Pathology of the musculoskeletal system Markéta Hermanová Pathology of the bones Osteoporosis nReduction of bone mass in the presence of normal mineralisation; due to increased bone resorption, decreased bone formation, or both n nCommon in elderly, particularly in females, follows any form of immobility n nComplication of steroid therapy and Cushing´s syndrome n nAssociated with alcoholism, diabetes, livers disease and smoking n nCommon predisposing factor of fractures, particularly neck of femur, causes skeletal deformities and bone pain (due to compression fractures) n Osteoporosis: increased porosity of the skeleton resulting from reduced bone mass nPrimary -postmenopausal -Senile n nSecondary n1. Endocrinopathies -hyperparathyreoidism -hypo-hyperthyreoidism -hypogonadism -pituitary tumors -type I diabetes mellitus -Addison disease n2. Neoplasia (multiple myeloma, carcinomatosis) n3. GIT disorders (malnutrition, malabsorption, hepatic insufficiency, vit. C,D deficiencies) n4. Rheumatologic diseases n5. Drugs (anticoagulans, chemotherapy, corticosteroids, alcohol, anticonvulsants) n6. Miscellaneous (osteogenesis imperfecta, immobilisation, pulmonary diseases, homocystinuria, anemia) - n Regulation of calcium metabolism nParathyroid hormone (PTH) nVitamin D -to stimulate bone calcium mobilisation (PTH) -to increase renal reabsorption of calcium in the distal tubule (PTH, vitamin D) -to stimulate intestinal calcium and phosphate absorption (vitamin D) - nCalcitonin -produced by parafollicular cells of the thyroid -to lower serum calcium, if elevated n Rickets and osteomalacia nDue to deficient mineralisation of organic bone matrix n nRickets occurs in children and causes bone deformities n nOsteomalacia occurs in adults, causes susceptibility to fracture but few deformities n nDue to lack of active metabolites of vitamin D n nHypovitaminosis D due to dietary deficiency of vitamin D, lack of sunlight, intestinal malabsroption, failure to metabolise vitamin D (in renal and liver diseases, in congenital enzyme deficiences) n Hyperparathyreoidism and hypercalcaemia nHyperparathyreoidism (↑PTH) causes increased osteoclastic breakdown of bone -primary: hyperplasia, tumor (adenoma) -secondary: in hypocalcemia resulting in increased secretion of PTH n(e.g. in renal failure: renal osteodystrophy (combination of osteomalacia and ↑PTH) -secretion of PTH related peptide by malignant tumor n nBone lesions: thin cortex, osteopenia, fibrovascular tissue within bone marrow spaces, hemorrhages, organisation of hematoms, pseudocysts, brown tumors (mass of reactive tissue) n Pathologic fracture and brown tumor in hyperparathyreoidism WHO-Bone Tumours_03 WHO-Bone Tumours_04 Moller-Barlow disease – avitaminosis C nvitamin C – hydroxylation of molecules of procollagen n ndecreased secretion of collagen by fibroblasts and osteoblasts n nhemorrhages, subperiostal hematomas, bleeding into joint spaces n ndecreased production of osteoid and proliferation of cartilage (mineralization normal) – infractions, fractures, lysis epiphyseos, periostitis ossificans n Paget disease (osteitis deformans) 1.osteolytic stage 2.osteoclastic-osteoblastic stage 3.osteosclerotic stage 4. nEtiology?? nslow virus infection (paramyxovirus) – viral particles seen in osteoclasts nhereditary component (linked to locus on 18q) n nPagetic bone enlarged with thick, coarsened cortices and cancellous bone nClinically pain, deformities, fractures, nerve compression nMonoostotic – Polyostotic (15 %) nHigher incidence of tumors and tumor-like lesions n n paget Osteomyelitis nInflammatory lesion due to bacterial infection of bone nBacteria enter bone either from blood or directly through skin wound over a compound fracture nNecrotic bone forms inner sequestrum nReactive new bone forms