MS II - Pathology of Bones and Skeletal Muscles - Lecture Notes

MS II - Pathology of Bones and Skeletal Muscles Objectives Discuss the different diseases involving the bone and skeletal muscle Discuss the pathogenesis of each disease Discuss the diagnostic modalities for each disease Discuss the treatment of skeletal and muscle diseases  Inorga...

MS II - Pathology of Bones and Skeletal Muscles Objectives Discuss the different diseases involving the bone and skeletal muscle Discuss the pathogenesis of each disease Discuss the diagnostic modalities for each disease Discuss the treatment of skeletal and muscle diseases  Inorganic elements calcium hydroxyapatite (65%) Bone Cells + Organic (35%) proteins Organic components Osteoprogenitor cells pluripotent mesenchymal stem cells that are located in the vicinity of all bony surfaces Osteoblasts and surface lining cells - synthesize, transport, and arrange the many proteins of matrix - initiate the process of mineralization  Osteocytes - more numerous ; outnumber osteoblasts (10:1) - control second-to-second fluctuations in serum calcium and phosphorus levels Osteoclasts Responsible for bone resorption Proteins Osteoblast-Derived Proteins Type 1 collagen Cell adhesion proteins Osteopontin, fibronectin, thrombospondin Calcium-binding proteins Osteonectin, bone sialoprotein Proteins involved in mineralization Osteocalcin Enzymes Collagenase, alkaline phosphatase Growth factors IGF-1, TGF-β, PDGF Cytokines Prostaglandins, IL-1, IL-6, RANKL Proteins Concentrated from Serum β2-microglobulin Albumin IGF, insulin-like growth factor; TGF, transforming growth factor; PDGF, platelet-derived growth factor; IL, interleukin; RANKL, RANK ligand  Homeobox genes – blueprint for skeletal morphogenesis Mesenchymal cells Bone Growth ↓ ↓ and Development Chondrocytes Osteoblasts ↓ ↓ Cartilage Bone  primary center of ossification the periosteum in the midshaft of the anlage produces osteoblasts that deposit the beginnings of the cortex secondary center of ossification in the epiphyses, a similar sequence of events leading to the removal of cartilage occurs such that a plate of the cartilage model becomes entrapped between the expanding centers of ossification (physis or growth plate) Figure 26-7 Active growth plate with ongoing enchondral ossification. 1, Reserve zone. 2, Zone of proliferation. 3, Zone of hypertrophy. 4, Zone of mineralization. 5, Primary spongiosa. Developmental (Genetic) and Acquired Abnormalities in Bone Cells, Matrix, and Structure 1. Defects in Nuclear Proteins and Transcription Factors 2. Defects in Hormones and Signal Transduction Mechanisms 3. Defects in Extracellular Structural Proteins 4. Defects in Folding and Degradation of Macromolecules 5. Defects in Metabolic Pathways  failure of development of a bone (congenital absence of a phalanx, rib, or clavicle) formation of extra bones (supernumerary ribs or digits) fusion of two adjacent digits (syndactyly) development of long, spider-like digits failure of closure of the spinal column and skull (craniorachischisis)  most common disease of the growth plate and is a major cause of dwarfism defect in paracrine cell signaling manifests as a reduction in the proliferation of the chondrocytes in the Achondroplasia growth plate (FGFR3) shortened proximal extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose  most common lethal form of dwarfism also caused by a mutation in FGFR3 micromelic shortening of the limbs, frontal bossing with relative macrocephaly, a Thanatophoric small chest cavity, and a bell-shaped dwarfism abdomen histologic changes in the growth plate show diminished proliferation of chondrocytes and poor columnization in the zone of proliferation Type 1 brittle bone disease mutations in the genes that code for the Collagen α1 and α2 chains of the collagen molecule cortical thinning and attenuation of Diseases trabeculae (Osteogenesis blue sclerae, hearing loss and dental imperfections (small, misshapen, and blue- Imperfecta) yellow teeth)  Subtype Inheritance Collagen Defect Major Clinical Features Postnatal fractures, blue OI I Autosomal dominant Decreased synthesis pro-α1(1) chain Compatible with survival sclerae Abnormal pro-α1(1) or pro-α2(1) chains Normal stature Skeletal fragility Dentinogenesis imperfecta Hearing impairment Joint laxity Blue sclerae Most autosomal OI II Perinatal lethal Abnormally short pro-α1(1) chain Death in utero or within days of birth recessive Some autosomal Skeletal deformity with excessive fragility and Unstable triple helix dominant multiple fractures ?New mutations Abnormal or insufficient pro-α2(1) Blue sclerae Autosomal dominant Altered structure of pro-peptides of OI III Progressive deforming Compatible with survival (75%) pro-α2(1) Autosomal recessive Impaired formation of triple helix Growth retardation (25%) Multiple fractures Progressive kyphoscoliosis Blue sclerae at birth that become white Hearing impairment Dentinogenesis imperfecta Postnatal fractures, normal OI IV Autosomal dominant Short pro-α2(1) chain Compatible with survival sclerae Unstable triple helix Moderate skeletal fragility Short stature Sometimes dentinogenesis imperfecta Figure 26-8 Skeletal radiograph of a fetus with lethal type II osteogenesis imperfecta. Note the numerous fractures of