Encased by bone

Control Calcium and Phosphorous levels

Respond to mechanical forces

Bone resorbtion cells

Break down matrix stimulate bone renewal

• Produced by osteoblasts
• Woven bone: Fetal skeleton and growth plates
• Formed quickly
• Replaced by lamellar bone
• Woven bone is deposited on the surface of preexisting lamellar bone (bottom)
• Soft bone, tends to fracture
• Layered pattern: lamellar bone
• Strong replacement of woven bone  

• Increased porosity due to loss of bone mass
• Usually refers to senile and postmenopausal forms with thinning of bone predisposing to fracture, especially femoral necks, wrists, and vertebrae
• Pathogenesis: Aging, decreased estrogen levels, slowing osteoblasic activity, and increased osteoclastic activity
• Current interest is in prevention and bone densitometry
• Menopause Osteoporosis Pathogenesis:
• Decreased serum estrogen
• Increased IL-1, IL-6, TNF
• Incrased expression of RANK and RANKL
• Increased osteoclast activity
• Aging Osteoporosis Pathogenesis:
• Decreased replicative activity of osteoprogenitor cells
• Decreased synthetic activity of osteoblasts
• Decreased biologic activity of matrix-bound growth factors
• Reduced physical activity

• Endocrine
• Hyperparathyroidism
• Neoplastic
• Multiple Myeloma
• GI
• Malnutrition
• Malabsorption
• Drugs
• Heparin
• Corticosteroids
• Miscellaneous
• Immobilization  

Paget Disease of the bone

Osteitis Deformans

• Causes are uncertain
• Initially osteoclasts and then osteoblasts are affected leading to disordered bone formation (mosaic pattern)
• Mosaic pattern: Tile like pattern, likened to a jigsaw puzzle is a histologic hallmark of Pagets disease and is pathonomonic
• Bone is soft, porous, lack stability, and is vunerable to fracture
• A paramyxovirus has been implicated but not proven  

Osteonecrosis

Avascular Necrosis

• Infarction of bone and marrow, due to vascular abnormality
• Steroid induced necrosis is most common and may be due to vascular compression
• Morphology: Geographic pale area of marrow secondary to bone cell necrosis, softening may lead to collapse of cartilage into underlying bone  

• Bacteria transported to bone by blood or direct extension from a nearby infected site.
• Staph aureus MC
• Sickle cell predisposes to Salmonella infection of bone
• TB: Lung and GI
• Syphilis: Congenital or acquired with formation of gummas (infectious granulomas) in bone  

• MC matrix producing primary bone tumor
• Bimodal distribution: Age < 20 yrs  or elderly
• Elderly usually have additional risk factors like Pagets disease, infarcts, or radiation therapy
• Also Hereditary form which is rare  
• Associated with Rb gene and p53 mutation
• Areas of rapid growth that often present with pain swelling or fracture.
• MC: Knee
• Growth through medullary canal, through cortex to lif periosteum to form a triangle on X-ray called Codman Triangle
• Gross Appearance:
• Bulky, gritty, gray-white tumors
• May be primary, secondary, solitary, or multicentric
• MC: Primary, solitary, intramedullary and poorly differentiated
• Formation of bone is most characteristic histologic feature
• Aggressice, hematogenos spread
• Mets: Lungs, bones, brain, and elsewhere
• Treatment: Chemotherapy, limb-salvage surgery, mets assumed

• Second most common matrix producing bone tumor
• Age: > 40 yrs
• Favors central skeleton: pelvis, shoulder, ribs
• Causes pain
• Classified by site of origin (radiographic) and histology
• > 10 cm tumors are more aggressive
• Mets: lungs, and other parts of skeleton
• Grossly is looks bulky, translucent bluish gray glistening tumors
• May be intramedullary or juxtacortical
• X-ray: prominent endosteal scalloping with flocculent densities
• Looks like a snow storm with lots of white flecks
• Histologic Hallmark is production of malignant cartilage
• Usually low grade but may be high grade (grade 3) or areas of de-differentiation to high grade sarcoma may occur
• Treatment is wide surgical excision for low grade tumors
• Chemotherapy is added for tumors with areas of de-differentiation or mesenchymal components
• Survival Rate:
• Grade 1: 90%
• Grade 2: 81%
• Grade 3: 43% 

• Sarcomas producing fibroblastic collagen
• Usually occurs in middle aged and elderly
• Usually arise de novo but can be associated with pre-existing bone tumors, bone infarcts, Paget Disease or previous irradiation pf bone
• Enlarging painful masses, usually metaphases of long bones and pelvic flat bones
• X-ray: permeative, lytic, with soft tissue extension causing pathologic fracture
• Fibrosarcoma differentiation determined by amounts of collagen produced and degree of cytologic atypia
• Herringbone storiform pattern on histology 

Ewing Sarcoma (EWS)

Primitive Neuroectodermal Tumor (PNET)