outer involcurum nMost common in children (most usual Staphylococcus aureus infection) nA comlication of advanced tuberculosis nMay complicate the use of internal fracture fixation divices n Infections - osteomyelitis nPyogenic osteomyelitis -Staphylococcus a., E. coli, Pseudomonas, Klebsiella, Haemophilus i., Salmonella,… -acute, subacute, chronic -acute inflammatory reaction, subperiostal abscess, necrosis (sequestrum), draining sinus -chronic osteomyelitis: reactive periostitis ossificans (involcurum) - nTuberculous osteomyelitis -hematogenous spread of BK into bones (rarely direct extension or lymphogenous spread) -Pott disease in the spine n nSkeletal syphilis -STD, Treponema pallidum -congenital syphilis (spirochetes localized in areas of active enchondral ossification (osteochondritis) and in the periosteum (periostitis) -acquired syphilis (tertiary stage; reactive periostitis: nose, palate, skull, extremities – tibia – saber shin) - Osteomyelitis Avascular necrosis: osteonecrosis nIdiopathic (m. Perthes – femur, m. Kohler – os naviculare) nTraumatic (mechanical vascular interruption, fracture) nCorticosteroids nInfections nDysbarism (nitrogen bubbles) nRadiation therapy (vessel injury) nConnective tissue disorders (vasculitis, vessel injury) nPregnancy nGaucher disease nSickle cells and other anemias nAlcohol abuse nChronic pancreatitis nTumors nEpiphyseal disorders Inherited disease nAchondroplasia -AD, single gene disorder (gene for fibroblast growth factor receptor) -short stature, rhizomelic shortening of the limbs, frontal bossing, midface deficiency n nOsteopetrosis -reduced osteoclast bone resorption, diffuse symmetric skeletal sclerosis -bones abnormaly brittle (osteosclerosis fragilis generalisata) -AR malignant type and AD benign type -Anemia (reduced bone marrow space), extramedullar hemopoiesis – hepatosplenomegaly, repeated infections, fractures, cranial nerves problems – the result of nerve compression (optic atrophy, deafness, facial paralysis) n Inherited disease - nmucopolysacharidoses -a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans. These long chains of sugar carbohydrates occur in each of our cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. -chondrocytes most severly affected -abnormalities of hyaline cartilage result in short stature, chest wall abnormalitites, malformed bones - nosteogenesis imperfecta (collagen I disorder) -phenotypically related disorders (types 1-4) ; variable severity of the disease within the types -Clinically: bone fragility, hearing loss, blue sclerae, dentinogenesis imperfekta - ntype 2, 10, and 11 collagen diseases -achondrogenesis (short trunk, severely shortened extremities, relatively enlarged cranium, flattened face) -hypochondrogenesis (similar phenotype) n - - n Malignant tumours of the bone Tumor % Usual age M:F Sites affected Behaviour Treatment, prognosis Osteosarcoma 30 Adolescents 2:1 Long bones, distal femur, proximal tibia Rapid growth, pain, swelling, lung metastases Surgery and chemotherapy 40% + cure rate Chondrosarcoma 15 35-60 2:1 Pelvis, ribs, spine, long bones Slow enlargement, lung metastases Surgery 75% cure rate Fibrosarcoma 20 Any age, peak 30-40 3:2 Femur, tibia, humerus, pelvis Local growth, vascular invasion Surgery 40% cure rate Ewing´s sarcoma 7 Children and teenagers 2:1 Long bones, pelvis, ribs Widespread metastases Surgery and chemotherapy 50% + cure rate + secondary, metastatic tumors: breast, lung, prostate, kidney, thyroid cancer,….. + osteolytic lesions in myeloma (plasmocytoma) Benign bone tumors nOsteochondorma (exostosis) nEnchondroma nChondroblastoma nChondomyxoid fibroma nOsteoma nOsteoid osteoma Locally aggressive or recurent tumors nGiant cell tumor (osteoclastoma) nOsteoblastoma nChordoma nAdamantinoma Pathology