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Pathology (Bone (Bone Tumors and Tumorlike Lesions (Cartilage-Forming…

- - - - • Simple: overlying skin intact
      - • Comminuted: bone fragmented
      - • Stress: a slowly developing fracture that follows a period of incr physical activity in which bone is subjected to repetitive loads
      - • Greenstick: extending only partially through bone, common in infants when bones are soft
      - • Pathologic: involving bone weakened by an underlying disease process, such as a tumor
      - • Compound: bone communicates w/ skin surface
      - • Displaced: ends of bone at fracture site not aligned
    - - Immediately after fracture: rupture of blood vessels --> hematoma: fills fracture gap & surrounds area of bone injury;
        clotted blood--> fibrin mesh, sealing off fracture site--> scaffold for influx of infl cells & ingrowth of fibroblasts & new capillaries;
        Simultaneously, degranulated platelets and migrating infl cells--> PDGF, TGF-β, FGF,..--> activate osteoprogenitor cells in periosteum, medullary cavity, surrounding soft tissues & stimulate osteoclastic and osteoblastic activity
        By end of first week: mass of predominantly uncalcified tissue— soft callus or procallus—provides anchorage betw ends of fractured bones [no weight bearing]
        After 2 weeks: soft callus transformed into a bony callus; activated osteoprogenitor cells deposit woven bone
        In some cases, activated mesenchymal cells in the soft tissues and bone surrounding fracture line also differentiate into chondrocytes--> newly formed cartilage along fracture line--> endochondral ossification--> contiguous network of bone w/ newly deposited bone trabeculae in medulla & beneath periosteum
        [eventually woven--> lamellar; can tolerate weight]
      - As callus matures & subjected to weightbearing forces, portions not physically stressed are resorbed: remodeling: reduces size of callus until shape and outline of the fractured bone are reestablished as lamellar bone
        healing process is complete w/ restoration of medullary cavity.
      - Displaced & comminuted fractures frequently result in some deformity
        Inadequate immobilization permits movement of callus and prevents its normal maturation--> delayed union or nonunion--> if a nonunion persists--> malformed callus undergoes cystic degeneration, and luminal surface may become lined by synovial-like cells--> a false joint or pseudoarthrosis
        Infection of fracture site, esp common in open fractures, a serious obstacle to healing
        Malnutrition & skeletal dysplasia also hinder fracture healing
  - - - Changes depend on stage (acute, subacute, or chronic) and location of infection
        acute phase: bacteria prolif--> neutrophilic infl reaction--> necrosis of bone cells and marrow ensues within first 48 hrs;
        bacteria and infl spread longitudinally and radially throughout Haversian systems to reach periosteum.
        In children, periosteum loosely attached to cortex--> sizable subperiosteal abscess may form that dissect for long distances along bone surface; Lifting of periosteum further impairs blood supply to affected region, contributing to necrosis; dead bone known as a sequestrum. Rupture of periosteum--> a soft tissue abscess--> channel to skin--> a draining sinus. Sometimes sequestrum crumbles--> fragments that pass through sinus tract. [brodie abscess]
        In infants (and uncommonly in adults), epiphyseal infection may spread through articular surface or along capsular and tendoligamentous insertions into a joint--> septic or suppurative arthritis--> destruction of articular cartilage & permanent disability.
        After first week, chronic infl cells--> cytokines--> osteoclastic bone resorption, ingrowth of fibrous tissue, deposition of reactive bone at periphery;
        newly deposited bone can form a shell of living tissue, known as an involucrum, around segment of devitalized infected bone
        histologic findings of chronic osteomyelitis are more protean but typically involve marrow fibrosis, sequestrum, and an infl infiltrate of lymphocytes and plasma cells.
        Sclerosing Osteomyelitis of Garre: in mandible, esp in ppl who have dental and gum surgery
      - Hematogenous osteomyelitis
        sometimes manifests as an acute systemic illness w/ malaise, fever, chills, leukocytosis, and marked throbbing pain over affected region
        In other instances presentation subtle, w/ only unexplained fever (most often in infants) or localized pain (most often in adults)
        dx strongly suggested by charac radiographic findings of a lytic focus of bone destruction surrounded by a zone of sclerosis.
        Biopsy and bone cultures required to identify pathogen in most instances.
        combination of antibiotics and surgical drainage u curative
        In 5% to 25% of cases, acute osteomyelitis fails to resolve and persists as chronic infection
        Chronic infections may develop when: delay in dx, extensive bone necrosis, inadequate antibiotic therapy or surgical debridement, or weakened host defenses
        course of chronic infections may be punctuated by acute flare-ups; u spontaneous and may occur after yrs of dormancy
        Other complications of chronic osteomyelitis: pathologic fracture, secondary amyloidosis, endocarditis, sepsis, development of squamous cell carcinoma in draining sinus tracts and [rarely] sarcoma in infected bone.
      - almost always caused by bacteria, rarely by fungi
        may reach bone by (1) hematogenous spread, (2) extension from a contiguous site, and (3) direct implantation after compound fractures or orthopedic procedures
        In healthy children, most osteomyelitis hematogenous in origin and develops in long bones
        In adults, more often occurs as a complication of open fractures, surgical procedures, and infections of feet in diabetics.
        Staph A. responsible for 80-90% cases of culture-positive pyogenic osteomyelitis
        express cell wall prs that bind to bone matrix components such as collagen and facilitate adherence to bone
        E. coli, Pseudomonas, and Klebsiella more frequently isolated from GU tract infections or IV drug abusers
        Mixed bacterial infections seen in setting of direct spread, inoculation of organisms during surgery, or into open fractures.
        neonatal period: H. influenzae & group B streptococci frequent pathogens
        individuals w/ sickle cell disease predisposed to Salmonella infection
        In 50% of suspected cases, no organisms can be isolated.
        
