BONES AND MUSCLES ROBERTO D. PADUA JR., MD, DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE.

BONES AND MUSCLESBONES AND MUSCLES

ROBERTO D. PADUA JR., MD, DPSPROBERTO D. PADUA JR., MD, DPSPDEPARTMENT OF PATHOLOGYDEPARTMENT OF PATHOLOGYFATIMA COLLEGE OF MEDICINEFATIMA COLLEGE OF MEDICINE

SKELETAL DEVELOPMENTAL AND SKELETAL DEVELOPMENTAL AND GENETIC DISORDERSGENETIC DISORDERS

• CHONDRODYSPLASIAS• Abnormalities in the size and shape of bones• Disproportionate shortness in stature• Named after the part of the bone affected• Other names refer to the appearance of the bone

– Diastrophic (twisted)– Thanatophoric (death-bearing)– Metatropic (changing)

• Family history of disease is obligatory• Radiologic appearance can be confused with other

metabolic bone diseases• Serum levels of biochemical markers are normal• Bone is well mineralized


• 1. ACHONDROPLASIA• Most common cause of disproportionately

short stature• 1 of 40,000 live births, autosomal dominant• Head is large, frontal region is protuberant,

nasal bridge is depressed• Lordosis and lumbar kyphosis are present• Anteroposterior flattening of the pelvic inlet• Failure of normal endochondral ossification at

the level of the proliferating and maturing cartilage


• 2. ACHONDROGENESIS• Affected infants are either stillborn or do not survive

the immediate neonatal period• 2 syndromes

– a) Achondrogenesis I (Parenti-Fraccaro)• Associated with congenital heart defects• No ossification in the skull & vertebral bodies

– b) Achondrogenesis II (Langer-Saldino)• Shortened limbs & disproportionately large head• Underdeveloped ossification centers in the vertebral

bodies and pelvis• Epiphyseal cartilage is lobulated with increased

vascularity• Completely disorganized endochondral ossification of

the growth plate and there is no column formation


• 3. THANATOPHORIC DYSPLASIA• Infants are either stillborn or die of respiratory

distress during the neonatal period• Pattern of inheritance is unknown• Length of trunk is normal but the head is large with

cranio-facial disproportion• Common CVS and CNS anomalies• Pronounced platyspondyly of the lumbar vertebrae

with an inverted U appearance • Curvature of femurs with medial and lateral spikes at

their lower ends; short, flared ribs• Endochondral ossification is disrupted at the growth

plate, no regular column formation


• 4. CHONDROECTODERMAL DYSPLASIA• Also known as Ellis-van Creveld syndrome• Short limb dwarfism• Consanguity is an important factor in the

etiology of the disease• Clinical presentation:

• Narrowing of rib cage• Congenital heart disease• Ectodermal abnormalities• Acromegalic micromelia (shortening of the

distal segment of the limb


• 5. ASPHYXIATING THORACIC DYSPLASIA

• Jeune’s syndrome• Narrowing of the chest and immobility• Stippled epiphyses and chondroplasia

punctata are striking features on x-ray


• 6. OSTEOPETROSIS• Marble bone disease• Defective osteoclast function that impairs

skeletal resorption• Primary spongiosa persists during adult life

• Increased incidence of parental consanguity• Early symptom is malformation of mastoid

and paranasal sinuses• Pathognomonic histologic finding is the

failure of osteoclast to resorb skeletal tissue


• 7. PROGRESSIVE DIAPHYSEAL DYSPLASIA

• Camurati-Engelman disease• Rare autosomal dominant disorder• Formation of new bone at both the

periosteal and endosteal surfaces


• 8. ENDOSTEAL HYPEROSTOSIS• Van Buchem disease• Autosomal dominant/recessive disorder• Progressive enlargement of mandible during

puberty• Radiographic feature: dense and

homogenous diaphyseal cortex with narrowing of the medullary canal


• 9. OSTEOPOIKILOSIS• Presence of numerous foci of sclerosis in

cancellous bone (“spotted bones”)• Autosomal dominant disorder• Bone changes are asymptomatic• Found incidentally on radiographs


• 10. OSTEOPATHIA STRIATA• Characterized by linear striations at the ends of

long bones and in the ilium• X-ray shows gracile linear striations in the

cancellous region of the skeleton• Autosomal dominant trait


• 11. MELORHEOSTOSIS• Characterized by hyperostosis of the limb

bones• X-ray : likened to appearance of melted wax

that is dripped down the side of the candle• Typical histologic finding is endosteal

thickening


• 12. PACHYDERMOPERIOSTOSIS• Hypertrophic osteoarthropathy• Characterized by clubbing of digits,

hyperhidrosis, thickening of skin around the face and forehead and periosteal new bone formation in the distal limbs

