IntroductionIntroduction toto OrthopedicOrthopedic OncologyOncology

JamesJames C.C. Wittig,Wittig, MDMD AssociateAssociate ProfessorProfessor ofof OrthopedicOrthopedic SurgerySurgery Chief,Chief, OrthopedicOrthopedic OncologyOncology MountMount SinaiSinai MedicalMedical CenterCenter ClassificationClassification ofof MusculoskeletalMusculoskeletal TumorsTumors

„ MusculoskeletalMusculoskeletal TumorsTumors areare rarerare typestypes ofof tumorstumors whenwhen comparedcompared toto allall typestypes ofof tumorstumors thatthat occuroccur throughoutthroughout thethe bodybody „ MostMost musculoskeletalmusculoskeletal tumorstumors originateoriginate fromfrom mesenchymalmesenchymal typetype tissuetissue oror fromfrom cellscells thatthat areare derivedderived fromfrom mesodermmesoderm „ AnAn embryoembryo oror fetusfetus isis composedcomposed ofof threethree layerslayers ofof cells:cells: EctodermEctoderm (outer(outer layer);layer); MesodermMesoderm (middle(middle layer);layer); EndodermEndoderm (inner(inner layer)layer) „ TheThe mesodermmesoderm isis thethe layerlayer thatthat normallynormally formsforms allall ofof thethe connectiveconnective tissuestissues inin thethe body,body, includingincluding bone,bone, muscle,muscle, cartilage,cartilage, fibrousfibrous tissue,tissue, tendons,tendons, ligamentsligaments bloodblood vessels,vessels, nerves,nerves, bloodblood cellscells ClassificationClassification ofof MusculoskeletalMusculoskeletal TumorsTumors

„ WhenWhen uncontrolleduncontrolled divisiondivision oror growthgrowth ofof aa mesodermalmesodermal oror mesenchymalmesenchymal cellcell occursoccurs itit reresultssults inin thethe productionproduction ofof aa tumortumor „ TheseThese mesodermalmesodermal tumorstumors cancan formform tissuetissue thatthat resembleresemble normalnormal mesodermalmesodermal tissuestissues likelike bonebone (osteoid),(osteoid), cartilagecartilage oror fibrousfibrous tissuetissue „ Hence,Hence, thesethese tumorstumors areare oftenoften namednamed accordingaccording toto thethe normalnormal typetype ofof mesodermalmesodermal tissuetissue thatthat theythey resembleresemble oror thethe typetype ofof tissuetissue theythey areare producingproducing „ ThereThere areare bothboth benignbenign andand malignantmalignant (cancerous)(cancerous) typestypes ofof tumors.tumors. CancerousCancerous typestypes ofof mesenchymalmesenchymal oror mesodermalmesodermal tumorstumors areare termedtermed SarcomasSarcomas ClassificationClassification ofof MusculoskeletalMusculoskeletal TumorsTumors

„ ForFor example,example, bonebone producingproducing (osteoid(osteoid producing)producing) tumorstumors fallfall intointo thethe categorycategory ofof OsseousOsseous Tumors.Tumors. AA typetype ofof benignbenign osseousosseous tumortumor isis calledcalled anan Osteoblastoma.Osteoblastoma. TheThe malignantmalignant oror cancerouscancerous typetype ofof OsseousOsseous TumorTumor isis calledcalled anan OsteosarcomaOsteosarcoma „ Similarly,Similarly, aa typetype ofof benignbenign cartilagecartilage producingproducing tumortumor isis calledcalled anan EnchondromaEnchondroma.. AA malignantmalignant cartilagecartilage producingproducing tumortumor isis calledcalled aa ChondrosarcomaChondrosarcoma.. „ MesenchymalMesenchymal oror MesodermalMesodermal tumorstumors cancan arisearise fromfrom musclemuscle oror thethe softsoft tissuestissues ofof anan extremityextremity oror fromfrom bone.bone. ForFor example,example, anan OsteosarcomaOsteosarcoma whichwhich isis aa malignantmalignant bonebone producingproducing tumortumor cancan originateoriginate fromfrom eithereither aa bonebone oror fromfrom musclemuscle oror fromfrom thethe softsoft tissuestissues inin betweenbetween thethe muscles.muscles. ItIt moremore commonlycommonly arisesarises fromfrom aa bonebone butbut cancan alsoalso arisearise fromfrom aa muscle.muscle. AlthoughAlthough itit producesproduces bonebone itself,itself, itit doesdoes notnot havehave toto developdevelop fromfrom bonebone andand cancan alsoalso developdevelop fromfrom softsoft tissues.tissues. ClassificationClassification ofof MusculoskeletalMusculoskeletal TumorsTumors