of the joints Osteoarthritis (osteoarthrosis) nCommon painful, disabling degenerative joint disease n nPrimarily affects cartilage of weight-bearing joints (e.g. hips, knees) n nErosion of cartilage leads to secondary changes in underlying bone n nOnly limited inflammatory changes in synovial membrane n nOsteoarthritis of hip and knee can be treated surgically by joint replacement Rheumatoid arthritis na chronic systemic inflammatory disorder affecting also joints n na nonsuppurative proliferative, inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints n nautoimmune disease, in a genetically susceptible host; 95 % RA patients have positivity of rheumatoid factor (IgM against Fc fragment of IgG – immunocomplexes); F>M n nsmall bones of the hands, wrist, ankels, elbows, knees, cervical spine, hips affected; lumbosacral region spared n n Rheumatoid arthritis nsystemic features include: subcutaneous rheumatoid nodules, anaemia, lymphadenopathy and splenomegaly, serositis (e.g. pericarditis), Sjögren syndrome, uveitis, vasculitis,…. njuvenile rheumatoid arthritis: children can be also affected n RA pannus Seronegative spondylarthropathies: spondylarthropaties assoc. with HLA-B27 haplotype nAnkylosing spondylitis -Inflammatory disorder of spinal joints -Chronic synovitis, destruction of cartilage, bony ankylosis (sacroiliac and apohyseal joints), ossification of tendinoligamentous insertion -Fusion of vertebral bodies inhibits flexion and rotation, especially in cervical segment, some patients develop fixed spinal deformities -90 % of cases have the HLA-B27 haplotype -Systemic feature include peripheral arthritis, uveitis, chronic inflammatory bowel disease - nReiter´s disease -arthritis + conjuctivitis + urethritis -80 % HLA-B27+; autoimmune reaction initiated by prior infection -infections of genitourinary (Chlamydia) and GIT (Shigella, Salmonella, Yersinia, Campylobacter) n n+ arthritis in psoriasis (distal interphalangeal joints); in IBD (inflammatory bowel disease) - - Ankylosing spondylitis nBacterial arthritis -Staphylococcus aureus -Staphylococcus albus (prosthetic joints) -Streptococcus pyogenes -Haemophilus influenzae -Diplococcus pneumoniae -Neisseria gonorrhoeae n ntbc arthritis -complication of tbc osteomyelitis or hematogenous dissemination from a visceral site of infection n nLyme arthritis -Borrelia burgdorferi (transmitted by ticks) n nVirus-associated arthritis -parvovirus B19, rubella, HCV n nInfective discitis -Staphylococcus aureus, Mycobacterium tuberculosis, Brucella abortus n - Infective arthritis Rheumatic arthritis – rheumatic fever nan acute immunologically mediated multisystem inflammatory disease occuring a few weeks after an episode of group A streptococcal pharyngitis n nmigratory polyarthritis of large joints npancarditis n n !!! Rheumatic fever: immunologically mediated post-streptococcal illness affecting heart and joints Rheumatoid disease: autoimmune disorder causing arthritis, completely unrelated to rheumatic fever Gout dna -Painful acute inflammatory response to tissue deposition of urate crystals -Most commonly affects metatarsopahlangeal joint of first toe -Much more common in males than females, onset 40-60 years, familial tendency -Serum auric acid levels are raised -May be associated with chronic renal disease Pathogenesis: -Idiopathic -Impaired uric acid excretion secondary to chronic renal failure, thiazide diuretics -Increased uric acid production (in increased cell turnover, in specific enzyme defects) -High dietary purine intake Connective tissues Connective tissue diseases, systemic nMultisystem disorders, often affecting joints, skin, subcutaneous tissues n nFemales preferentially affected (except polyartheritis nodosa ans ankylosing spondylitis), weak genetic tendency n nChronic