Bone Pathology

Front 1

what kind of bone is this?

Back 1

E= epiphysis
GP= growth plate
M= metaphysis
D= diaphysis
A= apophysis

*Cortical bone
*Center region is cancellous (spongy) bone

Front 2

id

Back 2

Cortical compact bone and the trabeculae of cancellous (spongy) bone

Front 3

what is this?
discuss

Back 3

-Osteoblasts
*Synthesize type I collagen, proteoglycans and glycoproteins for bone matrix
*Line up on the edges of bone resembling columnar epithelium
*The new bone they are laying down is called osteoid which will then be calcified

Front 4

id/discuss

Back 4

-Osteoclasts
*Large, branched, motile, multinucleated cells
*Osteoclasts secrete substances which digest collagen and dissolve calcium crystals.

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id

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OBs on left
OCs on right

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id

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-Lamellar Bone
*Aka secondary bone
*Collagen fibers are arranged in an orderly fashion in lamellae. Either as parallel sheets or as concentric lamellae around a vascular channel.
More osteocytes and more mineral content than in woven bone.

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left-lamellar bone
right- woven bone

*seen thru polarized light

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-woven bone
Aka primary bone – temporary, first formed. Either replaced by lamellar bone or resorbed to form marrow cavity. Found in growing skeletons under age 5 and (as here) in repair of fractures.

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SPECTRUM OF BONE DISEASES:

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*Congenital anomalies (dysostoses)
*Disorders associated with bone or cartilage growth/maintenance of normal matrix components (dysplasias)
*Acquired diseases of bone development
*Fractures
*Osteonecrosis (avascular necrosis)
*Osteomyelitis

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DYSOSTOSES:

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*Congenital Abnormalities
-Aplasia, e.g. absent digit or rib, caudal regression
-Supernumerary bones, e.g. polydactyly, cervical rib
-Fusion, e.g. fused ribs or cranial bones
-Often due to mutations in homeobox genes

Front 11

Micromelia-
Rhizomelia-
Acromelia-
Phocomelia-

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-Micromelia – shortness of one or more limbs
-Rhizomelia – shortening of the proximal segment of the limbs
-Acromelia shortening of the distal segment of the limbs
-Phocomelia – hands and feet are attached to shortened arms and legs (Thalidomide)

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PHOCOMELIA due to thalidimide exposure.

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Osteogenesis Imperfecta:

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*Dysplasia*
*Brittle bone disease
*A group of hereditary diseases
*Caused by mutations causing defective alpha 1 and alpha 2 chains in type I collagen
*The bones are fragile and easily fractured
*Some infants and children present in such a way as to raise the question of battered child syndrome

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type 1 OI:

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*Type I OI patients are subject to fractures but can live a normal lifespan
*They have characteristic blue sclerae and can have hearing loss and misshapen teeth

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BLUE SCLERAE in type 1 OI

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OI (TYPE I)

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What genetic defects cause type 2 OI?

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*The phenotype can be caused by mutation in either the COL1A1 gene on chromosome 17 or the COL1A2 gene on 7

*As a result of faulty collagen, I bone formation is markedly impaired

*Type II OI – Fetal, Neonatal, Lethal

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why is type 2 OI so bad?

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*The fetus suffers many fractures in utero
*The newborn has pulmonary hypoplasia as a result of chest compression
*Growth zones are normal but spicules in metaphysis are thin and cartilaginous
*Type II OI – Fetal, Neonatal, Lethal

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*Osteogenesis Imperfecta Congenita
*type 2
*white areas along ribs--these are fractures; chest collapses
*Type II OI – Fetal, Neonatal, Lethal
*"accordion" limbs

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-radiograph of type 2 OI
*Type II OI – Fetal, Neonatal, Lethal

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*Type II OI – Fetal, Neonatal, Lethal
-on the left you can see fractures that are starting to heal.

