Bone Disorders, Tumors of Bone, Tumors of Soft Tissue

Question 1

Osteogenesis imperfecta

Answer 1

• defective synthesis of Type I collagen, mutations in either alpha 1 or 2 chains.
• 4 major types; 2 to know are:
  1. Type I - mild bone fragility, rib deformities, BLUE SCLERA, normal lifespan, slight inc. risk of fracture; can include hearing loss and small misshapen teeth (from dentin deficiency)
  2. Type II - pre/perinatally lethal b/c of multiple fractures prior to birth

Question 2

Anchondroplasia

Answer 2

• most common form of dwarfism; AD or spontaneous mutation (80%)
• activating mutation in FGFR3 which constantly inhibits cartilage proliferation/growth
• therefore affects all bones that grow via enchondral ossification (cartilage intermediate)
• phenotype: short stature, disproportionate shortening of the proximal extremities, bowing of the legs, and frontal bossing with midface hypoplasia; cartilage that is there is disordered and hypoplastic
• type: thanatophoric is lethal due to small thorax and respiratory complications

Question 3

Osteopetrosis

Answer 3

• a deficiency of carbonic anhydrase II which leads to a loss of acidic environment needed for bone resorption - therefore, bones are dense like stone, eventually weaken and fracture like a piece of chalk
• clinically will see fractures, cytopenias, vision/hearing impairment, hydrocephalus, RTA/metabolic acidosis from reduced reabsorption of HCO3
• micro will see multiple irregular bony trabeculae with residual cartilage, no increased osteoclasts; hematopoiesis but in a smaller marrow cavity

Question 4

Rickets

Answer 4

-defective matrix mineralization and accumulation of unmineralized bone matrix because of a Vitamin D disturbance
-clinically will see pigeon chest deformity, frontal bossing, rachitic rosary ribs, and bowed legs. ON x-ray will see distal ends of long bones as flared, frayed, and cupped with large distance between the radius and metacarpals.
-microscopically will see thickened, non-calcified, poorly defined growth plate (von Kossa stain)
+Pathophysio = Vit D stimulates osteoblasts to produce osteocalcin, a Ca-binding protein needed for Ca deposition in bone development.

Question 5

Rickets vs. Osteomalacia

Answer 5

• Rickets is in kids; Osteomalacia is in adults - both are inadequate osteoid mineralization of trabeculae that leads to weak bones and fracture
• both have decreased Ca and P, increased PTH and alkaline phosphatase

Question 6

Osteomyelitis

Answer 6

• infection of bone, usually bacterial, usually kids
• caused by direct inoculation (trauma), contiguous spread (cellulitis), or hematogenous spread
• will have bone pain + systemic signs of infection; lytic focus (abscess, called “sequestrum”) on x-ray surrounded by sclerosis (“involurum”–subperiosteal shell of reactive viable new bone)
• draw blood for cultures before starting treatment
• one of the few conditions in which ESR >100mm/hr

Question 7

Osteoporosis

Answer 7

• reduction in trabecular bone mass, resulting in porous bone with inc. risk of fracture
• 2 types: senile, postmenopausal
• contributing factors include - aging: dec. synthetic and replicative activity of osteoblasts/progenitors, reduced physical activity; PM: dec. serum estrogen, inc. IL-1/6/TNF, RANK/RANKL, inc. osteoclast activity
• can treat with bisphosphonates, which inhibit bone resorption by binding to bone material

Question 8

Pathologic vs. Non-pathologic fractures

Answer 8

Pathologic = bones break after trivial trauma; most common underlying pathology is osteoporosis; may also be due to underlying malignancy or bone cyst

Question 9

Osteonecrosis

Answer 9

• Ischemic necrosis of bone and marrow; wedge-shaped pale area of necrosis
• causes: fracture/trauma, steroids, SCD, alcohol abuse, decompression sickness (bends)

