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🦴 MUHS 2nd MBBS Pathology - Bone Pathology (Exam Notes)

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TOPIC 1: OSTEOMYELITIS

Definition

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Pyogenic Osteomyelitis

Etiology / Causative Organisms

Exam tip: S. aureus is most common because its cell wall proteins (e.g., fibronectin-binding proteins) bind to bone matrix components such as collagen, facilitating adherence.

Route of Infection (3 routes - imp for exams)

1. Hematogenous spread (most common in children)
2. Extension from contiguous site (e.g., diabetic foot ulcer)
3. Direct implantation after compound fractures or orthopedic procedures

Age-Related Site of Infection

• Neonates: Metaphysis AND epiphysis (metaphyseal vessels cross the growth plate)
• Children: Metaphysis (rich blood supply, sluggish flow, no phagocytes)
• Adults: Epiphysis and subchondral region (after growth plate closure)

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GROSS FEATURES of Pyogenic Osteomyelitis

Acute Phase

• Pus formation in medullary cavity
• Suppurative inflammation -> bone necrosis within 48 hours
• Spread via Haversian canals to periosteum
• Subperiosteal abscess formation (periosteum loosely attached in children)
• Rupture of periosteum -> soft tissue abscess -> draining sinus to skin

Chronic Phase - Key Gross Terms (MUST KNOW FOR EXAM)

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MICROSCOPIC FEATURES of Pyogenic Osteomyelitis

Acute Phase (first 48 hours)

• Neutrophilic infiltration of medullary cavity
• Necrosis of bone cells and marrow
• Bacteria proliferating in marrow spaces

Subacute Phase (1-2 weeks)

• Chronic inflammatory cells (lymphocytes, plasma cells, macrophages) appear
• Cytokines stimulate osteoclastic bone resorption
• Fibrous tissue ingrowth begins
• Reactive bone deposition at periphery

Chronic Phase

• Marrow fibrosis
• Sequestrum - dead bone with empty lacunae (osteocytes absent)
• Dense lymphocytic and plasma cell infiltrate
• Granulation tissue with new bone formation (involucrum)
• Draining sinus tracts lined by squamous epithelium

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CLINICAL COURSE

Acute Presentation

• Systemic: fever, chills, malaise, leukocytosis
• Local: throbbing pain, tenderness, swelling over affected bone
• Infants: may present with only unexplained fever
• Adults: localized pain

Investigations

• X-ray: lytic focus of bone destruction + reactive bone (changes appear 10-14 days after onset)
• MRI - most sensitive and specific early on
• Blood cultures + bone biopsy for microbial identification
• ESR and CRP elevated

Treatment

• Antibiotics + surgical drainage

Complications (5-25% fail to resolve - become chronic)

1. Pathologic fracture
2. Septic arthritis (if epiphysis involved - especially in infants)
3. Draining sinus with squamous cell carcinoma risk (Marjolin's ulcer)
4. Secondary (reactive) amyloidosis
5. Endocarditis, sepsis
6. Sarcoma in infected bone (rare)
7. Osteomyelitis may remain dormant for years and flare up later

Exam Mnemonic for Complications: P-S-D-A-E-S = Pathologic fracture, Septic arthritis, Draining sinus (SCC), Amyloidosis, Endocarditis/sepsis, Sarcoma

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TOPIC 2: PRIMARY BONE TUMOURS - Classification + Osteosarcoma

Classification of Primary Bone Tumours

TABLE: Classification of Primary Bone Tumours (MUHS Exam Table)

Key principle: Benign tumors outnumber malignant ones. In OLDER ADULTS, a bone tumor is more likely to be MALIGNANT (or metastatic).

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OSTEOSARCOMA (Osteogenic Sarcoma)

Definition

Epidemiology

• Bimodal age distribution:
  • 1st peak: 75% before age 20 (adolescent growth spurt) - primary osteosarcoma
  • 2nd peak: Older adults - secondary osteosarcoma (in setting of Paget disease, bone infarcts, prior radiation)
• M:F = 1.6:1 (males more commonly affected)
• Location: Metaphysis of long bones - 50% around the knee (distal femur > proximal tibia > proximal humerus)

Predisposing Factors (Secondary Osteosarcoma)

• Paget disease of bone
• Bone infarcts
• Prior radiation therapy
• Germline RB mutations (1000x increased risk)
• Li-Fraumeni syndrome (TP53 mutations)