• Inherited as autosomal dominant trait• Men>women• X-ray shows thickening and sclerosis of the

distal portions of the tubular bones


• 13. OSTEOGENESIS IMPERFECTA• “Brittle bone disease”• Hereditary disorder involving defects in the synthesis

or structure of collagen type I• Cardinal features : osteopenia associated with

recurrent fracture and skeletal deformity• Biochemical findings : increased AP, increased level

of hydroxyproline, hypercalciuria• Histology : abnormal skeletal matrix; cartilaginous

bars formed by vascular invasion of the metaphyses do not become envelop by bones; cortical bone is almost non-existent

METABOLIC BONE DISEASESMETABOLIC BONE DISEASES

• 1. OSTEOPOROSIS• Loss of normally minerralized bone• Diagnosed clinically with non-invasive radiographic

techniques that measures bone density• Changes in the bone :

• Structurally weak• Loss of trabecular bone• Enlargement of the medullary space• Cortical porosity• Reduction in cortical thickness


• 2. RENAL OSTEODYSTROPHY• Seen in patients with advanced renal failure• Clinical presentations :

• Bone pain (most common), spontaneous fractures, aseptic necrosis of hip, myopathy

• Laboratory findings :• Low levels of 1;25(OH)2D3, hyperphosphatemia,

hypocalcemia, alterations in the secretion or activity of PTH

• X-ray : • Subperiosteal erosions, patchy osteosclerosis

(“rugger jersey” appearance of thoracic vertebral spine on lateral views, “salt and pepper” appearance of skull, slipped epiphyses


• 3. OSTEOMALACIA• Defective mineralization of the trabecular

and cortical bone matrix• Associated with decreased serum calcium

phosphate product• A common complication of chronic renal

failure in adults• Secondary to Vitamin D deficiency

• Histologically characterized by excessive quantities of osteoid because of the failed matrix calcification despite continued matrix synthesis by the osteoblasts


• 4. RICKETS• Defective mineralization of the epiphyseal growth

plate cartilage• Clinical features : craniotabes, frontal bossing,

rachitic rosary, pectus excavatum, “Harrison’s groove”, thoracic kyphosis, rachitic potbelly, genu varum/genu valgum

• Histologic appearance : • Rachitic growth plate is wide and irregular• Columnar rearrangement of the hypertrophic

chondrocyts is lost• Zone of provisional calcification disappears• Cartilage extends deep into the metaphyses

TRAUMATRAUMA

• FRACTURE REPAIR• Blastema wound closure scar formation• Initial repair tissue formed is called a CALLUS which is

composed of fibrous tissue, woven bone and cartilage• 3 phases of fracture healing :

• A) inflammatory phase• B) reparative phase = orderly removal and replacement of

immature woven bone by cartilage differentiation• C) modeling phase = realignment & mechanical shaping of

the bone and callus; restoration of the medullary cavity and bone marrow

• Complications of fracture healing :• A) nonunions• B) fibrous union

INFLAMMATORY BONE DISORDERSINFLAMMATORY BONE DISORDERS

• OSTEOMYELITIS• Classified according to several factors

• 1. its duration = acute, subacute or chronic• 2. nature of the exudate = hemorrhagic,

purulent, or nonsuppurative• 3. its location = bone, periosteum, or epiphyses• 4. etiologic agent = Staphylococcus, Tb, etc.

• Histologically, inflammatory cells are seen• Loss of normal marrow architecture• Hematopoietic elements and fat are replaced

by leukocytic infiltrates

INFLAMMATORY BONE DISEASESINFLAMMATORY BONE DISEASES

• OSTEOMYELITIS…..• “Chronic sclerosing osteomyelitis of Garre”

• A chronic form of osteomyelitis with findings of dense, scarred bone and few clinical symptoms without any abscess formation.

• “Brodies abscess”• Osteomyelitis sharply limited to one side with

formation of abscess cavity surrounded by a rim of sclerotic bone.

• Causes:• Coagulase (+) Staph. Aureus (60-90%)• Strep, Pneumococcus, E. coli, Klebsiella,

Salmonella, Bacteroides


• OSTEOMYELITIS…..• Causes :

– Tuberculosis• Spread hematogenously• Characteristic lesion : Chronic caseating

granulomatous inflammation which often involves the subchondral part of the joint. Sequestrum forms in the subchondral bone and articular cartilage resulting in a “kissing sequestrum”.

