Diseases of the musculoskeletal system

D S O’Briain

February 2009

Medical disease of bone and joint

• Metabolic disorders

• Arthritis

Medical disease of bone and joint (1) Metabolic diseases

• Vitamin D and parathyroid hormone

• Rickets and osteomalacia

• Hyperparathyroidism, renal osteodystropy

• Osteoporosis

• Importance of calcium phosphate product

Vitamin D

• Role: bone mineralisation, maintaining serum calcium and phosphate levels

• Source; skin, 7 dehydrocholesterol (sun) vitamin D3: diet ergosterol altered to vitamin D2

• Synthesis: travels on binding protein – to liver (hydroxylase) produces 25 (OH)D – to kidney (hydroxylase) produces 1.25 (OH)D

• Effects– GI absorbs calcium and phosphate– Bone: mobilises calcium phosphate (with PTH)– Kidney: absorbs calcium, loses phosphate (with PTH)

Parathyroid hormone

• 84 amino acid polypeptide from parathyroid glands, binds to cell plasma membrane receptor generating cAMP etc

• Supports serum calcium– Activates osteoclasts to release bone calcium– Increases renal tubular reabsorption of calcium– Increases conversion of vitamin D to 2(OH) in kidney– Increase urinary phosphate excretion– Increases GI calcium absorption

• Excess causes– Increased osteoclasts that erode bone– hypercalcemia

Rickets and osteomalacia

• Vitamin D deficiency: • 1) diet (sunlight),

• 2 malabsorption,

• 3 metabolism: liver or kidney disease (cyto P450, renal hydroxylase deficiency),

• 4 end organ resistance

• Phosphate deficiency (aluminium bound, failed renal tubular absorption

• Normal growing cartilage - becomes calcified - stops growing - endochondral ossification

• Children (rickets): growing cartilage not calcified, abnormal growth and poor ossification, abnormal bone in skull, ribs, vertebrae, lower limbs

• Adult (osteomalacia): growth finished, excess osteoid, osteopenia, fractures

Hyperparathyroidism

• Primary or secondary hyperparathyroidism

• Increased PTH signals osteoblasts which signal osteoclasts to resorb bone

• Effects: – Subperiosteal resorption (hand X-ray)

– Dissecting osteitis: resorption, fibrosis, microfractures of cancellous bone

– Brown tumour (osteitis fibrosa cystica, Von Recklinghausen) haemorrhage, haemosiderin, inflammatory repair, cystic change

Renal osteodystropy

• Renal failure causes defective 1,25 (OH)D, loss of phosphate and retention of H (acidosis)

• These induce changes of hyperparathyroidism, osteomalacia, osteoporosis, osteosclerosis and decreased growth.

• The bone loss may be high, low or mixed turnover

• Excess aluminium and amyloid may add to the effect

Osteoporosis

• Peak bone mass; effect of vitamin D, diet, exercise, hormones• Normal bone remodeling: bone loss less than 1% a year• Senile osteoporosis: with age, osteoblasts less effective (diet and

exercise influence) increased slow bone loss mainly in cortex• Post menopausal osteoporosis: decreased oestrogen allows

increase in cytokines (Il-1, Il-6 and TNF alpha) which mobilizes osteoclasts; reactive osteoblast mobilisation, high turnover bone loss, main effects on cancellous bone

• Result: (microfracture) vertebrae—pain, height loss, deformity; pelvis, hips—fractures (fatal secondary illnesses; pneumonia, pulmonary embolism)

Medical disease of bone and joint (2) Arthritis

• Osteoarthritis• Rheumatoid arthritis• Other forms of arthritis

– Juvenile rheumatoid arthritis– Ankylosing spondylitis– Reiter syndrome– Infectious arthritis– Lyme arthritis– Gout and pseudogout

Joint Features

• Solid joints: structural, little movement,– synarthroses (fibrous); symphyses (cartilage)

• Synovial joints: cavity, movement– Capsule, ligaments, muscles

– Synovial lining, phagocytic or fibroblast-like cells, hyaluronic acid lubricant

