Non-infective arthritis
Transient attacks of acute arthritis initiated by crystallization of urates and neutrophils, followed by chronic gouty arthritis with tophi in joints and urate nephropathy
Causes 2-5% of chronic joint disease
Sites: 50% have initial attack in first metatarsophalangeal joint; also ankles, heels, knees, wrists, fingers, elbows
Primary gout (90%): idiopathic (85%) with overproduction of uric acid (may have normal excretion) or known enzyme defects (partial hypoxanthine-guanine phosphoribosyl transferase deficiency [HGPRT])
Secondary gout (10%): increased nucleic acid turnover due to leukemia/lymphoma, chronic renal disease, HGPRT deficiency
Pathophysiology: there are two pathways for purine synthesis: de novo (creates purines) and salvage pathway (HGPRT)
HGPRT deficiency causes increased synthesis via de novo pathway, leading to hyperuricemia
Drawing #1 - XO is xanthine oxidase, more information
Lesch-Nyan syndrome: rare; men with HGPRT deficiency causing hyperuricemia, severe neurologic deficits with mental retardation, self-mutilation, gouty arthritis; chart; OMIM 300322
Gout is due to hyperuricemia (present in 10% of population, although only half develop gout) and deposition of monosodium urate crystals in joints and viscera and uric acid kidney stones
Need serum urate > 7 mg/dl for deposition (saturation threshold for urate at 98.6 F)
Risk factors for gout with hyperuricemia are age > 30 years, familial history of gout, alcohol use, obesity, thiazide administration, lead
Arthritis: synovial fluid is poorer solvent for sodium urate than plasma, so with hyperuricemia, urates in joint fluid crystallize, particularly in ankle due to lower temperature; crystals develop in synovial lining cells, stimulate formation of antibodies, which accelerates formation of new crystals; release of crystals attracts neutrophils and complement, generates C3a, C5a, attracts more neutrophils, releases free radicals, releases lysosomal enzymes which eventually causes acute arthritis that last days to weeks without treatment; repeated attacks of acute arthritis cause chronic arthritis and formation of tophi in synovial membranes and periarticular tissue, which eventually damages joints
Aspirate: grossly white-gray and granular; strongly negative birefringent needle-shaped crystals under polarized light; foreign body giant cells
Case reports: 73 year old man with elbow pain (Archives 2002;126:621)
Gross: chalky white appearance of gouty deposits
Micro: early - edematous synovium with acute and chronic inflammatory infiltrate; late - tophi (large aggregates of urate crystals, granulomatous inflammation, hyperplastic fibrotic synovium); gout crystals are long, slender, needle shaped, but difficult to visualize with routine staining because they are dissolved during formalin processing (crystals are water soluble); easier to identify on scrape or with alcohol fixation
With chronic disease, urate deposits may be present in soft tissue, ligaments, skin
Gouty deposits may be surrounded by fibrous tissue and be rimmed by histiocytes and giant cells
Micro images: A: Xray; B: Diff-Quick; C: Pap smear; D: polarized light; E: H&E
DD crystal deposition: deposition of calcium pyrophosphate, calcium phosphate, talc, methyl methacrylate (prosthetic joints)
Also called reactive arthritis
Triad of arthritis, uveitis/conjunctivitis, non-gonococcal urethritis/cervicitis is not always present
Typically affects men or women in 20-30's
80% are HLA-B27 positive
Occurs after GI infections (Salmonella, Shigella, Campylobacter, Yersinia), Chlamydia
Affects ankles, knees, feet
Synovitis of digital tendon sheath produces sausage fingers or toes, causes spurs
Treatment: doxycycline
Chronic systemic inflammatory disorder affecting synovial lining of joints, bursae and tendon sheaths; also skin, blood vessels, heart, lungs, muscles
Produces nonsuppurative proliferative synovitis, may progress to destruction of articular cartilage and joint ankylosis
1% of adults, 75% are women, peaks at ages 10-29 years; also menopausal women
Sites: small bones of hand affected first (MCP, PIP joints of hands and feet), then wrist, elbow, knee
