MSS Pathology SECTION 2

Tumors of Bones

INTEGRATION of Main Relevant Points  Good Clinical History Age of patient Site of lesion Duration of lesion Presence or absence of PAIN in the lesion  PLAIN X-ray of lesion*  CT of lesion*  MRI of lesion*  Combined clinical-radiological-pathologic approach

Relevant clinical information

SITE OF LONG BONE INVOLVEMENT Figure after Madewell, et al 1981Madewell, et al 1981

Tumors in Bone may be:  PRIMARY  SECONDARY (Metastatic)

 Secondary tumors are more common than primary.  Common sites of primary cancers that metastasize to bone : prostate, breast, thyroid, kidney, lung, GIT  Secondary tumor may radiologically be: osteoblastic (prostate, breast) osteolytic (kidney, lung and melanoma) mixed.

 In children: Neuroblastoma, Nephroblastoma Osteosarcoma Ewing sarcoma Rhabdomyosarcoma…  Sites involved by metastasis: axial skeleton (vertebral column, pelvis, ribs, skull, sternum), proximal femur humerus.

Primary Bone Tumors  Benign or malignant Hematopoietic. Bone-forming. Cartilage-forming. Miscellaneous: fibrous, unknown origin, neuroectodermal, notochordal... etc  Benign Ts outnumber their malignant counterparts  Multiple myeloma is the most common 1ry bone cancer in mid-late adulthood  Osteosarcoma is the most common 1ry bone cancer in children/adolescents.

Histologic typeBenignMalignant Hematopoietic (40%)Myeloma Lymphoma Chondrogenic (22%)Osteochondroma Chondroma Chondroblastoma Chondromyxoid fibroma Chondrosarcoma 2 Osteogenic (19%)Osteoid osteoma Osteoblastoma Osteosarcoma 1 FibrogenicFibrous cortical defect (fibroma) Non-ossifyinf fibroma Fibrous dysplasia Fibrosarcoma Unknown origin (10%)Giant cell tumor Unicameral (simple) cyst Aneurysmal bone cyst NeuroectodermalEwing sarcoma 3 NotochordalBenign notochordal cell tumor Chordoma

Bone-Forming Tumors

1-OSTEOID OSTEOMA/OSTEOBLASTOMA  O. Osteoma in proximal femur < cm.  Age: teenage & twenties, M:F is 2:1  Typical symptom: localized pain, worse at night, relieved by aspirin (O. Osteoma)  X-ray: well-defined cortical metaphyseal tumor with a radiolucent central nidus.  Histology: Interlacing trabeculae of woven bone surrounded by osteoblasts with a central vascularized nidus.  Simple OSTEOMA occurs in bones of skull – Multiple Osteomas in Gardner syndrome

NIDUS Osteoid Osteoma

OSTEOBLASTOMA

 Osteoblastoma is similar, but more than 1.5–2 cm. in size, more in axial skeleton  Less localized pain, non-responsive to aspirin  Slowly growing, but may be progressing & increasing in size: AGGRESSIVE OSTEOBLASTOMA Important to differentiate from Osteosarcoma

2- MALIGNANT: OSTEOSARCOMA  Malignant mesenchymal neoplasm, in which the neoplastic cells produce OSTEOID matrix  Most common primary malignant non- hematopoietic bone tumor.  M>F, 75% < 20 years old.  Majority in metaphyses of long bones, most (>= 50%) around the knee.  May be multiple in children with p53 mutation (Li-Fraumeni Syndrome)

Sites of Osteosarcoma

 Primary, arising de novo OR  Secondary to an underlying bone disease e.g. Paget disease, irradiation Most are intramedullary  cortex  periosteum  soft tissue Rarely extends into joints Location:  Classical (Intramedullary)  Paraosteal (Juxtacortical)  Periosteal

Pathogenesis:  Genetic mutations: RB gene mutation on chromosome 13 in 60-70% of sporadic cases Inherited in familial retinoblastoma x1000 Other mutations: p53, cyclins, CDKs…etc  Predisposing conditions

Clinical features:  Enlarging mass, with or without pain.  Sometimes pathological fracture.  Hematogenous metastasis is common, most likely to the lungs.  X-ray: Cortical destruction & extension to the marrow or soft tissue.  Codman’s triangle is a radiological term due to periosteal reaction with new bone formation.