        osseous vascular circulation, which varies w/ age, determines location of infection in most long bones
        In infants and adults, vascular communication allows spread of infection between metaphysis and epiphysis
        By contrast, avascular growth plate in child interrupts infection spread between metaphysis & epiphysis
  - - - Vertebral fractures that frequently occur in thoracic and lumbar regions painful, and, when multiple--> significant loss of
        height and various deformities (lumbar lordosis and kyphoscoliosis)
        immobility following fractures of femoral neck, pelvis, or spine--> pulmonary embolism, pneumonia,
        cannot be reliably detected in plain radio graphs until 30% to 40% of bone mass is lost, and measurement of blood levels of Ca, P, and ALP not diagnostic--> difficult to screen for in asymptomatic people.
        best estimates of bone loss, aside from biopsy (rarely performed), are specialized radiographic imaging techniques, (dual-energy x-ray absorptiometry and quantitative CT) which measure bone density
        prevention and treatment of senile and postmenopausal: exercise, appropriate Ca and vitamin D intake, and pharmacologic agents that decr resorption (bisphosphonates).
        Bisphosphonates reduce osteoclast activity and induce osteoclast apoptosis.
        Denosumab, an anti-RANKL Ab that blocks osteoclast activation,
        major challenge in pharmacotherapy of osteoporosis has been the inability to uncouple bone formation and resorption.
        menopausal hormone therapy has been used to prevent fracture, complications, particularly DVT and stroke, have prompted search for more selective estrogen receptor modulators
      - hallmark: histologically normal bone that is decr in quantity
        entire skeleton affected in postmenopausal and senile osteoporosis, but certain bones tend to be more severely impacted.
        In postmenopausal osteoporosis incr in osteoclast activity affects mainly bones or portions of bones that have incr surface area, such as cancellous compartment of vertebral bodies
        [in senile: cortical bones, in endosthial and subperiosteum]
        trabecular plates become perforated, thinned, and lose their interconnections--> progressive microfractures and eventual vertebral collapse
      - Peak bone mass: young adulthood
        magnitude influenced by hereditary factors, esp polymorphisms in genes that influence bone metabolism
        Physical activity, muscle strength, diet, and hormonal state also make important contributions.
        After maximal skeletal mass is attained, bone turnover continues w/ a net deficit in bone formation--> average loss of 0.7% of bone mass / yr.
        • Age-related changes.
        Osteoblasts from older individuals: reduced prolif and biosynth potential and reduced response to GFs; senile osteoporosis categorized as a low-turnover osteoporosis
        • Reduced physical activity.
        contributes to senile osteoporosis
        Mechanical forces stimulate normal bone remodeling
        type of exercise important: load magnitude influences bone density > number of load cycles--> resistance exercises more effective stimuli for incr bone mass than repetitive endurance activities
        • Genetic factors.
        Single gene defects (e.g., LRP5 mutations): only a small fraction of cases.
        Polymorphisms in other genes, in particular genes in Wnt signaling pathway. [in vit d receptor gene]
        • Calcium nutritional state.
        Adolescents (partic girls) tend to have low dietary Ca intake--> restricts peak bone mass.
        Ca deficiency, incr PTH, and reduced vit D also may play a role in the development of senile osteoporosis.
        • Hormonal influences.
        In decade after menopause, yearly reductions in bone mass may be as much as 2% of cortical bone and 9% of medullary bone.
        Estrogen deficiency: major role
        40% of postmenopausal women ffected by osteoporosis.
        Decr estrogen after menopause--> incr both bone resorption and formation but latter does not keep up w/ former--> high-turnover osteoporosis.
        decr estrogen may incr secretion of infl cytokines by monocytes--> stimulate osteoclast recruitment and activity by incr levels of RANKL, diminishing expression of OPG, decr osteoclast prolif, and preventing osteoclast apoptosis
        Cytokines such as IL-6, TNF-α, and IL-1 also implicated in postmenopausal osteoporosis, either independently or as downstream mediators of estrogen signaling.
      - osteopenia: decr bone mass, while osteoporosis defined as osteopenia that is severe enough to significantly incr risk of fracture
        Radiographically, osteoporosis considered bone mass at least 2.5 standard deviations below mean peak bone mass, whereas osteopenia is 1 to 2.5 standard deviations below mean
        disorder may be localized [like not using a limb for a long time] or generalized [most]
        Although osteoporosis can be secondary to endocrine disorders (e.g., hyperthyroidism), GI disorders (e.g., malnutrition), or drugs (e.g., corticosteroids), most osteoporosis: primary.
        most common forms of osteoporosis: senile [in both genders, after 30-40] & postmenopausal types
  - - - Osteoid Osteoma and Osteoblastoma
        
        benign, have similar histologic features but differ clinically and radiographically. Malignant transformation rare
        Osteoid osteomas:
        < 2 cm in diameter
        most common in young men
        50% involve femur or tibia, wherein they typically arise in cortex; U. a thick rim of reactive cortical bone that may be only clue radiographically
        present w/ severe nocturnal pain relieved by aspirin and other NSAIDs; pain probably caused by PGE2 produced by osteoblasts
        frequently treated by radiofrequency ablation
        Osteoblastoma
        , > 2 cm
        involves post components of vertebrae (laminae and pedicles) more frequently
        pain unresponsive to aspirin
        u. does not induce a marked bony reaction
        u. curetted or excised.
        
        round-to-oval masses of hemorrhagic gritty tan tissue
        well circumscribed, composed of randomly interconnecting delicate trabeculae of woven bone prominently rimmed by a single layer of osteoblasts
        stroma consists of loose connective tissue that contains many dilated & congested capillaries
        relatively small size, welldefined margins, and benign cytologic features of neoplastic osteoblasts help distinguish from osteosarcoma.
        Osteoid osteomas elicit formation of a large amount of reactive bone, which encircles lesion
      - Osteosarcoma
        
        malignant
        produces osteoid matrix or mineralized bone
        Excluding hematopoietic tumors (myeloma and lymphoma), osteosarcoma most common primary malignant tumor of bone.
        a bimodal age distribution;
        75%: < 20 yrs of age.
        smaller second peak: older adults, who frequently suffer from conditions known to predispose to osteosarcoma, such as Paget disease, bone infarcts, and previous radiation: secondary osteosarcomas
        m>f (1.6:1)
        most common sites in adolescents: metaphyseal regions of distal femur & proximal tibia; [60% in knees]
        present as painful, progressively enlarging masses.
        Sometimes a pathologic fracture is first indication
        Radiographs: large, destructive, mixed lytic and sclerotic mass w/ infiltrative margins (
        frequently breaks through cortex and lifts periosteum--> reactive subperiosteal bone formation
        triangular shadow between cortex and raised ends of periosteum, known radiographically as Codman triangle: indicative of an aggressive tumor, but not pathognomonic of osteosarcoma.
        
        70% have acquired genetic abnormalities; u. have mutations in well-known tumor suppressors and oncogenes:
        • RB (negative regulator of cell cycle); most important mutation; pxs w/ germline mutations in RB: a. w/ 1000x incr risk of osteosarcoma, and somatic RB mutations present in up to 70% of sporadic osteosarcomas.
        • TP53 (promoting DNA repair & apoptosis of irreversibly damaged cells); Li-Fraumeni syndrome (germline TP53 gene mutations: greatly elevated incidence of osteosarcoma)
        • CDKN2A (encodes two tumor suppressors, p16 and p14)
        • MDM2 and CDK4 (regulators that inhibit p53 and RB function, respectively)
        osteosarcomas peak in incidence around the time of adolescent growth spurt and occur most frequently in region of growth plate in bones w/ fastest growth
        
        [most common: arises from metaphyses, is in medulla, primary, solitary, low grade, forms bone matrix]
        bulky, gritty, gray-white, often contain areas of hemorrhage & cystic degeneration
        frequently destroy surrounding cortices & produce soft tissue masses
        spread extensively in medullary canal, infiltrating and replacing marrow
        Infrequently penetrate epiphyseal plate or enter joint
        [penetrate diaphyses]
        formation of osteoid matrix or mineralized bone by malignant tumor cells: diagnostic of osteosarcoma (in many other tumors, bone formation by cartilage or blood vessel) [sometimes malignant tumor cells may form cartilage instead--> chondroblastic osteosarcoma]
        neoplastic bone u. has a fine, lacelike configuration but also may be deposited in broad sheets or as primitive trabeculae
        tumor cells vary in size and shape (pleomorphic), frequently have large hyperchromatic nuclei
        Bizarre tumor giant cells, vascular invasion, and necrosis ommon. Mitotic activity high, including abnormal forms (ex tripolar mitoses)
        
        treated w/ a multimodality approach
        (1) neoadjuvant chemotherapy,
        (2) surgery, [if chemo doesn't respond, maybe amputation]
        (3) chemotherapy
        amount of chemotherapy-induced necrosis found at surgical resection an important prognostic finding
        aggressive, spread hematogenously to lungs, ...
        5-year survival rates reaching 60% to 70% in pxs w/o detectible metastases at initial diagnosis
        outcome for pxs w/ metastases, recurrent disease, or secondary osteosarcoma still poor.
    - - Osteochondroma
        
        known clinically as exostosis
        a benign cartilage-capped tumor, attached to underlying skeleton by a bony stalk
        85% solitary: u. first diagnosed in late adolescence & early adulthood
        15% as part of multiple hereditary exostoses syndrome:
        become apparent during childhood
        m>f 3:1
        develop in bones of endochondral origin and arise from metaphysis near growth plate of long tubular bones, esp near knee
        present as slow-growing masses, can be painful if impinge on a nerve or if stalk fractured
        In many cases detected incidentally
        In multiple hereditary exostoses: underlying bones may be bowed and shortened, reflecting an associated disturbance in epiphyseal growth
        