Pathophysiology: triggered by exposure of immunogenetically susceptible host to arthitogenic microbial antigen; autoimmune reaction then occurs with T helper activation and release of inflammatory mediators and cytokines that destroys joints; circulating immune complexes deposit in cartilage, activate complement, cause cartilage damage
Parvovirus B19 may be important in pathogenesis (Mod Path 2003;16:811)
Genetics: HLA-DR4, DR1 (65%); T-cell antigen receptor motif Q(K/R)RA in 75%
Laboratory: 80% have IgM autoantibodies to Fc portion of IgG (rheumatoid factor), which is not sensitive or specific; synovial fluid has increased neutrophils (particularly in acute stage), protein, low mucin
Other antibodies include antikeratin antibody (specific, not sensitive), antiperinuclear factor, anti-rheumatoid arthritis associated nuclear antigen (RANA)
Clinical course: variable; malaise, fatigue, musculoskeletal pain, then joint involvement; joints are warm, swollen, painful, stiff in morning; 10% have acute onset of severe symptoms, but usually joint involvement occurs over months to years; most damage occurs in first 5 years, joints are unstable with minimal range of motion; 50% have spinal involvement
Reduces life expectancy by 3-7 years, death due to amyloidosis, vasculitis, GI bleeds from NSAIDs, infections from steroids
Xray: joint effusions, juxta-articular osteopenia, erosions and narrowing of joint space; destruction of tendons, ligaments and joint capsules produce radial deviation of wrist, ulnar deviation of digits, swan neck finger abnormalities
Diagnosis: morning stiffness, arthritis in 3+ joint areas, arthritis in hand joints, symmetric arthritis, rheumatoid nodules, rheumatoid factor, typical radiographic changes
Treatment: nonsteroidal anti-inflammatory drugs (NSAIDs); immunosuppressive drugs; joint replacement (synovitis tends to lessen), synovectomy (inflamed synovium may recur and disease may continue to progress)
Gross: joints have edematous, thick, hyperplastic synovium, covered by delicate and bulbous fronds
Micro: dense perivascular inflammatory infiltrate of T lymphocytes, plasma cells (often with eosinophilic cytoplasmic inclusions called Russell bodies), macrophages; inflammation extends to subchondral bone (relatively specific for rheumatoid arthritis); proliferative synovitis with synovial cell hyperplasia and hypertrophy, lymphoplasmacytic infiltrate with variable germinal centers, necrobiotic nodules and fibrosis; increased vascularity with hemosiderin deposition; organizing fibrin floating in joint space as rice bodies; neutrophils present on synovial surface; osteoclasts present in bone forming cysts; erosions, osteoporosis; pannus formation (synovium, synovial stroma with inflammatory cells, granulomatous tissue, fibroblasts), progressing to fibrous ankylosis (bridges joints), then ossifying to form bony ankylosis; minimal evidence of repair (proliferative cartilage, sclerotic bone or osteophytes)
Weichselbaum’s lacunae: enlarged chondrocyte lacunae within articular cartilage due to dead chondrocytes
Skin: rheumatoid nodules in 25%, usually those with severe disease in skin subject to pressure (ulnar forearm, elbows, occiput, lumbosacral area); also present in viscera; firm, nontender, with central fibrinoid necrosis surrounded by palisading epithelioid histiocytes, lymphocytes, plasma cells; obliterative endarteritis in vasa nervorum and digital arteries causes ulcers, neuropathy, gangrene
Blood vessels: small to medium size vessels in vital organs (not kidney) affected by severe erosive disease; rheumatoid nodules present, high titers of rheumatoid factor
Cytology: may have inflammatory exudate with neutrophils, suggesting an infectious arthritis
Also called progressive systemic sclerosis
May be accompanied or even dominated by arthritis and arthralgia
Micro: superficial fibrin deposition in synovial membrane, mild mononuclear infiltrate, mild synovial hyperplasia, proliferation of collagen fibers, focal obliteration of small vessels
Micro: changes resemble rheumatoid arthritis, but with more intense surface fibrin deposition and less synovial proliferation
Joint tumors
Usually direct extension of bone tumors
May be related to fibrous histiocytoma of tendon sheath (below) due to similar location, clinical presentation and recurrence rate
