The Musculoskeletal System

The skeleton is made of cartilage and bone.
Cartilage helps in growth and repair of bone and forms joints.
Bone provides support, movement, and acts as a calcium reservoir.
Human body contains 206 bones which can be long, flat, or tubular.

Normal Structure of Bone

Two Types of Bone:

Cortical (Compact) Bone – 80% of skeleton
- Dense outer shell
- Strong and rigid
- Contains osteons with Haversian canals
Trabecular (Cancellous) Bone – 20% of skeleton
- Spongy with bone trabeculae
- Involved in mineral balance

Histology of Bone

Bone Cells and Matrix:

Osteoblasts
- Bone-forming cells
- Produce bone matrix (osteoid)
- Marker: ↑Alkaline Phosphatase
- Active in growth, fracture healing
Osteocytes
- Mature osteoblasts trapped in matrix
- Reside in lacunae
- Help maintain bone
- Woven vs. Lamellar Bone:
  - Woven bone = immature, random collagen (children, fractures)
  - Lamellar bone = mature, organized collagen (adults)
Osteoclasts
- Multinucleated, bone-resorbing cells
- Origin: Macrophages
- Found in Howship’s lacunae
- Marker: ↑Acid Phosphatase
Osteoid Matrix
- 90–95% collagen type I
- Contains hydroxyproline, hydroxylysine
- Can be woven or lamellar depending on synthesis rate

Bone Formation and Resorption

Bone is dynamic, constantly remodeled by:
- Osteoblasts – Form bone (deposition)
- Osteoclasts – Break bone (resorption)
Ossification types:
1. Membranous Ossification: Direct from collagen (e.g. skull bones)
2. Endochondral Ossification: Via cartilage stage (e.g. long bones)

Bone Matrix Formation:

Starts with uncalcified osteoid
Mineralized in 12–15 days
Mineralized matrix stains black (von Kossa (special histological staining method used to detect calcium deposits)), unmineralized is eosinophilic

Normal Structure of Cartilage

Avascular: No blood vessels, nerves, or lymphatics
Components:
1. Cartilage Matrix
  - 80% water
  - 20% collagen type II & proteoglycans (glycosaminoglycans: chondroitin sulfate & keratan sulfate)
  - Functions: Lubrication, shock absorption
2. Chondrocytes
  - Derived from mesenchymal cells
  - Mature cartilage cells

Types of Cartilage

Hyaline Cartilage
- Most common
- Found in joints, nose, trachea, growth plates (epiphyseal plate—is a hyaline cartilage plate located between the epiphysis and metaphysis of long bones in growing individuals)
- Seen in fracture callus and cartilage tumors (Cartilage tumors are neoplastic proliferations of chondrocytes)
Fibrocartilage
- Hyaline cartilage with extra collagen II
- Found in intervertebral discs, ligaments (dense regular connective tissue structures that connect bone to bone)
Elastic Cartilage
- Hyaline cartilage + elastin
- Found in ear, epiglottis, larynx

Diseases of Skeletal System

Infections – e.g. osteomyelitis
Growth disorders – skeletal dysplasias
Metabolic diseases – e.g. rickets, osteoporosis
Tumors – benign and malignant bone/cartilage tumors

OSTEOMYELITIS

Definition:
Osteomyelitis is an infection of the bone and bone marrow. It may occur due to haematogenous spread, direct inoculation, or extension from adjacent infections.

I. TYPES OF OSTEOMYELITIS

A. Pyogenic Osteomyelitis (Bacterial)

Causative Organisms:
- Most common: Staphylococcus aureus
- Others: Streptococci, E. coli, Pseudomonas, Klebsiella, anaerobes
- Mixed infections: Post-traumatic cases
Age Group Affected:
- Common in children aged 5–15 years, particularly in developing countries
Routes of Infection:
1. Haematogenous – more common in children
2. Direct Extension – from adjacent infected tissues (common in jaws and skull)
3. Direct Inoculation – compound fractures, surgery, implants
Risk Factors:
- Diabetes with gangrene
- Immunosuppression
- Debilitating conditions

Clinical Features

Painful, tender limb
Fever, malaise, leukocytosis
Bony destruction evident on radiographs
May remain undiagnosed → becomes chronic
Chronic cases may develop:
- Draining sinuses
- Secondary squamous cell carcinoma
- Secondary amyloidosis (extracellular deposition of abnormal, misfolded proteins)

Morphologic Stages and Features

Acute Osteomyelitis
- Infection starts in metaphysis
- Pus in marrow cavity → increased pressure
- Spread to endosteum, haversian and Volkmann canals
- Periosteitis
Subperiosteal Abscess
- Pus extends under periosteum
- May penetrate cortex → sinus tracts to skin
Sequestrum Formation
- Ischemic necrosis of cortical bone due to pressure and infection
- Sequestrum = dead bone fragment
Involucrum Formation
- New bone forms under periosteum
- Involucrum = sheath of new bone encasing the sequestrum
- Contains perforations for sinus tracts
Chronic Osteomyelitis
- Dense sclerotic bone seen
- Known as Garré’s osteomyelitis
Brodie’s Abscess
- Localized, walled-off infection in bone
- Surrounded by granulation and fibrous tissue
Vertebral Osteomyelitis
- Begins as discitis
- Spreads to vertebral bodies