Question 10

Pagets Disease of Bone

Answer 10

• like osteoporosis, it’s an imbalance of osteoclast and osteoblast activity; typically localized (differentiating feature)
• has 3 phases: lytic, mixed, and sclerotic; characteristic “cotton wool” appearance of skull
• unknown etiology but possible viral, familial predisposition - Chr18
• most common cause of isolated elevated alkaline phosphatase in pts >40yo; patients will notice that their hat size has gone up
• inc. risk of osteosarcoma

Question 11

Hyperparathyroidism

Answer 11

-Primary = hyperplasia or tumor (adenoma) of the
parathyroid gland
-Secondary = prolonged states of hypocalcemia with resulting hypersecretion of PTH
-Inc. PTH –> osteoblasts –> osteoclasts –> bone resorption
-substantial resorption of bone causes cyst-like brown tumors (fibrous tissue and woven bone without matrix)

Question 12

Renal Osteodystrophy

Answer 12

• term to collectively describe skeletal changes associated with CKD wherein the kidney fails to convert Vitamin D to active form (as such, Ca isn’t absorbed, so PTH is released to try and increase Ca absorption and also increases bone resorption)
• includes osteoclastic bone resorption that mimics OFC, osteomalacia, osteosclerosis, growth retardation, and osteoporosis

Question 13

Name the common bugs that cause osteomyelitis in these populations:
most common, sexually active young adults, diabetics/IVDAs, SCD patients; infection of the spine

Answer 13

• Staph aureus – 90%, most common
• N. gonorrhoeae – sexually active young adults
• Salmonella – sickle cell disease
• Pseudomonas – diabetics or IV drug abusers
• Mycobacterium tuberculosis – typically the spine (Pog disease)

Question 14

von Recklinghausen Disease of bone, aka osteitis fibrosa cystica (OFC)

Answer 14

seen with advanced hyperparathyroidism, it’s the combination of increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors

Question 15

Simple vs. compound fracture

Answer 15

simple = closed
compound = pierces skin, open; must use antibiotics

Question 16

Displaced vs. Spiral fracture

Answer 16

displaced = bone is move from anatomic position, must be reduced before healing
spiral = type of displaced fracture, result of torque trauma; may represent child abuse but spiral fracture of the distal tibia in a toddler may occur with regular activity

Question 17

Scaphoid fracture

Answer 17

• may not appear on X-ray during first week
• pain at snuffbox
• must be splinted or proximal scaphoid may undergo avascular necrosis

Question 18

Presentation of skull base fracture

Answer 18

periorbital ecchymoses, mastoid ecchymoses, or CSF leakage through the ears or nose (salty metallic taste)

Question 19

Child abuse fractures

Answer 19

• rib fractures, spiral fractures (other than toddler’s tibia fracture), and fractures of different ages may indicate some dark shit going down at home
• shaken baby syndrome - SDH, retinal hemorrhage may also be found

Question 20

Complications of fractures

Answer 20

• DVT, PE, fat emboli (long bones), compartment syndrome (most commonly in forearm and leg)
• identify compartment syndrome with the 5 P’s (pain, pallor, paresthesia, pulselesness, paralysis) treat with fasciotomy

Question 21

What is the most common benign bone-forming tumor in children/adolescents?
What is the most common malignant bone-forming tumor in children/adolescents?

Answer 21

Benign: osteoid osteoma
Malignant: osteosarcoma; second is Ewing sarcoma

Question 22

What is the most common benign cartilage-forming tumor in children/adolescents (

Answer 22

Benign: osteochondroma (outpouching of bone from main body of bone w/ mature bone stem & cartilaginous head)
Malignant: chondrosarcoma (the only malignant cartilage-forming tumor we discussed)

Question 23

Describe the tumors that commonly metastasize to bone, the radiologic manifestations of metastatic lesion involving bone, and the difference between osteoblastic and osteolytic metastases.

Answer 23

Common metastases: BLT+K+P
Radiologic manifestations: “punched out” lytic lesions
Difference between osteoblastic and osteolytic metastases: osteoblastic appear sclerotic and bright white, whereas osteolytic appears as “punched-out”, radiolucent lesions

Question 24

Describe the tumors that commonly metastasize to bone, the radiologic manifestations of metastatic lesion involving bone, and the difference between osteoblastic and osteolytic metastases.