Micro: lobulated, with lobules divided by narrow cleft like spaces; nodules composed of fibroblasts; narrow vessels, large amounts of dense collagenous tissue, markedly hyalinized; may have foci of myxoid change; compared to fibrous histiocytoma of tendon sheath is less cellular with no xanthoma cells and no giant cells
Fibrous histiocytoma of tendon sheath
Also called tenosynovial giant cell tumor, giant cell tumor of tendon sheath, nodular tenosynovitis, xanthogranuloma, benign synovioma
Ages 20-40's, usually women
Solitary, slow-growing, painless nodule on tendon sheaths of flexor surfaces of wrists/fingers, ankle/toes
15% erode adjacent bone by pressure
May be related to tendon sheath fibromas
Unclear if reactive or neoplastic
Treatment: excision (benign), but may recur locally
Gross: discrete encapsulated nodule, 1-3 cm on tendon sheath, may be attached to synovium by a pedicle; red-brown to orange-yellow, localized, well circumscribed, resembles small walnut; diffuse form may be larger and infiltrative
Micro: polymorphic infiltrate of small histiocytes, multinucleated giant cells within dense fibrous tissue with hemosiderin and foamy macrophages; mitotic figures and focal hyalinized areas
EM: synovial cells, fibroblasts, histiocytes, lymphocytes
DD: epithelioid sarcoma (granuloma-like formations, necrosis, invasive, epithelioid features, keratin+)
Malignant variant of fibrous histiocytoma of tendon sheath
High number of mitotic figures, marked nuclear hyperchromasia, few multinucleated giant cells
Often associated with cystic changes resembling ganglion cyst
Median age 43 years, range 16-83 years
72% male
Sites: knee (88%), also shoulder, elbow, ankle, hip
Often recurs, up to 4 times
References: Hum Path 1992;23:639
Pigmented villonodular synovitis (PVNS)
Rare neoplastic-like villonodular hyperplasia of synovium and tendon sheaths in young adults composed of mononuclear cells and multinuclear giant cells with hemosiderin deposition
May be similar to diffuse form of tenosynovial giant cell tumor
Develops in synovial lining of joints, tendon sheaths and bursae, usually of knee (80%), ankle, hip, shoulder, elbow joint; nodular variant occurs in hands and wrists
Almost always monoarticular
Occasionally invades underlying bone
May cause bone cyst formation, loss of bone and cartilage
Consists of CD68+ histiocytes with osteoclastic giant cell differentiation, may be hyperplastic, not neoplastic (Hum Path 2003;34:65)
Locally aggressive; may recur, but only rarely has malignant behavior (AJSP 1997;21:153)
Treatment: excision, but may recur locally if not completely excised; radiation therapy may be useful for recurrences
Case reports: 36 year old man with tumor at temporomandibular joint (Archives 2002;126:195), vertebral column (Archives 1984;108:228), rare cases of malignant behavior (Archives 2000;124:1636)
Gross: focal or diffuse; brown-yellow spongy tissue with variable color and firm nodular consistency
Micro: hyperplastic synovium with papillary projections composed of foamy cells and hemosiderin containing macrophages; also large clefts, pseudoglandular or alveolar spaces lined by synovial cells, multinucleated (10-70 nuclei) giant cells, epithelioid cells; abundant collagen may be present, but lymphocytes and plasma cells are sparse; no/rare mitotic figures
Malignant if nodular and solid invasive growth pattern are coupled with large round or oval cells with large nuclei, prominent nucleoli, necrotic areas, atypical mitotic figures
Micro images: image #1; #2; cytology, H&E; malignant cases
Cytology: round, spindled and multinucleated cells without atypia; round cells have minimal cytoplasm and eccentric nuclei; occasional cytoplasmic hemosiderin; no mitotic figures
Positive
stains: CD68 (stromal and giant
cells)
Negative stains: S100, CD45/LCA, EMA, keratin, HMB45, CD34, desmin, smooth
muscle actin
Molecular: trisomy 5 and 7
FISH: trisomy 5 and 7
DD: hemosiderotic synovitis (associated with hemophilia and intraarticular bleeding, no mononuclear or giant cell nodular cellular proliferation, hemosiderin primarily in synovial lining cells), fibrosarcoma, synovial sarcoma
References: more information #1; #2