Complications of Pyogenic Osteomyelitis

Septicaemia
Acute bacterial arthritis
Pathological fractures
Squamous cell carcinoma in sinus tracts
Secondary amyloidosis
Vertebral collapse, cord compression (in spinal involvement)

II. Tuberculous Osteomyelitis

Causative Agent: Mycobacterium tuberculosis
Route: Haematogenous spread from lungs or GIT
Common Sites:
- Vertebrae (Pott’s disease)
- Long bones of extremities
- Joints and synovium
Histopathologic Features:
- Caseating granulomas
- Central necrosis surrounded by tuberculous granulation tissue
- Necrotic bone fragments
- Multiple sinus tracts

Special Forms

Pott’s Disease:
- Tuberculous spondylitis
- Vertebral body destruction
- Collapse and compression fractures
- May lead to paraplegia
Psoas Abscess:
- Extension of infection from lumbar vertebra to psoas muscle sheath
- Forms a lumbar cold abscess
- May discharge via skin sinus
Complications:
- Permanent vertebral damage
- Paraplegia (partial or complete loss of motor and/or sensory function in both lower limbs)
- Secondary amyloidosis

Summary Chart

Feature	Pyogenic Osteomyelitis	Tuberculous Osteomyelitis
Cause	Bacteria (S. aureus)	M. tuberculosis
Route	Haematogenous, direct extension	Haematogenous from lungs/GIT
Site	Long bones (metaphysis)	Spine, long bones
Histology	Neutrophilic infiltration, necrosis	Caseating granulomas
Special Features	Sequestrum, Involucrum, Sinus tracts	Pott's disease, Psoas abscess
Complications	Septicaemia, fractures, carcinoma	Paraplegia, amyloidosis

AVASCULAR NECROSIS (OSTEONECROSIS)

Definition:

Bone death due to ischemia, especially in end-arterial areas.

Etiology:

Fracture/dislocation
Sickle cell disease
Corticosteroids
Radiation
Alcoholism
Idiopathic

Pathogenesis:

Interruption of blood flow by trauma, compression, or thromboembolism

Morphology:

Infarcts mainly in medulla of long bones (diaphysis)
Subchondral infarcts under joint surfaces
Microscopy: Saponified marrow fat (breakdown of necrotic adipocytes in bone marrow, where fatty acids combine with calcium salts, forming chalky, white, soap-like deposits); cortex/cartilage often spared

Complications:

Pathologic fractures
Secondary malignant tumors: Osteosarcoma, fibrosarcoma

SKELETAL DYSPLASIAS (Disorders of Bone Growth and Development)

Local Defects:

Absence/hypoplasia of bones
Fusion (e.g., syndactyly)
Supernumerary bones

Systemic Disorders:

Involve the epiphyseal growth plate and include:

1. Achondroplasia

Autosomal dominant
mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive.
Defective endochondral ossification (long bones)
Normal skull size; short stature
Most common cause of dwarfism

2. Osteogenesis Imperfecta (Brittle Bone Disease)

Genetic disorder (dominant or recessive)
Defective Type I collagen synthesis
Affects bones and other collagen-rich tissues
Fragile bones, blue sclerae, hearing loss, abnormal teeth
Forms:
- Congenita: At birth, severe
- Tarda: Adolescence, milder

3. Osteopetrosis (Marble Bone Disease)

Autosomal recessive (malignant) or dominant (benign)
Defective osteoclast function → excess dense bone
Marrow space obliteration → anemia, neutropenia, hepatosplenomegaly
Neurologic symptoms: Deafness, blindness
Histology: Increased, bizarre, non-functional osteoclasts

Metabolic and Endocrine Bone Diseases

These are a group of disorders that affect the entire skeleton due to systemic metabolic or hormonal imbalances. Major examples include:

1. Osteoporosis

Definition: Quantitative reduction of otherwise normal bone mass, leading to increased fragility.
Common in: Elderly and postmenopausal women.
Clinical Features:
- Often asymptomatic.
- Backache, fractures (distal radius, femoral neck, vertebrae).
Radiology:
- Changes visible only after >30% bone loss.
- Normal serum calcium, phosphate, and ALP.
Types:
- Primary:
  - Idiopathic: In young/juveniles (rare).
  - Involutional: Postmenopausal/aging (common).
- Secondary:
  - immobilization: Mechanical loading is essential for bone maintenance. ↓ Osteoblastic activity,↑ Osteoclastic resorption. Examples: Long-term bed rest, paralysis, space travel
  - chronic anemia: especially hemolytic and thalassemic states) leads to Marrow expansion → thinning of cortical bone. ↑ Osteoclastic resorption due to increased marrow demands
  - endocrine disorders (hyperparathyroidism, hyperthyroidism): ↑ PTH → Stimulates osteoclasts. Excess thyroid hormone →Preferential increase in bone resorption
  - medications: corticosteroids (↓ Osteoblast formation and function, ↑ Osteoclast lifespan, ↓ Calcium absorption (gut), ↑ renal calcium excretion), anticonvulsants (↑ Vitamin D catabolism → ↓ calcium), heparin (Direct osteoclast activation (long-term use)).
Pathogenesis:
- Imbalance between bone resorption and formation.
- Risk Factors: Genetics, sex (female), physical inactivity, hormone deficiencies (estrogen, androgen), low vitamin D, local bone turnover factors.
Morphology:
- Active osteoporosis: ↑ osteoclasts & osteoblasts, normal osteoid seam width.
- Inactive osteoporosis: ↓ bone turnover, ↓ osteoclasts and osteoblasts, reduced osteoid.