virtually all bones, resulting in accordion-like shortening of the limbs. Types 2, 10, and 11 Collagen Diseases Short trunk, severely shortened Achondrogenesis II COL2A1 Type 2 collagen extremities, relatively enlarged cranium, flattened face Short trunk, shortened extremities, Hypochondrogenesis COL2A1 relatively enlarged cranium, flattened face Myopia, retinal detachment, hearing Stickler syndrome COL2A1 Type 2 collagen loss, flattened face, premature osteoarthritis Multiple epiphyseal Short or normal stature, small COL9A2 Type 9 collagen dysplasia epiphyses, early onset osteoarthritis Mild short stature, bowing of lower Schmid metaphyseal COL10A1 Type 10 collagen extremities, coxa vara, metaphyseal chondrodysplasia flaring  group of lysosomal storage diseases caused by deficiencies in the enzymes that degrade dermatan sulfate, heparan sulfate, and keratan sulfate many of the skeletal manifestations result Mucopolysaccharidoses from abnormalities in hyaline cartilage, including the cartilage anlage, growth plates, costal cartilages, and articular surfaces short stature and have chest wall abnormalities and malformed bones  marble bone disease /Albers-Schönberg disease reduced osteoclast bone resorption, resulting in diffuse symmetric skeletal Osteopetrosis sclerosis 4 types of osteopetrosis: infantile malignant osteopetrosis type II carbonic anhydrase deficiency autosomal-dominant types I and II  bones lack a medullary canal, and the ends of long bones are bulbous (Erlenmeyer flask deformity) and misshapen neural foramina are small and compress exiting nerves primary spongiosa persists and fills the medullary cavity leaving no room for the hematopoietic marrow and preventing the formation of mature trabeculae Bone that forms is not remodeled and tends to be woven in architecture. Figure 26-9 Radiograph of the upper extremity in a patient with osteopetrosis. The bones are diffusely sclerotic, and the distal metaphyses of the ulna and radius are poorly formed (Erlenmeyer flask deformity). Figure 26-10 Section of proximal tibial diaphysis from a fetus with osteopetrosis. The cortex (1) is being formed, and the medullary cavity (2) is abnormally filled with primary spongiosa replacing the hematopoietic elements. Diseases with decreased bone mass Osteoporosis Diseases caused by Osteoclast Dysfunction Paget Disease Diseases associated with Abnormal Mineral Homeostasis Rickets and Osteomalacia Hyperparathyroidism Renal Osteodystrophy  increased porosity of the skeleton resulting from reduced bone mass Pathogenesis: Age-related changes Osteoporosis Reduced physical activity Genetic factors Nutritional state Hormonal influences  Primary Postmenopausal Idiopathic Senile Secondary Table 26-4 -- Endocrine disorders Hyperparathyroidism Hypo-hyperthyroidism Rheumatologic disease Drugs Anticoagulants Categories of Hypogonadism Pituitary tumors Chemotherapy Corticosteroids Generalized Diabetes, type 1 Anticonvulsants Addison disease Alcohol Neoplasia Miscellaneous Osteoporosis Multiple myeloma Carcinomatosis Gastrointestinal Osteogenesis imperfecta Immobilization Pulmonary disease Malnutrition Homocystinuria Malabsorption Anemia Hepatic insufficiency Vitamin C, D deficiencies Figure 26-12 Osteoporotic vertebral body (right) shortened by compression fractures, compared with a normal vertebral body. Note that the osteoporotic vertebra has a characteristic loss of horizontal trabeculae and thickened vertical trabeculae  Osteitis Deformans collage of matrix madness Stages Paget Disease 1. osteolytic stage 2. mixed osteoclastic-osteoblastic stage 3. osteosclerotic stage gain in bone mass Figure 26-14 Mosaic pattern of lamellar bone pathognomonic of Paget disease.  Pagetic bone is typically enlarged with thick, coarsened cortices and cancellous bone monostotic: 15% tibia, ilium, femur, skull, vertebra, and humerus polyostotic: 85% pelvis, spine, and skull axial skeleton or proximal femur: 80% ribs, fibula, and small bones of the hands and feet is unusual  Pain - most common leontiasis ossea - Bone overgrowth in the craniofacial skeleton Platybasia - invagination of the base of the skull and compression of the posterior fossa structures severe secondary osteoarthritis. Chalksticktype fractures- long bones of the lower extremities. Compression fractures of the spine result in spinal cord injury and the development of kyphoses. high-output heart failure or exacerbation of underlying cardiac disease  Benign lesions giant cell tumor, giant cell reparative granuloma, and extraosseous masses of hematopoiesis Sarcoma 0.7% to 0.9% of all patients 5% to 10% with severe polyostotic disease osteosarcoma, malignant fibrous histiocytoma, or chondrosarcoma arise in the long bones, pelvis, skull, and spine  defect in matrix mineralization lack of vitamin D or some disturbance in its metabolism Rickets Rickets and in children in which deranged bone growth produces distinctive skeletal deformities Osteomalacia Osteomalacia In adults because the bone that forms during the remodeling process is undermineralized results in osteopenia and predisposition to insufficiency fractures  Primary hyperparathyroidism autonomous hyperplasia or a tumor (adenoma) of the parathyroid gland, Hyperparathyroidism Secondary hyperparathyroidism caused by prolonged states of hypocalcemia resulting in compensatory hypersecretion of PTH.  ↑ osteoclast activity → ↓ bone mass entire skeleton is affected Fractures deformities caused by the stress of weight bearing joint pain and dysfunction  cortical bone (subperiosteal, osteonal, and endosteal surfaces) > cancellous bone. thinned cortices and the loss of the lamina dura around the teeth the x-ray pattern is most frequently identified along the radial aspect of the middle phalanges of the index and middle fingers cortical cutting cones composed of a spearhead arrangement of osteoclasts that bore along and enlarge haversian and Volkmann canals. dissecting osteitis in cancellous bone osteoclasts tunnel into and dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks decrease in bone density, or osteopenia. Figure 26-16 Hyperparathyroidism with osteoclasts boring into the center of the trabeculum (dissecting osteitis).  von Recklinghausen disease of bone Severe hyperparathyroidism osteitis Hallmark: 1. increased bone cell activity fibrosa 2. 3. peritrabecular fibrosis cystic brown tumors cystica - Mass of reactive tissue created by influx of multinucleated macrophages and an ingrowth of reparative fibrous tissue Figure 26-17 Resected rib, harboring an expansile brown tumor adjacent to the costal cartilage.  1. ↑ osteoclastic bone resorption 2. delayed matrix mineralization Renal (osteomalacia) 3. osteosclerosis Osteodystrophy 4. growth retardation 5. osteoporosis  1. High-turnover osteodystrophy - increased bone resorption and formation (former predominating) 2 types: 2. Low-turnover or aplastic disease - adynamic bone (little osteoclastic and osteoblastic activity) - less commonly, osteomalacia Fractures  Complete or Incomplete Closed (simple) when the overlying tissue is intact Compound fracture site communicates with the skin Classifications: surface Comminuted bone is splintered Displaced ends of the bone at the fracture site are not aligned  pathologic fracture break occurs in bone already altered by a disease process stress fracture slowly developing fracture that follows a period of increased physical activity in which the bone is subjected to new repetitive loads osteonecrosis  Avascular Necrosis result from ischemia Osteonecrosis medullary cavity of the metaphysis or diaphysis and the subchondral region of the epiphysis  (1) fracture (2) corticosteroids (3) thrombosis and embolism (4) vessel injury (secondary to vasculitis, Mechanisms radiation therapy) (5) increased intraosseous pressure with vascular compression (6) venous hypertension  Idiopathic Pregnancy Trauma Gaucher disease Table 26-5 -- Corticosteroid Sickle cell and other administration anemias Disorders Infection Alcohol abuse Associated with Dysbarism Chronic pancreatitis Osteonecrosis Radiation therapy Tumors Connective tissue Epiphyseal disorders disorders  medullary infarcts necrosis is geographic and involves the cancellous bone and marrow Subchondral infarcts necrosis involves a triangular or wedge-shaped segment of tissue that has the subchondral bone plate as its base and the center of the epiphysis as its apex Dead bone (empty lacunae) surrounded by necrotic adipocytes that frequently rupture, releasing their fatty acids, which bind calcium and form insoluble calcium soaps that may remain for life.  creeping substitution a process of necrotic trabeculae not resorbed by osteoclasts remain act as scaffolding for the deposition of new living bone In subchondral infarcts, the pace is too slow to be effective so there is eventual collapse of the necrotic cancellous bone and distortion, fracture, and even sloughing of the articular cartilage  subchondral infarcts cause chronic pain that is initially associated only with physical activity but then becomes progressively more constant as secondary changes supervene often collapse and may predispose to severe, secondary osteoarthritis medullary infarcts clinically silent except for large ones occurring in Gaucher disease, dysbarism, and hemoglobinopathies. remain stable over time and rarely are the site of malignant transformation Figure 26-19 Femoral head with a subchondral, wedge-shaped pale yellow area of osteonecrosis. The space between the overlying articular cartilage and bone is caused by trabecular compression fractures without repair. Infections  reach the bone by (1) hematogenous spread, (2) extension from a contiguous site (3) direct implantation Pyogenic Staphylococcus aureus : 80% to 90% Haemophilus influenzae and group B streptococci Osteomyelitis Escherichia coli, Pseudomonas, and Klebsiella patients with genitourinary tract infections or those who are intravenous drug abusers Salmonella patients with sickle cell disease  subperiosteal abscesses In children bec. the periosteum is loosely attached to the cortex sequestrum dead piece of bone suppurative and ischemic injury may cause segmental bone necrosis draining sinus rupture of the periosteum leads to an abscess in the surrounding soft tissue involucrum sleeve of living tissue around a segment of devitalized bone Figure 26-20 Resected femur in a patient with draining osteomyelitis. The drainage tract in the subperiosteal shell of viable new bone (involucrum) reveals the inner native necrotic cortex (sequestrum).  