• Pott’s disease – Tb of the spine

OSTEOMYELITISOSTEOMYELITIS

X-RAYGROSS : UPPER FEMUR


• SARCOIDOSIS• Noncaseating granulomatous process• Manifest as small lytic and sclerotic foci in

the bones of the hand• Large areas of destruction are not typically

found


• PAGET’S DISEASE OF BONE (OSTEITIS DEFORMANS)

• A chronic osteolytic and osteosclerotic disease of uncertain cause

• May involve one or more bones• Presents with pain, skeletal deformities, and

occasionally sarcomatous transformation• Usually affects 3% of white population over 40

y/o• Incidence increases with age; men>women• Most patients are asymptomatic (80-90%)


• PAGET’S DISEASE OF BONE…..• Common skeletal sites of involvement are the sacrum, spine,

pelvis, skull, femur, clavicle, tibia, ribs, and humerus• Histopathology:

• Normal marrow is replaced by a richly vascular, loose fibrous connective tissue

• Isolated clusters of inflammatory cells may be seen

• Osteoclasts aggregate on the existing bone trabeculae and within the cortex

• Innumerable small, irregularly shaped bone fragments (mosaic pattern)

• Grossly resembles the gritty but brittle texture of pumice or lava rock


• PAGET’S DISEASE OF BONE….• X-RAY : flocculant, radiopaque deposit

likened to cotton wool. Pelvis is the most common site of involvement.

• Elevated AP and osteocalcin level• Elevated urinary excretion of

hydroxyproline, pyridinoline and deoxypyridinoline

• Malignant transformation are also observed• Osteosarcomas• Fibrosarcomas• Giant cell malignant fibrous histiocytoma

PAGET’S DISEASE OF BONEPAGET’S DISEASE OF BONE

X-RAY OF TIBIA SHOWING BONE DESTRUCTION AND BONE FORMATION

EARLY CHANGES SHOWING PROMINENT OSTEOCLASTIC ACTIVITY

DEGENERATIVE DISEASES OF DEGENERATIVE DISEASES OF BONEBONE

• OSTEONECROSIS• Infarction of bone typically involving the femoral

head• 3 generic categories = postfracture, idiopathic, and

renal transplant associated• Also known as “avascular necrosis of bone”• Earliest histologic changes are death of the bone and

the surrounding hematopoietic & fatty marrow• X-ray : “Crescent sign” , a separation of fracture cleft

forms between the impacted fragments and the overlying subchondral plate. Increased density within the necrotic bone.

BONE TUMORSBONE TUMORS

• Most malignant tumors arise de novo• Benign bone lesions that predispose to the

development of skeletal malignancies• Paget’s disease, chondromatosis,

osteochondromatosis, fibrous dysplasia, and osteofibrous dysplasia

• Five basic parameters in the diagnosis of bone tumors

• Age of the patient• Bone involved• Specific area within the bone• Radiographic appearance• Microscopic appearance

BONE FORMING TUMORSBONE FORMING TUMORS

• 1. OSTEOMA• Seen almost exclusively in the flat bones of skull

and face• Microscopically: composed of dense, mature,

predominantly lamellar bone• Benign• Associated with Gardner’s syndrome

BONE-FORMING TUMORSBONE-FORMING TUMORS

• 2. OSTEOID OSTEOMA• Benign neoplasm seen in patients between 10 and 30 y/o• 2:1 male-female ratio• Intense pain is the most prominent symptom• Reported in practically every bone, most are centered in the

cortex (85%), spongiosa (13%), or subperiosteal region (2%)• X-ray: typical finding is a radiolucent nidus that is seldom

larger than 1.5 cm and may or may not contain a dense center. This nidus is surrounded by a peripheral sclerotic reaction.

• Microscopic: sharply delineated central nidus composed of more or less calcified osteoid lined by plump osteoblast and growing within vascularized connective tissue, without evidence of inflammation.

OSTEOID OSTEOMAOSTEOID OSTEOMA

X-RAY GROSS MICROSCOPIC


• 2. OSTEOBLASTOMA• Benign osteoblastoma, giant osteoid osteoma• Closely related to osteoid osteoma both microscopically and

ultrastructurally• It has a larger size of the nidus, absence of surrounding area

of reactive bone formation, and the lack of intense pain• A cartilaginous matrix is present in some cases• Most cases arise in the spongiosa of the bone involving the

spine or major bones of the lower extremity• Osteomalacia can be seen as a complication


• 3. OSTEOSARCOMA• The most frequent primary malignant tumor,

exclusive of hematopoietic malignancy• Usually occurs in patients between 10 and 25

years of age and is rare in pre-school children• Another peak age incidence occurs after the age of