        Hereditary exostoses:
        germline loss-offunction mutations in EXT1 or EXT2 gene and subsequent loss of the remaining wild-type allele in chondrocytes of growth plate.
        Reduced expression of EXT1 or EXT2 also seen in sporadic osteochondromas
        These genes encode Es that synthesize heparan sulfate GAGs; --> reduced or abnormal GAGs may prevent normal diffusion of Hedgehog factors (local regulators of cartilage growth)--> disrupting chondrocyte differentiation and skeletal development
        
        sessile or pedunculated
        range from 1 to 20 cm
        cap composed of benign hyaline cartilage & covered peripherally by perichondrium
        cartilage has appearance of a disorganized growth plate and undergoes endochondral ossification, w/ newly made bone forming inner portion of head and stalk; cortex of stalk merges w/ cortex of host bone--> continuity between medulla of osteochondroma & host bone.
        
        u. stop growing at time of growth plate closure
        Symptomatic tumors cured by simple excision [no recurrence]
        Rarely in sporadic cases, but more commonly in multiple hereditary exostosis (5%– 20%), osteochondromas progress to chondrosarcoma
      - Chondroma
        
        Heterozygous gain of function mutations in IDH1 and IDH2 genes, (isocitrate dehydrogenases): syndromic and solitary enchondromas
        enchondroma syndromes: mosaics, harboring IDH mutations in only a subset of otherwise normal cells throughout their bodies.
        --> new enzymatic activity on IDH--> synthesis of 2-hydroxyglutarate; this so-called “oncometabolite” interferes w/ regulation of DNA methylation and also implicated in certain glial tumors and a subset of acute myeloid leukemias
        
        u. < 3 cm
        grayblue, translucent
        composed of well-circumscribed nodules of hyaline cartilage containing benign chondrocytes
        peripheral portion of nodules may undergo endochondral ossification, and center can calcify and infarct
        Syndromic enchondromas sometimes more cellular w/ more atypia than sporadic enchondromas.
        
        benign
        u. occur in bones of endochondral origin
        arise within medullary cavity (enchondroma) or on cortical surface (juxtacortical chondroma)
        Enchondromas:
        u. dx in 20 to 50 yrs of age
        Typically appear as solitary metaphyseal lesions of tubular bones of hands & feet [short bones]
        radiographic features: circumscribed lucency w/ central irregular calcifications, a sclerotic rim, and an intact cortex [ o ring]
        Ollier disease and Maffucci syndrome: disorders charac by multiple enchondromas (enchondromatosis)
        Maffucci syndrome also a. w/ other rare tumors
        Most enchondromas of large bones asymptomatic and detected incidentally. Occasionally painful and cause pathologic fracture. tumors in enchondromatosis may be numerous and large, producing severe deformities, esp of digits.
        
        growth potential limited
        Treatment depends and u includes observation or curettage
        Solitary chondromas rarely undergo sarcomatous transformation, but those a. w/ enchondromatosis do so more frequently.
        Maffucci syndrome at risk of developing other neoplasms, including brain gliomas
      - Chondrosarcoma
        
        genetically heterogeneous but a few reproducible abnormalities have been identified.
        Chondrosarcomas arising in multiple osteochondroma syndrome exhibit mutations in EXT genes, and both chondromatosis-related and sporadic chondrosarcomas may have IDH1 and IDH2 mutations.
        Mutation of the collagen COL2A1 gene and silencing of the CDKN2A tumor suppressor gene by DNA methylation also relatively common in sporadic tumors
        
        Conventional:
        large bulky tumors composed of nodules of glistening gray-white, translucent cartilage, along w/ gelatinous or myxoid areas
        Spotty calcifications typically present, and central necrosis may create cystic spaces.
        tumor spreads through cortex into surrounding muscle or fat. Histologically, cartilage infiltrates marrow space and entraps normal bony trabeculae
        tumors vary in cellularity, cytologic atypia, and mitotic activity and are assigned a grade from 1 to 3
        grade 1 have relatively low cellularity, chondrocytes have plump vesicular nuclei w/ small nucleoli.
        grade 3 charac by high cellularity, extreme pleomorphism w/ bizarre tumor giant cells, mitoses; [in radiograph: the more translucent-->less calcification-->higher grade]
        
        Mesenchymal
        Composed of islands of well-differentiated hyaline cartilage surrounded by sheets of small round cells, which can mimic
        Ewing sarcoma
        
        malignant
        subclassified into conventional (hyaline cartilage–producing), dedifferentiated, clear cell, and mesenchymal types.
        90%: conventional type
        1/2 as common as osteosarcoma [but more as age incr; 2nd most common tumor in bone]
        conventional chondrosarcoma u. in 40s or older
        These tumors affect m>f 2:1
        clear cell and esp mesenchymal variants occur in children and young adults.
        Chondrosarcomas commonly arise in axial skeleton, esp pelvis, shoulder, and ribs [but osteosarcoma more around knee and metaphyses of peripheral bones]
        Unlike benign enchondroma, distal extremities rarely involved
        On imaging: calcified cartilage appears as foci of flocculent densities that may destroy cortex and form a soft tissue mass.
        15% of conventional chondrosarcomas are secondary, arising from a preexisting enchondroma or osteochondroma.
        
        u. present as painful, progressively enlarging masses
        80% 5-year survival for Grade 1 tumors to 43% for Grade 3 tumors
        Grade 1 rarely metastasize, whereas 70% of grade 3 tumors spread hematogenously, esp to lungs
        treatment of conventional: wide surgical excision
        mesenchymal and dedifferentiated tumors also excised and additionally treated w/ chemotherapy bc of their more aggressive clinical course
    - - Giant Cell Tumor
        
        multinucleated osteoclast-type giant cells dominate histology
        a locally aggressive neoplasm
        almost exclusively affects adults [20-40]
        arise in epiphyses of long bones, most commonly distal femur and proximal tibia [around knee].
        typical location of these tumors near joints frequently causes arthritis-like symptoms.
        Occasionally, present w/ pathologic fractures
        
        neoplastic cells of giant cell tumor: osteoblast precursors, which represent only a minority of cells in tumor
        neoplastic cells express high levels of RANKL--> promotes prolif & differentiation of normal osteoclast precursors into osteoclasts--> localized but highly destructive resorption of bone
        
        often destroy overlying cortex--> bulging soft tissue mass delineated by a thin shell of reactive bone
        gross: red-brown masses, frequently undergo cystic degeneration.
        Microscopically: conspicuously lacks bone or cartilage, consisting of numerous osteoclast-type giant cells w/ 100 or more nuclei w/ uniform, oval mononuclear tumor cells in between [prolif component of tumor, appear to grow in syncytium]
        [Necrosis, hemorrhage, hemosiderin deposition, and reactive bone formation are common secondary features]
        
        typically treated w/ curettage, but 40-60% recur locally
        4% of tumors metastasize to lungs, but these sometimes spontaneously regress and seldom fatal.
        RANKL inhibitor, Denosumab: shown promise
      - Aneurysmal Bone Cyst
      - Ewing Sarcoma
        
        malignant
        composed of primitive round cells w/ varying degrees of neuroectodermal differentiation and a charac molecular signature
        primitive neuroectodermal tumor (PNET) and Askin tumor have been unified into single category of Ewing sarcoma.
        10% of primary malignant bone tumors; follows osteosarcoma as the second most common bone sarcoma in children
        Of all bone sarcomas, Ewing sarcomas have youngest average age at presentation (80% < 20 years)
        m>f, predilection for Caucasians
        tumors u arise in diaphysis of long tubular bones but 20% are extraskeletal
        present as painful enlarging masses, affected site frequently tender, warm, and swollen
        Plain radiographs: destructive lytic tumor w/ permeative margins that extends into surrounding soft tissues.
        charac periosteal reaction produces layers of reactive bone deposited in an onion-skin fashion.
        
        85%: balanced (11;22) (q24;q12) translocation--> in-frame fusion of EWSR1 gene on chromosome 22 to FLI1 gene on chromosome 11.
        Variant translocations fuse EWSR1 to other members of the ETS transcription factor family.
        cell of origin still remains to be identified; leading candidates are mesenchymal stem cells & primitive neuroectodermal cells.
        