Codman’s

Osteosarcoma

Pathology and Treatment:  Pleomorphic large malignant cells, prominent mitoses  Lace-like osteoid formed directly by malignant cells.  Numerous osteoclasts may be seen  Histological Variants: Predominantly osteoblastic Chondroblastic Fibroblastic Telengiectatic & Others

Treatment: Chemotherapy → Assess amount of NECROSIS Surgery Radiation

Prognosis:  Aggressive tumor  The prognosis depends on the stage & variant of the tumor (conventional or other variants), location……etc  The grade is not as important as stage in osteosarcoma.

Primary Cartilage-Forming Tumors

1- Chondroma & Enchondroma  Solitary benign.  Intramedullary (enchondroma) or bone surface(juxtacortical chondroma)  Any age can be affected (20-40 yrs)  Small bones of hands, feet, long bones, pelvis…  Multiple (Ollier D. & Maffucci S.) w. IDH point mutations  chondrosarcoma in 1/3.  Morphology: well-circumscribed mass of mature cartilage

Enchondroma

2- Osteochondroma (exostosis)  Single or inherited multiple  Arise from the metaphysis near growth plate of long tubular bones cm  Majority around knee  Composed of outgrowth of cartilage cap overlying bone & bone marrow  May become ossified  Inactivating mutation of EXT1 or EXT2.  Very rare malignant transformation (<2%, unless MHE up to 10%)

3- Chondrosarcoma  Malignant tumor of mesenchymal cells that produce cartilaginous matrix.  Older patients, 40-60, M>F.  Site: axial skeleton (pelvis, shoulder, ribs), prox. Femur; rarely distal extremities  Primary (arise de novo) - majority. Secondary: multiple enchondromas or rarely osteochondromas.

Morphology:  Grossly: Glistening mass in the medullary cavity.  Histology: Chondrocytes with variable pleomorphism & binucleation. No osteoid.  Prognosis: depends on grade; Most are low grade, & recur.  10% dedifferentiated & metastasize to lung … Other histologic variants present

Chondrosarcoma

Dedifferentiated Chondrosarcoma

Fibrous Lesions

Fibrous Dysplasia:  Failure of normal bone elements to differentiate into mature bone.  Monostotic (70%) & Polyostotic Localized intramedullary fibrous lesion with curved woven bone ’Chinese letters’ No osteoblast rimming  GNAS-1 mutation  McCune-Albright Syndrome – 3%

Fibrous Cortical Defect & Non- ossifying Fibroma  Developmental.  FCD < 0.5 cm, cortical  NOF:  Larger  into medullary Cavity  Risk of pathologic fracture

Miscellaneous Tumors

1- Giant cell Tumor (osteoclastoma)  Bulky tumor at the end of long bones  Age: Mostly years, F>M  Sites: Epiphysis of long bones; femur, tibia, radius, may extend into metaphysis or joint  Majority are solitary.  Histology: 2 population of cells: Multinucleated large osteoclasts and giant cells Mononuclear stromal cells are neoplastic

Giant cell Tumor, cont.  Differential diagnosis: Similar picture may be seen in: Aneurysmal bone cyst. Brown tumor of hyperparathyroidism Osteosarcoma with giant cells. Many others!  All contain GIANT CELLS!  Clinical & Radiographic correlation: very Important!

Clinical behaviour: Unpredictable. Most tumors are benign. May be aggressive Recurrence may occur. May ‘metastasize’ to lung Sarcomatous transformation may occur  Check for mitoses in the stromal spindle cells  Treat by surgical curettage or resection

2- Ewing Sarcoma & PNET  Primitive Neuro-Ectodermal Tumor (PNET): undifferentiated round cells arising within the marrow cavity: Small Blue Cell Tumor  M>F, most in children & teenagers (5-20)  Classic translocation t(11;22) involving EWS gene.  X-ray: Lytic medullary lesion with concentric ‘onion skin’ layering of new periosteal bone.

Morphology:  Gross: often affects the diaphyses of long bones, pelvis and tibia with necrosis & hemorrhage.  Micro: sheets of undifferentiated small round blue cells, PAS positive material in cytoplasm consistent with glycogen  Homer-Wright rosettes –neural diff.  Tumoral cells destroy cortex and periosteum and invade surrounding tissues.

 Clinical Features: Mass, pain with local inflammation  Treatment : chemotherapy, surgery +/- irradiation  Prognosis: 5 year survival rate of 75% for localized tumors.