characteristic x-ray finding: a lytic focus of bone destruction surrounded by a zone of sclerosis complications of chronic osteomyelitis pathologic fracture secondary amyloidosis Endocarditis Sepsis development of squamous cell carcinoma in the sinus tract sarcoma  spreads through large areas of the medullary cavity and causes extensive necrosis spine (esp thoracic and lumbar vertebrae) > knees >hips Tuberculous Pott disease the infection breaks through intervertebral Osteomyelitis discs to involve multiple vertebrae and extends into the soft tissues, forming abscesses pain on motion, localized tenderness, low- grade fevers, chills, weight loss and rarely, cold fluctuant psoas abscess  congenital syphilis, 5th month of gestation and are fully developed at birth localize in areas of active enchondral ossification (osteochondritis) and in the periosteum (periostitis) Skeletal acquired syphilis seen 2 to 5 years after the initial infection Syphilis nose, palate, skull, and extremities, esp. long tubular bones (tibia) saber shin produced by massive reactive periosteal bone deposition on the medial and anterior surfaces of the tibia  Histology edematous granulation tissue containing numerous plasma cells and necrotic bone. Gummata also occur in the acquired disease The spirochetes can be demonstrated in the inflammatory tissue with special silver stains.  Bone-forming Osteoid Osteoma & Osteoma Osteosarcoma Tumors Osteoblastoma Bone Tumors and Tumor- Cartilage-forming Tumors Osteochondroma Chondroma Chondroblastoma Like Lesions Chondromyxoid Fibrous and Fibro- Fibrous Cortical Defect and Chondrosarcoma Fibroma osseous Tumors Nonossifying Fibroma Fibrosarcoma and Fibrous Dysplasia Malignant Fibrous Histiocytoma  bosselated, round to oval sessile tumors that project from the subperiosteal or endosteal surfaces of the cortex. slow-growing tumors of little clinical significance except when they cause Osteoma obstruction of a sinus cavity, impinge on the brain or eye, interfere with function of the oral cavity, or produce cosmetic problems do not transform into osteosarcoma.  Subperiosteal osteomas most often arise on or inside the skull and facial bones usually solitary and are detected in middle-aged adults. Gardner syndrome multiple osteomas composed of woven and lamellar bone that is frequently deposited in a cortical pattern with haversian-like systems some variants contain a component of trabecular bone in which the intertrabecular spaces are filled with hematopoietic marrow. Osteoid osteomas Osteoblastoma ˂ 2 cm in greatest dimension more frequently involves the spine 75% of patients under age 25 the pain is dull, achy, and not responsive to salicylates men outnumber women 2:1 predilection for the appendicular skeleton does not induce a marked bony reaction 50%:femur or tibia, where they commonly arise in the cortex and less frequently within the medullary cavity pain severe in relation to the small size of the lesion characteristically nocturnal dramatically relieved by aspirin.  Grossly: round to oval masses of hemorrhagic gritty tan tissue. Histologically Osteoid well circumscribed and composed of a morass of randomly interconnecting Osteoma & trabeculae of woven bone prominently rimmed by osteoblasts Osteoblastoma stroma surrounding the tumor bone consists of loose connective tissue that contains many dilated and congested capillaries. Figure 26-21 Osteoid osteoma composed of haphazardly interconnecting trabeculae of woven bone that are rimmed by prominent osteoblasts. The intertrabecular spaces are filled by vascular loose connective tissue. Figure 26-22 Specimen radiograph of intracortical osteoid osteoma. The round radiolucency with central mineralization represents the lesion and is surrounded by abundant reactive bone that has massively thickened the cortex.  malignant mesenchymal tumor in which the cancerous cells produce bone matrix most common primary malignant tumor of bone 20% of primary bone cancers Osteosarcoma Bimodal age distribution 75% in patients younger than age 20 Elderly Men > women (1.6:1)  anatomic portion of the bone from which they arise (intramedullary, intracortical, or surface) Degree of differentiation Multicentricity (synchronous, metachronous) Primary (underlying bone is unremarkable) or secondary (e.g., osteosarcoma associated with pre- existing disorders such as benign tumors, Paget Classification disease, bone infarcts, previous irradiation) Histologic variants (osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, and giant cell). most common subtype: primary, solitary, intramedullary, and poorly differentiated; and produces a predominantly bony matrix. Figure 26-24 Osteosarcoma of the upper end of the tibia. The tan-white tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and formed soft tissue masses on both sides of the bone. Figure 26-25 Osteosarcoma. Coarse, lacelike pattern of neoplastic bone produced by anaplastic malignant tumor cells. Note the mitotic figures. Figure 26-26 Distal femoral osteosarcoma with prominent bone formation extending into the soft tissues. The periosteum, which has been lifted, has laid down a proximal triangular shell of reactive bone known as a Codman triangle (arrow).  