        Arising in medullary cavity
        u invades cortex, periosteum, soft tissue
        soft, tanwhite, frequently contains areas of hemorrhage and necrosis.
        one of small, round blue cell tumors found in children
        composed of sheets of uniform small, round cells slightly larger & more cohesive than lymphocytes; have scant cytoplasm, which may appear clear bc rich in glycogen
        Homer-Wright rosettes (round groupings of cells with a central fibrillary core) may be present, indicate a greater degree of neuroectodermal differentiation
        tumor cells do not produce bone or cartilage.
        
        aggressive malignancies treated w/ neoadjuvant chemotherapy followed by surgical excision w/ or w/o radiation; survival not very good
    - - Nonossifying Fibroma
        
        benign, likely reactive, mesenchymal prolif
        may be present in 50% of children and young adults aged 2–25 yrs
        synonymous w/ fibrous cortical defect or metaphyseal fibrous defect if localized to cortex or medulla, respectively
        vast majority arises eccentrically in metaphysis of distal femur and proximal tibia.
        Plain radiographs: sharply demarcated oval radiolucency w/ long axis parallel to cortex
        findings sufficiently specific on plain radiography that biopsy is rarely necessary.
        form gray to yellow-brown cellular lesions containing fibroblasts & MQs
        cytologically bland fibroblasts frequently arranged in a storiform (pinwheel) pattern, and MQs may take the form of clustered cells w/ foamy cytoplasm or multinucleated giant cells
        Hemosiderin commonly present. Most small NOFs undergo spontaneous resolution within several yrs.
      - Fibrous Dysplasia
        
        benign, likened to a localized developmental arrest of bone constituents
        lesions arise during skeletal development, appear in several distinctive but sometimes overlapping clinical patterns:
        • Monostotic: involvement of a single bone; [>70% of cases; f=m; u. seen at beginning of puberty]
        • Polyostotic [37%; Earlier age than monostotic]
        • Mazabraud syndrome: fibrous dysplasia & soft tissue myxoma
        • McCune-Albright syndrome: polyostotic fibrous dysplasia, café-au-lait skin pigmentations [u. on same side as skeletal manifests], and endocrine abnormalities, esp precocious puberty; [3%]
        
        All variants result from a somatic gain-of-function mutation in GNAS1 (also mutated in pituitary adenomas)
        mutations produce a constitutively active Gs -pr that promotes cellular prolif by incr cAMP
        phenotype depends on stage of embryogenesis when mutation acquired and on fate of cell harboring mutation:
        early embryogenesis--> McCune-Albright syndrome
        during or after formation of skeleton in an osteoblast precursor--> monostotic fibrous dysplasia
        skeletal manifestations arise from a cAMP–mediated interruption of normal osteoblast differentiation.
        
        well circumscribed, intramedullary, vary greatly in size
        Larger lesions expand & distort bone
        lesional tissue composed of curvilinear trabeculae of woven bone surrounded by a moderately cellular fibroblastic prolif; [shapes of trabeculae mimic Chinese characters]
        trabeculae lack prominent osteoblastic rimming
        Cystic degeneration, hemorrhage, and foamy MQs common findings
        Nodules of hyaline cartilage present in 20% of cases
        
        Monostotic
        often stops enlarging at time of growth plate closure
        [ribs, femur, mandible, humerus freq involved; does not progress to polyostotic or malignancy]
        lesion frequently asymptomatic, u discovered incidentally
        may cause pain, fracture, and discrepancies in limb length. Symptomatic lesions cured by curettage
        Polyostotic
        may continue to cause problems into adulthood
        If involving limb girdles, can cause crippling deformities and fractures
        [Femur, skull, tibia, humerus, ribs, fibula, radius, ulna, mandible, and vertebrae most commonly affected]
        [may progress to malignancy]
        McCune-Albright syndrome
        u. presents w/ precocious sexual development, most often in girls
        skeletal manifestations managed as for other polyostotic fibrous dysplasia, whereas endocrinopathies treated medically.
        [skeletal manifestations u ipsilateral]
        [cutaneous macules classically large, dark to café au lait, have irregular serpiginous borders, found primarily on neck, chest, back, shoulder, and pelvic region]
    - - Metastatic tumors >>> primary bone cancers
        tumor spread to bone (1) direct extension, (2) lymphatic or hematogenous dissemination, and (3) intraspinal seeding (via Batson plexus of veins)
        Any cancer can spread to bone, but
        in adults >75% of skeletal metastases originate from cancers of prostate, breast, kidney, lung
        In children, from neuroblastoma, Wilms tumor, rhabdomyosarcoma
        Skeletal metastases typically multifocal, involve axial skeleton, esp vertebral column [bc more vessels in spongy bones]
        radiographic appearance of metastases may be purely lytic (bone destroying; ex: carcinomas of kidney, lung, GI tract and malignant melanoma), purely blastic (bone forming; ex: prostate; metastatic cells secrete substances such
        as PGs, ILs and PTH-RP, which stimulate osteoclastic bone resorption; tumor cells themselves do not directly resorb bone), or mixed[most]
        Bidirectional interactions betw metastatic cancer cells and native bone cells--> changes that manifest in bone matrix
        Tumor cells secrete substances (prostaglandins, cytokines, and PTH-like peptide)--> upregulate RANKL on osteoblasts and stromal cells--> stimulating osteoclast activity.
        tumor cell growth supported by release of matrixbound GFs (e.g., TGF-β, IGF-1, and FGF) as bone is resorbed
        Tumor cells secreting WNT prs that stimulate osteoblastic bone formation may produce sclerotic metastases
        presence of bone metastases carries a poor prognosis. Therapeutic options: systemic chemotherapy, radiation, and bisphosphonates.
        Surgery may be necessary to stabilize pathologic fractures.
  - - - also known as marble bone disease or Albers-schonberg disease
        a group of rare genetic diseases charac by reduced bone resorption & diffuse symmetric skeletal sclerosis resulting from impaired formation or function of osteoclasts
        osteopetrosis reflects stonelike quality of bones. However, bones abnormally brittle and fracture easily, like a piece of chalk.
      - Most of mutations interfere w/ process of acidification of osteoclast resorption pit:
        AR mutations in carbonic anhydrase 2 (CA2)
        mutations in TCIRG1 gene (encodes a component of a vacuolar ATPase that helps to maintain acidic pH in osteoclasts)
        Bones involved lack a medullary canal, and ends of long bones are bulbous (Erlenmeyer flask deformity) and misshapen
        neural foramina small and compress exiting nerves
        primary spongiosa, normally removed during growth, persists and fills medullary cavity, leaving no room for hematopoietic marrow.
      - Severe infantile osteopetrosis: AR & often fatal bc of leukopenia, despite extensive extramedullary hematopoiesis that can lead to prominent hepatosplenomegaly
        mild AD form may not be detected until adolescence or adulthood, discovered on radiographic studies for repeated fractures. also may have mild cranial nerve deficits and anemia.
- - - - benign tumor of fat
        most common soft tissue tumor in adults
      - subtypes:
        
        most common: conventional lipoma: well encapsulated, mature adipocytes; u. arises in subcutis of proximal extremities & trunk, most freq during middle adulthood; is motile
        