„ Similarly,Similarly, aa FibrosarcomaFibrosarcoma isis aa malignantmalignant fibrousfibrous tissuetissue producingproducing tumor.tumor. FibrousFibrous tissuetissue isis typicallytypically thoughtthought ofof asas aa softsoft tissuetissue ofof thethe body.body. FibrosarcomaFibrosarcoma mostmost commonlycommonly arisesarises fromfrom thethe softsoft tissuetissue ofof thethe bodybody butbut cancan alsoalso originateoriginate fromfrom aa bone.bone. „ TumorsTumors thatthat arisearise fromfrom thethe endodermalendodermal oror ectodermalectodermal cellscells ofof thethe bodybody usuallyusually dodo notnot originateoriginate fromfrom thethe bonesbones oror softsoft tissuestissues ofof thethe body.body. TheyThey usuallyusually involveinvolve thethe musculoskeletalmusculoskeletal systemsystem byby spreadingspreading oror metastasizingmetastasizing toto aa bonebone oror muscle.muscle. TheseThese typestypes ofof malignantmalignant oror cancerouscancerous tumorstumors areare termedtermed Carcinomas.Carcinomas. CarcinomasCarcinomas constituteconstitute moremore commoncommon tumorstumors likelike breast,breast, prostate,prostate, kidney,kidney, lung,,lung,, thyroid,thyroid, gastrointestinalgastrointestinal cancers.cancers. ClassificationClassification ofof MusculoskeletalMusculoskeletal TumorsTumors

„ TheThe nestnest threethree slidesslides demonstratedemonstrate aa generalgeneral classificationclassification schemescheme forfor mesenchymalmesenchymal tumorstumors andand sarcomassarcomas thatthat originateoriginate fromfrom thethe musculoskeletalmusculoskeletal system,system, bonesbones andand softsoft tissues.tissues. „ ItIt isis importantimportant toto memorizememorize thesethese classificationclassification systems.systems. Bone Tumors

Category Benign Malignant

Osseous Osteoma Osteosarcoma Osteoid Osteoma Intramedullary Osteoblastoma Conventional Telangiectatic Low Grade Intraosseous Juxtacortical/ Surface Parosteal Periosteal High Grade Surface Intracortical Secondary osteosarcoma Paget’s Osteosarcoma Radiation Induced Bone Infarct Osteogenesis Imperfecta

Cartilaginous Enchondroma Chondrosarcoma Osteochondroma Conventional/Intramedullary Chondroblastoma Clear cell Chondromyxofibroma Mesenchymal Dedifferentiated Juxtacortical/Periosteal Secondary Osteochondroma Multiple Enchondromas Ollier’s disease Maffucci’s Syndroma

Fibrous Fibrous dysplasia Fibrosarcoma Fibrocartilaginous Dysplasia Malignant Fibrous Histiocytoma Osteofibrous Dysplasia Non Ossifying Fibroma Benign Fibrous Histiocytoma Fibroxanthoma Desmoplastic Fibroma (Desmoid/Fibromatosis)

Small Round Blue Cell Eosinophilic Granuloma Ewing’s Sarcoma/PNET Infection Lymphoma Multiple Myeloma

Giant Cell Giant Cell Tumor Category Benign Malignant

Vascular He ma ngio ma He ma ngioe ndothe lio ma Lymphangioma Angiosarcoma Glomus Tumor Hemangiopericytoma Kaposi’s sarcoma

Neurogenic Schwannoma

Cystic Aneurysmal Bone Cyst Primary ABC Secondary ABC Unicameral Bone Cyst Intraosseous Ganglion

Myogenic Leiomyosarcoma Rhabdomyosarcoma

Miscellaneous Lipoma Liposarcoma Parosteal Lipoma Adamantinoma Chordoma Chondroid Chordoma

Metastatic Lesions Lung Breast Kidney Thyroid Prostate Gastrointestinal

Synovial Chondromatosis Pigmented Villonodular synovitis Synovial lipoma Hemangioma Chondrosarcoma Soft Tissue Tumors

Category Benign Malignant

Fibrous/Myofibroblastic Fibromatosis/Desmoid Fibrosarcoma Elastofibroma Solitary Fibrous Tumor Fibrohistiocytic Benign Fibrous Histiocytoma MFH Dermatofibrosarcoma Protuberans Pleomorpphic Myxoid Inflammatory Lipomatous Lipoma Liposarcoma Hibernoma Well Differentiated Myxoid Round Cell Pleomorphic Smooth Muscle Leiomyoma Leiomyosarcoma