Answer 24

Common metastases:
Radiologic manifestations:
Difference between osteoblastic and osteolytic metastases:

Question 25

Osteoma

Answer 25

What: Bone forming tumor composed of compact or mature trabecular bone limited almost exclusively to craniofacial bones, especially paranasal sinuses. Associated with Gardner syndrome (AD APC [5q21] mutation that causes multiple colon polyps and extracolonic tumors).
Gross: sessile with a polypoid shape, usually ~3cm
Micro: dense compact bone with a paucicellular stroma

Question 26

Osteoid osteoma

Answer 26

What: Benign tumor of osteoblasts, typically in cortex of long bones, that produces osteoid (pink stuff), surrounded by a rim of reactive bone. Presents as bone pain that’s relieved with ASA.
Gross: On X-ray appears as bony mass with radiolucent core.
Micro: randomly interconnected trabeculae of woven bone, prominently rimmed by a single cell layer of osteoblasts; stroma surrounding the neoplastic bone consists of loose connective tissue containing dilated and congested capillaries.

Question 27

Osteoblastoma

Answer 27

What: similar to an osteoid osteoma (benign tumor of osteoblasts) but is larger, arises in the vertebrae. Presents with bone pain that doesn’t respond to aspirin.
Gross: typically found in vertebrae, on X-ray appears as bony mass with radiolucent core.
Micro: anastomosing trabeculae of osteoid and woven bone rimmed by osteoblasts

Question 28

Osteosarcoma

Answer 28

What: Malignant proliferation of osteoblasts (“malignant osteoid/cartilage”). Most commonly arises in the knee, 60% males, age 10-20. Highly associated with RB mutation, TP53, INK4a, and MDM2(Rb)/CDK4(p53)
Gross: Codman triangle (periosteal reaction to the advancing tumor) on X-ray is characteristic but not diagnostic, indicates aggressive tumor
Micro: poorly formed bone spicules in a hypercellular matrix of osteoid, , often described as “lace-like”. Numerous pleomorphic malignant cells that vary in size and shape (bizarre tumor giant cells) and often have large hyperchromatic nuclei.

Question 29

Chondroma

Answer 29

What: Benign cartilaginous tumor; either enchondroma, subperiosteal/juxtacortical chondroma, or soft tissue chondroma. Associated with mutations in IDH1/IDH2 genes.
Gross: gray-white mass with color and consistency similar to
normal cartilage
Micro: numerous chondrocytes closely packed near the
periphery, in a pink ground substance that vaguely resembles normal cartilage (but normal hyaline cartilage has blue ground substance)

Question 30

Osteochondroma

Answer 30

What: benign tumor of bone that starts as outpouching of cartilage from epiphyseal plate; slow-growing and can be painful, usually stops growing at puberty and ossifies but can transform to chondrosarcoma
Gross: resembles a mushroom with a cap of cartilage
Micro:

Question 31

Chrondrosarcoma

Answer 31

What: Malignant cartilage forming tumor (no osteoid) that arises in the medulla of the pelvis or central/axial skeleton
Gross: tumor does not respect joint spaces and will invade the joint
Micro: pretty cellular; cells that mimic normal chondrocytes appear to float in a chondroid-like matrix. At high will see the tumor cells have large nuclei, high nuclear:cytoplasmic ratio, and abundant mitotic figures

Question 32

Fibrous cortical defect

Answer 32

What: Large (>5cm), benign non-ossifying fibroma, typically asymptomatic, likely a developmental defect; occurs in teens
Gross: intramedullary, radiolucent on X-ray
Micro: spindle cells in storiform pattern with scattered giant cells, histiocytes, cholesterol clefts, and hemosiderin

Question 33

Giant cell tumor

Answer 33

What: tumor of giant cells and stromal cells in the epiphysis of long bones (typically knee), in young adults and expresses high levels of RANKL
Gross: “soap bubble” on X-ray
Micro: regular/uniform distribution of tumor cells with ovoid, prominent nucleoli; fibroblast activity and formation of reactive bone and osteoid surround the tumor

