radius, humerus & fibula

• Pathogenesis

  • Neoplastic cells = osteoblast precursor cells

    • Mutation in gene encoding histone 3.3

    • Expresses high RANKL (mononuclear stromal cells)

  • RANK -> Osteoclast dif.

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Clinical Features

• Often present with:

  • Arthritis-like symptoms

  • Pathologic fractures

---

Morphology

• large, red-brown masses that frequently undergo cystic degeneration

• Frequently destroy the cortex, with growth limited by the periosteum

  • More aggressive tumors invade through cortex & periosteum into surrounding soft tissue

• Histologically two main cell types:

  • Multinucleated osteoclast-type giant cells

  • Mononuclear stromal cells

• Necrosis & mitotic activity may be prominent

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• Prognosis:

  • 40 – 60% recur locally

  • 2%–5% metastasize to the lungs

    •  regress spontaneously & are seldom fatal

    • Virtually all metastases have occurred after an initial surgical intervention

• Tx:

  • Usually treated with curettage

  • The RANKL inhibitor denosumab has shown promise as an adjuvant Rx

Giant cell tumor of bone. Radiograph of the proximal tibia shows a lytic lesion with no new bone formation (arrows). The tumor extends to the subchondral bone plate and invades through the cortex into soft tissue. Giant cell tumors are lytic lesions, since the numerous osteoclastic giant cells result in destructive bone resorption.

Giant cell tumor of bone. Histologic section revealing multinucleated osteoclast-type giant cells, accompanied by uniform-appearing oval mononuclear stromal cells. The multinucleated osteoclast-type giant cells are reactive cells that form in response to high levels of RANKL expressed by the neoplastic mononuclear stromal cells.