Exostosis benign cartilage-capped outgrowth that is attached to the underlying skeleton by a bony stalk relatively common Osteochondroma solitary or multiple long tubular bones, esp. knee occasionally, pelvis, scapula, and ribs Rarely, short tubular bones of the hands and feet  slow-growing masses can be painful if they impinge on a nerve or if the stalk is fractured. In multiple hereditary exostosis, the underlying bones may be bowed and shortened mushroom shaped and range in size from 1 to 20 cm Cap - benign hyaline cartilage varying in thickness and is covered peripherally by perichondrium. Cartilage -disorganized growth plate and undergoes enchondral ossification, with the newly made bone forming the inner portion of the head and stalk. Cortex of the stalk merges with the cortex of the host bone so that the medullary cavity of the osteochondroma and bone are in continuity.  benign tumors of hyaline cartilage Enchondromas within the medullary cavity subperiosteal or juxtacortical chondromas on the surface of bone Chondroma Ollier disease multiple enchondromas, or enchondromatosis Maffucci syndrome enchondromatosis is associated with soft tissue hemangiomas  usually solitary metaphyseal region of tubular bones (short tubular bones of the hands and feet) smaller than 3 cm and grossly are gray-blue, translucent, and have a nodular configuration Figure 26-29 Enchondroma of the phalanx with a pathologic fracture. The radiolucent nodules of hyaline cartilage scallop the endosteal surface. Figure 26-28 Enchondroma with a nodule of hyaline cartilage encased by a thin layer of reactive bone.  rare benign tumor that accounts for less than 1% of primary bone tumors young patients male-to-female 2:1 Chondroblastoma Most arise near the knee Less commonly pelvis and ribs predilection for epiphyses and apophyses Painful and restrict joint mobility Figure 26-30 Chondroblastoma with scant mineralized matrix surrounding chondroblasts in a chicken wire-like fashion  rarest teens and twenties, male preponderance Most frequently, metaphysis of long tubular bones Chondromyxoid localized dull, achy pain Fibroma eccentric geographic lucency that is well delineated from the adjacent bone by a rim of sclerosis. Occasionally the tumor expands the overlying cortex.  3 to 8 cm in greatest dimension and are well-circumscribed, solid, and glistening tan-gray Figure 26-31 Chondromyxoid fibroma with prominent stellate and spindle cells surrounded by myxoid matrix. Occasional osteoclast-type giant cells are also present. Chondrosarcoma production of neoplastic cartilage Classification accdg to site intramedullary Juxtacortical histologically conventional (hyaline and/or myxoid) clear cell Dedifferentiated mesenchymal variants arise in the central portions of the skeleton, including the pelvis, shoulder, and ribs. clear cell - epiphyses of long tubular bones In contrast to enchondroma, rarely involves the distal extremities  composed of malignant hyaline and myxoid cartilage The large bulky tumors are made up of nodules of gray-white, somewhat translucent glistening tissue Figure 26-32 Chondrosarcoma with lobules of hyaline and myxoid cartilage permeating throughout the medullary cavity, growing through the cortex, and forming a relatively well-circumscribed soft tissue mass.  10% of conventional low-grade chondrosarcomas have a second high-grade dedifferentiated poorly differentiated sarcoma, such as chondrosarcomas malignant fibrous histiocytoma, fibrosarcoma, or osteosarcoma sheets of large malignant chondrocytes that have abundant clear cytoplasm, numerous clear cell osteoclast-type giant cells, and intralesional reactive bone formation. composed of islands of well-differentiated Mesenchymal hyaline cartilage surrounded by sheets of chondrosarcoma small round cells, which can mimic Ewing sarcoma. Figure 26-33 Anaplastic chondrocytes within a chondrosarcoma.  common, found in 30% to 50% of all children older than age 2 years Fibrous developmental defects arise eccentrically in the metaphysis of the Cortical distal femur and proximal tibia, and almost one half are bilateral or multiple. Defect and small, about 0.5 cm in diameter Nonossifying 5 or 6 cm in size develop into nonossifying fibromas Fibroma not detected until adolescence. asymptomatic Figure 26-34 Nonossifying fibromas of the distal tibial metaphysis, producing an eccentric lobulated radiolucency surrounded by a sclerotic margin. Figure 26-35 Storiform pattern created by benign spindle cells with scattered osteoclast-type giant cells characteristic of a fibrous cortical defect and nonossifying fibroma.  Benign tumors likened to a developmental local arrest three distinctive patterns: (1) involvement of a single bone (monostotic) Fibrous (2) involvement of multiple, but never Dysplasia all, bones (polyostotic) (3) polyostotic disease, associated with café au lait skin pigmentations and endocrine abnormalities, especially precocious puberty Monostotic fibrous dysplasia ribs, femur, tibia, jawbones, calvaria, and humerus Asymptomatic Polyostotic fibrous dysplasia associated with café au lait skin pigmentation and endocrinopathies is known as the McCune-Albright syndrome most common clinical presentation is precocious sexual development  well-circumscribed, are intramedullary, and vary greatly in size tan-white and gritty and is composed of curvilinear trabeculae of woven bone surrounded by a moderately cellular fibroblastic proliferation. shapes of the trabeculae mimic Chinese characters bone lacks osteoblastic rimming Nodules of hyaline cartilage with the appearance of disorganized growth plate Cystic degeneration, hemorrhage, and foamy macrophages Figure 26-36 Fibrous dysplasia composed of curvilinear trabeculae of woven bone that lack conspicuous osteoblastic rimming and arise in a background of fibrous tissue.  