– hyaline cartilage shock absorber, wear resistant

– chondrocytes synthesise and digest matrix of type 2 collagen, proteoglycans

Osteoarthritisprogressive degeneration of articular cartilage

• Usually age-related and oligoarticular; vertebrae, hips, knees, feet and hands (DIP, PIP)

• May be secondary to obesity, trauma, or joint disease (haemophilia)

• Pain, morning stiffness, crepitus, decreased movement, root compression, nerve pressure effects

• Cartilage degenerates, chondrocytes cluster, increased water, decreased proteoglycans, fibrillation, fragmentation, joint mice, bone exposed, fractures, cysts, eburnation, osteophytes (Heberden’s nodes), reactive synovium, fibrous pannus

• Chondrocytes produce Il-1, TNF alpha, Il-6, prostaglandins

Rheumatoid Arthritischronic systemic inflammatory disorder

• 1% of population, majority (x5) women, peak 20-40 years

• Involves many sites: skin (rheumatoid nodules), blood vessels (vasculitis), heart, lungs

• Principally involves joints: hands, feet; later wrists, elbows, ankles, knees

• Onset: gradual systemic or acute arthritis, swollen, hot, painful and stiff joints

Rheumatoid Arthritis

• Pathogenesis– Genetic susceptiblity (HLA Dr4, common motif of antigen binding site of DR molecule)– Antigen: microbial? Epstein Barr, mycoplasma, borrelia– Autoimmunity: to collagen or cartilage proteoglycan, driven by CD4 cells

• Joint damage: – activated cells cytokine loop, – B cell activation, IgM autoantibodies to IgG (rheumatoid factor) – immune complexes

• Effect: – inflamed synovium, oedema, thickened hyperplastic papillae form– Increased vascularity, lymphocytes, plasma cells, fibrin– Bone eroded, subchondral cysts, osteopenia, – pannus (granulation tissue obliterating synovium); ankylosis

Other forms of arthritis (1)

• Juvenile rheumatoid arthritis: large joints, oligo involvement, RF negative, ANA+

• Ankylosing spondylitis, HLA B27, males, axial, sacroiliac joints

• Reiter syndrome: Arthritis, urethritis, conjunctivitis, autoimmune reaction following infection of GI or urethra

• Psoriatic arthritis: 5% of psoriasis, like RA

Other forms of arthritis (2)

• Infectious: suppurative, tuberculous• Lyme arthritis: borrelia burgdorferei, late in disease,

large joints• Gout: uric acid crystals, giant cell reaction, acute

arthritis, chronic tophaceous arthritis, tophi• Pseudogout: calcium pyrophosphate, knees

Bone tumours

• Secondary tumours• Marrow tumours• Primary bone tumours

– Osteosarcoma– Chondrosarcoma– Ewing sarcoma– Giant cell tumour– Others

Bone Features (1)

• Bone profile: joint - cartilage - epiphysis - plate - metaphysis - diaphysis (shaft)

• Bone section: periosteum - cortical bone - cancellous bone - medulla

• Growth: at metaphysis, site of most tumours

• Long bone growth: metaphyses near knee (lower femur, upper tibia) remote from elbow (upper humerus)

• Effects of age: closure of epiphyses

Bone Features (2)

• Periosteum: produces reactive bone if stimulated (causes Codman’s triangle, sunburst, or onion skin patterns on X-ray)

• Osteoblasts, contain alkaline phosphate, become osteocytes, produce osteoid (like collagen) which becomes mineralised as bone (fibres are at first irregular - woven - later become parallel - lamellar

• Osteoclast: multinucleated cell of monocyte-histiocyte lineage, contains acid phosphate, lyses bone.