40, in association with other disorders• Most osteosarcomas arise de novo, but others

arise within the context of a preexisting condition• Paget’s disease, radiation exposure, chemotherapy,

preexisting benign bone lesions, foreign bodies, trauma


• OSTEOSARCOMA…..• Located in the metaphyseal area of long bones,

particularly the lower end of femur, upper end of the tibia, and the upper end of the humerus

• Large majority arise within the medullary cavity from which they extend into the cortex

• Gross appearance varies depending on the relative amounts of bone, cartilage, cellular stroma and vessels bony hard to cystic, friable, and hemorrhagic

• From its usual origin in the metaphysis of a long bone, the tumor may spread along the marrow cavity, invade the adjacent cortex, or elevate or perforate the periosteum (Codman’s triangle)


• OSTEOSARCOMA…..• Extend into the soft tissues, extend into the

epiphysis, extend into the joint space, form satellite nodules independent from the main tumor mass proximal to the primary lesion (“skip metastases”), metastasize through the blood stream to distant sites particularly the lung.


• OSTEOSARCOMA…..• Microscopic features

• May destroy preexisting bone trabeculae or grow around them in an appositional fashion

• Key feature is the presence of osteoid and or bone produced directly by tumor cells without interposition of cartilage

• Osteoblastic areas are often mixed with fibroblastic and chondroblastic foci

• Tumor cells may grow in diffuse, nesting or pseudopapillary arrangements


• OSTEOSARCOMA…..• OS cells usually exhibit strong AP activity,

regardless of their appearance• Ultrastructurally, tumor cells resemble normal

osteoblasts• Consistently expresses Vimentin• In some cases, they are positive for smooth

muscle actin, desmin, EMA, S-100 protein• Osteonectin, osteocalcin, osteopontin bone

morphogenetic protein and bone GLA protein have been identified immunohistochemically


• OSTEOSARCOMA…..• Microscopic variants

• Telangiectatic• Small cell • Fibrohistiocytic• Anaplastic• Well-differentiated intramedullary• Others = parosteal (juxtacortical), periosteal

OSTEOSARCOMAOSTEOSARCOMA

GROSS SHOWING SKIP METASTASIS

MICROSCOPIC APPEARANCE


TELANGIECTATIC VARIANT OF OSTEOSARCOMA


JUXTACORTICAL OSTEOSARCOMA


• OSTEOSARCOMA…..• Diagnosis: characteristic radiographic appearance,

open biopsy, needle biopsy, FNAB, frozen section.• Therapy: amputation or disarticulation. At present,

limb-sparing procedures coupled with other therapeutic modalities.

• Prognosis: • Poor : presence of Paget’s disease, multifocal OS,

chondroblastic type, Telangiectatic variant, elevated AP, low postchemotherapy tumor necrosis, loss of heterozygosity of the RB gene, HER2/neu expression, expression of P-glycoprotein

CARTILAGE-FORMING TUMORSCARTILAGE-FORMING TUMORS

• 1. CHONDROMA• A common benign cartilaginous tumor that occurs most

frequently in the small bones of the hands and feet, particularly the proximal phalanges

• 30% are multiple• Microscopically, they are composed of mature hyaline

cartilage. Foci of myxoid degeneration, calcification, and endochondral ossification are common

• Enchondromas begins in the spongiosa of the diaphysis from which they expand and thin out the cortex

• Lesions with predominantly unilateral distribution are referred to as Ollier’s disease

• Its association with soft tissue hemangiomas is known as Maffucci’s syndrome

CHONDROMACHONDROMA

X-RAY GROSS

MICROSCOPIC


• 2. OSTEOCHONDROMA• Most frequent benign tumor• Usually asymptomatic, but may lead to deformity or interfere with

the function of adjacent structures such as tendons and blood vessels

• Most common locations are metaphyses of the lower femur, upper tibia, upper humerus and pelvis

• Average age of onset is 10 y/o, majority appears before the age of 20

• Average greatest diameter is 4 cm but may reach 10 cm or more• A cap of cartilage covered by fibrous membrane continous with the

periosteum of the adjacent bone• Microscopically, the cells resemble those of normal hyaline

cartilage. Eosinophilic, PAS-(+) inclusions may be seen in the cytoplasm. The bulk of the lesion is composed of mature bone trabeculae located beneath the cartilaginous cap and containing normal bone marrow.

OSTEOCHONDROMAOSTEOCHONDROMA

GROSS, CUT SECTION MICROSCOPIC


• 3. CHONDROBLASTOMA• Occurs predominantly in males under 20 y/o• Usually arises in the epiphyseal end of long bones before the

epiphyseal cartilage has disappeared, particularly in the distal end of femur, proximal end of humerus, and proximal end of tibia

• X-ray: tumor is fairly well delimited and contains areas of rarefaction

• Microscopic:• the basic tumor cell is an embryonic chondroblast with

only a limited capacity for the production of cartilaginous matrix.