fibroblastic collagen-producing sarcomas Fibrosarcoma of bone enlarging painful masses and metaphyses of long bones and pelvic flat Malignant bones pathologic fracture Fibrous Radiographically Histiocytoma permeative and lytic and often extend into the adjacent soft tissue Grossly large, hemorrhagic, tan-white masses that destroy the underlying bone and frequently extend into the soft tissues. Fibrosarcoma malignant fibroblasts arranged in herringbone pattern. have the appearance of a low- to intermediate-grade malignancy Malignant fibrous histiocytoma background of spindled fibroblasts arranged in a storiform pattern admixed with large, ovoid, bizarre multinucleated tumor giant cells some tumor cells resemble neoplastic histiocytes but are actually fibroblasts high-grade pleomorphic tumor Diseases of the Skeletal Muscle   Segmental necrosis: destruction of only a portion of the length of a myocyte, may be followed by myophagocytosis as macrophages infiltrate the region; loss of Reactions of muscle fibers → extensive deposition of collagen and fatty infiltration the muscle  Vacuolation: alterations in structural fiber proteins or organelles & accumulation of intracytoplasmic deposits   Regeneration occurs when peripherally located satellite cells proliferate & reconstitute the destroyed portion of the fiber. Reactions of >regenerating muscle fiber: large internalized nuclei & prominent nucleoli, and the cytoplasm, laden with RNA, becomes basophilic. the muscle fiber  Fiber hypertrophy: occurs in response to increased load, either in the setting of exercise or in pathologic conditions in which muscle fibers are injured  Progressive, autosomal recessive Spinal Destroys the anterior horn cells in the muscular spinal cord and cranial nerve motor neurons atrophy Begin in childhood and adolescence (Infantile Survival motor neuron 1 (SMN1) motor neuron SMN protein: for normal axonal transport & integrity of neuromuscular functions disease)  Werdnig- Hoffman disease (SMA type 1) > Most common form of SMA Clinical > onset at birth or within 1st 4 months > severe hypotonia course > leads to death within the 1st 3 years of life Histologic findings Large number of atrophic fibers involving the entire fascicle (Panfascicular atrophy) Scattered large fibers 2- 4x normal size   Duchenne muscular dystrophy (DMD) & Becker muscular dystrophy (BMD)  DMD > most severe & common form X linked > 1 per 3500 live male births muscular >manifest by age 5 & progresses to wheelchair dependence by age 10- 12 dystrophy >Carriers: clinically asymptomatic females often with elevated creatine kinase & minimal histologic abnormalities on muscle biopsy  DMD  normal at birth, early motor milestones are met on time  Muscle weakness Clinical > delayed walking > clumsiness course >begins in pelvic girdles then extends to shoulder girdle  Pseudohypertrophy: enlargement of muscles of lower leg associated with weakness  Pathogenesis DMD: gene located in Xp21 region encoding a 427 kD protein, dystrophin Due to deletions, frameshift & point mutations BMD Onset occurs in later childhood or adolescence followed by variable rate of progression Cardiac disease is more frequent Histological changes Variation in fiber size due to presence of both small & enlarged fibers, sometimes with fiber splitting increased numbers of internalized nuclei (beyond the normal range of 3% to 5%); (3) degeneration, necrosis, and phagocytosis of muscle fibers (4) regeneration of muscle fibers; (5) proliferation of endomysial connective tissue Necrotic & regeneratingmyofibers Advanced DMD. Severe loss of Muscle fiber with fat replacement & fibrosis  Autosomal dominant (type 1) or recessive Limb girdle (type 2) affect the proximal musculature of the muscular trunk and limbs similar to the X-linked muscular dystrophies dystrophy Mutations on sarcoglycan protein  Myotonia: sustained involuntary Myotonic contraction of a group of muscles CC: "stiffness" & difficulty in releasing grip dystrophy elicited by percussion of the thenar eminence  autosomal dominant Associated with CTG trinucleotide repeat expansion affecting the mRNA for the dystrophia myotonia protein kinase Pathogenesis Anticipation: a phenomenon in which the disease tends to increase in severity & appear at a younger age in succeeding generations Morphology striking increase in the number of internal nuclei ring fiber with a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber > may be associated with an irregular mass of sarcoplasm (sarcoplasmic mass) extending outward from the ring  rim contains myofibrils that are oriented circumferentially around the longitudinally oriented fibrils in the rest of the fiber only myotonic dystrophy shows Morphology pathologic changes in the intrafusal fibers of muscle spindles, with fiber splitting, necrosis, and regeneration  presents in late childhood with abnormalities in gait secondary to weakness of foot dorsiflexors → progresses to weakness of the hand intrinsic muscles & wrist extensors Clinical Atrophy of muscles of the face and ptosis course Cataracts, may be detected early in the course of the disease with slit-lamp examination  Other assoc abnormalities: frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, decreased plasma IgG, & abnormal glucose tolerance test response.  