Skeletal Muscle Rhabdomyoma Rhabdomyosarcoma Embryonal Alveolar Pleomorphic Vascular Hemangioma Hemangioendothelioma Glomus Hemangiopericytoma Angiosarcoma Synovial PVNS Malignant PVNS GCT Tendon Sheath Neural Schwannoma Malignant Peripheral Nerve Sheath Tumor MPNST Extraskeletal Osseous/ Myositis Ossificans Osteosarcoma Cartilaginous Chondroma Chondrosarcoma Myxoid Mesenchymal Miscellaneous Myxoma Clear Cell Sarcoma Synovial Sarcoma Alveolar soft Part Sarcoma Epithelioid Sarcoma Ewing’s Sarcoma/PNET Desmo p last ic Sm all Cell T umo r NormalNormal TissuesTissues vsvs TumorsTumors „ In order to be able to diagnose abnormal tissue or a tumor/cancer, it is important to understand the microscopic characteristics of the normal tissues of the body. „ The normal tissues of the body consist of epithelial tissue, connective tissue, muscle and nervous tissue. They each have a characteristic microscopic appearance. „ In general, normal tissues have an orderly arrangement of cells. The cells are similar size and shape. The tissue is hypocellular. The nucleus is small. There are no mitotic figures. There are no necrotic or dead areas in the tissue. „ Tumors usually demonstrate a haphazard or disorderly arrangement of cells. The cells are usually different sizes and shapes (cellular pleomorphism). The nuclei are usually large and there is usually less cytoplasm than in a normal cell. There may be mitotic figures in malignant/cancerous tumors. There may also be necrotic or dead areas associated with cancerous tumors. Malignant tumors have more bizarre features than benign tumors, more haphazard arrangement, more pleomorphism. Benign/NormalBenign/Normal TissueTissue

„ HypocellularHypocellular (Low(Low CellularityCellularity/High/High Matrix)Matrix) „ CellsCells ArrangedArranged inin anan OrderlyOrderly MannerManner „ NoNo MitosesMitoses „ LowLow NuclearNuclear toto CytoplasmicCytoplasmic RatioRatio (Small(Small Nuclei)Nuclei) „ UniformUniform NucleiNuclei „ MinimalMinimal toto NoNo CellularCellular PleomorphismPleomorphism MalignantMalignant TumorsTumors

„ HypercellularHypercellular (Low(Low Matrix)Matrix) „ CellularCellular PleomorphismPleomorphism „ MitosesMitoses „ HighHigh Nuclear/Nuclear/CytoplasmicCytoplasmic RatioRatio (Large(Large Nuclei/MinimalNuclei/Minimal Cytoplasm)Cytoplasm) „ DarkDark NucleiNuclei „ HaphazardHaphazard ArrangementArrangement ofof CellsCells „ CrowdingCrowding ofof CellsCells „ NecrosisNecrosis NormalNormal TissuesTissues „ 44 TissueTissue TypesTypes inin thethe BodyBody „ EpithelialEpithelial TissueTissue „ ConnectiveConnective TissueTissue „ Bone „ Cartilage „ Fibrous Connective Tissue „ Tendons, Ligaments „ Fat „ Fascia covering muscle, nerves and blood vessels „ Blood Cells „ MuscleMuscle „ NervousNervous TissueTissue EpithelialEpithelial TissueTissue

„ CloselyClosely packedpacked cellscells withwith littlelittle oror nono intercellularintercellular materialmaterial inin extracellularextracellular spacespace „ FormForm membranesmembranes oror occuroccur asas secretorysecretory elementselements knownknown asas glands;glands; AlsoAlso formsforms thethe skin.skin. „ ClassificationClassification ofof typestypes ofof epithelialepithelial tissue:tissue: „ Squamous,Squamous, Cuboidal,Cuboidal, ColumnarColumnar „ SimpleSimple (single(single layer)layer) „ StratifiedStratified (2(2 oror moremore layers)layers) SkinSkin

„ StratifiedStratified SquamousSquamous EpitheliumEpithelium „ NormalNormal „ VeryVery OrderlyOrderly ArrangedArranged „ CellsCells neatlyneatly stackedstacked onon toptop ofof eacheach otherother „ MinimalMinimal cellularcellular pleomorphismpleomorphism „ UniformUniform nucleinuclei „ AbundantAbundant cytoplasmcytoplasm

NormalNormal KidneyKidney

„ TheThe kidneykidney isis composedcomposed ofof simplesimple cuboidalcuboidal epitheliumepithelium thatthat formsforms tubulestubules „ TheThe cellscells areare arrangedarranged orderlyorderly andand areare notnot packedpacked onon toptop ofof eacheach other.other. TheThe cellscells looklook similarsimilar andand havehave abundantabundant cytoplasm.cytoplasm. ““LL”” isis thethe lumenlumen ofof thethe tubuletubule wherewhere thethe fluid/urinefluid/urine passes.passes. ““NN”” isis aa nucleusnucleus EpithelialEpithelial TissueTissue „ GlandsGlands „ Most glands are formed by epithelial down growths into connective tissue „ The next three slides are examples of normal glands formed by epithelial cells. „ The cells typically form round tubular like structures with a lumen. The cells of a gland all function together to secrete substances or fluid into the lumen of the gland. In a normal gland the cells are orderly arranged, There may be more than one layer of cells. The nucleus is distinct and the cells are similar in size and shape. Examples of glands include breast, thyroid, prostate, salivary, parathyroid, sweat glands. Uncontrolled growth of these cells can lead to cancers of the breast, prostate, thyroid, etc. These are types of carcinomas.