Front 22

discuss

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*One of the more common forms of dwarfism; autosomal dominant but many cases arise de novo
*The ambulatory individuals you see are heterozygotes
*Homozygotes suffer fetal or neonatal death
*A mutation which activates FGFR3, which inhibits chondrocyte proliferation, resulting in disorganized, hypoplastic growth plates

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Discuss Thanatophoric Dysplasia:

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*Lethal
*Mutations in FGFR3 which differ from those in achondroplasia
*As in homozygous achondroplasia the chest is underdeveloped and the neonate dies of pulmonary hypoplasia...like in OI 2.
*Characteristic “telephone receiver” femora
*There is a variant with a cloverleaf skull

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Thanatophoric Dysplasia
-"telephone receiver" limbs

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Growth zone – disorganized and retarded
-in Thanatophoric Dysplasia

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Discuss Osteopetrosis:

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*Marble bone disease AKA Albers-Schönberg disease
*Genetic diseases which cause malfunction of osteoclasts resulting in improper bone remodeling; osteoclasts may be normal numerically
*Bones are solid as stones but fracture readily
*Mutations result in interference with acidification of osteoclast resorption pit (CA2 gene--carbonic anhydrase)

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OSTEOPETROSIS

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*OSTEOPETROSIS
1- cortex
2- medulla has been replaced by material that looks like primary spongiosa

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OSTEOPOROSIS:

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*Diminished bone mass and progressive discontinuity of bone microarchitecture, leading to structural failure and susceptibility to fracture.

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1˚ and 2˚ osteoporosis classification:

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Primary:
-Postmenopausal
-Senile
-Idiopathic

Secondary:
-Endocrine disorders
-Neoplasia
-Gastrointestinal
-Drugs
-Disuse (i.e. cast)
-Others

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t-score:

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*T-Score: Difference between a patient’s bone mineral density (BMD) and BMD at same site in healthy young adults matched for gender and ethnicity
*T > -1.0 (Normal)
*T < -2.5 (Osteoporosis)
*T score between normal and osteoporosis = osteopenia

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Relationshit b/t peak bone mass and osteoporosis:
-discuss factors leading to osteoporosis:
-what cytokines are involved?

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*RANK=receptor activator for nuclear kappa B; expressed on surfaces of cells that give rise to osteoclasts

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-OSTEOPOROSIS (SPINE)
-you can see the collapse of one of the vertebral bodies (think about shrinking, stooping old people)

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L: normal
R: Osteoporotic vertebral body shortened by compression fractures, compared with a normal vertebral body. Note that the osteoporotic vertebra has a characteristic loss of horizontal trabeculae and thickened vertical trabeculae.

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L: normal
R: osteoporosis
*affects spongy bone more than cortical bone--hip fractures, vertebral bodies

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NORMAL ILIAC CREST
-all trabeculae are interconnected

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iliac crest in OSTEOPOROSIS

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discuss PAGET DISEASE:

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*Increased and disordered bone remodeling
*Mono- or poly-ostotic (# sites involved)
*Pelvis (70%), femur (55%), lumbar spine (53%), skull (42%), tibia (32%)
*Increased prevalence with age (rare before 55 years)

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-poly-ostotic Paget Disease
-frontal thickening

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*poly-ostotic Paget Disease
*bowed legs

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-PAGET DISEASE
*Focal osteolysis (lucency in the bone)
*Coarsening of trabecular pattern
*Bone expansion
*Cortical thickening

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-PAGET DISEASE RADIONUCLIDE SCAN
-done to localize disease sites

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PAGET DISEASE
note skull thickening

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EARLY PAGET DISEASE
-lots of blood vessels (accounts for heat you can feel in palpation
-note the number of multinucleate osteoclasts
-lots and lots of bone resorption going on

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What are the 3 phases of Paget's disease?