• Presence of occasional scattered giant cells


• CHONDROBLASTOMA…..• Microscopic:

• Cells are usually polyhedral with round to indented nuclei. Reticulin fibers surround each individual cell.

• Presence of small zones of focal calcification (“chicken wire”)

• Diagnosis can be made by fine needle aspiration which will show neoplastic chondroblast, multinucleated osteoclast-like giant cells, and chondroid myxoid fragments

• Treatment is by curettement with bone grafting

CHONDROBLASTOMACHONDROBLASTOMA

X-RAY GROSS

CHONDROBLASTOMACHONDROBLASTOMA

MICROSCOPIC


• 4. CHONDROMYXOID FIBROMA• An unusual benign tumor• Usually occurs in long bones of young adults• Radiographically, it is sharply defined and may attain a large

size• Grossly, it is solid and yellowish white or tan, replaces bone

and thins the cortex.• Microscopically, shows hypocellular lobules with a

chondromyxoid appearance separated by intersecting bands of fibroblast-like spindle cells and osteoclasts

• Strong positivity to S-100 protein• Treatment is by curettage with a recurrence rate of 25%

CHONDROMYXOID FIBROMACHONDROMYXOID FIBROMA

X-RAY GROSS MICROSCOPIC


• 5. CHONDROSARCOMA• A malignant tumor of cartilage-forming tissues• Divided into conventional and variants• Conventional chondrosarcoma can be

• Central = located in the medullary cavity, usually of flat or long bone. X-ray show osteolytic lesion with splotchy calcification with ill-defined margins, fusiform thickening of the shaft, and perforation of the cortex

• Peripheral = may arise de novo or from the cartilaginous cap of a preexisting osteochondroma

• Juxtacortical (periosteal) = involves the shaft of a long bone characterized by a cartilaginous lobular pattern with areas of splotchy calcification and endochondral ossification


• CHONDROSARCOMA…..• Microscopically, there is production of cartilaginous

matrix and the lack of direct bone formation by the tumor cells

• Soft tissue implantation following biopsy is a well known complication

• Chondrosarcoma variants• Clear cell chondrosarcoma• Myxoid chondrosarcoma• Dedifferentiated chondrosarcoma• Mesenchymal chondrosarcoma

CHONDROSARCOMACHONDROSARCOMA

GROSS APPEARANCES OF CHONDROSARCOMA


X-RAY, FEMUR


WELL-DIFFERENTIATED CLEAR CELL VARIANT

GIANT CELL TUMORGIANT CELL TUMOR

• Osteoclastoma• Patients are over 20 years of age• More common in women then men• More frequently in Oriental than Western countries• Classic location is epiphysis of long bone• Affects more commonly the lower end of femur, upper

end of tibia, and lower end of the radius. It also occurs in the humerus, fibula, and skull particularly the sphenoid bone.

• Multicentricity has been reported particularly in young patients and in the small bones of hands and feet


• X-ray: • The typical appearance is that of an entirely lytic,

expansile lesion in the epiphysis, usually without peripheral bone sclerosis, or periosteal reaction

• Gross:• The size of the tumor varies; when large, it may be

associated with a pathologic fracture• The cut surface is solid and tan or light brown,

traversed by fibrous trabeculae, and often contains hemorrhagic areas

• The cortex is thinned, but periosteal new bone formation is rare


• Microscopic:• Two main components are stromal cells and

giant cells• The giant cells are usually large and have over

twenty or thirty nuclei, most of then are arranged toward the center. – They resemble osteoclasts at all levels: ultrastructurally,

enzyme histochemically and immunohistochemical– Result of fusion of circulating monocytes that have

been recruited into the lesion• Possible mechanisms: 1. Autocrine or paracrine loop mediated by

transforming growth factor beta


• Microscopic…..• Possible mechanisms….

2. Production of osteoprotegerin ligand (a factor essential for osteoclastogenesis)

3. Expression of the ligand for RANK (receptor activator of nuclear factor Kappa B)

• Mononuclear stromal cells is the only proliferating element in the lesion and the one exhibiting atypia in the rare cytologically malignant examples of this tumor

• These changes may be focal, hence a thorough sampling is required

• Produces type I & III collagen and has receptors for PTH


X-RAY GROSS APPEARANCE


• Frequent positivity for S-100 protein• Many benign lesions with giant cells have

been diagnosed as giant cell tumor in the past– A diagnosis of a lesion other than GCT should

be favored if:• 1. patient is a child• 2. lesion is located in the metaphysis or diaphysis

of a long bone• 3. lesion is multiple• 4. lesion is located in the vertebrae, jaw, or bones

of the hands or feet


• Treatment : – Surgical = consists of curettage with

bone grafting or en bloc resection with allograft or artificial material

– Use of radiation therapy should be reserved only for cases in which surgical removal is impossible