        Infreq: lipomas large, intramuscular, poorly circumscribed
        [3. angiolipoma (an exception among lipomas that it can be painful) 4. myelolipoma 5. spindle cell lipoma]
      - Most lipomas u. cured by simple excision.
    - - malignant
        one of most common sarcomas of adulthood
        occurs mainly in 50s to 60s in deep soft tissues & retroperitoneum
      - three subtypes:
        • Well-differentiated: adipocytes w/ scattered atypical spindle cells; harbor amplification of chromosome region 12q13-q15, which includes gene for MDM2 (encodes a potent inhibitor of p53)
        • Myxoid: abundant basophilic ECM, arborizing capillaries, and primitive cells at various stages of adipocyte differentiation reminiscent of fetal fat; t(12;16) translocation charac it--> resultant fusion gene arrests adipose differentiation.
        • Pleomorphic: sheets of anaplastic cells, bizarre nuclei, variable amounts of immature adipocytes (lipoblasts); complex karyotypes.
        [• round cell]
        [hallmark of all types: lipoblasts: centric nuclei indented bc of pressure of lipid droplets]
      - All types recur locally & often repeatedly unless adequately excised
        well-differentiated relatively indolent, myxoid/round cell intermediate, whereas pleomorphic u. aggressive & frequently metastasizes
        [jozve: round cell aggressive; round cell and pleomorphic have high recurrence but little metastases :////]
  - - - a self-limited fibroblastic & myofibroblastic prolif
        typically occurs in upper extremities of young adults [most common: volar surface of forearm]
        hx of trauma present in 25-50%, tumors grow rapidly during a period of several ws or mths; [can be painful]; [reaches 2 cm then stops growing]
        [reactive pseudosarcoma prolif]
        t(17;22) translocation producing a MYH9-USP6 fusion gene--> it is a clonal, yet self-limited, prolif
        prolif cells lack some key hallmark of cancer, perhaps ability to avoid senescence
        ABC, another tumor that sits in a gray zone between reactive & neoplastic prolifs, also contains a USP6 fusion gene
        can spontaneously regress; if excised, rarely recurs; [well circumscribed, not encapsulated though]
        Malignant transformation virtually nonexistent.
      - arises in deep dermis, subcutis, fascia, or muscle
        Gross: lesion < 5 cm, circumscribed, or slightly infiltrative
        highly cellular: plump, immatureappearing fibroblasts and myofibroblasts
        A gradient of maturation (zonation) from cellular, loose, and, myxoid, to organized and fibrous typical; [half hazard??]
        cells vary in size & shape (spindle to stellate) & have conspicuous nucleoli; mitotic figures abundant
        Lymphocytes & extravasated RBCs common but neutrophils unusual
    - - Superficial Fibromatosis
        
        an infiltrative prolif; can cause local deformity but has an innocuous clinical course; [most cells: myofibroblasts--> abundant coll and contracture]
        All forms affect m>fs
        charac by nodular or poorly defined broad fascicles of fibroblasts in long, sweeping fascicles, surrounded by abundant dense coll
        clinical subtypes
        • Palmar (Dupuytren contracture): Irregular or nodular thickening of palmar fascia either unilaterally or bilaterally; [esp digits 4 & 5; slowly progressive flexion contracture]
        • Plantar: Common in young pxs, unilateral & w/o contractures [but jozve: flexion contracture; also jozve: bilateral uncommon] [kafe pa; causes flexion of plantar surface]
        • Penile (Peyronie disease): Palpable induration or mass on dorsolateral aspect of penis
        [may cause abnormal curvature of shaft or constriction of urethra]
        In 20-25%, palmar & plantar fibromatoses stabilize, do not progress, in some instances resolving spontaneously. Some recur after excision, partic plantar variant.
      - Deep Fibromatosis
        
        also called desmoid tumors
        large, infiltrative masses; frequently recur but do not metastasize
        most freq occur in teenage yrs to 30s, predominantly in women.
        Abdominal fibromatosis generally arises in musculoaponeurotic structures of ant abdominal wall but tumors can arise in limb girdles or mesentery
        contain mutations in CTNNB1 (β-catenin) or APC--> incr Wnt signaling
        Most sporadic, but familial adenomatous polyposis (Gardner syndrome) who have germline APC mutations predisposed to deep fibromatosis
        [Intraabdominal: in pelvis, mesentery; very common in Gardner syndrome
        Abdominal: in many cases in fs after pregnancy
        Extraabdominal: shoulder girdle, pelvic gilder, thorax; in both m & f]
        
        gray-white, firm, poorly demarcated masses, from 1 to 15 cm
        rubbery, tough, marked infiltration of surrounding muscle, nerve and fat.
        Cytologically bland fibroblasts arranged in broad sweeping fascicles amid dense coll: charac histologic pattern; resembles a scar; [myofibroblasts,..]
        
        extensively infiltrative nature--> complete excision often difficult; recurrence high
  - - - Alveolar freq contains fusions of FOXO1 gene to PAX3 or PAX7 gene, rearrangements marked by presence of (2;13) or (1;13) [rare] translocations, respectively
        PAX3: transcription factor that initiates skeletal muscle differentiation, and it appears that chimeric PAX3-FOXO1 fusion pr interferes w/ differentiation
      - Embryonal:
        [common sites: nasal cavity-orbit-middle ear-prostate-paratesticular, sometimes urethra]
        soft gray infiltrative mass
        tumor cells mimic skeletal muscle at various stages of differentiation: sheets of both primitive round and spindled cells
        Rhabdomyoblasts w/ straplike cytoplasm & visible cross-striations may be present.
        variants:
        
        Sarcoma botryoides: develops in walls of hollow viscera such as urinary bladder, vagina; khushe angur; [begins from under epith, in submucosa cells more dense & hypercellular: cambium zone (near surface; density of cells decr as it goes deeper); both spindle cell and malignant round cell]
        
        [spindle cell: in myxoid stroma]
        
        alveolar:
        [common sites: deep muscles of limbs
        in older ages than embryonal, very aggressive]
        network of fibrous septae divide cells into clusters or aggregates;
        tumor cells uniformly round w/ little cytoplasm, only minimally cohesive
        Pleomorphic
        charac by numerous large, sometimes multinucleated, bizarre eosinophilic tumor cells that can resemble other pleomorphic sarcomas. [many giants cells, u. in deep soft tissue]
        
