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most common soft tissue tumor of childhood. RMSs are malignant tumors presumed to arise from primitive mesenchymal progenitors destined to form striated skeletal muscle cells.
Clinical presentation:
- Young children (usually <6 years of age)
- Most commonly occur in the head and neck, but may also occur in the genitourinary tract — e.g., botryoid variant (sarcoma botryoides) = unique form of embryonal-type RMS that occurs in the bladder or vaginal wall in infants
Although most commonly the result of sporadic mutation, RMS may occur as part of certain inherited syndromes, including:
1. Neurofibromatosis type 1
2. Li-Fraumeni syndrome
3. Beckwith-Wiedemann syndrome
Dx: RMS is strongly suggested in a child that presents with a mass → biopsy demonstrating positive IHC (immunohistochemical) staining for muscle-specific proteins, including MyoD1, polyclonal desmin, muscle-specific actin, myosin, myogenin
Note:
1. MyoD1 = protein normally found in developing skeletal muscle cells that disappears after the muscle matures and becomes innervated ∴ MyoD1 serves as a useful IHC marker of RMS because MyoD1 is present in developmentally immature muscle (e.g., RMS) but is not found in normal, mature skeletal muscle.
2. Myogenin = muscle-specific transcription factor essential for muscle development. Myogenin is expressed in developing skeletal muscle but not expressed in mature muscle ∴ myogenin is also a useful IHC marker of RMS.
Liposarcoma = most common soft tissue sarcoma. Liposarcomas are malignant tumors that arise in fat cells in deep soft tissue, such as that inside the thigh or in the retroperitoneum → will recur unless adequately excised
Clinical presentation:
- Middle-aged and older adults (usually ≥40 years of age)
- Large bulky tumors which tend to have multiple smaller satellites extending beyond the main confines of the primary tumor.
Lipoma = most common soft tissue tumor. Lipomas are benign tumors composed of fatty tissue → surgical excision is curative
Clinical presentation:
Lipomas present as masses which are:
1. Soft to the touch
2. Usually moveable
3. Generally painless — angiolipomas are the only painful lipomas
There is a correlation between the HMG I-C gene (previously identified as a gene related to obesity) and lipoma development
Degenerative disorder characterized by muscle wasting and replacement of skeletal muscle by adipose tissue
Due to mutations of dystrophin
dystrophin is important for anchoring the muscle cytoskeleton to the extracellular matrix
mutations are often spontaneous large gene size predisposes to high rate of mutation.
Becker’s muscular dystrophy: same gene is mutated, but symptoms are less severe
Gene: Dystrophin, on X-chromosome → rarely affects girls
1 in 3500 boys
The dystrophin links the actin cytoskeleton of smooth, cardiac and skeletal muscle cells to the extracellular matrix.
Disease phenotype requires mutations at the reading frame level (deletion, nonsense, frameshift)
Clinical course: pelvic muscle weakness that ascends
cell-mediated (CD8 cytotoxic T cells and macrophages) damage of muscle fibers → endomysial inflammation (necrotic and regenerating muscle fibers scattered throughout the fascicle, not limited to the fascicle periphery as in DM)
DM: antibody-mediated damage of blood vessels surrounding muscle fascicles (in the perimysial connective tissue) → perifascicular inflammation and atrophy
Dermatomyositis (DM) and Polymyositis (PM) are noninfectious inflammatory myopathies that present with symmetric proximal muscle weakness; normal reflexes, normal sensation
Both DM and PM are more common in women than men; peak incidence in adults 40 – 50 years of age
In DM there is skin involvement; in PM the skin is not involved.
Both DM and PM are associated with visceral malignancy, especially lung cancer
Skin involvement in DM
Gottron’s sign: erythematous scaly eruption or dusky purple patches over the extensor surfaces of the knuckles (metacarpophalangeal and/or interphalangeal joints), elbows, and knees
Heliotrope rash (“racoon eyes”): lilac or violaceous eyelid discoloration with periorbital edema
Shawl sign: erythema of the chest and shoulders
V-sign: erythema in a V-shaped distribution over the anterior neck and chest
Avascular Necrosis
ischemic necrosis of bone and bone mmarrow
causes include trauma or fracture , steroids sickle cell anemia and caisson disease
osteorthritis and fracture are major complications
impaired cartilage proliferation in the growth plate common cause of dwarfism
Due to an activating mutation in fibroblast growth factor receptor 3 FGFR
autosomal dominant
Most mutations are sporadic and related to increased paternal age.