autosomal dominant familial diseases characterized clinically by myotonia, relapsing episodes of hypotonic paralysis Ion channel (induced by vigorous exercise, cold, or a myopathies high-carbohydrate meal), or both (Channelopathies) hyperkalemic, hypokalemic & normokalemic periodic paralysis: hypotonia variants of serum potassium levels during attacks  Ion channel Paramyotonia congenita: disorder of myopathies childhood wherein myotonia & periods of hypotonia appear during exercise & (Channelopathies) increase with continued exercise, esp with exposure to cold  Mutations in genes that encode ion channels Hyperkalemic periodic paralysis: mutations Pathogenesis in the gene that encodes a skeletal muscle sodium channel protein (SCN4A) Hypokalemic periodic paralysis: encodes a voltage gated L- type Ca channels   Malignant hyperpyrexia > syndrome characterized by a marked hypermetabolic state triggered by anesthetics (halogenated inhalational anesthetics & succinylcholine) Pathogenesis > occur in predisposed individuals with hereditary muscle diseases > mutations in genes encoding rynodine receptor (RyRI)  Malignant hyperpyrexia o exposure to anesthetic→ efflux of Ca to sarcoplasm → tetany, inc muscle Pathogenesis metabolism, excessive heat production o Dx: identification of genetic mutation or exposure of ms biopsy to anesthetic agent & observing contraction  disorders defined largely on the basis of the pathologic findings within muscle Common clinical features: early onset, Congenital nonprogressive or slowly progressive course, proximal or generalized muscle myopathies weakness, and hypotonia Infants affected present as “floppy” due to hypotonia or may have severe joint contractures (arthrogryposis) Nemaline myopathy with numerous rod-shaped, intracytoplasmic inclusions (dark purple structures). B, Electron micrograph of subsarcolemmal nemaline bodies, showing material of Z-band density Myopathies Associated With Inborn A. Lipid myopathies Errors of Metabolism B. Mitochondrial myopathies   Abnormalities of carnitine transport or deficiencies of the mitochondrial dehydrogenase enzyme systems which lead to blocks in fatty acid oxidation & Lipid accumulation of lipid droplets within muscle myopathy  Carnitine deficiency may be limited to muscle (myopathic carnitine deficiency) or may be secondary to diminished systemic levels (systemic carnitine deficiency) Lipid SSx: muscle pain, tightness & myoglobinuria following prolonged myopathy exercise or exercise during fasting states   Mutations in both nuclear and mitochondrial genes Mitochondrial  Involve proteins encoded by myopathies mitochondrial genome (mtDNA) (oxidative  show maternal inheritance  may present in young adulthood & phosphorylation manifest with proximal muscle weakness, diseases) sometimes with severe involvement of the muscles that move the eyes (external ophthalmoplegia)  Morphology  aggregates of abnormal mitochondria  occur subsarcolemmally in early stages, but with severe involvement may extend throughout the fiber  ragged red fibers: distortion of the myofibrils, making the muscle fiber contour appear irregular on cross-section Morphology Electron microscopy: > Increased numbers of mitochondria with irregular shapes > paracrystalline “parking lot inclusions” – alterations in the structure of cristae  3 general mutations: 1. Point mutations in mtDNA Clinical ✓ show maternal pattern of inheritance ✓ I.E.: myoclonic epilepsy with ragged red course fibers (MERFF), Leber hereditary optic neuropathy (LHON), and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)  2. Genes encoded by nuclear DNA ✓ shows autosomal dominant or recessive inheritance Clinical ✓subacute necrotizing encephalopathy course (Leigh syndrome), exertional myoglobinuria, and infantile X-linked cardioskeletal myopathy (Barth syndrome)  3. Deletions or duplications of mtDNA ✓ Chronic progressive external ophthalmoplegia (CPEO): characterized by a myopathy with prominent Clinical weakness of external ocular movements course ✓Kearns-Sayre syndrome (KSS) ("ophthalmoplegia plus"): characterized by ophthalmoplegia with pigmentary degeneration of the retina & complete heart block Non Most likely immune mediated and characterized by injury & inflammation of skeletal muscle infectious inflammatory May occur as an isolated myopathy or a component of an immune mediated systemic myopathies disease such as sclerosis  A. Dermatomyositis Non ✓ Inflammatory disorder infectious of skin & skeletal muscle inflammatory ✓ SSx: classic rash (may accompany or myopathies precede the onset of dse) taking the form of a lilac or heliotropic discoloration of the upper eyelids assoc. with periorbital edema  A. Dermatomyositis Non ✓ SSx: Grotton lesions, infectious scaling erythematous eruption or dusky red inflammatory patches over the knuckles, elbow, & myopathies knees Non infectious inflammatory