        Immunohistochemical identification of muscle specific pr such as myogenin u. necessary to confirm rhabdomyoblastic differentiation. [ex: skeletal muscle: desmin, myogenin, myod1] [embryonal desmin +]
        [all have rhabdomyoblast: eccentric nuclei, very eosinophilic cytoplasm]
      - a malignant mesenchymal tumor w/ skeletal muscle differentiation
        Three main subtypes:
        alveolar (20%)
        embryonal (60%)
        pleomorphic (20%)
        (alveolar & embryonal): most common soft tissue sarcoma of childhood and adolescence, u. appearing < 20
        Pleomorphic predominantly in adults
        pediatric forms often arise in sinuses, head and neck, and GU tract, locations that do not normally contain much skeletal muscle,
        embryonal and pleomorphic subtypes genetically heterogeneous.
      - aggressive neoplasms, u. treated w/ surgery and chemotherapy, w/ or w/o radiation
        botryoid variant: best prognosis [followed by embryonal, pleo, alveolar]
        pleomorphic subtype often fatal
        [65% of children cured, adults fare worse]
  - - - benign tumor of smooth muscle,
        most common in uterus, can arise in any soft tissue
        Uterine leiomyomas common, may cause infertility, menorrhagia,..
        may arise from erector pili muscles (pilar leiomyomas) in skin [very painful]
        rarely in deep somatic soft tissues [smooth muscles of vessel walls] or GI tract
        [genital leiomyoma: nipple scrotum labia]
      - germline loss-of-function mutation in fumarate hydratase (FH) gene on chromosome 1q42.3--> multiple cutaneous leiomyomas, uterine leiomyomas, renal cell carcinoma.
      - u. 1 to 2 cm in size
        composed of fascicles of densely eosinophilic spindle cells that tend to intersect each other at right angles
        tumor cells have blunt-ended, elongated nuclei, minimal atypia, few mitotic figures.
      - Solitary lesions cured w/ surgery
    - - 10-20% of soft tissue sarcomas
        occur in adults and affect f>m
        Most develop in deep soft tissues of extremities and retroperitoneum or arise from great vessels, [uterus]
      - have complex genotypes that stem from acquired defects that lead to profound genomic instability.
      - painless firm masses
        Retroperitoneal tumors may be large, bulky, cause abdominal symptoms; consist of eosinophilic spindle cells w/ blunt-ended, hyperchromatic nuclei arranged in interweaving fascicles
        express smooth muscle prs (actin, desmin, caldesmon, [vimentin]) detected by IHC
        mitotic activity, necrosis common, pleomorphism and atypia
      - Treatment depends on tumor size, location, and grade. Superficial leiomyosarcomas u. small and have a
        good prognosis, whereas retroperitoneum difficult to control and cause death by both local extension and metastatic spread, esp to lungs
  - - - Most show a charac chromosomal translocation t(x;18)(p11;q11) producing fusion genes composed of portions of SS18 gene and one of three SSX genes that encode chimeric transcription factors that derail cell cycle control
      - a misnomer, can present in locations that lack synovium (<10% in synovium) and their morphologic features are inconsistent w/ an origin from synoviocytes
        [more in tissues around joint (juxtaarticular) and deep tissues]
        10% of all soft tissue sarcomas [4th most common sarcoma in adults]
        Most occur in 20s to 40s
        u. present w/ a deep-seated mass present for several yrs
      - Monophasic [rarely]: uniform spindle cells w/ scant cytoplasm and dense chromatin growing in short, tightly packed fascicles
        biphasic: glandlike structures composed of cuboidal to columnar epithelioid cells in addition to aforementioned spindle cell component
        IHC helpful, since tumor cells, esp in biphasic type, positive for epithelial antigens (e.g., keratins, [epithelial membrane Ag]), differentiating them from many other sarcomas.
        [radiography: soft tissue lesion sometimes w/ calcification]
      - treated aggressively w/ limbsparing surgery & frequently chemotherapy
        5-yr survival varies from 25-62%, related to stage and patient age. [prognosis not that bad]
        Common sites of metastases: lung and, unusual for sarcomas, regional lymph nodes. [have both hematogenous and lymphatic spread]
    - - includes malignant mesenchymal tumors w/ high-grade, pleomorphic cells that ,cannot be classified, into another category by a combination of histomorphology, immunophenotype, ultrastructure, and genetics.
        Most arise in deep soft tissues of extremity, esp thigh of middleaged or older adults.
        dx of malignant fibrous histiocytoma (MFH), sometimes used interchangeably w/ UPS: out of use bc
        (1) category included both undifferentiated tumors and others that could be reclassified w/ IHC & genetics
        (2) no consensus exists for morphologic definition of fibrohistiocytic lineage.
      - Most aneuploid w/ multiple structural and numerical chromosomal changes.
      - u. large, grey-white fleshy masses (10–20 cm) depending on anatomic compartment
        Necrosis, hemorrhage common.
        some of the most ,pleomorphic, malignancies encountered
        consist of sheets of large, anaplastic, spindled to polygonal cells w/ hyperchromatic irregular, sometimes bizarre nuclei
        , Mitotic figures, including atypical nonsymmetric forms, abundant as is necrosis
        tumor cells , lack differentiation, along recognized lineages or characteristic genetic defects.
      - are aggressive malignancies treated w/ surgery and adjuvant chemotherapy and/or radiation.
        prognosis generally poor, w/ metastases arising in 30% to 50% of cases
- - - - a heterogeneous group that share:
        • Absence of RhF
        • Pathologic changes in ligamentous attachments rather than synovium
        • Involvement of sacroiliac joints, w/ or w/o other joints
        • A. w/ HLA-B27
        • Bony prolif--> ankylosis
        manifestations immune mediated, triggered by a T cell response against an undefined Ag, possibly infectious, that may crossreact w/ Ags expressed on cells of musculoskeletal system
      - Ankylosing spondylitis
        prototypical spondyloarthritis, causes destruction of articular cartilage & bony ankylosis, esp of sacroiliac joints
        becomes symptomatic in 2nd & 3rd decades as lower back pain & spinal immobility
        Involvement of peripheral joints (hips, knees, shoulders) in at least 1/3
        90% HLA-B27 +
        antiIL-17 Ab shown some efficacy in this disease
      - Reactive arthritis
        triad of arthritis, nongonococcal urethritis or cervicitis, and conjunctivitis
        Most are men in 20s / 30s, >80% HLA-B27 +
        AI reaction initiated by previous infection of GU system (Chlamydia) or GI (Shigella, Salmonella, Yersinia, Campylobacter)
        Within several ws of urethritis or diarrhea--> low back pain;
        ankles, knees, and feet affected most often, freq in an asymmetric pattern
        Pxs w/ severe chronic disease: involvement of spine indistinguishable from AS
    - - by hematogenous dissemination, direct inoculation through skin, or from contiguous spread from a soft tissue abscess or osteomyelitis
      - can cause rapid, permanent joint destruction-->potentially serious
      - Suppurative Arthritis
      - Bacterial infections causing acute suppurative arthritis u. enter joints from distant sites by hematogenous spread; But in neonates: contiguous spread from underlying epiphyseal osteomyelitis may occur
      - H. influenza arthritis predominates in < 2 yrs old
      - S. aureus main agent in older children & adults
      - gonococcus prevalent during late adolescence & young adulthood
      - sickle cell disease prone to infection w/ Salmonella
      - joint infections affect sexes equally except for gonococcal arthritis (mainly in sexually active F)
      - deficiencies of complement components (C5, C6, C7, or C9): susceptible to disseminated gonococcal infections--> arthritis.
      - classic presentation: sudden development of an acutely painful, warm, swollen joint w/ restricted range of motion
      - Systemic findings: fever, leukocytosis, ESR common
      - in 90% of nongonococcal cases: only a single joint, most commonly knee, followed in decr freq by hip, shoulder, elbow, wrist, sternoclavicular joints
      - axial joints more often involved in drug users
      - Joint aspiration diagnostic if yielding purulent fluid in which causative agent identified
      - cartilage has limited repair potential--> prompt recognition & effective anti-microbial therapy vital to prevent permanent joint destruction.
    - - heterogeneous group of disorders of unknown cause; present w/ arthritis <16yrs, persist for at least 6 ws
        In contrast to RA:
        (1) oligoarthritis more common
        (2) systemic disease more frequent
        (3) large joints affected more often than small
        (4) rheumatoid nodules & RhF u. absent
        (5) ANA seropositivity common.
      - pathogenesis unknown but similar to adult RA;
        RFs: HLA & PTPN22 variants
        like adult RA, damage appears to be caused by TH1 & TH17 cells & cytokines produced by these & other infl cells
        Treatment similar to adult RA: IL-6 R Ab in systemic form
        Long-term prognosis: very variable; many have chronic disease, but only 10% of those develop serious functional disability.
    - - chronic infl, AI, principally attacks joints-> a nonsuppurative prolif & infl synovitis
        Often--> destruction of articular cartilage; sometimes--> ankylosis (adhesion) of joints
        Extraarticular lesions: skin, heart, blood vessels, and lungs
        F>M
      - MORPHOLOGY
        
        symmetric arthritis principally affecting small joints of hands & feet
        
        Gross: synovium edematous, thickened, and hyperplastic, smooth contour--> contour covered by delicate & bulbous villi
        
        Histologic: charac features:
        (1) synovial cell hyperplasia & prolif
        (2) dense infl infiltrates of CD4+ helper T, B, plasma, dendritic cells, MQs
        (3) incr vascularity (angiogenesis)
        (4) neutrophils & aggregates of organizing fibrin on synovial & joint surfaces
        (5) osteoclastic activity in underlying bone--> synovium penetrates into bone--> periarticular erosions & subchondral cysts
        
        aforementioned changes--> a pannus: a mass of edematous synovium, infl cells, granulation tissue, fibroblasts that grows over articular cartilage & causes its erosion; In advanced untreated cases pannus can bridge bones--> fibrous ankylosis--> later ossify as a bony ankylosis
        
        Rheumatoid nodules: an infreq manifestation of RA, typically occur in subcut (forearm, elbows, occiput, and lumbosacral area); Microscopic: resemble necrotizing granulomas
        