clinical features
short extremitles with normal sized head and chest - due to poor endochondral bone formation intramembranous bone formation is not affected.
endochondral bone formation is charactrerized by formation of cartilage matrix, which is then replaced by bone it is the mechanism by which long bones grow
intramembramous bone formation ois characterized by formation of bone without a prextisting cartilage matrix it is the machanism by which flate bone develop
Osteopetrosis
inherited defect of bone resorpiton resulting in abnormally think, heavy bone that fractures easily
Due to poor osteoclast function.
multiple genetic variants exist carbonic anhydrase II MUTATION LEADS to loss of the acidic microenviroment required for bone resorption
clnical features include
bone fractures
anemia
thrombocytopenia
luckopenia
extramedullary hematopoiesis - due to replacement of bone merrow
vison and hearing impairment - due to impingement on cranial nerves
hydrocephalus - due to narrowing of the foramen magnum
renal tubular acidosis - seen with carbonic anhydrase II mutation
- lake of carbonic anhydrase results in decreased tubular reabsorption of HCO3- leading to metabolic acidosis
treament is bone marrow transplant - osteoclasts are derived from monocytes.
congentile defect of bone resorption resulting in structurally weak bone.
most commonly due to an autosomal dominant defect in collegen type 1 synthesis
multiple fractures of bone - please differenciate with child abuse - absent of brusing
bule sclera thining of scleral colleen reveals underlying choroidal veins
Hearining loss - bones of the middle ear easily fracture.
LEMS is believed to be caused by a Type II hypersensitivity reaction: autoantibodies bind presynaptic PQ-type voltage-gated calcium channels → ↓ fusion of synaptic vesicles with presynaptic membrane ∴ ↓ release of ACh into synaptic cleft ∴ less ACh is available to stimulate postsynaptic receptors → muscle weakness, which:
1. Improves with muscle use
2. Usually begins with proximal symmetric involvement of limbs, especially the proximal legs → difficulty climbing stairs or rising from a seated position, gait abnormalities
MG is caused by a Type II hypersensitivity reaction: autoantibodies bind postsynaptic acetylcholine receptors (AChR) → inhibition of ACh binding, internalization/degradation of AChRs, and complement-mediated postsynaptic membrane damage → ↓ number of functional AChRs and simplification of the postsynaptic membrane architecture → myasthenic muscle weakness, which:
Worsens with muscle use (eg, exercise, high rate repetitive nerve stimulation) and is ∴ worse at the end of the day, improves with rest
2. Fluctuates in the course of minutes/hours/days
3. Usually begins with the extraocular muscles → ptosis and diplopia are the most common initial complaints
Commonly occurs in the diaphysis of long bones (femur, tibia, humerus, ribs) and in the pelvis in young male patients (10-20 years of age).
Usual presentation is a painful enlarging mass, however patients may also present with fever, weight loss and:
- anemia
- ↑ ESR (erythrocyte sedimentation rate)
- ↑ WBC count (leukocytosis)
- ↑ LDH (lactate dehydrogenase).
85% of cases are associated with a t(11:22) chromosomal translocation, resulting in the formation of a EWS-FLI fusion protein
X-ray:
- large destructive lesion with a “moth-eaten” appearance
- characteristic “onion-skin” periosteal elevation – evidence of the periosteal reaction to irritation and penetration by this extremely aggressive tumor
Commonly found in the intramedullary portion of bones of the pelvis and intramedullary (diaphyseal) portion of the proximal femur and shoulder girdle in middle-aged males (30-60 years of age)
Usual presentation: localized pain and swelling.
May arise de novo or secondary to malignant transformation of an enchondroma or an osteochondroma
High grade chondrosarcomas are prone to lung metastasis
X-ray:
- radiolucent lesion with reactive thickening of the cortex
- intralesional speckled calcification (either a diffuse “salt and pepper” or more discrete/punctate “popcorn” pattern) suggestive of cartilage
Usual presentation: localized pain and swelling.
When all age groups are considered, osteosarcoma is the second most common malignant primary bone tumor:
Multiple myeloma > Osteosarcoma > Chondrosarcoma > Ewing’s sarcoma
However, osteosarcoma is the most common malignant primary bone tumor in children/adolescents.
~50% of patients have ↑ alkaline phosphatase (remember: osteosarcoma is a bone-producing tumor, and increased osteoblastic activity raises alkaline phosphatase levels)
Risk factors for osteosarcoma:
1) Paget’s disease of bone
2) Familial Retinoblastoma – like osteosarcoma, retinoblastoma is associated with a loss-of-function mutation of the Rb tumor suppressor gene on chromosome 13q
3) Fibrous dysplasia
4) Irradiation
Most common site of metastasis is the lung: about 10-20% of patients present with pulmonary metastases
X-ray:
- Codman’s triangle – due to elevation of the periosteum by the tumor
- “Sunburst” appearance – spiculated pattern due to calcification of the malignant osteoid (immature woven bone) produced by the tumor
Commonly found in the intramedullary (diaphyseal) portion of the small bones of the hands and feet in middle-aged patients (20-50 years of age).
X-ray: radiolucent defect that typically shows prominent stippled, punctate, popcorn-like calcification; phalanges may show thinning and endosteal scalloping
The risk of malignant transformation of an enchondroma into a chondrosarcoma varies — in a patient with…
- a solitary enchondroma — malignant transformation occurs in < 2% of cases
- Ollier’s syndrome (multiple enchondromas) — 10-25% of cases
- Maffucci’s syndrome (multiple enchondromas + soft tissue hemangiomas) — ~100% of cases
Commonly occurs in the epiphysis of the distal femur or proximal tibia of middle-aged female patients (20-40 years of age).
Unlike most bone tumors, which occur more commonly in males, giant cell tumors are more common in females
Histology: reactive multinucleated giant cells of osteoclastic origin and behavior (“osteoclastoma”) on a background of neoplastic mononuclear cells
X-ray: destructive lytic lesions near joints with characteristic “double bubble” or “soap bubble” appearance
benign bone-producing tumor that is not self-limited (nidus usually > 2cm), it usually does not cause localized nocturnal pain, and if pain occurs it usually is not relieved by aspirin.
Most commonly occurs in spine > long bones (diaphysis > metaphysis) in young patients (10-30 years of age).
Gross and microscopic pathology are the same as osteoid osteomas (nidus of vascular osteoblastic tissue — interlacing trabeculae of immature woven bone lined by regularly arranged osteoblasts — surrounded by normal reactive bone), except osteoblastomas are larger.
Usually occurs in the long bone metaphysis (most commonly the distal femur, proximal femur, or proximal humerus) of 10-30 year-old male patients
Usual presentation: hard painless mass that has been there for years
Exostosis (bony outgrowth) of medullary and cortical bone capped by cartilage that initially grows at a right angle from the epiphyseal growth plate. The cartilaginous cap functions as an ectopic growth plate, allowing the osteochondroma to grow by enchondral ossification until the patient reaches skeletal maturity.
Why are osteochondromas found in the metaphysis if they grow out from the epiphyseal growth plate? Because young patients are still growing – bone formerly at the epiphyseal plate moves into the metaphysis (and even into the diaphysis if enough long bone lengthening occurs)
Malignant transformation of an osteochondroma into a chondrosarcoma is rare, occurring in < 1% of cases
benign tumor of osteoblasts surrounded by a rim of reactive bone
occures in young adult <25 years of age more common in males
Arises in cortex of long bones (ex femur)
presents as bone pain that resolves with aspirin
imagining reveals a bony mass (<2cm) with radiolucent core (osteoid)
osteoblastoma is similar to osteoid osteoma but is layer (>2cm) arises in vertebrae, and presents as bone pain that does not respond to asprin.
benign tumor of bone
most commonly arise on the surface of facial bone
associated with gardner syndrome
APC gene
connection between two bones
solid joints are tightly connected to provide structural strengh
Synovial joints have a joint space to allow for motion.
1. articular surface of adjoining bones is made of hyaline cartilage (type 2 collagen ) that is surrounded by a joint capsule
synovium lining the joint capsule secretes fluid rich in hyaluronic acid to lubricate the joint and faciliate smooth motion.
Buildup of uric acid (most commonly caused by underexcretion of uric acid) → crystals of monosodium urate are deposited in the articular cartilage of joints, tendons and surrounding tissues → gout
Usually affects the large joints, classically the knee. It usually affects people >50 years old and affects both sexes equally
Using polarized light microscopy, calcium pyrophosphate dihydrate crystals:
have rhomboid, square, or rodlike structures
are weakly and positively birefringent: think “blue when parallel, yellow when perpendicular”—i.e., the crystals are blue when the long axis of the crystal is parallel to the axis of slow rotation of light of the red plate compensator and yellow when the crystal is perpendicular to the axis of the compensator
Like primary gout, secondary gout can be caused by overproduction or underexcretion of uric acid.
↑ nucleated cell turnover → overproduction of uric acid. Examples include:
1. Cancer
2. Psoriasis
3. Treating leukemia; tumor lysis due to chemotherapy
Inborn errors of metabolism → overproduction of uric acid. For example, Lesch-Nyhan syndrome:
1. X-linked recessive, complete HGPRT (hypoxanthine-guanine phosphoribosyltransferase) deficiency ∴ cannot re-use free purines via the salvage pathway
2. HGPRT deficiency → ↑ PRPP (5-phosphoribosyl 1-pyrophosphate), which activates enzymes in the de novo purine synthesis pathway → ↑ de novo purine synthesis → hyperuricema, which may cause gout.
3. The main clinical expression of Lesch-Nyhan syndrome is mental retardation and self-mutilation ∴ if gout occurs it is considered secondary gout.
Chronic renal disease → ↓ excretion of uric acid
Overproduction of uric acid may cause primary gout. For example:
Alcoholism → ↑ turnover of adenine nucleotides (ie, ATP) during the conversion of acetate to acetyl-CoA → ↑ urate production
Protein-rich diets: red meat, seafood, beer
Unknown enzyme defects
Primary gout may also occur secondary to ↓ excretion of uric acid. For example:
Thiazide diuretics
Lead poisoning → interstitial nephritis → ↓ urate excretion
Alcoholism → ↑ production of lactate, which is an antiuricosuric agent because lactate competes with urate for the same renal excretion sites → ↓ urate excretion
[Note: Alcohol can cause hyperuricemia by both increasing urate production and by decreasing urate excretion, as describe above]
If gout is poorly controlled, monosodium urate crystals may deposit in periarticular soft tissues → tophi: granulomas with multinucleated giant cells and negatively birefringent monosodium urate crystals (yellow when parallel to the slow ray)
Brisk granulomatous reaction within tophi can destroy bone → erosive arthritis
Tophi may form around joints, but are also commonly found in earlobes, Achilles tendons, and olecranon and patellar bursae.
Acute Gout
S/Sx:
Excruciating, sudden, unexpected, burning pain, as well as swelling, redness, warmth, and stiffness in the affected joint.
Mild fever; tachycardia, but only as a transient sympathetic response to the excruciating pain of an acute attack
Acute gout most commonly involves the 1st MTP (metatarsophalangeal) joint—podagra = gouty arthritis of the 1st MTP.
The extensor tenosynovium on the dorsum of the midfoot is also commonly affected during an acute gouty attack.
arthritis without ANA or rheumatoid factor (anti-IgG antibody), hence “seronegative”
- strongly associated with HLA-B27
- occur more commonly in males
Seronegative spondyloarthropathies include ankylosing spondylitis, reactive arthritis, and psoriatic arthritis.
Psoriatic arthritis
asymmetric inflammatory polyarthritis that affects 10-30% of people suffering from psoriasis; usually involves small joints in the upper extremities
When associated with psoriatic nail pathology (pitting of the nails), psoriatic arthritis commonly involves the DIP (distal interphalangeal) joints. Resorptive changes at the DIP joint with hyperemia (dactylitis) → involved fingers appear “sausage-shaped” and demonstrate a characteristic “pencil-in-cup” deformity on x-ray.
The underlying process in psoriatic arthritis is inflammation ∴ 1st line therapy = anti-inflammatory agents like NSAIDs (eg, diclofenac, naproxen)
Reiter Syndrome
Can’t pee, Can’t see, Can’t climb a tree” to remember the classic triad of Reiter syndrome, a type of reactive arthritis
ongonococcal urethritis (Ureaplasma, Chlamydia):
1. Urethritis — “Can’t pee”
2. Inflammation of the eyes (conjunctivitis and/or uveitis) — “Can’t see”
3. Inflammatory arthritis of large joints — “Can’t climb a tree”
In addition to the classic triad above, patients with Reiter syndrome frequently develop:
4. Oral ulcers
5. Keratoderma blenorrhagica—erythematous scaly hyperkeratotic skin lesions on palms and soles
6. Circinate balanitis—red scaly area on the glans penis with a gray, serpiginous annular edge that spreads outwards in phases
Ankylosing spondylitis
chronic degenerative inflammatory arthritis primarily affecting the axial skeleton (spine, sacroiliac joints); also commonly affects peripheral joints (eg, shoulder, hip)
Typical presentation:
Young male in his 20s – 30s with chronic low back pain and stiffness that is:
- worse with inactivity and in the morning
- better with exercise, hot showers, and towards the end of the day
Patients also often have constitutional Sxs—eg, low-grade fever, fatigue, weight loss
Pathophysiology:
1. Synovitis (inflammation of synovia) and enthesitis (inflammation of entheses—complex structures that attach ligaments and tendons to bone).
2. At sites of synovitis/enthesitis there is bone destruction (mediated by osteoclasts, cathepsin K, metalloproteinases) and concomitant bone production with formation of syndesmophytes. Bone destruction → osteopenia or frank osteoporosis → ↑ risk of pathologic fracture—minimal trauma may cause:
(a) lumbar spine fracture with resulting spinal cord injury (eg, cauda equina syndrome)
(b) atlantoaxial subluxation due to odontoid fracture and/or transverse cervical ligament laxity
3. Bony syndesmophytes eventually bridge gap between vertebrae → spinal fusion → rigid “bamboo” spine with decreased lumbar flexion (positive Schoberg test), obliteration of lumbar lordosis
1. Anterior uveitis or iridocyclitis (confirm dx on slit lamp exam) → acute monocular pain, photophobia, blurry vision
2. Aortitis, aortic root dilation → aortic regurgitation, which may progress to CHF (congestive heart failure)
3. Cardiac conduction defects (eg, 3rd degree heart block)
4. Involvement of thoracic spine → costovertebral rigidity and chest pain → ↓ chest expansion → restrictive pattern on pulmonary function tests
Infectious Arthritis
arthritis due to an infectious agent, uslly bacterial
causes include
N gonorrhoeae - young adults most common cause
S. aureus older children and adults , 2nd most com cause
Bacteria that are commonly found to cause septic arthritis are:
Streptococci: the second most common cause
Hemophilus influenzae: was the most common cause in children but is now uncommon in areas where Hemophilus vaccination is practiced
Neisseria gonorrhea: in young adults (although this is now thought rare in western Europe).
Escherichia coli: in the elderly, IV drug users, and the seriously ill
callsically involves a single joints, usally he knee
presents are a warmjoint with limited range of motion fever increased white cell count and eleveted ESR are often present.
noninflammatory progressive degeneration of articular cartilage primarily targeting weight-bearing joints (hip, knee, cervical/lumbar vertebrae), however the hands can also be affected — Heberden’s nodes at the DIP (distal interphalangeal) joint, Bouchard’s nodes at the PIP (proximal interphalangeal) joint.
Joint stiffness and pain after inactivity—for example, morning stiffness after awakening, which generally lasts < 30 min.
Joint stiffness and pain are aggravated by activity ∴ symptoms worsen as the day progresses, thus distinguishing osteoarthritis from rheumatoid arthritis
Crepitus (feeling of crunching/crackling) when moving the joint
Osteoarthritis in the fingers usually involves the DIP and PIP joints — vs. rheumatoid arthritis, which usually involves the MCP and PIP joints
Chronic, Systemic autoimmune disease
classically arise in women of late childbering age
associatd with HLA - DR4
- Hallmark is synovitis leag to formation of a pannus ( inflamaed granulation tissue)
lead to destruction of cartilage and ankylosis joint
clinical features
arthrities with morning stiffness that improves with activity
symmertirc involement of pip joints of the finger Dip is usally spared.
joint space narrowing, loss of cartilage, and osteopenia are seen on xray
fever malaise weight loss and myalgias
Rheumotoid nodules - central zone of necrosis surrounded by epithelioid histocytes arise in skin and visceral organ
vasculitis - multiple organ may be involved
baker cyst - swelling of bursa behind the knee
pleural effusion lymphadenopathy and interestial lung fibrosis
Mnumonic
L – loss of joint space
E – erosions
S – soft tissue swelling
S – soft bones (osteopenia)
Igm autoantibody against Fc portion of IGG
neutrophils and high protein in synovial fluid
complication invluede anemia of chronic disease and secondary amyloidosis