clinical course, may respond to antiinfalmmatory drugs, immunosuppressive drugs (e.g. steroids) n nFirst presentation may be during adolescence or early adult life n nImmunological abnormalities often present (circulating auto-antibodies or evidence of immune complexes) Clinical and pathological features of the major connective tissue diseases Disease F:M Age (onset) Clinical features Immune abnormality Pathology Rheumatoid arthritis 3:1 Young and middle aged adults, also children Chronic polyarthritis Subcutaneous nodules Splenomegaly autoAb against native Ig (rheumatoid factor) Chronic synovitis Granuomas in subcutaneous tissues Fibrinous pericarditis Systemic lupus erythematosus 8:1 Young and middle aged adults Erytematous (butterfly) skin rash Renal disease, glomerular damage Light sensitivity Arthritis, arthralgia. Anaemia, leukopenia autoAb against nuclear and cytoplasmic proteins and other cellular component Synovitis, glomerulonephritis, erytematous skin rashes Polyarteritis nodosa 3:1 Any age, chiefly middle aged adults Arthralgia Abdominal pain Ischaemic lesions in many organs, neuropathy, renal damage Fever, Leukocytosis, eosinofilia Some antinuclear antibodies and rheumatoid factor Necrotising vasculitis of medium-sized arteries Ankylosing spondylitis 2:1 Young adults Back pain Arthritis Uveitis Most HLA-B27+ Spondylitis, bony fusion of spine and SI joints Clinical and pathological features of the major connective tissue diseases Disease F:M Age at onset Clinical features Immune abnormality Pathology Poly- and dermatomyositis 3:1 Adults (DM also in children) Muscle weakness, pain, tenderness, skin rashes in DM Myositis assoc. autoAb Inflammatory myositis, in some cases paraneoplastic Polymyalgia rheumatica 2:1 Elderly Malaise, weakness, muscle aching, esp. shoulders, pelvis, hips No consistent changes Raised ESR Non specific muscle biopsy changes, some overlap with temporal arteritis Temporal, giant cell arteriis 2:1 Elderly Headache Visual loss Tender scalp No consistent changes Raised ESR Chornic granulomatous arteritis, head and neck arteries Systemic sclerosis (scleroderma) 3:1 30-50 years Raynaud´s phenomenon Thick skin Polyarthritis Dysphagia. Dyspnoe. Hypertension RF (25 %) Antinuclear Ab (50 %) Fibrosis of subcutaneous and submucosal tissue, fibrosis of muscular arteries Soft tissue tumors Benign Malignant Lipoma Liposarcoma Angioma Angiosarcoma Leiomyoma Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma Fibroma Fibrosarcoma „Synovial“ sarcoma (=soft tissue sarcoma) + Tumor-like lesions of connective tissues: -Fibromatoses (palmar, palntar, abdominal,….) -Nodular fasciitis -Myositis ossificans Skeletal muscle pathology: Neuromuscular disorders Neuromuscular disorders nNeurogenic disorders – neurogenic atrophy n nDisorders of neuromuscular transmission n nMyogenic disorders -Muscular dystrophies -Congenital structural myopathies n nInflammatory myopathies – myositis n nMyopathies associated with metabolic diseases -Glycogenosis (glycogen storage diseases) -Carnitine deficiency -Mitochondrial disorders n nOthers -myopathies in endocrinopathies (thyreotoxic and hypothyreoid myopathy, steroid myopathy,… ) -drug induced myopathy (steroid myopathy, myopathy in patients treated with hydrochloroquine,…) -ethanol myopathy - n n - - Neurogenic disorders (denervation atrophy) nMotor neuron diseases -Amyotrophic lateral sclerosis -Spinal muscular atrophy - nRadiculopathies -discopathies -extramedullar tumors -polyradiculoneuropathy-immune mediated-Guillain-Barré syndrome – demyelinating disorder n nDamage of peripheral nerves/peripheral neuropathies n inflammatory, traumatic, metabolic (diabetic), toxic, genetic (hereditary motor and sensory neuropathies), neoplastic n n n n Motor neuron tract Upper motoneuron Lower