Molecular Pathogenesis

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RADIOLOGICAL FINDINGS of Osteosarcoma

• Large, destructive, mixed lytic and sclerotic mass with infiltrative margins
• Codman triangle (MOST IMPORTANT SIGN):
  • Periosteum is lifted by tumor -> triangular wedge of reactive subperiosteal bone = Codman triangle
  • Indicates aggressive tumor but is NOT pathognomonic (also seen in Ewing sarcoma, infection)
• Sunburst pattern - bone formation extending into soft tissue in radiating spicules
• Tumor confined to metaphyseal side of growth plate (does not cross epiphyseal plate)
• Extension into soft tissue frequently seen

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GROSS FINDINGS of Osteosarcoma

• Bulky tumor in the metaphysis
• Gritty, tan-white cut surface (due to calcified/ossified areas)
• Areas of hemorrhage and necrosis (giving brownish discoloration)
• Cortical destruction - breaks through cortex and invades soft tissue
• Intramedullary spread - infiltrates and replaces marrow
• Subperiosteal expansion prominent
• Epiphyseal plate usually NOT crossed (tumor stays in metaphysis)
• Infrequently, tumor may penetrate the epiphyseal plate and enter the joint

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MICROSCOPIC (HISTOPATHOLOGY) FINDINGS of Osteosarcoma

Key Histological Features:

1. Malignant tumor cells with pleomorphism
   • Large hyperchromatic nuclei
   • Bizarre tumor giant cells
   • Abundant mitoses including abnormal (bipolar/tripolar) mitotic figures
2. Production of osteoid (DIAGNOSTIC CRITERION)
   • Fine, lacelike unmineralized osteoid OR broad sheets OR primitive trabeculae
   • Malignant cells must be seen producing the osteoid - this is the sine qua non of diagnosis
3. Extensive necrosis
4. Intravascular invasion (lymphovascular invasion)
5. Preexisting lamellar bone bridged by lacelike osteoid ("bridges" preexisting bone)

Important Histological Variants

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CLINICAL COURSE of Osteosarcoma

Presentation

• Painful, progressively enlarging mass in the metaphysis of a long bone
• Often adolescent with knee pain / swelling
• Pathologic fracture may be the first sign

Behavior

• All osteosarcomas assumed to have occult metastases at diagnosis
• Metastasizes hematogenously to: Lungs > bones > brain > other sites

Treatment

• Neoadjuvant chemotherapy (pre-operative) + Surgery (limb salvage or amputation) + Post-operative adjuvant chemotherapy
• Key chemotherapy agents: Doxorubicin, Cisplatin, Methotrexate (high-dose), Ifosfamide

Prognosis

• 5-year survival: ~70% in patients without overt metastases at diagnosis
• With clinically evident metastases, recurrent disease, or secondary osteosarcoma: 5-year survival <20%
• Histologic response to neoadjuvant chemotherapy is the best prognostic indicator

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TOPIC 3: RHEUMATOID ARTHRITIS

Definition

• Prevalence: 0.25-1% of the population
• F:M = 3:1 (three times more common in females)
• Peak incidence: 3rd to 5th decades of life

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Pathogenesis

Key Mechanism

• Initiated by CD4+ helper T cells reacting to a joint antigen (collagen, citrullinated peptides)
• Molecular mimicry: citrullinated vinculin mimics microbial epitopes -> presented by HLA-DR4
• HLA-DR4 allele strongly associated with ACPA-positive RA

Key Inflammatory Mediators

Autoantibodies

• ACPA (Anti-citrullinated peptide antibody): Present in 70% of RA patients - diagnostic marker
• Rheumatoid Factor (RF): IgM or IgA antibodies against Fc region of IgG; present in 80% of RA patients
  • RF deposits in joints as immune complexes
  • NOT specific to RA (also present in some healthy individuals and other diseases)
• ~20% of patients are seronegative (no RF or ACPA)

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MORPHOLOGY (Histopathology)

Joint Changes (Synovium)

1. Synoviocyte hyperplasia and proliferation (synovial lining becomes multilayered)
2. Dense inflammatory infiltrates - CD4+ T cells, B cells, plasma cells, macrophages, dendritic cells; lymphoid follicles with germinal centers
3. Increased vascularity (angiogenesis)
4. Fibrin-rich exudate with neutrophils on synovial and joint surfaces
5. Osteoclastic activity in subchondral bone -> periarticular erosions and subchondral cysts

PANNUS (KEY TERM - MUST KNOW)

Pannus = A mass of edematous synovium + inflammatory cells + granulation tissue + fibroblasts that grows over and erodes the articular cartilage.