KidneyKidney CancerCancer (Renal(Renal CellCell Carcinoma)Carcinoma)

„ Notice that the cells are cuboidal or columnar like in shape suggestive of a carcinoma „ The cells are disorganized and stacked on top of each other; they appear crowded „ Some cells lack nuclei and some have multiple nuclei „ The lumen are lacking in certain areas „ All these characteristics are consistent with a cancerous tumor/carcinoma RenalRenal CellCell CarcinomaCarcinoma ExamplesExamples ofof NormalNormal EpithelialEpithelial TypeType TissuesTissues andand TheirTheir CancerousCancerous CounterpartsCounterparts

„ TheThe followingfollowing severalseveral slidesslides showshow examplesexamples ofof normalnormal epithelialepithelial typetype tissuestissues andand theirtheir malignantmalignant counterpartscounterparts „ PleasePlease taketake noticenotice ofof thethe differencesdifferences inin cellularcellular architecturearchitecture betweenbetween benignbenign andand malignantmalignant tumorstumors NormalNormal ThyroidThyroid GlandGland

„ NormalNormal thyroidthyroid „ OrderlyOrderly arrangementarrangement ofof cellscells andand folliclesfollicles „ FolliclesFollicles containcontain thyroglobulinthyroglobulin (pink(pink material)material) „ NoNo mitosesmitoses „ OneOne layerlayer ofof cellscells aroundaround folliclefollicle ThyroidThyroid CancerCancer

„ CellsCells areare crowdedcrowded andand packedpacked onon toptop ofof eacheach otherother „ CellularCellular pleomorphismpleomorphism „ FolliclesFollicles areare arrangedarranged haphazardhaphazard andand notnot allall folliclesfollicles containcontain thyroglobulinthyroglobulin „ VeryVery darkdark nucleinuclei ThyroidThyroid CarcinomaCarcinoma ConnectiveConnective TissueTissue

„ ComposedComposed mainlymainly ofof intercellularintercellular materialmaterial (matrix)(matrix) withwith aa limitedlimited numbernumber ofof cellscells ((hypocellularhypocellular/small/small numbernumber ofof cells)cells) „ ClassifiedClassified mostlymostly onon basisbasis ofof materialmaterial componentscomponents ratherrather thanthan cellularcellular constituentsconstituents „ Classification:Classification: „ EmbryonicEmbryonic ConnectiveConnective TissueTissue „ AdultAdult ConnectiveConnective TissueTissue ConnectiveConnective TissueTissue

„ EmbryonicEmbryonic ConnectiveConnective TissueTissue „ MesenchymeMesenchyme——derivedderived fromfrom mesodermmesoderm „ Mucous/Mucous/MyxoidMyxoid EmbryonicEmbryonic ConnectiveConnective TissueTissue „ CellsCells areare spindlespindle shapedshaped oror cigarcigar shapedshaped „ TheThe nucleusnucleus isis largelarge inin comparisoncomparison toto thethe cytoplasmcytoplasm „ TheseThese cellscells areare primitiveprimitive mesenchymalmesenchymal cellscells thatthat formform thethe connectiveconnective tissuestissues inin thethe bodybody (bone,(bone, cartilage,cartilage, tendons,tendons, ligaments,ligaments, etc)etc) „ SarcomasSarcomas developdevelop fromfrom mesenchymalmesenchymal typetype cellscells MyxoidMyxoid oror MucousMucous TypeType TissueTissue

„ Myxoid tissue produces a mucous-like substance that is composed of mucopolysaccharides and glycosaminoglycans „ The tissue stains a bluish color because of the mucous „ The tissue appears loose and not very dense almost like whisps of cotton candy „ Notice the low cellularity, small nuclei and slender spindled shape of the cells consistent with benign connective tissue ConnectiveConnective TissueTissue „ AdultAdult ConnectiveConnective TissueTissue „ ConnectiveConnective TissueTissue ProperProper „ Loose (areolar) „ Reticular „ Adipose „ Dense Irregular „ Dense Regular „ Collagenous „ Elastic „ SpecializedSpecialized ConnectiveConnective TissueTissue „ Supporting (Bone, Cartilage) „ Blood NormalNormal ConnectiveConnective TissueTissue