MARROW TUMORSMARROW TUMORS

• 1. EWING’S SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOR (PNET)

• Undifferentiated type of bone sarcoma in children

• Related to the neoplasm originally described in the soft tissues as primitive (peripheral) neuroectodermal tumor

• Usually seen in patients between the ages of 5 and 20 years

• Clinically, the tumor may simulate OM because of pain, fever, and leukocytosis

EWING’S/PNETEWING’S/PNET

• Occurs most often in long bones (femur, tibia, humerus, and fibula) and in the bones of the pelvis, rib, vertebrae, mandible and clavicle

• It generally arises in the medullary canal of the shaft, from which it permeates the cortex and invade the tissues

• Can present clinically as a soft tissue neoplasm with a normal appearance of the underlying bone on plain x-ray films

• X-ray : cortical thickening and widening of the medullary canal. With progression of the lesion, reactive periosteal bone may be deposited in layers parallel to the cortex (“onion-skin” appearance) or at right angle to it (“sun-ray” appearance)

EWING’S SARCOMA/PNETEWING’S SARCOMA/PNET

• Microscopic :• Consists of solid sheets of cells divided into irregular

masses by fibrous bands• Individual cells are small and uniform• The cells outline are indistinct, resulting in a

“syncitial” appearance• The nuclei are round, with frequent indentations,

small nucleoli and variable but usually brisk mitotic activity

• There is well developed vascular network• Pseudorosettes and rosettes arrangement of cells

may be seen


• Cells contains large amounts of cytoplasmic glycogen --- (+) PAS

• Ultrastructurally, a few dense core granules will be found either in the cell cytoplasm or in cell prolongations

• Immunohistochemically, positive for vimentin, LMW keratin, NSE, protein gene product 9.5, Leu7, and neurofilaments

• Over 95% of cases show a reciprocal translocation 11;22 (q24;q12), which results in the fusion of EWS gene with FLI or ERG genes


• Metastatic spread is to the lungs and pleura, other bones (particularly the skull), CNS, and (rarely) regional LN

• About 25% of the patients have multiple bone and/or visceral lesions at the time of presentation

• Treatment:• Combination of high-dose irradiation and

multidrug chemotherapy– sometimes combined with limited surgery

MARROW TUMORSMARROW TUMORS

• 2. MALIGNANT LYMPHOMA• Can involve the skeletal system primarily or as a

manifestation of a systemic disease• LARGE CELL LYMPHOMA

• More common in adults than in children• 60% of cases occurring in patients over 30 y/o• No sex predilection• Most cases involve the diaphysis or metaphysis og

long bones or vertebrae producing patchy cortical and medullary destruction associated with minimal to moderate periosteal reaction

• The tumor is pinkish gray and granular, frequently extends into the soft tissues and invades the muscle

MALIGNANT LYMPHOMAMALIGNANT LYMPHOMA

• LARGE CELL LYMPHOMA…..• Radiographically, a combination of bone

production and bone destruction often involves a wide area of a long bone

• Microscopically, the appearance is similar to that of the large cell lymphoma in nodal and other extranodal sites, some cases are accompanied by prominent fibrosis

• The 5-year survival rate for localized B-cell lymphoma of bone has ranged from 30-60%

• The stage of the disease is the single most important prognostic determinator


X-RAY MICROSCOPIC APPEARANCE


• HODGKIN’S LYMPHOMA• Produces radiographically detectable bone lesions

in approximately 15% of the patients• Involvement is multifocal in about 60% of cases,

most frequent sites being vertebrae, pelvis, ribs, sternum, and femur

• Osseous lesions are often asymptomatic and in half of the cases are not demonstrable radiographically


• Anaplastic large cell lymphoma

• Burkitt’s lymphoma

• Lymphoblastic lymphoma

ACUTE LEUKEMIAACUTE LEUKEMIA

• Associated with radiographic abnormalities in the skeletal system in 70-90% of cases

• Destructive bone lesions are extremely rare in the chronic leukemias

VASCULAR TUMORSVASCULAR TUMORS

• 1. HEMANGIOMA• Often seen in the vertebrae as an incidental post-mortem

finding• The most common locations are the skull, vertebrae, and jaw• Cut section has a currant jelly appearnce• Microscopically, there is a thick-walled lattice-like pattern of

endothelial lined cavernous spaces filled with blood• Multiple hemangiomas are mainly seen in children and are

associated in about half of the cases with cutaneous, soft tissue, or visceral hemangiomas