• Pannus destroys articular cartilage
• In advanced disease, pannus bridges apposing bones -> fibrous ankylosis
• Fibrous ankylosis eventually ossifies -> bony ankylosis (joint fusion)

Rheumatoid Nodules

• Infrequent manifestation
• Located subcutaneously over: forearm, elbows, occiput, lumbosacral area
• Gross: Small, firm, nontender, oval masses
• Micro: Central zone of fibrinoid necrosis surrounded by palisaded macrophages (activated), with lymphocytes and plasma cells at periphery
• Resemble necrotizing granulomas

Extraarticular Manifestations

• Skin: Rheumatoid nodules, vasculitis
• Lungs: Interstitial lung disease, rheumatoid nodules, pleural effusion
• Heart: Pericarditis, rheumatoid nodules in myocardium
• Vessels: Leukocytoclastic vasculitis
• Eyes: Uveitis, keratoconjunctivitis sicca (Sjogren overlap)

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CLINICAL FEATURES of Rheumatoid Arthritis

Onset

• Insidious: malaise, fatigue, generalized musculoskeletal pain over weeks-months
• Then joints become involved

Joint Distribution (Symmetric Polyarthritis)

• Hands and feet first -> wrists, ankles, elbows, knees
• MCP (Metacarpophalangeal) and PIP (Proximal Interphalangeal) joints involved
• (Unlike OA which affects DIP joints)
• Symmetric involvement - bilateral

Symptoms

• Morning stiffness lasting >1 hour (key distinguishing feature from OA)
• Warm, swollen, painful joints
• Waxing and waning course
• Progressive joint enlargement and decreased range of motion

Deformities (Chronic RA - Exam Favourites)

Radiographic Hallmarks

• Joint effusions
• Juxtaarticular osteopenia (periarticular bone loss)
• Erosion and narrowing of joint space
• Loss of articular cartilage

Diagnosis

• ACPA positive (~70%)
• Rheumatoid factor positive (~80%)
• 20% are seronegative - diagnosis by clinical/radiographic findings
• ACR/EULAR criteria used

Treatment

• NSAIDs (symptomatic)
• Corticosteroids
• DMARDs: Methotrexate (cornerstone)
• Biologic agents: TNF antagonists (Infliximab, Etanercept, Adalimumab) - most important advance; not curative, must be maintained
  • Risk: Reactivation of latent TB with anti-TNF therapy
• Other biologics: Anti-IL-6 (Tocilizumab), Anti-CD20 (Rituximab), CTLA4-Ig (Abatacept)

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Comparison: RA vs OA (MUHS Exam Favourite Table)

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QUICK REVISION BOXES (Exam Points)

Osteomyelitis - Must Remember

Sequestrum = dead bone | Involucrum = new bone around sequestrum | Cloaca = opening in involucrum Most common organism = S. aureus Site in children = Metaphysis Most sensitive investigation early = MRI

Osteosarcoma - Must Remember

Most common primary malignant bone tumor (excluding hematopoietic) Age peak = adolescents | Site = distal femur / proximal tibia (around knee) X-ray = Codman triangle + sunburst pattern | Gross = gritty, tan-white, hemorrhagic Micro = lacelike osteoid from pleomorphic malignant cells + abnormal mitoses Prognosis = 70% 5-year survival with chemotherapy + surgery (without metastases) Genes = RB (70%), TP53, MYC amplification

Rheumatoid Arthritis - Must Remember

Autoimmune | F:M = 3:1 | Peak 30-50 yrs Key lesion = PANNUS (synovium + inflammatory cells + granulation tissue + fibroblasts) Antibodies = RF (80%) + ACPA (70%) Histology = synoviocyte hyperplasia, lymphoid follicles, fibrinoid necrosis (nodules) Deformities = ulnar deviation, swan-neck, boutonniere Treatment = MTX + TNF antagonists | Morning stiffness >1 hr is key feature Complications = fibrous/bony ankylosis, AA amyloidosis, atlantoaxial subluxation (C1-C2 cervical spine - dangerous!)

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