motoneuron Motor neuron diseases -Amyotrophic lateral sclerosis n (both upper and lower motorneurons affected, distal and proximal muscle weakness and wasting spasticity) n -Progressive muscular atrophy n (lower motor neuron involvement, weakness an wasting of distal muscles, fasciculations and absent reflexes) n -Progressive bulbar pulsy n (cranial nerves involvement results in weakness of the tongue, palate, pharyngeal muscles) n Amyotrophic lateral sclerosis n90 % sporadic ALS nF:M – 1,7:1 nolder people, survival 3-4 years, first symptoms in 56-63 years, upper extremities preferentially affected, bulbar symtomatology n n10 % hereditary ALS n4th decade, juvenile forms, F:M – 1:1 Spinal muscular atrophy nInherited; AR; homozygous loss of SMN1 (survival motor neuron gene) n noccuring in 1/6000-10000 births; 2-3 % of populations are carriers n n2nd most common inherited disorder after cystic fibrosis (mucoviscidosis) n n n n Allelic variants of SMA nType 1 (Werdnig-Hoffmann disease) -Rapidly progressive, onset before 3 months of age, death before the age of 18 months - nType 2 -Onset between 6-12 months of age, more slowly progressive with variable life expectancy - nType 3 (Kugelberg-Welander disease) -Onset between 2-15 years of age, slowly progressive - nType 4 -Affects adults, very slow course causing mild disability n n Peripheral neuropathy: peripheral nerve disorders nMononeuropathy -a single nerve involved -e.g. carpal tunnel syndrome - nMononeuritis multiplex -several isolated nerves involved -e.g. polyarteritis nodosa, sarcoidosis n nPolyneuropathy: multiple nerve involvement nMainly motor: e.g. Guillain-Barre sy (autoimmune polyradiculoneuritis) nMainly sensory: carcinomatous neuropathy nSensorimotor: e.g. alcoholism nAutonomic: e.g. diabetes Intervertebral disc prolapse Disorders of neuromuscular transmission nMyasthenia gravis -autoimmune disease, loss of acetylcholine receptor due to production of autoAb -fluctuating progressive muscle weakness (ocular, bulbar and proximal limb muscles preferentially affected) -females more often affected -thymic hyperplasia or thymoma in many patients -immunosuppressive treatment and thymectomy n nLambert-Eaton myasthenia syndrome -paraneoplastic, complication of malignancy (e.g. lung cancer – small cell carcinoma) -limb girdle and proximal muscle weakness -autoimmunity to calcium channels??? n Muscular dystrophies nheterogeneous group of inherited disorders of muscles n nprogressive muscle weakness and wasting n n„dystrophic“ muscle biopsy changes and replacement of muscle by fibrofatty tissue n ndefects in muscle proteins n nclinical and genetic heterogeneity n nsome are associated with multisystem involvement (including cardiac (arrhytmias, both dilated and hypertrophic cardiomyopathies) and CNS) n Muscular dystrophies nDystrophinopathies (X-linked) nLimb-girdle muscular dystrophies; LGMDs (AR, AD) nEmery-Dreifuss muscular dystrophy (X-linked, AD) nFacioscapulohumeral muscular dystrophy (AD) nCongenital muscular dystrophy (AR) nOculopharyngeal muscular dystrophy (AD) nDistal myopathy (AR, AD) nBethlem´s myopathy (AD) nBarth´s syndrome (X-linked) nMyotonic dystrophy (AD) n Diagnosis of muscular dystrophies nClinical assessment -general neurological examination -serum creatine kinase (CK) level -neurophysiology – electromyography (exclusion of neuropathy) -muscle imaging (MRI, CT) n nMuscle biopsy (2/3 genetically defined LGMD are suggested by biopsy) -histopathology -immunohistochemistry (IH), immunofluorescence (IMF) -immunoblotting n nMolecular genetic testing – mutational analysis (the gold standard for diagnosis) -DNA -mRNA Duchenne muscular dystrophy (DMD) nDue to severe mutations in dystrophin gene n nX-linked; female carriers n nMedian age of presentation: 3.5 