myopathies Dermatomyositis SSx: muscle weakness that is slow in onset, bilaterally asymmetric & often accompanied by myalgias; typically affects proximal ms 1st Extramuscular manifestations: interstitial lung dse, vasculitis & myocarditis  Unknown Capillaries: principal target in Etiology & dermatomyositis Deposits of antibodies & complement are pathogenesis present in small blood vessels & are associated w/ foci of myocyte necrosis B cells & CD4+ T cells Morphology Inflammatory infiltrates located around small blood vessels & in perimysial connective tissue Atrophic fibers are prominent at the periphery of fascicles most likely related to the hypoperfusion of periphery of ms fascicles  Marked reduction in intramuscular capillaries 2ndary to vascular endothelial injury & fibrosis Morphology Necrotic muscle fibers & regeneration B. Polymyositis ✓ Accompanied by symmetric proximal ms involvement ✓ Differs from dermatoyositis by the lack of cutaneous involvement & its occurrence in adults Pathogenesis ✓Caused by cell mediated injury of myocytes ✓CD8+ cytotoxic cells & macrophages are present in near- damaged ms fibers ✓Inc expression of HLA-I & II molecules in sarcolemma  Inflammatory cells are found in the endomysium CD8+ & other lymphoid tissues surround the healthy fibers Morphology Necrotic & regenerating ms fibers are scattered throughout the fascicle w/o atrophy  ✓begins w/ involvement of distal ms especially knee extensors (quadriceps) & flexors of wrists & fingers ✓Weakness may be asymmetric C. Inclusion ✓Typically affects individuals over 50 yrs ✓Most cases are sporadic, but may also be familial body Pathogenesis myositis ✓ CD8+ cells are also found w/in the ms but is non responsive to immunosuppressive therapy ✓May be realated to aging due to presence of amyloid ß sheets, amyloid ß proteins & hyperphosphorylated tau protein  Presence of rimmed vacuoles within myocytes highlighted by basophilic granules at the periphery Morphology Electron microscopy: show tubular & filamentous inclusions in the cytoplasm & amyloid ß sheets & hyperphosphorylated tau in the nucleus   presents most commonly as an acute or a chronic proximal muscle weakness that may precede the onset of other signs of thyroid dysfunction  Exophthalmic ophthalmoplegia: Thyrotoxic characterized by swelling of the eyelids, edema of the conjunctiva, and diplopia myopathy  Hypothyroidism: cramping or aching of muscles, w/ slowed movements and reflexes  myofiber necrosis, regeneration, and interstitial lymphocytosis In chronic thyrotoxic myopathy, there may be only slight variability of muscle fiber size, mitochondrial hypertrophy, and focal myofibril degeneration; fatty infiltration of muscle   An acute toxic syndrome of rhabdomyolysis with accompanying myoglobinuria, which may lead to renal failure 2ndary to binge alcoholic drinking Ethanol  Acute pain either generalized or confined to a single muscle group myopathy  Histologic: swelling of myocytes, with fiber necrosis, myophagocytosis, & regeneration There may also be evidence of denervation  Steroid myopathy: occurrence of proximal ms weakness & atrophy during therapeutic administration of steroids Drug induced Characterized predominantly by type 2 ms fiber atrophy myopathy Chloroquine: presence of vacuoles within myocytes (autophagic membrane nound vacuoles & curvilinear bodies with short curved membranous structures)  A. MYASTHENIA GRAVIS ✓ caused by immune-mediated loss of Diseases of the acetylcholine receptors ✓ Occur equally in both sexes in older pxs Neuromuscular but may be more common in women if Junction it arises before age 40 ✓ decrease in the number of muscle acetylcholine receptors (AChRs), and circulating antibodies to the AChR are present Pathogenesis Autoantibodies against AchR lead to loss of functional AChRs at the NM junction by: 1. Fixing complement & causing direct injury to the postsynaptic membrane 2. increasing the internalization & degradation of receptors 3. inhibiting binding of Ach  Type 2 fiber atrophy Electron microscopy: simplified Morphology postsynaptic membrane & loss of AChR from the region of synapse   weakness begins with extraocular muscles; drooping eyelids (ptosis) and double vision (diplopia)  initial symptoms may include generalized weakness which fluctuates with alterations occurring during Clinical days, hours, or even minutes, and intercurrent medical conditions can lead to exacerbations of the course weakness  Effective forms of treatment include anticholinesterase drugs, prednisone, plasmapheresis, and resection of thymoma if it is present  usually develops as a paraneoplastic LAMBERT- process, most commonly with small cell carcinoma of the lung (60% of cases) EATON proximal muscle weakness along with autonomic dysfunction MYASTHENIC No clinical improvement is produced by SYNDROME anticholinesterase agents & electrophysiologic studies show evidence of enhanced neurotransmission with repetitive stimulation LAMBERT- Normal anticholinesterase NMJ synaptic EATON vesicles &postsynaptic membrane is normally responsive to anticholinesterase, MYASTHENIC but fewer vesicles are released in response to each presynaptic action potential SYNDROME  END References Robbins, Stanley L., eds. Robbins Basic Pathology. Philadelphia, PA : Elsevier/Saunders, 2013. Print.