„ TheThe nextnext threethree slidesslides demonstratedemonstrate normal,normal, benignbenign connectiveconnective tissue.tissue. PleasePlease taketake noticenotice ofof thethe lowlow cellularitycellularity,, highhigh matrixmatrix contentcontent (intercellular(intercellular material),material), nono mitoses,mitoses, orderlyorderly arrangementarrangement ofof cells,cells, lacklack ofof cellularcellular pleomorphism,pleomorphism, smallsmall nucleinuclei——allall characteristicscharacteristics ofof benignbenign tissuetissue „ TheThe fourthfourth slideslide isis aa sarcoma,sarcoma, derivedderived fromfrom aa primitiveprimitive connectiveconnective tissuetissue cell;cell; itit isis hypercellular;hypercellular; thethe nucleinuclei areare largelarge andand cigarcigar shaped;shaped; thethe cellscells areare crowdedcrowded andand arrangedarranged haphazardly;haphazardly; therethere isis disorganizationdisorganization——allall characteristicscharacteristics ofof aa cancerouscancerous tumortumor ofof connectiveconnective tissuetissue originorigin oror aa sarcomasarcoma LooseLoose ConnectiveConnective TissueTissue DenseDense IrregularIrregular ConnectiveConnective TissueTissue DenseDense RegularRegular ConnectiveConnective TissueTissue TendonTendon Sarcoma/FibrosarcomaSarcoma/Fibrosarcoma FibrosarcomaFibrosarcoma // MalignantMalignant SpindleSpindle CellCell TumorTumor

„ SarcomaSarcoma——CancerCancer „ LargeLarge NucleiNuclei andand SmallSmall amountamount ofof CytoplasmCytoplasm „ NuclearNuclear PleomorphismPleomorphism „ HypercellularHypercellular andand CrowdedCrowded „ DisorganizedDisorganized ArchiterctureArchitercture „ MitoticMitotic FiguresFigures „ SmallSmall AmountAmount ofof MatrixMatrix ElasticElastic ConnectiveConnective TissueTissue

„ The dark stained wiry and wavy fibers are elastic (elastin) fibers produced by the fibroblasts „ Elastofibromas are benign soft tissue tumors that are composed of cells that produce elastin fibers Adipose/FattyAdipose/Fatty TissueTissue

„ TheThe cellscells ofof normalnormal maturemature adiposeadipose tissuetissue havehave aa largelarge cytoplasmcytoplasm thatthat containscontains thethe lipidslipids „ TheThe nucleusnucleus isis small,small, eccentriceccentric andand compressedcompressed upup againstagainst thethe cellcell membranemembrane „ ThereThere areare nono mitoticmitotic figuresfigures „ TheThe cellscells appearappear organizedorganized andand areare similarsimilar sizesize andand shapeshape Adipose/FatAdipose/Fat TissueTissue CartilageCartilage

„ 33 TypesTypes ofof CartilageCartilage „ HyalineHyaline „ Articulating surfaces of bone „ ElasticElastic „ Epiglottis, Ear „ FibrocartilageFibrocartilage „ Symphyses, eustacian tube, intervertebral discs, tendon insertions FetalFetal ChondroblastsChondroblasts ofof FemurFemur

„ NucleiNuclei areare UniformUniform „ LargeLarge NucleiNuclei withwith PlumpPlump CytoplasmCytoplasm „ AppearsAppears OrganizedOrganized „ NoNo MitosesMitoses ChondroblastomaChondroblastoma

„ A chondroblastoma is a benign bone tumor „ It is composed of immature chondroblasts that resemble fetal hyaline chondroblasts „ They have a thick cell membrmembrane,ane, large , often bean shaped nucleus and plump cytoplasm „ The cells are uniform and there are no mitoses CartilageCartilage „ Characteristics:Characteristics: „ NonNon vascular,vascular, strongstrong andand pliablepliable „ Matrix:Matrix: glycosaminoglycansglycosaminoglycans inin whichwhich fibrousfibrous andand cellularcellular elementselements areare embeddedembedded „ Fibers:Fibers: collagencollagen oror collagencollagen andand elasticelastic „ Cells:Cells: ChondrocytesChondrocytes embeddedembedded inin spacesspaces (Lacunae)(Lacunae) „ MatrixMatrix appearsappears smoothsmooth andand glassyglassy becausebecause thethe fibersfibers areare finefine andand areare maskedmasked byby thethe glycosaminoglycansglycosaminoglycans;; thethe orientationorientation ofof thethe fibersfibers leadsleads toto itsits glassyglassy appearanceappearance underunder aa microscopemicroscope „ NormalNormal CartilageCartilage isis hypocellularhypocellular;; thethe cellscells areare orderlyorderly placed;placed; therethere areare nono mitosesmitoses HyalineHyaline CartilageCartilage