        Rarely, RA can involve lungs (rheumatoid nodules, interstitial lung disease).
      - Pathogenesis
        
        pathologic changes mediated by Abs against self-Ags & infl caused by cytokines, predominantly secreted by CD4+
        
        CD4+ Th may initiate AI response by reacting w/ an arthritogen (perhaps microbial / chemically modified self-Ag)--> stimulate other infl cells to effect tissue injury:
        • Th1-->IFN-γ--> stimulate MQs & synovial cells
        • TH17-->IL-17--> recruits neutrophils & monocytes
        • RANKL expressed on activated T cells--> osteoclasts & bone resorption
        • MQs-->TNF & IL-1--> resident synovial cells to secrete proteases--> destroy hyaline cartilage.
        Of these, TNF most firmly implicated--> TNF antagonists effective therapies
        
        synovium of RA: germinal centers w/ secondary follicles &
        abundant plasma cells--> Abs--> some may be against selfAgs
        Many of serum autoAbs in px specific for citrullinated peptides (Arg posttranslationally converted to citrulline)
        complexes of Abs w/ citrullinated fibrinogen, type II coll, α-enolase, and vimentin deposit in joints
        anti-citrullinated pr Abs (ACPA) + a T cell response to citrullinated prs--> disease chronicity
        30% of pxs do not have ACPA in blood
        80% of pxs have serum IgM or IgA autoAbs that bind to Fc portions of their own IgG: rheumatoid factor; may also deposit in joints as immune complexes, although not uniformly present in all pxs w/ RA and found in other diseases
        
        50% of risk of developing RA: genetic susceptibility
        HLA class II locus a. w/ ACPA-positive RA
        an epitope on a citrullinated pr, vinculin, mimics an epitope on many microbes and is target of CD4+ T when presented by predisposing HLA-DQ alleles.
        second gene linked to RA: PTPN22, encodes a pr tyrosine phosphatase postulated to inhibit T cell activation
        
        min 70% of pxs: ACPA in blood
        Insults (infection (including periodontitis), smoking may promote citrullination of self-pr--> new epitopes triggering AI reactions
        
        infl localizes to joint, recruiting MQs & triggering activation &/ prolif of synovial cells, chondrocytes, fibroblasts
        production of proteolytic Es & cytokines--> destruction of cartilage & (through incr osteoclast activity) bone
      - Clinical Course
        
        distinguished from other forms of polyarticular infl arthritis by:
        ACPA & by charac radiographic findings
        in 1/2 of pxs: begins slowly, insidiously w/ malaise, fatigue, generalized musculoskeletal pain
        After several w-mths: joints involved
        pattern of joint involvement: generally symmetrical; hands and feet, wrists, ankles, elbows, knees most commonly affected.
        metacarpophalangeal & proximal IP joints freq involved (in contrast to OA)
        
        Infl in tendons, ligaments, occasionally adj skeletal muscle freq accompanies arthritis--> charac ulnar deviation of fingers & flexion-hyperextension of fingers (swan-neck deformity,
        boutonnière deformity)
        Radiographic hallmarks: joint effusions & juxtaarticular osteopenia w/ erosions & narrowing of joint space & loss of articular cartilage
        
        treatment for RA: corticosteroids, other immunosuppressants (methotrexate), most notably, TNF antagonists
        anti-TNF agents not curative, pxs must be maintained on TNF antagonists to avoid disease flares; Long term treatment w/ TNF antagonists: incr risk of infections w/ organisms such as M. tuberculosis.
        
        Involved joints swollen, warm, painful
        In contrast to OA: joints stiff when px rises in morning or following inactivity
        typical px: progressive joint enlargement, decr range of motion pursuing a chronic waxing & waning course
        minority px, esp lacking RhF & ACPA: disease may stabilize or even regress.
    - - caused by infection w/ spirochete Borrelia burgdorferi, transmitted by deer ticks of Ixodes ricinus complex
      - classic form: progressively involves multiple organ systems through three clinical phases:
      - initial infection of the skin, or early localized stage
      - an early disseminated stage involving skin, cranial nerves, heart, and meninges
      - If left untreated, arthritis, esp of knee, occurs w-ms after infection.
      - arthritis in < 10% of cases bc most pxs cured at an earlier stage;
      - if left untreated--> 60-80% develop a migratory arthritis (Lyme arthritis) lasting for w-ms
      - Spirochetes identified in 25% of joints w/ arthritis, but dx confirmed by serologic testing for anti-Borrelia Abs
      - Treatment: antibiotics w/ activity against Borrelia
      - Cure rates of 90% w/ standard regimens
      - a chronic arthritis that is antibiotic refractory can develop in late disseminated stage; In many of these pxs, Borrelia cannot be detected in joint fluid even by PCR; cellular (esp TH1) & humoral responses to Borrelia outer surface pr A may initiate this late, AI, arthritis
      - chronic manifestations: joint pain, nonspecific symptoms (fatigue, cognitive complaints), known collectively as posttreatment Lyme disease syndrome (PTLDS).
      - Infected synovium: chronic synovitis marked by synoviocyte hyperplasia, fibrin deposition, mononuclear cell infiltrates (esp CD4+ T), and onionskin thickening of arterial walls; morphology in severe cases can closely resemble that of RA
    - - MORPHOLOGY
        early stages: chondrocytes prolif--> clusters; water content of matrix incr & [PGs] decr; normally horizontally arranged coll type II cleaved-> fissures & clefts at articular surface--> a granular soft articular surface;
        Eventually, full-thickness portions of cartilage sloughed; dislodged pieces of cartilage & bone tumble into joint--> loose bodies (joint mice)
        exposed bone plate becomes new articular surface--> friction burnishes bone--> appearance of polished ivory (bone eburnation)
        Small fractures through articulating bone common---> synovial fluid forced into subchondral regions in a one-way, ball valve–like mechanism forming fibrous-walled cysts
        Outgrowths (osteophytes) develop at margins of articular surface & capped by fibrocartilage & hyaline cartilage that gradually ossify.
        synovium u. only mildly congested & fibrotic, may have scattered chronic infl cells
      - Clinical Course
        Primary OA: in 50s
        Charac symptoms: joint pain that worsens w/ use, morning stiffness, crepitus, limitation of range of movement
        Impingement on spinal foramina by osteophytes--> cervical & lumbar nerve root compression and radicular pain, muscle spasms, muscle atrophy, and neurologic deficits
        joints commonly involved: hips, knees, lower lumbar and cervical vertebrae, proximal and distal IP joints of fingers, first carpometacarpal joints, and first tarsometatarsal joints.
        Heberden nodes: prominent osteophytes at distal IP joints, common in women (but not in men)
        joint deformity can occur BUT unlike RA, no joint fusion
        level of disease severity detected radiographically does NOT correlate well w/ pain and disability
        no means of preventing primary OA, no effective methods of halting progression.
        Therapy: management of pain, NSAIDs to reduce infl, intra-articular corticosteroids, activity modification, and, for severe cases, arthroplasty.
      - Pathogenesis
        degeneration & disordered repair of articular cartilage
        Articular cartilage: low-friction surface, transmits loads to underlying bone; resists compression through viscoelastic properties of ECM (principally type II coll, PGs, water) secreted by chondrocytes.
        Repeated biomech stress + genetic factors (encoding components of matrix & signaling molecules--> predispose to chondrocyte injury)
        chondrocytes prolif & synth & secrete PGs but degradation ultimately exceeds synth & composition of PGs changes as disease progresses.
        MMPs secreted by chondrocytes degrade type II coll network
        Cytokines and diffusible factors from chondrocytes and synovial cells, partic TGF-β (which induces MMPs), TNF, prostaglandins, and nitric oxide, implicated in OA
        Chronic, low-level infl contributes to progression
        Ultimately, chondrocyte loss & a severely degraded matrix mark late stage of disease.
      - Osteoarthritis (OA) (degenerative joint disease)
        charac by: degeneration of cartilage--> structural & functional failure of synovial joints.
        most common disease of joints
        although itis-->infl, considered an intrinsic disorder of cartilage: biochem & mechanical stresses--> chondrocytes respond--> breakdown of matrix & failure of repair; infl mediators: worsen damage.
        most OA: idiopathic or primary: insidious, w/o apparent initiating cause, an aging phenomenon:
        u. oligoarticular (affects few joints).
        In 5%: secondary: younger w/ some predisposing condition (ex joint deformity, previous joint injury, underlying systemic disease affecting joints)
        P incr exponentially >50, (40% of >70 yrs affected)
    - - Gout
        
        urate crystals deposited within & around joints--> transient attacks of acute arthritis
        