Question 34

Ewing sarcoma

Answer 34

What: malignant proliferation of primitive neuroectoderm cells, undifferentiated, usually in white males

Question 35

Solitary bone cyst

Answer 35

What: benign lytic lesion, fluid-filled cyst, thin wall; usually in males

Question 36

Aneurysmal bone cyst

Answer 36

What: benign cyst in the bone filled with blood (like a sponge); grows rapidly
Gross: x-ray shows radiolucent bone deformity
Micro: highly vascularized tissue and clotted blood; may contain giant cells but the difference between this and giant cell tumor is the rich capillary bed

Question 37

Encondroma

Answer 37

What: a type of benign cartilaginous tumor; usually asymptomatic that occurs in the small bones of hands and feet. Ages 20-49. If multiple, associated with chondrosarcomal transformation; also associated with Maffuci syndrome and Ollier disease
Gross: Radiolucent nodule
of hyaline cartilage with
scalloped endosteal surface.

Question 38

Maffuci syndrome

Answer 38

syndrome of multiple enchondromas and soft tissue hemangiomas, ovarian carcinoma, and brain glioma

Question 39

Syndromes of fibrous dysplasia (2)

Answer 39

1. Mazabraud syndrome: fibrous dysplasia plus soft tissue myxomas
2. McCune-Albright syndrome: fibrous dysplasia plus cafe-au-lait skin pigmentations and endocrine abnormalities (esp. precocious puberty)

Question 40

What is Pott’s Disease?

Answer 40

Disseminated TB to the spine, resulting in tuberculous arthritis of the vertebral joints.

Question 41

Ganglion cyst

Answer 41

• Small cyst-like spaces with no epithelial lining; contain myxoid material
• Best thought of as a degenerative phenomenon in tendons or other connective tissue near joints
• Usually subcutaneous and relatively common.

Question 42

Giant Cell Tumor of Tendon Sheath

Answer 42

• Benign tumor of multinucleated giant
  cells
• Background of histiocytes and cells that resemble synoviocytes.
• Often located near joints, can interfere with function.
• Well-circumscribed tumor and yellow because it contains many lipid laden macrophages.

Question 43

Tenosynovial Giant Cell Tumor

Answer 43

• Localized, benign, destructive lesion within a single joint, usually knee
• Proliferation of synovium, hemosiderin, pigment deposition, and destruction of the joint
• Used to be called “pigmented villonodular synovitis” (still accurate description)

Question 44

Lipoma

Answer 44

• Most common benign ST tumor.
• Benign tumor of mature adipose tissue; usually found on superficial extremity or trunk
• Most are mobile, slow growing, and painless (angiolipomas can manifest with local pain).
• Well-circumscribed yellow mass and complete excision is usually curative.
• Some have cytogenetic abnormalities - 55-75% with HMG on chromosome 12.

Question 45

Liposarcoma

Answer 45

• Malignant adipose tumor, 3 subtypes:
  1 - Well differentiated liposarcoma with adipocytes and scattered spindled cells - indolent prognosis
  2 - Myxoid liposarcoma with lots of basophilic matrix, arborizing vessels, variable adipocyte differentiation reminiscent of fetal fat - interm. prognosis
  3 - Pleomorphic liposarcoma with anaplastic cells, bizarre nuclei and lipoblasts (immature adipocytes, look bubbly) - worst prognosis
• Occurs in deep ST of the prox extremities and in RP, in pts 50-60yo
• Immuno+ for MDM2 & CDK4 or molec. test + for 12q13-15 amplification
• Recur locally and repeatedly unless adequately excised

Question 46

Nodular Fasciitis

Answer 46

Benign fibrous tumor

• Rapidly growing, benign, fibroblast proliferation in subcutis
• Highly cellular, plump fibroblasts in fascicles (looks like tissue culture) and abundant mitotic figures
• Commonly in the arms
• 25% have history of trauma
• Shown to be clonal but self- limited

Question 47

Myositis ossificans

Answer 47

• metaplastic bone mass that arises in proximal extremities following trauma (commonly athletes)
• see periosteal reaction with eggshell calcification/mature bone at periphery 3-6wk after injury, fibrous tissue resembling nodular fasciitis at center, osteoid in between
• can be hard to distinguish from osteosarcoma, but excision usually curative

Question 48

Fibromatosis - superficial

Answer 48

• infiltrative fibroblastic
  proliferation that causes local deformity; M>F
• nodular or poorly defined broad fascicles of fibroblasts in dense collagen
• 3 location types:
  1 - Palmar (Dupuytren
  contracture) - Irregular nodular thickening of palmar fascia, 50% bilateral, progressive contracture of 4th and 5th fingers
  2 - Plantar - Young patients, unilateral and without contractures
  3 - Penile (Peyronie)
  disease - Palpable induration or mass on the dorsal penis, eventual curvature of the shaft and/or constriction of the urethra

Question 49

Fibromatosis - deep

Answer 49

• Large infiltrative masses that recur but do not metastasize; technically benign but can cause non-benign effects like abdominal obstruction
• teens to 30’s, female
• Broad fascicles amid dense collagen, similar to a scar; immuno+ for beta-catenin
• Assoc. with APC gene or Beta-Catenin, both lead to inc. WNT signaling; also assoc. w/ Gardner’s syndrome, so look for colon polyps, forehead masses, etc.

Question 50

Fibrosarcoma

Answer 50

• malignant neoplasm of fibroblasts
• adults, typically deep thigh or RP; local recurrence common and 25% hematogenous spread to lungs
• unencapsulated with necrosis and hemorrhage; micro patterns vary: fibromatosis-like, herringbone, or architectural disarray

Question 51

Rhabdomyoma

Answer 51

• Most frequent primary tumor of pediatric heart
• benign tumor of cardiac muscle, maybe hamartoma rather than true neoplasm, most spontaneously regress
• 50% assoc. with tuberous sclerosis, mutations of TSC1/TSC2 genes

Question 52

Rhabdomyosarcoma

Answer 52

*Alveolar and embryonal are most common ST sarcoma of childhood
- malignant mesenchymal tumor with skeletal muscle differentiation
- rhabdomyoblasts with sarcomeres, Z bands, and eosinophilic inclusions are hallmark histo finding
- the sarcoma is usually made up of bizarre cells with abundant cytoplasm, elongated “strap” cells may look like sk. muscle cells with cross striations
- 3 subtypes:
1 - alveolar - predominantly in kids, resembles lung tissue due to the fibrous septae that divide cells into clusters
2 - embryonal - soft grey infiltrative mass composed of spindled and round cells in myxoid stroma, in kids; variant = sarcoma botyoides in hollow mucosa-lined areas
3 - pleomorphic - predominantly in adults, numerous large, multinucleated bizarre eosinophilic tumor cells that can stain for myogenin

Question 53

Leiomyoma

Answer 53

• Most common neoplasm in women
• benign tumor of smooth muscle
• Fascicles of densely eosinophilic spindle cells that often intersect at right angles
• Germline LOF mutation in fumarate hydratase gene assoc. with hereditary leiomyomatosis and RCC syndrome
• uterus is a common site

Question 54

Leiomyosarcoma

Answer 54

• malignant tumor of smooth muscle
• arises in deep ST of extremities and RP; particularly deadly form can arise from great vessels; usually painless, can be large/bulky
• eosinophilic spindle cells with blunt- ended, hyperchromatic nuclei in interweaving fascicles
• tend to metastasize to lung via hematogenous spread; major COD

Question 55

Synovial sarcoma

Answer 55

• mass that was first found in synovium near the knee but can present in locations with or without synovium
• characteristic t(X;18) translocation
• arises in pts 20-40yo, mets to lung common, sometimes lymph node
• 2 histo types: monophasic and biphasic, first phase is uniform spindle cells, biphasic also include gland-like structures

Question 56

Undifferentiated pleomorphic sarcoma

Answer 56

• Malignant high grade waste basket (can’t otherwise be identified)
• large, grey-white fleshy masses (10-20 cm) with sheets of anaplastic spindled to polygonal cells; atypical mitotic figures and bizarre nuclei
• Necrosis and hemorrhage common