2. Osteomalacia and Rickets

Cause: Vitamin D deficiency → impaired bone mineralization.
Osteomalacia: In adults.
Rickets: In children.

3. Scurvy

Cause: Vitamin C deficiency (cofactor for prolyl and lysyl hydroxylase)
Effect: Impaired collagen synthesis → subperiosteal hemorrhages.

Pathological Process	Explanation
↓ Hydroxylation of collagen	Leads to formation of defective, unstable collagen → weak connective tissue and capillaries
Fragile capillaries	Prone to rupture → bleeding into tissues, especially under the periosteum
↓ Osteoid formation	Poor matrix formation → defective bone structure
↓ Wound healing	Due to impaired collagen deposition in granulation tissue

4. Osteitis Fibrosa Cystica (OFC)

🔄 Pathogenesis Overview

Osteitis Fibrosa Cystica is a skeletal manifestation of hyperparathyroidism, driven by excess parathyroid hormone (PTH), which increases osteoclastic bone resorption, leading to bone loss, fibrosis, cyst formation, and brown tumors.

Mechanism: Role of Excess PTH

PTH Action	Effect on Bone
Stimulates osteoblasts	Indirectly ↑ RANKL expression
RANKL binds to RANK on osteoclast precursors	Promotes osteoclast differentiation and activity
↑ Osteoclastic resorption	Leads to bone demineralization and matrix degradation
Bone microenvironment damage	Results in fibrosis, microfractures, and hemorrhage

Types of Hyperparathyroidism

Type	Cause
Primary	Parathyroid adenoma (most common), hyperplasia
Secondary	Chronic renal failure → hypocalcemia → ↑ PTH

Morphological Stages

1. Early Stage

Subperiosteal bone resorption (classic feature)
- Seen especially in phalanges
- Thinning or disappearance of the lamina dura in the jaw

2. Intermediate Stage

Widespread osteoclastic activity
Marrow spaces replaced by fibrous tissue
Called “osteitis fibrosa” (fibrosis of bone)

3. Advanced Stage

Formation of cystic lesions containing:
- Hemorrhage
- Multinucleated giant cells
- Fibrous tissue
These are called “brown tumors”
- Brown color due to hemosiderin deposition
- Not true neoplasms
- Histologically resemble giant cell reparative granulomas

Common Sites Involved

Long bones
Jaw
Vertebrae

🧪 Biochemical Profile (Primary Hyperparathyroidism)

Parameter	Level
Calcium	↑ (hypercalcemia) (Increases calcium reabsorption in the distal tubules)
Phosphate	↓ (hypophosphatemia) (Decreases phosphate reabsorption in the proximal tubules)
PTH	↑
Alkaline phosphatase	↑ (due to high bone turnover)
Urinary calcium	↑ (hypercalciuria)

Clinical Features

Symptom	Explanation
Bone pain	Due to microfractures and periosteal stress
Skeletal deformities	Bone loss and remodeling
Pathologic fractures	Weakened structure due to osteolysis
Brown tumor masses	Can be palpable if near the surface

5. Pituitary Dysfunctions

Hyperpituitarism:
- ↑ GH → Gigantism (before epiphyseal closure) and Acromegaly (after closure).
Hypopituitarism:
- ↓ GH → Dwarfism.

6. Thyroid Dysfunctions

Hyperthyroidism: Causes osteoporosis (↑ bone turnover).
Hypothyroidism: In children causes cretinism (growth retardation) (delayed endochondral ossification)

7. Renal Osteodystrophy

Occurs in: Chronic renal failure (CRF), dialysis patients.
Clinical Signs: Usually subclinical; evident on X-ray/histology.
Pathogenesis:
- Hyperphosphatemia (due to ↓ renal excretion) → hypocalcemia → ↑ PTH → secondary hyperparathyroidism.
- ↓ Vitamin D activation → ↓ calcium absorption.
- Metabolic acidosis → bone resorption.
- Aluminium toxicity (from dialysis) → inhibits mineralization.
- β2-microglobulin accumulation → dialysis-related amyloidosis.
Skeletal Manifestations:

8. Skeletal Fluorosis

Cause: Excess fluoride (from soil/water).
Effect: Dense but brittle bones; joint stiffness and pain.

Summary Table: Key Differences

Disease	Main Cause	Bone Mineral Content	Histology	Serum Calcium	Unique Features
Osteoporosis	Aging, inactivity, estrogen loss	↓	Thin trabeculae, normal osteoid	Normal	Fragility fractures
Osteomalacia/Rickets	Vit D deficiency	↓↓ (due to poor mineralization)	↑ Osteoid seams	Low/normal	Looser zones, soft bones
Osteitis Fibrosa Cystica	Hyperparathyroidism	Variable	Fibrosis, giant cells, brown tumors	↑	Bone resorption, cysts
Renal Osteodystrophy	Chronic kidney disease	Mixed	Depends on type	↓ or normal	Mixed lesions, osteosclerosis
Fluorosis	Excess fluoride	↑ or normal	Dense but abnormal	Normal	Joint rigidity

Paget’s Disease of Bone (Osteitis Deformans)

Overview:

Chronic bone disease characterized by both osteolysis and osteosclerosis (excessive bone formation)
More common in males over 50 years.
Can be monostotic (single bone) or polyostotic (multiple bones).