EnchondromaEnchondroma „ An enchondroma is a benign bone tumor composed of cartilaginous tissue „ Cartilage also grows in lobules „ Cells are in lacunae „ It is hypocellular „ Cells are small and orderly placed; Nuclei are small and similar size and shape „ Matrix stains bluish due to glycosaminoglycans EnchondromaEnchondroma ChondrosarcomaChondrosarcoma „ In a chondrsarcoma (malignant cartilage tumor) the cells are in lacunae but are large, bizarre in shape and pleomorphic „ The tumor is hypercellular „ Cells are crowded „ There may be mitotic figures „ The cartilage may entrap oror invade bone „ Binucleated or multinucleated cells often exist ChondrosarcomaChondrosarcoma Enchondroma/ChondrosarcomaEnchondroma/Chondrosarcoma Enchondroma/ChondrosarcomaEnchondroma/Chondrosarcoma BoneBone

„ VascularVascular ConnectiveConnective TissueTissue „ TypesTypes „ DenseDense oror CompactCompact (Cortical)(Cortical) „ SpongeSponge--likelike oror CancellousCancellous BoneBone „ CellsCells „ Osteoblasts—immature cells that make bone „ Osteocytes—mature cells that maintain bone homeostasis „ Osteoclasts---mature multinucleated cells that resorb bone „ Bone is in a constant state of flux where bone is being resorbed by osteoclasts and new bone layed down by osteoblasts „ OsteoidOsteoid isis immatureimmature bonebone composedcomposed ofof collagencollagen beforebefore itit becomesbecomes calcified.calcified. OsteoblastsOsteoblasts produceproduce osteoidosteoid whichwhich isis usuallyusually layedlayed downdown onon prepre--existingexisting bone.bone. TheThe osteoidosteoid ultimatelyultimately becomesbecomes calcifiedcalcified andand reorganizedreorganized intointo aa maturemature formform ofof bonebone (either(either trabeculaetrabeculae oror becomesbecomes incorporatedincorporated intointo aa haversionhaversion system).system). BoneBone producingproducing tumorstumors likelike osteosarcoma,osteosarcoma, osteoblastomaosteoblastoma andand osteoidosteoid osteomaosteoma areare characterizedcharacterized byby theirtheir productionproduction ofof osteoid.osteoid. BoneBone

„ AA BoneBone isis composedcomposed ofof CancellousCancellous BoneBone andand CorticalCortical Bone.Bone. „ CancellousCancellous (Forms(Forms medullarymedullary canal/incanal/in thethe centercenter ofof bonebone wherewhere thethe marrowmarrow exists)exists) „ LargeLarge openopen spacesspaces surroundedsurrounded byby thinthin anastomosinganastomosing platesplates ofof bonebone (trabeculae)(trabeculae) Cancellous/TrabecularCancellous/Trabecular BoneBone „ The trabeculae (T) consist of narrow interconnecting plates of bone „ The bone marrow fills the space between the trabeculae „ The trabeculae are narrow so they do not need blood vessels in the center of them (The blood vessels are in the marrow) „ Ob = osteoblast; „ Oc = osteocyte

NormalNormal BoneBone TrabeculaTrabecula „ The Osteoblasts (Ob) are plump and similar size and shape. They have a prominent nucleus. They are laying down osteoid on a pre- existing piece of bone. The osteoid is not calcified and therefore appears as a clear area between the osteoblasts and pre- existing bone (stains red or dark pink) „ The osteoblasts ultimately become incorporated into the bone and become less active. Once they become incorporated into the bone they become the osteocytes (Oc). The osteocytes are smaller, less plump and sit in lacunae (spaces) within the bone. BoneBone „ CompactCompact bonebone (Cortical(Cortical bone)bone) „ DenserDenser thanthan cancellouscancellous bonebone „ OrganizedOrganized intointo lamellaelamellae „ SpacesSpaces areare smallsmall „ HasHas bloodblood vessels/haversianvessels/haversian systemssystems „ Cells:Cells: Osteoblasts,Osteoblasts, Osteocytes,Osteocytes, OsteoclastsOsteoclasts „ OsteocytesOsteocytes occupyoccupy lacunaelacunae „ OsteonOsteon (haversian(haversian CanalCanal System):System): HaversianHaversian canalcanal withwith surroundingsurrounding lamellaelamellae ofof bonebone containingcontaining canaliculicanaliculi radiatingradiating toto itit fromfrom thethe osteocytesosteocytes trappedtrapped inin lacunaelacunae „ HaversianHaversian canals:canals: ParallelParallel toto longlong axis;axis; VolkmanVolkman’’ss canalscanals connectconnect thethe haversianhaversian canalscanals BoneBone