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3 phases
Osteolytic
Osteoclastic-osteoblastic with latter predominant
Osteosclerosis (burnt-out)

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-Mosaic Pattern in Paget's disease.
-arrows point to basophilic cement lines

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Pathogenesis of Paget Disease:

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*Osteitis Deformans, a disease of the elderly

*Caused by osteoclast dysfunction

*Bone becomes enlarged and is subject to easy fracture

*Involved bone subject to many tumors, benign and malignant (e.g. giant cell tumor, osteosarcoma, fibrosarcoma)

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Genetic components of Paget Disease:

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*15% have + family history
*Mutations of SQSTM1 gene that encodes p62
*Mutations in 50% patients with familial and 5-10% patients with sporadic disease
*p62 plays a key role in function of osteoclasts
*Other genes involved in osteoclast function may also be involved

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L: normal
middle: rickets
R: rickets

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OSTEOMALACIA

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Hyperparathyroidism:

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*Increased osteoclastic activity
*Bone resorption – cortical bone more than cancellous bone
*Microfractures lead to "brown tumors" as a result of hemorrhage and hemosiderin (Fe)
*Severe disease leads to osteitis fibrosa cystica

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*Hyperparathyroidism – note osteoclasts dissecting a trabeculum. Note that osteoblast activity is also increased. The cortices will be thin and the dissections will produce a railroad track pattern on x-ray.
*Giant cells at arrow

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A brown tumor in a rib in a patient with hyperparathyroidism. These lesions can undergo cystic degeneration.

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sequence of events in bone healing:

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*Hematoma 
*Organization 
*Soft tissue callus (pro-callus) 
*SUBPERIOSTEAL woven bone (produced by activated osteoprogenitor cells) 
*Cartilage formation (from activated mesenchymal cells)
*ENDOCHONDRAL OSSIFICATION (bony callus)  *Remodeling of bone

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FRACTURE SITE AT 1-2 WEEKS
-blue spot on the right is cartilage

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Woven Bone
*Aka primary bone – temporary, first formed. Either replaced by lamellar bone or resorbed to form marrow cavity. Found in growing skeletons under age 5 and (as here) in repair of fractures.

Front 57

NON-UNION OF FRACTURE SITES:

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*Inadequate immobilization leads to delayed union or non-union
*Pseudoarthrosis (central portion of callus undergoes cystic degeneration and can become lined by synovium-like cells)

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NON-UNION FRACTURE SITE- Pseudoarthrosis

Arrows =Pseudoarthrosis

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Avascular Necrosis:

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*Osteonecrosis/ischemic necrosis
Medullary region of bone (cancellous bone and marrow).

*Often asymptomatic

*Subchondral region. Can cause severe osteoarthritis as a result of articular collapse (Responsible for > 10% of joint replacement surgeries)

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causes of Avascular Necrosis:

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Fracture
Infection
Corticosteroids
Dysbarism (bends)
Radiation Therapy
Connective Tissue Disorders
Pregnancy
Gaucher Disease
Sickle Cell Anemia
Alcohol Abuse
*lots of causes

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Femoral head with avascular necrosis (osteonecrosis). Note subchondral wedge of necrotic yellow tissue (arrows).

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Creeping substitution is the simultaneous removal of necrotic bone (a) and replacement with newly formed, woven bone (b). The more basophilic woven bone is termed juxtaposed bone.

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Pathology of Osteomyelitis:

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*Acute, subacute or chronic
*An acute inflammatory reaction is induced
*Bacteria spread within the shaft and may reach the periosteum
*In children subperiostial abscesses may develop
*Bone dies forming a sequestrum
*The periosteum may rupture forming a draining sinus

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central whitish area= dead bone filled with neutrophils

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Illustration of a draining sinus tract with the dead sequestrum (dead bone fragment) and the involucrum around it.

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sequestrum=

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dead bone fragment

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Acute osteomyelitis
Note giant cells, neutrophils
arrow points to necrotic bone

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SUBACUTE AND CHRONIC OSTEOMYELITIS
arrow points to necrotic bone

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CHRONIC OSTEOMYELITIS (HEALING)
Viable bone overlying necrotic bone
Arrows = viable bone

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how does osteomyelitis develop?

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*Can be related to systemic infection or exclusively in bone
*Viruses, protozoa, fungi, bacteria (including syphilis and TB)
*Pyogenic osteomyelitis is almost always secondary to bacteria
*The organisms reach bone via
Hematogenous route
Local extension
Direct implantation
*S. aureus is the most common cause

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*SQUAMOUS CELL CARCINOMA / CHRONIC OSTEOMYELITIS

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BONE TUMOR types:

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Hematopoietic
Chondrogenic
Osteogenic
Fibrogenic
Neuroectodermal
Notochordal
Unkown origin
Metastatic (Secondary)

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Bone Forming Tumors - Osteoma:

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*Usually solitary
*Can be multiple as in this case of Gardner syndrome
*An 18 year old with visible mass as seen
*Multiple masses on reconstruction CT scan
*Had severe dental problems
*Histology – composite of woven and lamellar bone in a cortical pattern

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Osteoma

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Osteoma
multiple= Gardner syndrome

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Osteoid Osteoma:

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*Occur in the young, especially males
*Less than 2 cm in diameter
*Histology – haphazardly arranged trabeculae of woven bone lined by osteoblasts
*The neoplastic osteoblasts have benign cytological features

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Osteoid Osteoma
*Occur in the young, especially males
*Less than 2 cm in diameter
*Histology – haphazardly arranged trabeculae of woven bone lined by osteoblasts
*The neoplastic osteoblasts have benign cytological features

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*Osteoid Osteoma
*X-ray of an intracortical osteoid osteoma. The dark lesion is the tumor (the nidus). In the center of the lesion is mineralization. Reactive bone formation surrounds the lesion.

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*Osteoblastoma
*Benign tumor with similar histology to osteoid osteoma but tumor > 2cm
More likely to involve spine

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Osteoblastoma

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Benign tumor with similar histology to osteoid osteoma but tumor > 2cm
More likely to involve spine

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Osteosarcoma:

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*Malignant bone forming tumor

*Bimodal age distribution
-Biggest peak in patients under 20
-Smaller peak in older patients most of whom have a pre-existing condition such as Paget, bone infarct, history of radiation or chronic osteomyelitis
-Most commonly arise in metaphysis of long bones – one half at the knee

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major sites of origin of osteosarcoma?

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Major sites of Origin – note large percentage near the knee.

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Genetics in osteosarcomas:

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Frequent mutations of 2 genes – RB and p53

Patients with germline mutations of RB have 1000 fold increase in incidence of osteosarcoma

Patients with germline mutation of p53 (Li-Fraumeni syndrome) also susceptible

For the dog lovers – high incidence in large dogs. This together with the fact that most lesions are associated with growth plates may suggest that normal proliferation of osteoblasts may lead to mutations in some individuals.

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*Osteosarcoma
*Grossly, gritty gray-white, areas of hemorrhage, sometimes cystic degeneration. Can destroy cortex and extend into soft tissue.

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CLASSIC Osteosarcoma (osteoid in upper right)

Malignant tumor cells producing bone (osteoid). Contrast these malignant cells with the benign cells of osteoid osteoma and osteoblastoma. In some cases malignant cartilage is also produced. The tumor is then called a chondroblastic osteosarcoma.

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prognosis and treatment of osteosarcoma:

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*Metastases occur – mostly to the lung (20% at diagnosis) but also to other bone and elsewhere including brain.

*Until the past few decades osteosarcoma was treated by amputation. Presently, a diagnosis is made and the patient is treated with chemotherapy followed by limb-sparing surgery. In the past amputation era, 5-yr survival was 10-20%. Now, cure rates are reported to be up to 80-90%.

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Cartilage-Forming Tumors:

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*Majority of bone tumors; benign tumors are more common than malignant tumors.
*Usually produce hyaline cartilage
*Robbins also refers to myxoid cartilage; I believe this refers to myxoid degeneration of hyaline cartilage
*Occasionally fibrocartilage or elastic cartilage is formed.

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Osteochondroma:

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*An exostosis with cartilage capping attached to the bone by a stalk
*Most are solitary but there is a multiple hereditary exostosis syndrome
*Appear mostly in childhood to early adulthood
*Only in bones of enchondral origin and arise near a growth plate

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A. X-ray showing an osteochondroma arising from the posterior aspect of the tibia
B. CT scan – fibula to the left, tibia to the right and tumor in the middle attached to the tibia. Note continuity of tumor with tibia.
C. A sessile osteochondroma with a cap of hyaline cartilage showing enchondral ossification
D. Cartilage cap – disorganized growth plate

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Chondroma:

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*Tumors of hyaline cartilage

*Arise in enchondral bones
-Enchondromas arise in medulla
-Subperiostal or juxtacorical chondromas arise on surface of bone

*Ollier syndrome
-Multiple enchondromas

*Maffuci syndrome
-Enchondromatosis associated with soft tissue hemangiomas

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ENCHONDROMA

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Chondroma
An enchondroma showing a nodule of hyaline cartilage surrounded by a thin layer of reactive bone
In the syndromes there may be sufficient atypia in the cells to raise the question of chondrosarcoma.

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chondrosarcoma:

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*A group of malignant cartilage-forming tumors of bone
*Location - Intramedullary vs juxtacortical
*Histology
-Conventional (hyaline and/or myxoid) – will discuss
-Clear cell
-Dedifferentiated
-Mesenchymal
(Regarding the latter 3 above just be aware there are such things)

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Conventional Chondrosarcoma

Intramedullary tumor growing through the cortex to form a soft tissue mass

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Conventional Chondrosarcoma

Anaplastic chondrocytes

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Fibrous Tumors:

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*Fibrous Cortical Defects – very common
-may be developmental defects

*When large, develop into non-ossifying fibromas

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*Fibrous Cortical Defect
Storiform (cartwheel) pattern
of benign spindle cells and occasional osteoclast-type giant cells

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Fibrous Dysplasia:

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*Benign tumor or tumors - ? neoplasm ? hamartoma – all bone elements are present but normal bone does not develop.

*Monostotic – most common
*Polyostotic – one quarter of cases

*Polyostotic with syndrome – 3%
-McCune-Albright with sexual precocity, hyperthyroidism, pituitary adenomas secreting growth hormone, adrenal hyperplasia
-Mutations in the GNAS gene

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*Note fibroblast like cells (pink on left pic) and lots of woven bone (look disarrayed in polarized light)

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Fibrosarcoma:

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*Mostly in middle-aged and elderly
*Usually arise denovo but, just as in osteosarcoma, some develop in prior lesions such as bone infarcts, previously radiated tissue or Paget disease.
*Can also arise in previously benign tumors.

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fibrosarcoma

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fibrosarcoma- herringbone pattern

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Miscellaneous Tumors:

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Ewing sarcoma/Primitive Neuroectodermal Tumor
Giant Cell Tumor
Aneurysmal Bone Cyst

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EWING SARCOMA:

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*6-10% of primary bone tumors
*2nd most common bone sarcoma of children
*Diaphysis of long tubular bones and pelvis
*Pain, fever, increased sedimentation rate
*11;22 (q 24: q 12) Translocation
EWS (22) and FLI1 (11)

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ewing sarcoma

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ewing sarcoma
-cells have a neural phenotype
-cells are small and round

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Giant Cell Tumor:

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Giant cell tumor replaces most of the femoral condyle and extends to the subchondral plate.

These tumors are locally aggressive and rarely metastasize to the lung.

Aka Osteoclastoma

“Benign” tumor of midlife

Large red-brown tumors

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Giant Cell Tumor

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Giant Cell Tumor
Aka Osteoclastoma
“Benign” tumor of midlife
Large red-brown tumors

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Aneurysmal Bone Cyst:

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*Tumor with multiloculated cysts filled with blood
*All age groups but mostly children
*Lesions appear aggressively lytic on x-ray but behave benignly
*17p13 translocations

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Aneurysmal Bone Cyst

Blood-filled central space. Wall contains proliferating fibroblasts, osteoclast-like giant cells and reactive woven bone.

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Aneurysmal Bone Cyst