Etiology:

Possible slow-virus infection (paramyxovirus) of osteoclasts.
Genetic predisposition:
- Autosomal dominant inheritance
- Gene on chromosome 18q → RANK (Receptor Activator of Nuclear Factor κB)

Clinical Features:

Monostotic: Often asymptomatic.
Polyostotic: Pain, fractures, skeletal deformities, possible sarcoma (arise from mesenchymal (connective) tissues).
Biochemical marker: Elevated alkaline phosphatase, normal/high calcium.

Morphologic Stages:

A. Osteolytic Phase:
- Excessive bone resorption by large, multinucleated, abnormal osteoclasts.
- Bone becomes weakened and porous.
B. Mixed Osteolytic-Osteoblastic Phase:
- Active osteoblasts attempt to lay down new bone.
- However, this bone is poorly organized.
- This phase is often the longest.
C. Quiescent (Sclerotic) Phase:
- abnormally dense and hardened
- Osteoclastic and osteoblastic activity subsides.
- Bone becomes dense but disorganized, mechanically weak, and prone to fractures.

4. Tumour-like Lesions of Bone

These are non-neoplastic but mimic bone tumors. Common types:

A. Fibrous Dysplasia

Developmental anomaly.
Replacement of normal bone with fibrous tissue + irregular trabeculae of woven bone (Immature, disorganized bone. Randomly oriented collagen fibers, Haphazard arrangement of trabeculae, High cellularity (many osteocytes)

Types:

Monostotic (70% cases): Solitary bone, usually ribs, craniofacial bones, femur, tibia.
Polyostotic (25%): Multiple bones
Albright Syndrome (McCune-Albright):
- Polyostotic fibrous dysplasia
- Café-au-lait spots (caused by increased melanin)
- Sexual precocity & endocrine abnormalities (more common in females)

Morphology:

Gross: 2–5 cm lesions in cancellous bone, smooth cortex.
Microscopy: Fibroblastic stroma with irregular, curved trabeculae (fish-hook/Chinese letter pattern). No osteoblastic rimming.

B. Fibrous Cortical Defect (Metaphyseal Fibrous Defect)

Common in children.
Affects metaphyseal cortex of tibia or femur.

Radiology: Eccentric lesion with sharp margins.

Morphology:

Gross: Small (<4 cm), granular, brown.
Microscopy: Storiform fibrous tissue, osteoclast-like giant cells, haemosiderin-laden macrophages, foamy histiocytes (macrophages with a vacuolated cytoplasm due to the accumulation of lipids, cholesterol, or other metabolic products)

BONE TUMOURS

General Overview

Incidence: Comparatively infrequent but clinically significant, particularly due to potential malignancy.
Classification:
- Primary: Arise from the bone itself.
- Metastatic: Secondary spread from other organs.

2. Classification of Bone Tumors

A. Primary Bone Tumors

Tumors that originate directly from bone tissue or its components (osteoblasts, chondrocytes, marrow cells, etc.)

Type	Examples	Benign/Malignant
Osteogenic	Osteoid osteoma, Osteoblastoma, Osteosarcoma	Both
Chondrogenic	Enchondroma, Chondroblastoma, Chondrosarcoma	Both
Fibrous	Fibrous dysplasia, Fibrosarcoma	Both
Vascular	Hemangioma, Angiosarcoma	Both
Hematopoietic	Multiple Myeloma, Lymphoma	Malignant
Other	Ewing sarcoma, Giant cell tumor	Usually malignant or locally aggressive

B. Metastatic Bone Tumors

Tumors that spread to the bone from a primary malignancy elsewhere in the body.

Common primary sources:
- Breast
- Prostate
- Lung
- Kidney
- Thyroid
Clinical clue: In adults over 40, bone lesions are more likely metastatic than primary.

3. Diagnosis of Bone Tumors

Accurate diagnosis requires multi-modality correlation:

A. Clinical Examination

History: Pain, swelling, pathological fracture
Physical exam: Palpable mass, tenderness, deformity, neurovascular compromise

B. Radiological Imaging

Modality	Purpose
X-ray	First-line; identifies location, size, type of lesion (lytic/blastic/mixed)
CT scan	Detailed bony architecture, cortical involvement
MRI	Soft tissue extension, marrow involvement, skip lesions
Bone scan (Tc-99m)	Detects multifocal disease or metastasis
PET-CT	For staging of malignant tumors and response assessment

C. Histopathology (Biopsy)

Core needle biopsy or open biopsy is essential for:
- Confirming tumor type
- Grading and staging
- Planning surgery or chemotherapy
Histological features: Cell type, mitosis, matrix (osteoid, chondroid), necrosis, giant cells