„ CompactCompact BoneBone (Cortical(Cortical Bone)Bone) „ BonyBony lamellaelamellae areare organizedorganized intointo 44 lamellarlamellar systems:systems: „ ExternalExternal circumferentialcircumferential lamellaelamellae „ InternalInternal circumferentialcircumferential lamellaelamellae „ InterstitialInterstitial lamellaelamellae „ OsteonsOsteons CorticalCortical Bone/CompactBone/Compact BoneBone

„ Cortical bone is thick and needs blood vessels to distribute the nutrients to all areas and cells. The blood vessels run in the Haversian Canals (HC) and Volkman’s Canals(VC) „ The bone is oriented in a circumferential pattern around these canals. „ Os = Osteon „ L = Lamellae

Cortical/CompactCortical/Compact BoneBone

„ ArrowsArrows == CementCement LineLine „ OcOc == OsteocyteOsteocyte „ ObOb == OsteoblastOsteoblast „ BVBV == BloodBlood VesselVessel OsteosarcomaOsteosarcoma (High(High Grade)Grade) OsteosarcomaOsteosarcoma (High(High Grade)Grade)

„ AnAn osteosarcomaosteosarcoma isis aa highhigh gradegrade sarcomasarcoma thatthat producesproduces immatureimmature bonebone oror osteoidosteoid „ TheThe cellscells areare pleomorphicpleomorphic,, andand spindlespindle shapedshaped likelike aa sarcoma.sarcoma. ItIt isis hypercellularhypercellular andand thethe cellscells appearappear crowdedcrowded andand disorganizeddisorganized „ TheThe cellscells areare layinglaying downdown osteoidosteoid inin aa haphazard,haphazard, disorganized,disorganized, lacelace likelike mannermanner (arrows;(arrows; pinkpink lacelace-- like,like, amorphousamorphous substance)substance) OsteoblastomaOsteoblastoma OsteoblastomaOsteoblastoma

„ An osteoblastoma is a benign, bone forming tumor „ There are osteoblasts that appear plump and similar size and shape; no mitoses; no pleomorphism „ The osteoblasts are laying down bone and the bone/osteoid appears to be trying to form a shape like a normal trabecula of bone OsteosarcomaOsteosarcoma (Low(Low Grade)Grade)

„ There are also low grade forms of osteosarcoma in which the cells are less bizarre, smaller and less pleomorphic. There are fewer mitoses. There is usually a fibrous matrix associated with a low grade osteosarcoma „ The key to diagnosis is identification of the osteoid (arrows) BoneBone „ HistogenesisHistogenesis (Intramembranous(Intramembranous andand Endochondral)Endochondral) „ IntramembranousIntramembranous OsiificationOsiification „ Arises in richly vascularized mesenchymal membrane „ Mesenchymal cells differentiate into osteoblasts that elaborate bone matrix and form trabeculae „ Trabeculae fuse and form cancellous bone „ Remodeling yields compact bone „ Primary or woven Bone: Newly formed bone—haphazard arrangement of collagen bundles—not as orderly as older bone „ Woven bone is replaced via remodeling to form secondary or mature bone BoneBone

„ EndochondralEndochondral OssificationOssification „ ResponsibleResponsible forfor formationformation ofof longlong andand shortshort bonesbones „ HyalineHyaline cartilagecartilage modelmodel isis replacedreplaced byby bonebone „ InvadedInvaded byby periostealperiosteal budbud thatthat bringsbrings inin bloodblood vessels,vessels, mesenchymalmesenchymal cellscells andand osteogenicosteogenic cellscells „ OsteoblastsOsteoblasts elaborateelaborate aa bonybony matrixmatrix onon calcifiedcalcified cartilagecartilage andand formsforms aa primaryprimary ossificationossification centercenter „ SecondarySecondary ossificationossification centercenter occursoccurs inin thethe epiphysiepiphysi BloodBlood

„ ErythrocyteErythrocyte „ LymohocyteLymohocyte „ MonocyteMonocyte „ NeutrophilNeutrophil „ EosinophilEosinophil „ BasophilBasophil „ PlateletsPlatelets

PlasmaPlasma CellsCells PlasmaPlasma CellsCells

„ Characteristics:Characteristics: „ EccentricEccentric NucleusNucleus „ PerinuclarPerinuclar HaloHalo „ PlumpPlump CytoplasmCytoplasm (making(making antibodies)antibodies) „ ClockfaceClockface nucleusnucleus MyelomaMyeloma (Plasma(Plasma CellCell Cancer)Cancer) MyelomaMyeloma MyelomaMyeloma