Also called synovial chondrometaplasia, synovial osteochondromatosis
Mean age 41 years, range 17-64 years, 2/3 male
Primary disease is uncommon, unknown etiology, aggressive
Usually monoarticular, affecting knee, hip, elbow and communicating bursae; may affect adjacent soft tissue
Aggravated by infection and trauma
Xray: usually calcific densities within joint; may be negative or show diffuse joint swelling
May be extra-articular (tenosynovial chondromatosis)
Treatment: excision, but frequently recurs; 5% become malignant
Gross: numerous round osteocartilaginous nodules cover a thickened synovial surface or float freely within the joint space
Micro: cartilage cells with variable atypia or binucleated forms within synovium; clusters of chondrocytes are often arranged in lobules; no underlying arthritis
DD: secondary synovial chondrometaplasia due to degenerative joint disease, neuropathic arthropathy or osteochondritis dissecans (no lobulation, clustering or atypia), chondrosarcoma (not within a joint, no characteristic clustering pattern, marked myxoid change, spindling of nuclei), cartilaginous loose bodies (more common, but associated with arthritis)
References: Hum Path 1998;29:683, Hum Path 1979;10:439
Secondary disease
Associated with degenerative joint disease - growth of fragments of articular cartilage
Initially intrasynovial disease without loose bodies; then intrasynovial proliferation and free loose bodies, then multiple free osteochondral bodies without intrasynovial disease
No atypia
Very rare
Gross: may be more expansile than synovial osteochondromatosis
Micro: cartilage cells have cytologic features of malignancy
Axial skeleton tumor; often cervical spine
<50 cases reported
Mean age 32 years, range 17-44 years
Xray: mass of posterior aspect of adjoining vertebrae, often involving facet joints, with bone abnormalities present
Treatment: resection; may persist if incompletely excised; no metastases reported
Case reports: malignant synovial giant cell tumor (Hum Path 1989;20:765)
Gross: 1-6 cm
Micro: epithelioid cells with mixed osteoclast-like giant cells, hemosiderin containing macrophages, xanthoma cells, fibroblasts, lymphocytes; often with infiltrative growth; variable mitotic activity
Positive stains: CD68, CD163, vimentin
DD: giant cell tumor of bone (10% involve spine, usually sacrum, giant cells have abnormally large number of nuclei), osteoblastoma (well circumscribed, surrounded by cortical bone or periosteum, osteoblastic rimming with scattered osteoclasts), aneurysmal bone cyst (younger patients, well demarcated, lytic lesion bordered by thin rim of new bone, cavernous blood filled spaces), schwannoma
References: Hum Path 2003;34:670
Uncommon; usually young adults, more common in males
Sites: knee, elbow, finger
Xray images: various images
Gross: tumor usually confined to intra-articular synovium, may be in adjacent bursa
Micro: resembles either cavernous hemangioma, lobular capillary hemangioma, arteriovenous hemangioma or venous hemangioma
DD: pigmented villonodular synovitis, organizing hemorrhage
References: Hum Path 1993;24:737
Also called Hoffa’s disease
Rare; usually knee but may occur in any joint
Gross: enlargement of infrapatellar fat pad with pain in anterior compartment of knee; synovium is papillary, yellow and fatty
Micro: synovial hyperplasia with unremarkable fat extending to synovial lining; occasional chronic inflammatory infiltrate
Rare; may be extraarticular counterpart of synovial chondromatosis
Mean age 46 years, range 20-86 years
Painless mildly tender mass present for median 2 years
Usually recurs, perhaps due to subclinical micronodules
Sites: fingers (50%), feet (20%); also wrists, ankles, palm, knee, forearm
Treatment: complete excision in a conservative, function-preserving fashion
Micro: multinodular cartilaginous proliferation arising from tenosynovial membranes; often mild or moderate atypia similar to chondroma of soft parts or synovial chondromatosis; occasionally has prominent mineralization; often minute cartilaginous nodules; cartilaginous matrix more intensely basophilic than chondroma of soft parts
DD: chondroma of soft parts (not multinodular, younger patients overall although overlap exists)
References: AJSP 2003;27:1260