D. Biochemical Markers

Marker	Use
Serum calcium	↑ in bone resorption or metastasis (e.g., myeloma, breast CA)
Serum phosphate	Altered in metabolic bone disease
Alkaline phosphatase	↑ in bone turnover (e.g., osteosarcoma, Paget’s disease)
Acid phosphatase	↑ in prostate carcinoma with bone metastases

E. Special Tests for Specific Tumors

Tumor Type	Special Test
Multiple Myeloma	Serum/urine protein electrophoresis (M-protein), Bence-Jones proteins
Neuroblastoma	Urinary catecholamines (VMA, HVA)
Lymphoma/Leukemia	Bone marrow aspiration/biopsy

Benign Bone-Forming Tumours

1. Osteoma

Nature: Rare, benign, slow-growing
Sites: Flat bones of the skull and face; may extend into paranasal sinuses or orbit.
Associations: May be part of Gardner’s syndrome.
Radiology: Dense, ivory-like bony mass.
Microscopy: Mature lamellar bone trabeculae with fibrovascular stroma.

2. Osteoid Osteoma

Age: Young individuals, <30 years.
Size: Small (<1 cm).
Location: Cortex of long bones.
Symptoms: Painful (often nocturnal, relieved by NSAIDs).
Radiology: Central radiolucent nidus with dense sclerotic surrounding bone.

3. Osteoblastoma

Age: Adolescents and young adults.
Size: Larger (>1 cm).
Location: Medullary cavity—vertebrae, ribs, ilium, long bones.
Symptoms: Painless.
Radiology: No sclerotic rim.
Histology: Similar to osteoid osteoma; difficult to distinguish microscopically.

Malignant Bone-Forming Tumour

Osteosarcoma (Osteogenic Sarcoma)

Most common primary malignant bone tumour.
Age: 10–20 years (primary); >40 years in secondary cases.
Sex: M > F.
Site: Metaphysis of long bones:
- Around the knee (distal femur, proximal tibia) – 60%
- Proximal humerus – 10%
- Pelvis & proximal femur – 15%
- Rare: jaws, vertebrae, skull, soft tissues (extraskeletal osteosarcoma)

Classification by Pathogenesis

Primary Osteosarcoma:
- No predisposing condition.
- Etiology: Likely genetic and environmental.
  - RB gene mutation (retinoblastoma link)
  - p53 mutation
  - MDM2, cyclin D1, p16, CDK4 alterations
  - Exposure to radiation, viruses.
Secondary Osteosarcoma:
- Develops on pre-existing lesions:
  - Paget’s disease, fibrous dysplasia, chronic osteomyelitis, infarcts, fractures.
- More aggressive.

Pathology

Location: Metaphyseal region, starts in medulla.
Spread: Expands to cortex, periosteum, and surrounding soft tissues.
Epiphyseal plate may delay spread.
Radiology:

Sunburst appearance (spiculated bone formation)
Codman’s triangle (periosteal lifting)

Clinical:
- Pain, swelling, tenderness.
- Raised serum alkaline phosphatase; normal Ca²⁺ and PO₄³⁻.
Metastasis:
- Via bloodstream.
- Commonly to lungs, other bones, brain.

Cartilage-forming Tumors and Giant Cell Tumors of Bone

1. Enchondroma

Definition: A benign cartilage-forming tumor located within the medullary cavity of bone.
Common Sites: Long bones and ribs.
Age/Sex: Any age, both sexes.
Clinical Features:
- Often asymptomatic.
- May present with pain or pathological fractures.
Radiology: Radiolucent, lobulated lesion with spotty calcifications.
Malignant Potential:
- Solitary lesions rarely become malignant.
- Multiple enchondromas (enchondromatosis) may transform into chondrosarcoma.
Morphology:
- Gross: Translucent lobulated mass in medullary cavity.
- Microscopy: Lobules of mature hyaline cartilage separated by vascular fibrous stroma ± calcification.
- Differentiation: No tissue invasion or cellular atypia (distinguishes it from chondrosarcoma).

2. Chondroblastoma

Definition: A rare benign cartilage-producing tumor of the epiphysis.
Common Sites: Around knee (upper tibia, lower femur), upper humerus.
Age/Sex: <20 years, male > female (2:1).
Radiology: Sharply circumscribed lytic lesion (area of bone destruction seen on imaging , where normal bone has been resorbed or replaced, leading to a radiolucent (dark) appearance.) with foci of calcification.
Clinical Features: Local pain, tenderness, discomfort; may recur after curettage (curettage is frequently used for the removal of benign bone tumors or cysts).

Morphology:
- Gross: Epiphyseal mass up to 5 cm, soft, chondroid (tissue that resembles cartilage—specifically hyaline cartilage) with hemorrhage, necrosis, calcification.
- Microscopy:
  - Highly cellular with small, round to polygonal chondroblasts.
  - Multinucleated osteoclast-like giant cells.
  - Chondroid matrix and focal calcification.

3. Chondromyxoid Fibroma

Definition: An uncommon benign tumor of immature cartilage.
Common Sites: Metaphysis of long bones (e.g., upper tibia, lower femur).
Age/Sex: 2nd–3rd decade, male > female.
Radiology: Well-demarcated radiolucent lesion with some calcification and bone expansion.
Clinical Features: Pain, swelling, discomfort; may recur after curettage.
Morphology:
- Gross: Gray-white, lobulated mass <5 cm, in metaphysis, often with sclerotic rim (increased bone density or hardening, typically seen on radiologic imaging as a white or bright (radiopaque) area).
- Microscopy:
  - Lobules separated by fibrous tissue and giant cells.