        Primary or second: common feature: excessive uric acid in tissues & body fluids
        
        primary form (90%): gout major manifestation of disease, cause unknown
        
        Pathogenesis
        
        Hyperuricemia (P urate >6.8 mg/dL) necessary, but not sufficient, for development
        
        Uric acid metabolism:
        
        • Synthesis: end product of purine catabolism; synth of purine nucleotides: two interlinked pathways:
        
        de novo pathway: purine nucleotides synth from nonpurine precursors
        
        salvage pathways: synth from free purine bases from diet or catabolism of purine nucleotides.
        
        • Excretion: filtered by glomerulus and virtually completely resorbed by PT; small fraction of resorbed uric acid secreted by distal nephron
        
        primary gout:
        
        elevated uric acid most commonly from reduced excretion; small minority by overproduction as a result of identifiable E defects (ex partial deficiency of HGPRT in salvage pathway--> purine metabolites instead, degraded into uric acid; Complete absence of HGPRT also--> hyperuricemia, but significant neurologic manifestations of this condition (Lesch-Nyhan syndrome) dominate clinical picture so it is classified as secondary gout)
        
        Secondary gout: incr production (rapid cell lysis during chemotherapy for leukemia, so-called tumor lysis syndrome) or decr excretion (chronic renal disease)
        
        precipitation of urate crystals in joints--> production of cytokines--> recruit leukocytes: MQs & neutrophils phagocytose crystals--> inflammasome--> caspase-1--> production of active IL-1β (proinfl, promotes accumulation of more neutrophils & MQs in joint)--> these cells release other cytokines, free radicals, proteases, and arachidonic acid metabolites
        
        ingested crystals also damage membranes of phagolysosomes--> leakage of mediators
        
        Activation of complement by alternative pathway may contribute to more leukocyte recruitment
        
        Result: acute arthritis, typically remits spontaneously in d-ws; Repeated attacks--> formation of tophi, aggregates of urate crystals & infl tissue, in inflamed synovial membranes & periarticular tissue; Severe damage to cartilage develops, function of joints compromised.
        
        Only 10% w/ hyperuricemia develop clinical gout. Other Fs
        
        • Age & duration of hyperuricemia: u. appears >20-30 yrs of hyperuricemia
        
        • Genetic predisposition: well-defined X-linked abnormalities of HGPRT, polymorphisms in genes involved w/ urate or ion transport and possibly infl also a.
        
        • Alcohol consumption
        
        • Obesity
        
        • Drugs (e.g., thiazides) that reduce excretion
        
        MORPHOLOGY
        
        distinctive morphologic changes: (1) acute arthritis, (2) chronic tophaceous arthritis, (3) tophi in various sites, (4) gouty nephropathy.
        
        Acute arthritis
        
        Charac by a dense infl infiltrate that permeates synovium & synovial fluid
        
        Urate crystals freq found in cytoplasm of neutrophils & arranged in small clusters in synovium; long, slender, needle-shaped, negatively birefringent
        
        synovium edematous, congested, ontains scattered lymphocytes, plasma cells, and macrophages.
        
        Chronic tophaceous arthritis evolves from repetitive precipitation of urate crystals during acute attacks; crystals encrust articular surface & form visible chalky deposits in synovium; synovium becomes hyperplastic, fibrotic, thickened by infl cells & forms a pannus that destroys underlying cartilage
        
        Tophi in articular cartilage, ligaments, tendons, bursae: pathognomonic of gout: large aggregations of urate crystals surrounded by an intense foreign body giant cell reaction
        
        Gouty nephropathy: renal complications caused by urate crystals or tophi in renal medullary interstitium or tubules. Complications: uric acid nephrolithiasis & pyelonephritis
        
        Clinical Course
        
        A. w/ male sex, obesity, metabolic syndrome, excess alchohol intake, renal failure, >30 yrs
        
        Four clinical stages:
        
        • Asymptomatic hyperuricemia appears around puberty in m, after menopause in w
        
        • Acute arthritis: after several yrs as sudden onset excruciating joint pain, localized hyperemia,
        
        Warmth; Most first attacks: monoarticular; 50%: in first metatarsophalangeal joint. Untreated, acute gouty arthritis may last for hrs to weeks, but gradually complete resolution.
        
        • Asymptomatic intercritical period: Resolution of acute arthritis--> symptom-free interval; absence of therapy--> attacks recur at decr intervals & freq become polyarticular
        
        • Chronic tophaceous gout: 12 yrs after initial acute attack; radiographs: charac juxtaarticular bone & loss of joint space.
        
        Treatment: lifestyle modification, medication to reduce symptoms (e.g., NSAIDs) & lower urate levels (e.g., xanthine oxidase inhibitor).
      - CPPD (Pseudogout)
        
        U. >50 yrs; more common w/ incr age; genders, races equally affected
        
        divided into sporadic (idiopathic), hereditary, secondary types
        
        AD variant: germline mutations in PP transport channel
        
        Various disorders (previous joint damage, hyperPTH, hemochromatosis, DM, predispose to secondary form
        
        articular cartilage PGs: normally inhibit mineralization: are degraded, allowing crystallization around chondrocytes. As in gout, infl caused by activation of inflammasome in MQs.
        
        MORPHOLOGY
        
        crystals first develop in articular cartilage, menisci, and intervertebral discs, and as deposits enlarge they may rupture and seed joint.
        form chalky, white friable deposits, seen histologically in H&E preparations as oval blue-purple aggregates
        individual crystals rhomboid, 0.5 to 5 µm in greatest dimension, positively birefringent
        Infl u milder than in gout.
        
        Clinical Course CPPD is frequently asymptomatic. However, it may
        
        produce acute, subacute, or chronic arthritis
        joint involvement may last from several days to weeks and may be monoarticular or polyarticular;
        knees, followed by wrists, elbows, shoulders, and ankles, most commonly affected.
        50% of affected individuals experience significant joint damage. Therapy supportive. no known treatment that prevents or slows crystal formation.
  - - - reciprocal somatic chromosomal translocation, t(1;2) (p13;q37)--> fusion of type VI coll α-3 promoter to M-CSF gene--> cells overexpress M-CSF--> through autocrine and paracrine, stimulates prolif of MQs in a manner similar to giant cell tumor of bone
      - diffuse tumors
        normally smooth joint synovium converted into a tangled mat by red-brown folds, fingerlike projections, and nodules
        localized (nodular)
        well circumscribed.
        neoplastic cells, account for only a minority of the cells in mass, are polygonal, moderately sized, and resemble synoviocytes
        Both diffuse and localized heavily infiltrated by MQs containing hemosiderin and foamy lipid, or are multinucleated.
      - a benign neoplasm that develops in synovial lining of joints, tendon sheaths, and bursae
        Clinical variants:
        diffuse type (pigmented villonodular synovitis): tends to involve large joints
        localized type: u occurs as a discrete nodule attached to a tendon sheath, commonly in hand
      - Diffuse
        presents in knee in 80%, followed by hip and ankle
        typically complain of pain, locking, and recurrent swelling similar to monoarticular arthritis
        Sometimes, a palpable mass
        localized
        a solitary, slow-growing, painless mass that frequently involves hand
        Both types amenable to surgical excision, but recurrence more common in diffuse