Bone tumours

• Presentation: pain, tenderness, swelling, deformity, pathological fracture

• 1) secondary tumours: 70% of cancer involves bone; spreads to bone by blood or vertebral lymphatics– Deposits are usually: multiple, in axial skeleton, in the red marrow, lytic,

may be sclerotic (prostate, breast)

– (role of vessels, prostaglandins, osteoclast activing factor)

– Effect: hypercalcemia, leukoerythroblastic anaemia

• 2) marrow tumours: leukaemia, lymphoma, myeloma

• 3) primary bone tumours: benign or malignant

Primary bone tumours

• Majors– Osteosarcoma– Chondrosarcoma– Ewing sarcoma– Giant cell tumour

• Others– Paget’s disease– Fibrous dysplasia– Other cartilage tumours– Other bone tumours– cysts

Osteosarcoma

• Primary (70%): 10-25 years, males x 2, some familial or follow retinoblastoma

• Secondary (30%): paget’s disease, enchondromatosis, chronic osteomyelitis, fibrous dysplasia, bone infarcts or fractures, radiation (radium or external), alkalating agents

• Aetiology: ? Virus, immunological, genetic, related to bone mass• Usual findings: in medulla of long bones at metaphysis, 70% about the knee

as bulky mass– Codman’s triangle on x-ray– 25% have metastases (usually lung) at diagnosis, mean survival 3 years– Variants: may be cortical, periosteal, parosteal, extraskeletal– Microscopy: osteoblastic (but also chondroblastic, fibroblastic, angioblastic

areas)

Chondrosarcoma

• Males x 2, age 50s and 60s

• Primary (90%)

• Secondary (10%) enchondromas etc. as for osteosarcoma

• Presentation: lobulated mass with spotty calcification; pelvic bone (50%) or other central sites

• Correlation of clinical, x-ray and histopathology essential (malignant central lesion histologically similar to a benign peripheral lesion)

• Microscopy: most are low grade (grade 1) 90% 5-year survival; grade 3 have poor survival (40% 5-year survival)

Ewing’s Sarcoma

• Presentation: Pain, tenderness, swelling, systemic symptoms (may simulate osteomyelitis), age 5-20, males x 2, involves pelvis or long bones, 25% have metastases (to lung, brain, other bones) at diagnosis

• Begins in medulla of metaphysis or of diaphysis but spreads to periosteum producing Codman’s triangle and onion layering effect on x-ray

• Microscopy: small round cells with cytoplasmic glycogen (PAS+)

• Cell of origin unknown: ?mesenchymal, related to peripheral neuroectodermal tumour (PNET) which has neural feature; both have t(11-22), produce a fusion gene EWS-FLI1, stain with antibodies to CD99

• Survival: has improved from 10% to 75% with modern chemotherapy

Giant cell tumour

• Microscopy: neoplastic stromal cells with prominent giant cells• Exclude other lesions which may have giant cells including

brown tumour of hyperparathyroidism, gingival epulis, fibrous cortical defect, aneurysmal bone cyst, chondroblastoma. Carcinoma and soft tissue sarcoma may sometimes have prominent giant cells but rarely cause diagnostic difficulties

• Occur in epiphysis after closure (age 15-55 years), 50% about knee, more frequent in females

• Most are benign, one-third to one-half recur, 10% are aggressive or malignant but such behaviour can not reliably be predicted histologically

Paget’s disease

• Bone disease with osteoclastic (early), mixed , and osteosclerotic (late) stages

• May be monostotic or polyostotic; usually involves axial skeleton

• Involves 1-3% of the older population, males (4:3) more frequently

• Prodominantly a disease of people of N European stock, ? Viral cause, viral type particles in osteoclasts

• Usually asymptomatic (identified incidentally on x-ray or by raised alkaline phosphatase). Causes excess production of collagen products (hydroxyproline)

• May cause pain, deformity, nerve pressure, haemodynamic shunting of blood, pathological fracture, sarcoma

• Therapy: calcitonin, diphosphonates, mithramycin, fluorides

Fibrous dysplasia

• A developmental defect showing impaired bone formation with disorganised osseous and fibrous tissue which fractures and causes deformities

• Usually monostotic, ribs, skull, jaw, femur (in teens and 20s)

• In 25% polyostotic (usually children)

• Occasionally (3%) with pigmentation, precocious puberty (females) and endocrinopathy (hyperthyroidism, hyperparathyroidism, hyperpituitarism, diabetes) as Allbright’s syndrome