4. Chondrosarcoma

Definition: A malignant cartilage-producing tumor.
Types:
- Central (primary): Arises within the medulla.
- Peripheral: Arises in cortex/periosteum; can be secondary to benign tumors like osteochondroma or enchondroma.
Sites: Central skeleton – pelvis, ribs, shoulders; also around knee.
Age/Sex: 30–60 years, male > female.
Radiology: Large, osteolytic mass with calcification.
Clinical Features: Slow-growing mass with pain and swelling; metastasizes in higher grades (lungs, liver, kidney, brain).
Morphology:
- Gross: Large, lobulated, firm mass; bluish-white, gelatinous with ossification.
- Microscopy:
  - Invasive growth of lobules of anaplastic cartilage cells (Anaplastic refers to cells that have lost their normal structure and function).
  - Cytologic malignancy: hyperchromatism, pleomorphism, multinucleation, tumor giant cells (reflects abnormal cell fusion or proliferation)

5. Giant Cell Tumor (Osteoclastoma)

Definition: Aggressive, potentially malignant tumor with numerous osteoclast-like giant cells.
Sites: Epiphysis of long bones – distal femur, proximal tibia, distal radius, upper fibula.
Age/Sex: 20–40 years, both sexes.
Radiology: Osteolytic lesion with "soap bubble" appearance.
Clinical Features: Pain (on movement/weight-bearing), swelling, pathological fracture.
Morphology:
- Gross: Eccentric epiphyseal lesion, hemorrhagic and necrotic with cystic changes.
- Microscopy:
  - Numerous multinucleate giant cells (~100 nuclei).
  - Stromal mononuclear cells are the true tumor cells – round/spindle, mitotically active.
  - Stroma is vascular with scant collagen, hemorrhage, and macrophages.
Biologic Behavior:
- Recurrent in 40–60% cases after curettage.
- 4% metastasize to lungs (histologically benign).
- May transform into sarcoma (especially post-radiotherapy).
Differential Diagnosis: Brown tumor, aneurysmal bone cyst.
Cell of Origin: Likely mesenchymal stromal cells; giant cells formed by monocyte fusion facilitated by TGF-β.

6. Ewing’s Sarcoma

Definition: Highly malignant small round cell tumor of neuroectodermal origin.
Variants:
1. Skeletal (classic) Ewing’s sarcoma.
2. Soft tissue Ewing’s sarcoma.
3. Primitive neuroectodermal tumor (PNET).
Age/Sex: 5–20 years, female > male.
Genetics: Translocation t(11;22)(q24;q12) – common to all 3 variants.
Sites: Arises in medullary cavity of diaphysis or metaphysis of long bones.

JOINTS

Types of Joints

Diarthrodial (Synovial) Joints:
- Have a joint cavity.
- Ends of two bones are held by a joint capsule reinforced by ligaments and tendons.
- Articular surfaces covered by hyaline cartilage, thicker in weight-bearing areas.
- Joint cavity lined by synovial membrane (synovium) which produces synovial fluid for lubrication.
Synarthrodial (Nonsynovial) Joints:
- No joint cavity.
- Less commonly affected by diseases.

Synovial Membrane Structure

Two layers:
- Inner layer: 1–4 cells thick made of synoviocytes (2 types on EM):
  - Type A synoviocytes: Macrophage-like, produce degradative enzymes.
  - Type B synoviocytes: Fibroblast-like, synthesize hyaluronic acid.
- Outer layer: Loose, vascular connective tissue.

OSTEOARTHRITIS (OA) / DEGENERATIVE JOINT DISEASE (DJD)

Definition

The most common chronic disorder of synovial joints, characterized by progressive degeneration of articular cartilage especially in weight-bearing joints.

Types and Pathogenesis

Primary OA
- Occurs in elderly (starting after 40 years), more common in women.
- Etiology unclear; associated with wear and tear, minor trauma, aging, obesity, heredity.
- Genetic susceptibility (e.g., mutations in FRZB gene affecting cartilage growth).
Secondary OA
- Can occur at any age due to previous joint damage: injury, fracture, inflammation.
Molecular Mechanism
- Cartilage breakdown mainly due to degradation of type II collagen.
- Mediated by cytokines like IL-1, TNF, and nitric oxide.

Morphologic Features of OA

Articular Cartilage
- Cartilage loosens, flakes, fissures → fragments break off exposing subchondral bone.
- Radiology: Narrowed joint space due to cartilage loss.
Bone Changes
- Death of superficial osteocytes, increased osteoclast activity.
- Bone remodeling causes flattening and mushroom-like shape of joint ends.
- Loose osteophytes may form joint mice (loose bodies).
Synovium
- Initially normal.
- Advanced cases show low-grade chronic synovitis.
- Possible synovial effusion.

Commonly Involved Joints

Weight-bearing joints: hips, knees, vertebrae.
Interphalangeal joints of fingers also affected.