• 2. MASSIVE OSTEOLYSIS• Gorham’s disease• Not a vascular neoplasm• Has microscopic similarities with skeletal

angiomatosis• It has a destructive character• It results in reabsorption of a whole bone or

several bones and the filling of the residual spaces by a heavy vascularized fibrous tissue


• 3. LYMPHANGIOMAS• Most cases are multiple and associated with soft

tissue tumors of similar appearance

• 4. GLOMUS TUMOR• May erode the underlying bone

• 5. HEMANGIOPERICYTOMA• Can present as a primary bone lesion, most

common location is the pelvis


• 6. EPITHELIOID HEMANGIOENDOTHELIOMA

• A borderline type of vascular neoplasm characterized microscopically by the presence epithelial- or histiocyte-like endothelial cells with abundant acidophilic and often vacuolated cytoplasm, large vesicular nucleus, modest atypia, scanty mitotic activity, inconspicous or absent anastomosing channels, recent and old hemorrhage and an inconstant but sometimes prominent inflammatory component rich in eosinophils


• 7. ANGIOSARCOMA• Malignant hemangioendothelioma,

hemangioendothelial sarcoma• Exhibits obvious atypia of the tumor cells,

formation of solid areas alternating with others with anastomosing vascular channels, and foci of necrosis and hemorrhage

• Multicentricity is common• Distant metastasis are common, particularly lungs


CAVRNOUS HEMANGIOMA OF BONE


EPITHELIOID HEMANGIOENDOTHELIOMA

METASTATIC TUMORSMETASTATIC TUMORS

• In most cases the lesions are multiple• More than 80% arises from the breast, lung,

prostate, thyroid, or kidney• These metastases can be accompanied by

visceral deposits or represent the only apparent site of dissemination

• Soft tissue sarcomas rarely metastasize to the bones except embryonal rhabdomyosarcoma in children

• They are usually osteolytic but maybe osteoblastic or mixed

Metastatic tumorsMetastatic tumors

• The mechanism is thought to be the production of bone growth factors by tumor cells, such as TGF-beta, fibroblast growth factor, and bone morphogenetic proteins

• Symptoms is usually pain• Treatment is relief of pain and to prevent

fracture of weight-bearing bones

TUMORLIKE LESIONSTUMORLIKE LESIONS

• 1. SOLITARY BONE CYST• Unicameral bone cyst• Usually occur in long bones, most often in the

upper portion of the shaft of the humerus and femur

• Also seen in the short bones, calcaneus• Mostly affects males and are seen in patients

under 20 years• Usually are advanced when first seen, most are

centered in the metaphysis and they migrate away from the epiphyseal line


• SOLITARY BONE CYST….• The cysts contains a clear or yellow fluid that is

lined by a smooth fibrous membrane• Maybe hemorrhagic if previous fracture occurred• Microscopic: well-vascularized connective tissue,

hemosiderin and cholesterol clefts are frequent• Treatment of choice is curettement and

replacement of the cyst with bone chips

SOLITARY BONE CYSTSOLITARY BONE CYST



• 2. ANEURYSMAL BONE CYST• Usually seen in patients between 10 and 20 years

of age• More common in females• Occurs mainly in the vertebrae and flat bones but

can also arise in the shaft of long bones• Multiple involvement is common in the vertebral

lesions• X-ray: shows eccentric expansion of the bone with

erosion and destruction of the cortex and a small area of periosteal new bone formation


• ANEURYSMAL BONE CYST….• GROSS: it forms a spongy hemorrhagic mass

covered by a thin shell of reactive bone, which may extend into the soft tissue

• Microscopic: • show large spaces filled with blood• They do not contain endothelial lining but are rather

delimited by cells with similar features to fibroblast, myofibroblasts, and histiocytes

• A row of osteoclasts is often seen immediately beneath the surface

• There is significant deposition of generated calcifying fibromyxoid tissue.