Other cartilage tumours

Osteochondroma• Disordered growth from epiphysis to form abnormal metaphyseal spur• Mainly a sporadic disorder of long bones in adolescence• Occasionally multiple as an autosomal dominant disorder• Rarely sarcoma may superveneEnchondroma• Sporadic single lesions, may be asymptomatic or cause deformity• Multiple (enchondromatosis) (Ollier’s disease) as a non-hereditiary disease

involving hand and feet in childhood• Multiple with multiple cavernous haemangiomas as a familial disease

(Maffucci’s disease)Rare lesions: Chondromyxoid fibroma, Chondroblastoma

Other bone tumours

Osteoma• Rare, usually involves face of skull• Gardner’s syndrome: osteomas with epidermal cysts, teeth disorders,

desmoid tumours, and colonic adenomatous polyps

Osteoid osteoma• Tiny (3-10 mm) vascular osteoblastic lesion (nidus), regarded as a benign

neoplasm, surrounded by a large reactive osteosclerotic rim• Larger, histologically similar lesion in vertebrae and lower limbs is painless

(osteoclastoma)• Causes severe night pain relieved by aspirin, cured by excision• Age 5-25, males x 3• Site: metaphysis of long bones especially of lower limb

Bone Cysts

• Simple: solitary fluid-filled lesions in metaphysis near epiphyseal plate. Two-thirds in proximal long bones, males x 3, childhood and adolescence

• Aneurysmal bone cyst: blood-filled spaces separated by fibrous septae distend bone and may extend into surrounding tissue (may be secondary to degeneration of another lesion). Involve vertebrae and flat bones (10-20 years; M=F)

• Fibrous cortical defect (non-ossifying fibroma): Defect of epiphyseal plate growth extending into the metaphysis, usually about the knee, in children

Soft tissue tumours

• Muscle, fat, fibrous tissue, vessels, nerves

• Benign (-oma): (leio/rhabdo)myoma, lipoma, neuroma, angioma, fibroma, neurofibroma

• Malignant (sarcoma): leio/rhabdo myosarcoma, liposarcoma, fibrosarcoma, angiosarcoma

Connective tissue neoplasms

Leiomyoma Leiomyosarcoma

Rhabdomyoma Rhabdomyosarcoma

Lipoma Liposarcoma

Fibroma Fibrosarcoma

Chondroma Chondrosarcoma

Osteoma Osteosarcoma

Synovioma Synovial sarcoma

Angioma Angiosarcoma

Neuroectodermal tumours

Central• Glial: astrocytoma, oligodendroglioma,

ependyoma• Neural: medulloblastoma, neuroblastoma,

ganglioneuroma, meningomaPeripheral• Schwannoma, Neurofibroma, • Naevus, Melanoma

Vascular Tumours

• Haemangioma, benign. capillary, cavernous, granuloma pyogenicum, Lindau von Hipple glomus, telangiectasia, spider naevus, naevus flammeus (simple birthmark). port-wine stain (disfiguring birthmark), Sturge Weber, Osler Weber Rendau

• Malignant.• Haemangioendothelioma: Skin (spleen, liver), low grade malignancy.• Epithelioid: soft tissue, lung - 20% metastasise.• Haemangiopericytoma: lower extremites, retroperitoneal - 50% metastasise• Angiosarcoma: Skin, soft tissue, breast, liver (arsenic, thorotrast, PVC) .

High grade malignancy • Kaposi’s sarcoma: immune deficiency, herpes HHV8

Some varieties of soft tissue tumours (1)

• Synovial sarcoma: biphasic, t(X:18), metastasise to lymph nodes (most sarcomas spread to lung)

• Small round blue cells (broad differential, children)• Spindle cell (broad differential; use of

immunohistochemistry, grade 1-3)• Fibrohistiocytic tumours: classification problem

Some varieties of soft tissue tumours (2)

• Nodular fasciitis: a reactive pseudosarcomatous proliferation

• Myositis ossificants: a reactive proliferation forming bone

• Fibromatosis (Dupuytren of hand, deeper desmoids, locally infiltrative)

• Lipoma: commonest soft tissue tumour• Haemangioma: wide variety