years; progressive course; life expectancy 20 years; calf pseudohypertrophy n nMyogenic lesion in muscle biopsy, loss of dystrophin 29-b11a immunofluorescence, loss of dystrofin in DMD nBecker muscular dystrophy (BMD) nDue to in-frame deletion in dystrophin gene nMilder allelic variant of DMD nTruncated protein dystrophin is produced n nFemale carriers of DMD/BMD nSymptomatic nAsymptomatic n Limb-girdle muscular dystrophies nGenetically and clinically heterogeneous group of progressive muscular dystrophies n nMuscles of the pelvic and shoulder girdle are preferentially affected n n21 forms autosomal recessive n8 forms autosomal dominant n + AR, AD and X-linked muscular dystrophies with LGMD phenotype n fa-lgmd01 Congenital muscular dystrophies (CMD) nCongenital, presented at birth, progressive n nInherited, AR, genetically and phenotypically heterogeneous n nMuscle weakness, hypotonia, contractures; in some subtypes structural lesions of CNS and retina n nmuscle biopsy: myogenic lesion, often degeneration, regeneration, and also inflammatory pattern in muscle biopsy Congenital structural myopathies nA distinctive abnormality in skeletal muscle fibres on the cellular level; observable via light microscope n nSymptoms of muscle weakness and hypotonia. n nIs a congenital disorder, meaning it occurs during development and symptoms present themselves at birth or in early life. n nIs a genetic disorder n nClinically and genetically heterogeneous n Congenital structural myopathies nCentral core disease nMulti and minicore disease nNemaline myopathy nCentronuclear myopathy nCongenital fibre type disproportion n n 47-b18 50-b21c Inflammatory myopathies -myositis nPolymyositis -females, autoimmune disease, ofted associated with other autoimmune diseases (anti-Jo-1 protilátky) -Endomysial inflammatory infiltration n nDermatomyositis -Juvenile and adult, more in females, dermatitis and myopathy -Perivascular inflammatory infiltration (CD20+, CD4+, MAC+) -Perifascicular atrophy - nMyositis/myopathy with inclusion bodies -Sporadic and hereditry -Resistent to imunosupresive therapy n 60-f07 Polymyositis: endomysial lymhocytic inflammatory infiltration Myotonia: the sustained involuntary contraction of a group of muscles; patients complain of stiffness, difficulties in releasing their grip n1. Myotonia congenita (reduction of functional chloride channels) -Becker type (AR) -Thomsen type (AD) - n2. Myotonic dystrophy -DM1 (AD; 19q13.3, myotonin proteinkinase) n congenital (dementia, hypotonia), classic (myotonia, muscle weakness, atrophy, cataract, endocrinopathies), milder form -DM2 (AD; 3q21; zinc finger protein)- PROMM – proximal myothonic dystrophy Malignant hyperpyrexia nInherited disorder; AD; diagnostic in vitro contraction test n nMutation in ryanodin receptor gene; association with central core disease n nHypermetabolic state triggered by the induction of anesthesia, usually with halogenated inhalational agents and succinylcholine n nTachycardia, tachypnoe, muscle spasms, hyperpyrexia; without intensive treatment fatal clinical outcome n nChannelopathy; increased levels of free calcium in sarcoplasms of myofibers Storage of glycogen in muscles in glycogenosis (inherited; AR) nPAS+ (glycogen) n 52-b22b PAS Muscle biopsy nSpecialized laboratories in departments of pathology (FN Brno, FN Motol) nGuided using imaging and results of clinical assessment nOpen versus needle biopsy nStandard histological techniques, enzyme histochemistry nImmunohistochemistry and immunoblotting -panel of antibodies -evaluation of primary and secondary changes on immunoanalysis nDirection of reasonable mutational analysis n n n sval-herm-10772-03-20x-nadh-2 sval-herm-16368-03-20x-he-1 Lobulated fibers in LGMD2A Dystrophic features in biopsy Thank you for your attention….