„ ComposedComposed ofof plasmaplasma cellscells „ CellsCells havehave similarsimilar characteristicscharacteristics toto normalnormal plasmaplasma cellscells MuscleMuscle

„ SmoothSmooth MuscleMuscle „ SkeletalSkeletal MuscleMuscle „ CardiacCardiac MuscleMuscle SkeletalSkeletal MuscleMuscle SkeletalSkeletal MuscleMuscle

„ Skeletal muscle has striations that consist of the ctin and myosin filaments or contractile elements „ The nucleus is cigar shaped and sit eccentrically within the cell „ The majority of the cell consists of the contractile elements SkeletalSkeletal MuscleMuscle——CrossCross SectionSection SmoothSmooth MuscleMuscle----LongitudinalLongitudinal

„ Smooth muscle exists in the organs and blood vessels and is responsible for the contractile activities of these structures. For instance, in the digestive tract, it is resonsible for propelling food through the tract „ The nuclei are long and slender/cigar shaped „ The nuclei of some of the cells have a cork screw appearance indicating that they were actively contracting SmoothSmooth MuscleMuscle SmoothSmooth MuscleMuscle——CrossCross SectionSection LeiomyosarcomaLeiomyosarcoma

„ A leiomyosarcoma is a sarcoma (cancer) of smooth muscle origin „ This is a very well differentiated example in which the long spindled cells and nuceli are apparent „ Often, it is only possible to tell that the tumor is of smooth muscle origin by performing specific immunochemical stains that identify the presence of smooth muscle actin NervousNervous TissueTissue

„ PeripheralPeripheral NervesNerves „ SympatheticSympathetic GangliaGanglia PeripheralPeripheral NerveNerve PeripheralPeripheral NerveNerve

„ A peripheral nerve consists of axons (Ax) that are surrounded by schwann cells (ScC). The nuceli that are seen are the nuclei of the schwann cells. The schwann cells provide an insulating layer (myelin; M) around the axon so that the conductivity through the nerve is rapid „ The schwann cells have a clear to light pink cytoplasm „ NR = Node of Ranvier „ MS = Myelin Sheath „ P = Perineurium PeripheralPeripheral NerveNerve——CrossCross sectionsection SchwannomaSchwannoma SchwannomaSchwannoma

„ AA schwannomaschwannoma isis aa benignbenign tumortumor thatthat arisesarises fromfrom aa nerve.nerve. ItIt arisesarises fromfrom thethe nervenerve sheathsheath oror coatingcoating aroundaround thethe nerve.nerve. UnknownUnknown ExamplesExamples

„ TheThe followingfollowing slidesslides demonstratedemonstrate somesome commoncommon musculoskeletalmusculoskeletal neoplasmsneoplasms.. FirstFirst youyou areare givengiven andand unknownunknown andand thethe slideslide thatthat followsfollows givesgives thethe diagnosis.diagnosis. „ PleasePlease firstfirst thinkthink aboutabout whatwhat broadbroad categorycategory thethe tumortumor fitsfits intointo (bone(bone producing,producing, cartilage,cartilage, fibrous,fibrous, nervous,nervous, smallsmall roundround blueblue cell,cell, giantgiant cell,cell, vascularvascular tumor,tumor, etc)etc) andand thenthen whetherwhether itit appearsappears benignbenign oror malignant.malignant. ThisThis isis aa goodgood approachapproach forfor determiningdetermining oror narrowingnarrowing thethe diagnosis.diagnosis.

ChondromaChondroma

GiantGiant CellCell TumorTumor GiantGiant CellCell TumorTumor

ChondroblastomaChondroblastoma

ChondrosarcomaChondrosarcoma

EwingEwing’’ss SarcomaSarcoma

HemangiomaHemangioma

HemangioendotheliomaHemangioendothelioma

NonossifyingNonossifying FibromaFibroma

FibrosarcomaFibrosarcoma NOF/FibrosarcomaNOF/Fibrosarcoma Benign/MalignantBenign/Malignant

OsteoblastomaOsteoblastoma

OsteosarcomaOsteosarcoma (High(High Grade)Grade)

OsteosarcomaOsteosarcoma (Low(Low Grade)Grade)

LeiomyosarcomaLeiomyosarcoma

EnchondromaEnchondroma

MalignantMalignant FibrousFibrous HistiocytomaHistiocytoma

FibFibromatosisromatosis/D/Desmoidesmoid/D/Desmoplasticesmoplastic FibromaFibroma

LipomaLipoma

WellWell DifferentiatedDifferentiated LiposarcomaLiposarcoma LipomaLipoma vs.vs. WellWell DifferentiatedDifferentiated LiposarcomaLiposarcoma

RhabdomyosarcomaRhabdomyosarcoma

„ StriationsStriations consistentconsistent withwith SkeletalSkeletal musclemuscle originorigin