• Tumors of neural phenotype
• Share a common chromosome fusion gene: (EWS FL11) as a part of a (11; 22) (q24;q12) translocation
• EWS histology: small round blue cells
• Must be distinguished from leukemia/lymphoma
• PNET: histologic feature or neural differentiation
• Homer-Wright rosette
• Histological distinction has no clinical significance
• Second in frequency to osteosarcoma as most common primary malignany bone sarcomas in children
• Presents in youngest age group: 1-15 yrs
• Clinical Presentation: 
• Painful enlarging mass of the diaphysis of long tubular bones, especially femur and flat bones of the pelvis
• Lytic tumor with permeative margins that extends into surrounding soft tissue  
• Characteristic periosteal reaction deposited in an onion-skin fashion
• Systemic inflammatory response may mimic infection: pathologic exam important
• Treatment: surgery, chemotherapy, irradiation
• 5 year survival rate: 75%
• > 50% have long term cures

• Most common form of skeletal malignancy
• Any malignancy may be the primary
• Children: neuroblastoma, Wilms tumor, osteosarcoma, Ewing sarcoma, rhabdomysarcoma
• Adults: Prostate Cancer, Breast, kidney, and lung
• Deposits may be multifocal or solitary involving any bone
• Hands/Feet are uncommon
• X-ray: blastic, lytic, or mixed lesions
• Lytic lesions are due to cell products rather than cells themselves
• Most commonly purely osteoblastic metastasis of bone: Prostate CA 

In class question:

What type of anemia is associated with carcinoma metastic to bone?

In class question:

A 65 yr old female falls and fractures her wrist. What condition is likely to be the single most important factor contributing to the fracture?

1. Mesenchymal Proliferations arise from stem cells capable of mesenchymal differentiation
2. Tumors are classified based on the tissue they resemble
3. Tumors located outside bone, blood vessels, viscera, brain and lymphoreticular system, mucosal linings, skin 

• Arise from mutated mesenchymal stem cells found throughout the body
• Mustated cells have new fusion genes
• Classified for tissues the resemble, NO evidence that they are derived from these tissues
• Some tumors have no known normal tissue counterpart, so classification is different from others studied in this course  

• Cause is often unknown
• Environmental Factors
• Radiation
• Chemical and thermal burns
• Trauma
• Herbicides
• Immunosupression
• Immunologic alterations
• Genetic syndromes (minority) 

• Locations
• 40% lower extremity
• 30% trunk and retroperitoneum
•  20% upper extremity
• 10% head and neck
• 1.4 male to 1 female
• 15% in children

• Accurate histologic typing for prognosis
• Grading of sarcomas (I-III)- reflects mitotic activity, necorsis, and differentiation
• Size, depth, stage, location determine prognosi
• Extremities have a better prognosis than retroperitoneal
•  Superficial tumors have better prognosis
• Metastasize to lug, bone
• Usually do NOT involve lymph nodes

• Smooth Muscle: Fascicles of eosinophilic spindle cells intersecting at right anles
• Fibrohistocytic: Short fascicles of spindle cells radiating from a central point (like spokes on a wheel) storiform
• Schwann Cell: Nuclei arranged in columns-palisading
• Fibrosarcoma: Herringbone
• Synovial sarcoma: Mixture of fascicles of spindle cells and groups of epithelioid cells-biphasic  

• Spindle Cells
• Rod-shaped, long axis twice as great as short axis
• Tumor Types
• Fibrous
• Fibrohistiocytic
• Smooth Muscle
• Schwann Cell
• Small Round Cells
• Size of a lymphocyte with a little cytoplasm
• Tumor Types
• Rhabdomyosarcoma
• Prmitive neuroectodermal tumor
• Epithelioid Cells
• Polyhedral cells wih abundant cytoplasm, nucleus is centrally located
• Tumor Types
• Smooth muscle
• Schwann cell endothelial
• Epithelioid Sarcoma 

• Accurate histologic diagnosis is crucial
• Make sure it is not lymphoma, or metastatic carcinoma
• Immunohistochemistry or confirm lineage
• High grade/High Stage = Poor outcome
• Superficial better than deep
• Extremities better than retroperitoneum 

• Fat cell lineage
• Most common adult soft tissue tumor
• Varients with fibrosis, vessels, spindle cells, pleomorphic cells, and marrow elements (myelolipoma)
• Usually encapsulated with mature fat cells
• Soft, mobile, and painless
• Cured by excision
• Benign 

• Common adult sarcoma in >40 (40-60) yr age group
• DOES NOT OCCUR IN YOUNG PEOPLE
• Fat cell lineage
• Arise as large tumors in deep tissues of proximal extremities and retroperitoneum
• May be well differentiated, myxoid, round cell, or pleomorphic
• Myxoid and round cells are on a spectrum
• Possess lipoblasts
• Vary from indolent (well differentiated) to aggressive with vascular metastases
• Recur locally unless adequately excised
• Can have necrotic areas, hemorrhagic areas  

• Fibrocytes cell lineage
• Non-neoplastic lesion usuall due to trauma (physical or ischemic)
• Plump reactive fibroblasts or primitive mesenchymal cells
• Develop suddenly and grow rapidly
• Mimic sarcomas with hypercellularity, mitoses, and primitive cells (history imperative)
• Include nodular fascitis and myositis ossificans
• Nodular Fasclitis 
• Trauma 15-20%
• Rapidly growing painful tumors of adults
• Volar apect of forearm, chest, and back
• Cellular, mitotically active plump immature fibroblasts
• Needs to be distinguished from other adult sarcomas: fibrosarcoma
• Myositis Ossificans 
• Trauma 50%
• MC: Young athletic
• Has metaplastic bone after 3 weeks
• Symptoms depend on stage
• Early: swollen and painful
• Late: Painless, hard, well-demarcated mass, may mimic sarcoma
• Fibroblastic proliferation with metaplastic bone
• Eventually tumor may turn completely to bone with a bone marrow space
• Cured by excision

• Tumors of myofibroblasts
• Superficial Types: 
• Dupuytren Contracture- Palmar variant
• Plantar Varient
• Peyronie disease- penile variant
• All more frequent in males
• Cause contractions and masses
• May recur after excision
• Deep Types  
• Desmoid Tumors
• Extra-abdominal and intra-abdominal types
• Involve muscles in trunk and proximal extremities, abdominal wall, mesentery and pelvic walls

• Rare
• Can occur anywhere including th retroperitoneum, thigh, knee, and distal extremities
• Unencapsulated
• Infiltrative
• Soft fish-flesh masses with hemorrhagic and necrosis
• Spindle cells in herringbone fashion to high cellular and pleomorphic with mitoses
• Aggressive-recurring in more than 50% and metastasizing in more than 25%
• Herringbone pattern on histology  

• Tumor is from the facultatice fibroblast: makes collagen (fibro) and resembles phagocytic cells (histiocytic)
• The faculative fibroblasts most closely resemble a fibroblast but this is not necessarily the cell of origin
• Ex. Benign fibrou histiocytoma AKA Dermatofibroma
• Common lesion of dermis and subcutis
• Usually mid life, simply excised
• Usually do not recur 
• Bland fibrohistiocytic cells in a storiform pattern
• Benign

• Infiltrative Dermal Neoplasm
• Now regarded as a well differentiated primary fibrosarcoma of the skin
• Slow growing, locally agressive
• Can Recurr
• Rarely metastasize
• Most frequently on trunk, protrude above skin surface, firm
• Storiform growth pattern
• Uncertain potential  

• Indicative of a clinically agressive lesion
• 30-50% recur and metastasize
• Even after wide excision
• Needs adjuvant radiotherapy or chemotherapy
• Deep and retroperotoneal  locations: poor outcome
• Large lesions, deceptively circumscribed
• May resemble fibromatosis
• Neoplastic cell is now recognized to be phenotypically a fibroblast
• Not considered to be a cell of origin
• Storiform or pleomorphic pattern

• Most common-benign muscle tumor (leiomyoma) in uterus, GI tract and skin
• Skeletal muscle tumors (not proliferations or nodular myositis), usually malignnt (rhabdomyosarcoma), benign tumor (rhabdomyoma) in heart 

• Rhabdomyoblasts in three patterns 
• Embryonal
• Pleomorphic- less common and controversial
• Alveolar
• Agressive
• Treated with surgery, chemotherapy, and radiation
• Most common childhood sarcoma
• Head, neck, GI are most common sites
• Not associated wtih normal skeletal muscles
•  In extremities it is associated with skeletal muscles

• Most common tumor of women (uterus)
• Arise in skin, nipples. scrotum, and labia
• May arise in deep soft tissue- not very common here
• May arise in arrector muscle
• Small (1-2 cm) tumor made up of spindle cells
• Aligned at right angles
• Little to no mitotic activity

• Adult soft tissue sarcoma (10-20% of total)
• W>M
• Dermis, deep extremities and retroperitoneum
• Present as painless firm masses
• Malignany biologic potential
• Excised superifical dermal lesions: Good outcome
• Non-resectable deep lesions- kill host
• Invade locally and metastasize
• Fascicles of malignant spindle cells arranged at right angles
• Cigar shaped nuclei
• Pleomorphic Nuclei
• Many mitosis

• Develop near large joints of extremities (65% in lower extremities) not from synovium
• Deep masses with biphasic tumor cells (epithelial-like and spindle), many are monomorphic
• Calcified concretions may be seen
• Can metastasize through blood and lymph vessels
• Most have a t(x;18) and fused genes (SYT-SSX)
• Limb-sparing therapy wtih 40% 5 year survival rate