• ANEURYSMAL BONE CYST….• Pathogenesis is still unknown• In a few cases, the lesion is preceded by trauma with fracture

or subperiosteal hematoma• It may also arise in some preexisting bone lesion as a result

of changed hemodynamics• Insulin-like growth factor-I may play in its pathogenesis• Ddx: chondroblastoma, GCT, fibrous dysplasia, nonossifying

fibroma, osteoblastoma, chondrosarcoma• Treatment : en bloc resection or curettage with bone grafting

ANEURYSMAL BONE CYSTANEURYSMAL BONE CYST


TUMORS OF SKELETAL MUSCLESTUMORS OF SKELETAL MUSCLES

• RHABDOMYOSARCOMA• Most common soft tissue sarcoma of childhood

and adolescence• Usually appears before the age of 20• Commonly occurs in the head and neck or

genitourinary tract, extremities• Cytogenic abnormalities

• t(2;13)(q35;q14)• t(1;13)(q36;14)


• RHABDOMYOSARCOMA• In the more common translocation, t(2;13), the

PAX3 gene on chromosome 2 fuses with the FKHR gene on chromosome 13

• PAX3 gene functions upstream of genes that control muscle differentiation

• Pathogenesis of tumor involves dysregulation of muscle differentiation by the chimeric PAX3-FKHR protein


• RHABDOMYOSARCOMA – MORPHOLOGY• EMBRYONAL • ALVEOLAR• PLEOMORPHIC*** Diagnostic cell is the RHABDOMYOBLAST

= contains eccentric eosinophilic granular cytoplasm rich in thick and thin filaments = may be round or elongated (tadpole or strap

cells= Ultrastructurally, contain sarcomeres = Immunohistochemically, they stain with antibodies to the myogenic markers

desmin, MYOD1 and myogenin


• RHABDOMYOSARCOMA – MORPHOLOGY

• EMBRYONAL RHABDOMYOSARCOMA• Most common type, accounting to 60%• Includes Sarcoma Botryoides• Occurs in children under 10 years of age• Typically arises in the nasal cavity, orbit, middle

ear, prostate and paratesticular region• Allelic loss of chromosome 11p15.5 as its major

genomic abnormality



• EMBRYONAL RHABDOMYOSARCOMA• Grossly,they present as a soft gray infiltrative

mass• Microscopically, the tumor cells mimic skeletal

muscle cells at various stages of embryogenesis and consist of sheets of both malignant round and spindled cells in a variably myxoid stroma

• Sarcoma botryoides grows in a polypoid fashion, producing the appearance of a cluster of grapes protruding into a hollow structure such as the bladder or vagina



• ALVEOLAR RHABDOMYOSARCOMA• Most common in the early and mid-adolescence

and usually arises in the deep musculature of the extremities

• Histologically, the tumor is traversed by a network of fibrous septae that divide the cells into clusters or aggregates; as the central cells degenerate and drop out, resembles pulmonary alveolae

• Tumor cells are moderate in size and have little cytoplasm



• ALVEOLAR RHABDOMYOSARCOMA• Cells with cross-striations are identified in about

25% of cases• Cytogenetic studies show a t(2;13) or t(1;13)

chromosomal translocations



• PLEOMORPHIC RHABDOMYOSARCOMA• Characterized by numerous large, sometimes

multinucleated, bizarre eosinophilic tumor cells• This variant is rare• Arises in the deep soft tissue of adults • Resemble malignant fibrous histiocytoma

histologically


• RHABDOMYOSARCOMA • Usually treated with a combination of surgey and

chemotherapy with or without radiation• Histologic variant and location of the tumor

influence survival• Sarcoma botryoides have the best prognosis,

followed by embryonal, pleomorphic, and alveolar variants

• Overall prognosis for children is good = 65%; less for adults

TUMORS OF SMOOTH MUSCLETUMORS OF SMOOTH MUSCLE

• LEIOMYOMA• Benign smooth muscle tumor, commonly arises in

the uterus• May also arise in the erector pili muscles found in

the skin, nipples, scrotum and labia and less in the deep soft tissues

• Multiple lesions is thought to be hereditary and transmitted as an autosomal dominant trait

• Occur in adolescence and early adult life


• LEIOMYOMA• Tumors are usually not larger than 1 to 2 cm in

greatest dimension • Composed of fascicles of spindle cells that tend to

intersect each other at right angles• Tumor cells have blunt-ended, elongated nuclei

and show minimal atypia and few mitotic figures• Treatment is surgical


• LEIOMYOSARCOMA• Account for 10 to 20% of soft tissue sarcomas• Occurs in adults, women>men• Most develop in the skin and deep soft tissues of

the extremities and retroperitoneum• Present as painful, firm masses• Retroperitoneal tumors may be large and bulky

and cause abdominal symptoms


• LEIOMYOSARCOMA• Histologically, characterized by malignant spindle

cells that have cigar-shaped nuclei arranged in interweaving fascicles

• Immunologically, they stain with antibodies to vimentin, actin, smooth muscle actin and desmin

• Treatment depends on the size, location and grade of the tumor

BONES AND MUSCLES ROBERTO D. PADUA JR., MD, DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE.

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Transcript of BONES AND MUSCLES ROBERTO D. PADUA JR., MD, DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE.