Bone pathology for medical student

1. BONE PATHOLOGY III
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DEFINITION OF BONE JOINT
 Definition: A connection between two bones
 Type of bone joint:
I. Synovial joint
-Movable
-Contain cavity
-Eg: knee joint and elbow joint
II. Cartilaginous joint (bone-hyaline cartilage-fibrocartilage-hyaline cartilage-bone)
-Slightly moveable
-Eg: intervertebral disks and sternoclavicular joint
III. Fibrous joint (bone-dense fibrous tissue-bone)
-Fixed
-Eg: cranial sutures
STRUCTURES OF SYNOVIAL JOINT
 Structures of a synovial joint
i. Articular surface:
-Covered by hyaline cartilage (cartilage has a poor blood supply, so healing of a damaged cartilage is
poor)
-Function (s):
 Shock absorber
 Reduce friction between bones
-Functions of chondrocytes
 produce the matrix (cartilage)
 enzymes and cytokines that are involved in degradation of cartilage

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-Compositions of hyaline cartilage:
 Collagen type II (osteoid is collagen type I)
 Proteoglycans
 H2O
ii. Joint capsule
-Pain sensitive
-Lined by synovium
-Synovium + fibrous capsule = articular capsule
iii. Ligaments
-Bands of fibrous connective tissue
iv. Bursa
-Fibrous sac
-Function: Act as a cushion to ease movement in areas that are subject to friction
v. Synovium @ synovial membrane
-Lines all non-articular surfaces of the joint
-Lack of basement membrane to allow quick exchange of fluid between synovium and blood
-Two types of synovial cells:
 Type A synovial cells:
 macrophage-like
 Functions: phagocytic and production of hyaluronic acid
 Type B synovial cells:
 Fibroblast-like
 Functions: production of protein and collagen
vi. Synovial fluid
-Colour: colourless to pale yellow
-Clarity: transparent
-WCC in fluid: <200/mm3
-PMNs: <25%
-Glucose: nearly equal to blood
-Sterility: sterile (Gram stain result is negative)
-Functions:
 Lubrication
 Nourishment for cartilage

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CLASSIFICATION OF ARTHRITIS
A. OSTEOARTHRITIS
 Definition: Degenerative disease characterised by progressive erosion of articular cartilage
 Non-inflammatory process
 Most common type of rheumatic disease
 Common in elderly
 Classification of osteoarthritis:
I. Primary(idiopathic)
-elderly and overweight
-Sites: Weight-bearing joints (hips and knees) and interphalangeal joints (DIP and PIP)
-Some have familial pattern of primary generalised osteoarthritis
II. Secondary
-Any age
-Site: Damaged joint
-Causes:
o Trauma
o Rheumatoid arthritis
o Gout
o TB
o Acromegaly
o Haemochromatosis
o Deformity (eg dislocated hip)
ARTHRITIS
OSTEOARTHRITIS
ARTHRITIS RELATED TO INFECTIOUS AGENTS
(eg: Reiter's Disease)
ARTHRITIS RELATED TO IMMUNOLOGICAL DISEASE
(eg: Rheumatoid Arthritis and Seronegative
Spondyloarhtropathies)
ARTHRITIS RELATED TO CRYSTALS
(eg: Gout Arthritis and Pseudogout)
ARTHRITIS RELATED TO SYSTEMIC DISEASE

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 Pathogenesis:
I. Aging and mechanical ‘wear and tear’ effect (biomechanical stresses of weight-bearing joint over
time)
II. Genetic factor
III. Changes in the composition and mechanical properties of the cartilage:
o increased water + decreased proteoglycans
o chondrocytes produce IL-1, TNF-alpha and nitric oxide to:
 stimulate production of metalloproteinase to degrade the matrix
 inhibit production of collagen type II and proteoglycan
 Morphology of osteoarthritis (Primary changes)
I. Destruction of ARTICULAR CARTILAGE
-Chondromalacia (thinning and weakening)
-Cartilage fibrillation (fragmentation)
-Erosion
II. Exposure of subchondral bone plate
-Subchondral sclerosis (eburnation @ ivory)
-Cyst formation
-Small fractures (pathological fractures)
III. Osteophyte formation
-outward growth of bone at the margins of articular surfaces, derived from cartilage (so it is
formed by enchondral ossification!!)
-Two types of osteophytes:
 Heberden’s nodes
-Site: distal interphalangeal (DIP) joints
-EARLY manifestation of OA
 Bouchard nodes
-Site: proximal interphalangeal (PIP) joints
IV. Joint mice (detached fragments of bone pain and recurrent locking

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 Secondary changes in OA:
I. Synovium thickening + minimal inflammation
II. Muscle atrophy
III. Joint deformity (due to osteophyte and subluxation @ partial dislocation)
IV. Osteoporosis
 CPs:
I. Asymptomatic
II. Symptomatic
-Severe pain
-Morning stiffness
-Restricted movement
-Crepitus joint (crackling sound when joint is moved)
-Compression of nerve root by osteophytes
-Deformity
 Investigations:
I. Clinical (Hx and physical exam)
II. Radiography: X-ray modality
III. Lab: (samples: blood and synovial fluid aspirate, modalities: serology and microscopy)
-Negative serology
-Synovial fluid is clear and viscous + slightly high/normal cell count
 Tx:
I. Pharmaco:
-Glucosamine
-Chondroitin, a adenosylmethionine

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B. INFECTIOUS ARTHRITIS
 Route of transmission:
I. Haematogenous (most common)
II. Adjacent infective foci
III. Direct inoculation
-in local trauma
-in prosthetic insertion surgery
 Causative agents:
I. Staph. Aureus
-Most common in very young and old
-Most destructive
II. Haemophilus influenza type B
-Common in young children <2y/o
III. Gonorcoccus
-Common in healthy young and sexually-active individuals
IV. Streptococcus
V. E.coli
VI. Pseudomonas
VII. Salmonella
-Common in sickle cell disease patient
 CPs:
I. Acute joint pain
II. Swelling
III. Fever
IV. Decreased mobility

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 Investigations:
I. Lab: (sample: synovial fluid aspirate)
-Colour: yellow/green
-Clarity: purulent
-WCC: >50 000
-PMNs: >75%
-Glucose: less than blood
-Gram stain: result is positive
-Culture: result is positive
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TB ARTHRITIS
 Causative agent: mycobacterium
 Typical granulomatous inflammation
 Destructive arthritisankylosis and
deformity
 Cross cartilage barriers unlike other
bacterial infections
 Route of infection:
I. Adjacent TB osteomyelitis
II. Haematogenous
 Site (s):
I. Spine (most common) @Pott’s
disease
II. Hip joint
LYME’S ARTHRITIS
 By tick bites
 Causative agent: Borrelia burgdorferi

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C. ARTHRITIS RELATED TO IMMUNOLOGICAL DISEASE
a. RHEUMATOID ARTHRITIS
 Definition: Autoimmune systemic disorder that affects many organs such as joints, skin, heart,
lungs, eyes, lymph nodes, and marrow)
 Epidemiology:
-F>M
-Young or middle-aged
 Clinical course: insidious or remittent
 Criteria for RA: (four or more of the following)
I. Morning stiffness
II. Arthritis of 3 or more joints
III. Arthritis of hands
IV. Symmetrical
V. Rheumatoid nodules
VI. Serum rheumatoid factor (RF)
VII. Charateristics X-ray findings
 Pathogenesis:
I. Genetic susceptibility
-associated with HLADR4
-30% concordance between monozygotic twins
II. Microbial agents
-Parvovirus, mycobacteria, mycoplasma
-EBV
 EBV detected in synovium
 EBV and type II collagen share similar epitopes
 B cell produces RF when infected with EBV
III. Autoimmune reactions
-Type III hypersensitivity: immune complex formation (RF + Fc portion of IgG)
-Type IV hypersensitivity: CD4+ T cells mediated
-Cytokines (IL-1 and TNF-alpha) injury!
Rheumatoid factor
 Definition: IgM antibody that against Fc portion of IgG
 In 80% RA patients, <5% in elderly
 RF-IgG complex deposited in….
I. Synovial fluid and synovial membrane (synovium)
II. Extra-articular sites (heart, eyes, kidneys, lungs, skin
etc) by circulating around in the body
 Low specifity

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 Pathological features of RA:***
I. Synovial hyperplasia
II. Lymphocytes and plasma cells infiltration in synovium + lymphoid follicular formation
and occasionally PMNs in synovium
III. Fibrin
IV. Pannus formation: an organised inflammatory tissue within synovium that can erode
the articular surface
V. Subchondral cyst formation
VI. Juxta-articular erosion at the joint margin
VII. Fibrous ankylosis
 Morphology (primary changes) of RA joint
I. Classically affecting the SYNOVIUM of small joints of the hand
-PIP joints: swan-neck deformity, boutonniere deformity, ulnar deviation of fingers
-MCP joints: radial deviation of the wrist
II. Symmetrical
III. Polyarticular (more than 1 joint)
 Secondary changes of RA joint
I. Osteoporosis
II. Osteoarthritis
-degeneration of articular cartilage subsequently
III. Muscle wasting

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 Extra-articular manifestations:
I. Lungs
-Pulmonary fibrosis
-Pulmonary nodules
II. Eyes
-Uveitis
-Scleritis
III. Vasculitis
IV. Amyloidosis (AA type)
V. Skin
-Subcutaneous nodule
VI. Lymphadenopathy
VII. Sjogren’s syndrome
-Xerostomia (dry mouth)
-Keratoconjunctivitis (dry eyes)
VIII. Felty’s syndrome
-Splenomegaly
-Severe leucopenia and anaemia
-Sever longstanding rheumatoid arthritis
 Investigations:
I. Lab: (sample (s): blood and synovial fluid aspirate)
-Normochromic normocytic anaemia
-High ESR
-Positive RF
-Positive anti-CCP
-Positive other antibodies such as anti-DNA in 10-20% patients
 Tx:
I. Non-pharmaco tx:
-Surgery: joint replacement, subluxation of cervical spine
-Occupational tx
-Social tx

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II. Pharmaco tx:
-Non-biological drugs
 NSAIDs (to treat pain and to suppress immune system)
-Celebrex (COX-2 inhibitor)
 Steroid (intra-articular injection)
 Analgesics
-Tramadol or codeine (for moderate pain)
-Morphine (for severe pain)
 Gold
 Antimetabolites
-Methotrexate
-Azathioprine
-Cyclosporine
-Biological drugs
 Anti-TNFalpha -Adalimumab
-Infliximab
-Etanercept
 Anti-IL1 -Anakinra
 Anti-IL6 -Toclizumab
 Anti-CD20 -Rituximab
 Anti-CTLA4 -Abatacept
 Blocks production of leukotriene B4 and IL-
1
-Omega 3

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b. SERONEGATIVE ANKYLOSING SPONDYLOARTHROPATHIES
 Definition: A group of diseases with NEGATIVE RF and POSITIVE HLA-B27
 Site (s): sacroiliac joint and spine (sacroilitis and spondylitis)
 Example of disease:
I. Ankylosing spondylitis (Bamboo spine)
o Chronic inflammatory disorder of lumbar vertebrae and sacroiliac joints
o 90% positive for HLA-B27
o Young male
o Pathogenesis:
 -Autoantibodies against joint elements after an infection
o CPs (other than sacroilitis and spondylitis):
 -Peripheral arthritis
 -Uveitis
 -Aortic incompetence
 -Amyloidosis
II. Reiter’s disease
o 80% positive for HLA-B27
o Young male
o Pathogenesis:
-Autoimmune reactions because of…
 GU infection (Chlamydia)
 GI infection (Salmonella, Shigella, Yersinia, Campylobacter)
o CPs (a triad): JOINTS, GU TRACT, EYES
-Arthritis (knees, ankles and SPINE)
-Urethritis (male)/ cervicitis (female)
-Conjuctivitis (global redness of conjunctiva)
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D. ARTHRITIS RELATED TO CRYSTALS
a. GOUT
 Definition: Transient attacks of acute arthritis initiated by crystallization of urates around joint chronic
gout arthritis and tophi (large aggregate of urate crystals)
 Disorder of purine metabolism hyperuricaemia (serum urate level > 7mg/dl)
 Epidemiology:
-M>F
-Peak incidence 50s
-25% familial
 Site (s): Metatarsophalangeal joint of big toe (most common)
 Hyperuricaemia can be primary or secondary:
 Primary hyperuricaemia (90%)
 Risk factors:
-Age (>30s)
-Family history
-Alcohol consumption
-Obesity
 Secondary hyperuricaemia (10%)
 Excessive breakdown of nucleic acids (due to leukemia, multiple myeloma, cytotoxic dru
 Renal undersecretion (due to renal failure, diuretic drugs (affecting urea cycle of renal
tubule), salicylate and ethanol)
 Enzyme deficiency: reduced Hypoxanthine guanine phosphoribosyl transferase (HGPRT)
 Pathogenesis:
 Deposition of urate crystal on the surface of articular cartilage
-Interaction with leucocytes degeneration of articular cartilage
 Deposition of uric acid in tissue tophus formation
 Stages of gout:
I. Acute arthritis
II. Asymptomatic periods between attacks
III. Chronic arthritis:
-deposition of ureate in and around joints (tophi)
 Investigation:
I. Lab: (sample (s): synovial fluid aspirate and synovial biopsy and modalities: microscopy)
-Microscopy:
 Needle-shaped crystals + neutrophils (sample is fixed using alcohol and NOT formalin
because crystal is water-soluble and it will dissolve upon sample processing)

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 Complications: (Gouty Nephropathy)
I. Interstitial nephritis
II. Renal calculi (uric acid stone)
III. Renal failure
b. PSEUDOGOUT
 Definition: Deposition of calcium pyrophosphate crystal on articular cartilage (CPPD @
chondrocalcinosis)
 Epidemiology:
I. M=F
II. >50s
 Site (s): Knee, wrist and shoulders
 Classifications:
I. Primary (idiopathic)
II. Hereditary
III. Secondary
-Hyperparathyroidism
-Hypothyroidism
-Haemochromatosis (commonest)
-DM
 CPs:
I. Asymptomatic (until the crystals are shed into the joint space due to trauma or
spontaneously)
 Investigations:
I. Lab: (sample: synovial fluid aspirate and modalities : microscopy)
 Rhomboid crystals + neutrophils
E. ARTHRITIS RELATED TO SYSTEM IC DISEASE
HYPERTROPHIC OSTEOARTHROPATHY
 Features:
I. New bone formation at distal end of long bone, in metacarpal and
metatarsal bones, and in proximal phalanges
II. Arthritis of adjacent joint (eg MCP, PIP)
III. Clubbing of digits
 Patients usually have underlying disease (most commonly bronchogenic
carcinoma)
 Idiopathic cause is rare! And occasionally familial

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TUMOURS OF SOFT TISSUE
 Definition:
-Tumours of mesenchymal origin that are classified according to their histological differentiation
 Classifications:
I. Benign
II. Malignant (rare, M>F, occurs in organs and soft tissues)
-Primary
-Benign
 Risk factors:
I. Radiation
II. Chemical agent (venyl chloride and angiosarcoma)
III. Viruses
IV. Genetic (Li Fraumeni)
Type of soft tissue Benign Malignant
Adipose tissue Lipoma Liposarcoma
Smooth muscle Leiomyoma Leiomyosarcoma
Skeletal muscle Rhabdomyoma Rhabdomyosarcoma
Fibrohistiocytic cell Fibrous histiocytoma Malignant fibrous histiocytoma
Vascular Haemangioma Angiosarcoma
Peripheral nerve Neurofibroma Malignant peripheral nerve sheath
tumour
Tumour of uncertain histogenesis - Synovial sarcoma
 Prognosis:
I. Histological type
II. Grade
-Degree of differentiation
-Cellularity
-Pleomorphism
-Mitotic activity
-Presence of necrosis
III. Stage
IV. Location (superficial is a better prognosis)

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 Investigations:
I. Lab: (modalities: IHC, microscopy, molecular diagnosis)
 Histological examination
 IHC:
-Nearly all vimentin positive
-Leiomyosarcoma: desmin and actin positive
-Rhabdomyosarcoma: myoglobin positive
 Molecular diagnosis of sarcomas:
 GIST have a c-Kit mutations or PDGFR A mutations and treated with STI-571 (Gleevec)