Clinical Features

Joint stiffness, reduced mobility, pain—worse after rest (morning stiffness).
Enlarged bony nodules on distal finger joints called Heberden’s nodes (common in women, hereditary tendency).
In spine, osteophytes may compress nerve roots → pain, spasms (sudden, involuntary contraction of a muscle or group of muscles), neurological signs.

Rheumatoid Arthritis (RA)

Overview

Chronic autoimmune disease of unknown exact cause.
Predominantly causes inflammatory arthritis, usually symmetrical and mainly affects peripheral joints.
Systemic effects may involve hematologic, pulmonary, neurological, and cardiovascular systems.

System	Common Manifestations
Hematologic	Anemia, thrombocytosis, Felty’s syndrome
Pulmonary	Pleuritis, nodules, pulmonary HTN
Neurological	neuropathies
Cardiovascular	Atherosclerosis, pericarditis, myocarditis

Peak incidence: 3rd to 4th decades of life. (Genetic Susceptibility, Immune Dysregulation, Hormonal Factors, Environmental Triggers).
Female predominance: 3–5 times more common in females.
Strong genetic association with HLA-DR4 and HLA-DR1.
Familial aggregation common.

Clinical Features

Insidious onset: fatigue, weakness, joint stiffness, arthralgia, and myalgia.
Followed by symmetrical joint pain and swelling.
Most commonly involved joints: hands, wrists, feet.
Unlike rheumatic fever’s migratory arthritis, RA arthritis persists in involved joints.
About 20% develop rheumatoid nodules (extensor surfaces of elbows, fingers).

Approximately 80% are seropositive for rheumatoid factor (RF) (an autoantibody—usually of the IgM class—that targets the Fc portion of IgG antibodies).
RF can be elevated in other diseases: viral hepatitis, cirrhosis, leprosy.
Advanced radiological features: joint space narrowing, ulnar deviation of fingers, radial deviation of wrists.
Labs: mild normocytic normochromic anemia, elevated ESR, mild leukocytosis, hypergammaglobulinemia.

Etiopathogenesis

Immunologic Factors

Autoimmune phenomenon with production of rheumatoid factor (RF) (IgM and IgG).
Circulating immune complexes (IgG-RF).
Other autoantibodies: ANA, anti-collagen type II, anti-cytoskeleton (against proteins of the cell’s cytoskeleton, which includes actin filaments, intermediate filaments, and microtubules)
Inflammatory infiltration predominantly by CD4+ T cells, macrophages in synovium.

Trigger Factors

Infectious agents suspected: mycoplasma, EBV, CMV, rubella virus.
Genetic predisposition (HLA-DR4, HLA-DR1) important.
Superantigens from microorganisms may activate immune response.

(Superantigens are potent microbial proteins that hyperactivate the immune system by binding non-specifically to MHC class II molecules and T-cell receptors (TCRs), leading to massive T-cell activation)

Immunopathogenesis (Simplified Model)

Antigenic trigger in genetically predisposed (HLA-DR) individual → activation of CD4+ T cells.
T cells release cytokines: TNF-α, IFN-γ, IL-1, IL-6.
Cytokines activate endothelial cells, B cells, macrophages.
B cells produce RF (IgM anti-IgG antibody).
Immune complexes cause inflammation → synovium, vessels, collagen damaged.
Macrophages release more cytokines → pannus formation (vascularized granulation tissue).
Pannus destroys cartilage and bone → fibrosis → joint deformities.

Morphologic Features

Articular Lesions

Initially affects small joints of hands and feet; symmetric.
Involves wrists, elbows, ankles, knees; cervical spine commonly affected.
Histology: proliferative synovitis with pannus formation.
Features:
- Villous hypertrophy of synovium.
- Thickened synovial membrane (edema, congestion).
- Dense mononuclear infiltrate (lymphocytes, plasma cells, macrophages).
- Fibrinoid necrosis and fibrin deposits.
Pannus invades cartilage and bone → cystic resorption, demineralization.
Tendons may weaken or rupture.

Extra-Articular Lesions

Vasculitis affecting vessels, lungs, pleura, pericardium, myocardium, nerves, eyes.
Rheumatoid nodules: subcutaneous, especially over pressure points (elbows, occiput, sacrum).
- Central fibrinoid necrosis surrounded by epithelioid macrophages and lymphocytes.
- Similar nodules may occur in lungs, pleura, heart valves, other organs.

Variants of RA

Juvenile RA:
- Onset under 16 years.
- Acute fever, mainly knees and ankles.
- RF rarely present.
Felty’s Syndrome:
- RA with splenomegaly and hypersplenism.
- Leads to hematologic abnormalities.
Ankylosing Spondylitis (Rheumatoid spondylitis):
- Involves sacroiliac joints, spine.
- More common in young males.
- Strong association with HLA-B27.
- May be linked with inflammatory bowel disease, anterior uveitis, Reiter’s syndrome (Triad of arthritis, urethritis, conjunctivitis).

SKELETAL MUSCLES

Normal Structure

Striated skeletal muscles are made up of bundles called fascicles.
Each fascicle is surrounded by perimysium, a connective tissue sheath containing blood vessels and nerves.
Each individual muscle fiber within a fascicle is enveloped by a delicate connective tissue called endomysium.
A muscle fiber is a long, multinucleated cell (~100 μm diameter, several cm length).
Nuclei are located peripherally beneath the sarcolemma (muscle fiber plasma membrane).
Cytoplasm contains myofilaments:
- Thick filaments: Myosin
- Thin filaments: Actin
Arrangement of myofilaments produces cross-striations seen under light microscopy.
Functional unit: Sarcomere (distance between two Z bands), composed of:

Central A band (anisotropic)
Lateral I band (isotropic)

Functions:
- Convert chemical energy → mechanical energy (contraction)
- Store energy and proteins (Glycogen (stored glucose) and Phosphocreatine (rapid ATP source)
- Play a role in body metabolism (glucose metabolism, thermogenesis)
Muscle contraction requires nerve supply, with each motor unit including:
1. Motor neuron cell body (spinal cord anterior horn or cranial nerve nucleus)
2. Axon of motor neuron
3. Neuromuscular junction
4. Innervated muscle fibers (muscle cells (fibers) that receive signals from a motor neuron through a structure called the neuromuscular junction (NMJ))
Contraction initiated by acetylcholine release across synaptic gap, generating muscle fiber action potential.

Diseases Affecting Skeletal Muscles

Neurogenic Diseases

Characterized by muscle weakness and fatiguability.
Common examples:
- Myasthenia gravis (MG)
- Congenital myasthenia
- Eaton-Lambert syndrome (associated with lung carcinoma)
- Denervation atrophy

Myasthenia Gravis (MG)

Autoimmune disorder damaging acetylcholine receptors (AChR) at motor end-plates.
More common in adult women (3:2 ratio).
Symptoms: weakness starting with ocular muscles → spreading to trunk & limbs.
Mortality ~10%, mainly due to respiratory muscle involvement.
Associated with other autoimmune diseases: autoimmune thyroiditis, rheumatoid arthritis, SLE, pernicious anemia.
Pathogenesis:
- Reduced AChRs and flattened postsynaptic folds → impaired neuromuscular transmission.
- Autoantibodies against AChRs block receptor sites.
- Thymus involvement: thymoma or thymic hyperplasia common; thymectomy may help. (Faulty T-cell selection in the thymus may fail to eliminate AChR-reactive T-cells.)
Morphology:
- Grossly normal muscles early; atrophy later.
- Light microscopy: lymphocytic infiltrates, degenerating fibers.
- Electron microscopy: reduced synaptic area, fewer AChRs.
- Immunocytochemistry: IgG and complement deposits at neuromuscular junction.

Denervation Atrophy

Loss of nerve supply leads to muscle atrophy. Without nerve signals, muscles shrink, weaken, and lose function over time.
Features:

Small angulated muscle fibers alternating with normal/hypertrophic fibers.
May progress to dystrophic changes.

Dystrophic Feature	Description
Muscle fiber necrosis	Dying muscle fibers due to prolonged disuse
Fibrosis	Replacement of muscle tissue with connective tissue
Fatty infiltration	Muscle replaced by fat cells
Regeneration attempts	Muscle tries to regenerate, causing fiber size variation
Internal nuclei	Nuclei shift from periphery to center (a dystrophic feature)

Seen in diseases like:
- Amyotrophic lateral sclerosis (ALS)
- Peripheral neuropathies

Myopathic Diseases (Myopathies)

Primary muscle diseases with chronic muscle weakness.
Five groups: hereditary (muscular dystrophies), inflammatory, endocrine, metabolic, toxic.
Focus on Muscular Dystrophies.

Muscular Dystrophies

Genetically inherited, progressive muscular weakness.
Six major types with differences in inheritance, onset, symptoms, and course:

Type	Inheritance	Age of Onset	Clinical Features	Other Systems Involved	Course
Duchenne’s	X-linked recessive	By age 5	Symmetric weakness (pelvifemoral), pseudohypertrophy of calves	Cardiomegaly; reduced intelligence	Progressive; death ~20 y
Becker’s	X-linked recessive	2nd decade	Slow progressive weakness (girdle)	Cardiomegaly	Benign variant of Duchenne
Myotonic type	Autosomal dominant	Any decade	Weakness + myotonia (eyelids, face, limbs)	Cardiac conduction defects, cataracts	Benign
Facioscapulohumeral	Autosomal dominant	2nd–4th decade	Weakness of face, scapula, humerus	Hypertension	Benign
Limb-girdle	Autosomal recessive	Early childhood–adult	Weakness of shoulder and hip girdle	Cardiomyopathy	Variable
Oculopharyngeal type	Autosomal dominant	5th–6th decade	Weakness of extraocular, eyelids, face, pharynx	—	Rarely progressive

Morphology common to all:
- Muscle fiber necrosis, regeneration.
- Replacement by fibrosis and adipose tissue.

Table 28.4: Classification of Neuromuscular Diseases by Motor Unit Site

Site of Motor Unit	Disease Examples
I. Anterior Horn Cell	Spinal muscular atrophy; Amyotrophic lateral sclerosis (ALS)
II. Peripheral Nerve	Carpal tunnel syndrome; Mononeuritis multiplex; Diabetic neuropathy
III. Neuromuscular Junction	Myasthenia gravis
IV. Muscle	Duchenne’s muscular dystrophy