2.6.4. PATH LAB - Bone Pathology I (Part 2 of 3)

Question 1

Type of Fracture: Simple

Answer 1

Simple - overlying skin is intact

Question 2

Type of Fracture: Compound

Answer 2

Compound - bone breaks the skin surface

Question 3

Type of Fracture: Comminuted

Answer 3

Comminuted - bone is fragmented

Question 4

Type of Fracture: Displaced

Answer 4

Displaced - ends of the bone at the fracture site are not aligned

Question 5

Type of Fracture: Stress

Answer 5

Stress - slowly developing facture

Question 6

Type of Fracture: Greenstick

Answer 6

Greenstick - extending only partially through the bone (common in infants)

Question 7

Type of Fracture: Pathologic

Answer 7

Pathologic - bone weakened by an underlying disease process

Question 8

What happens immediately after fracture?

Answer 8

Immediately after fracture, rupture of blood vessels results in a hematoma, which fills the fracture gap

Clot forms (fibrin mesh)

Question 9

After a fracture, degranulated platelets and migrating inflammatory cells release what?

Answer 9

Degranulated platelets and migrating inflammatory cells release PDGF, TGF-β, FGF and other factors

Question 10

Callus formation following a fracture

Answer 10

At the end of one week, a soft tissue callus is formed

After ~2 weeks, the soft tissue callus is transformed into a bony callus.

As the callus matures and is subjected to weight-bearing forces, the portions that are not physically stressed are resorbed.

Question 11

When is a fracture technically healed?

Answer 11

The healing process is complete with restoration of the medullary cavity.

Question 12

What is osteonecrosis?

Answer 12

AKA Avascular Necrosis

Infarction of bone and marrow can occur in the medullary cavity or involve both the medulla and cortex

The cortex is not usually affected because of its collateral blood flow

Question 13

What do most cases of osteonecrosis stem from?

Answer 13

Most cases stem from fractures or corticosteroid administration

Question 14

Presentation of the infarcts of osteonecrosis:

Answer 14

Typically, subchondral infarcts cause pain that initially only occurs with activity, but then becomes constant

Medullary infarcts are usually small and clinically silent except when they occur in the setting of Gaucher’s disease, dysbarism (the “bends”), or sickle cell anemia.

Question 15

What is/causes osteomyelitis?

Answer 15

Osteomyelitis is inflammation of bone and marrow, virtually always secondary to infection

Question 16

What causes Pyogenic Osteomyelitis? Who is usually the culprit?

Answer 16

Almost always caused by bacterial infections, 80-90% are caused by S. aureus.

Question 17

What specific abscess is associated with osteomyelitis?

Answer 17

Brodie abscess is a small intraosseous abscess that frequently involves the cortex and is walled off by reactive bone

Question 18

What is Sclerosing osteomyelitis of Garre?

Answer 18

Sclerosing osteomyelitis of Garre typically develops in the jaw and is associated with extensive new bone formation that obscures much of the underlying osseous structure.

Question 19

Clinical course of osteomyelitis?

Answer 19

Sometimes manifests as an acute systemic illness with malaise, fever, chills, leukocytosis, and marked-to-intense throbbing pain over the affected region.

Question 20

What is mycobacterial osteomyelitis and how does it present?

Answer 20

Mycobacterial osteomyelitis tends to be more destructive and resistant to control than pyogenic osteomyelitis.

Present with localized pain, low-grade fevers, chills, and weight loss

Question 21

Though syphilis can affect bone, bone involvement remains infrequent because the disease is usually diagnosed and treated before this complication develops.

What about congenital syphillis and what is its characteristic finding?

Answer 21

In congenital syphilis, bone lesions appear around the 5th month of gestation and are fully developed at birth.

Characteristic finding is “syphilitic saber shin”

Question 22

Morphology of syphillitic bone?

Answer 22

Syphilitic bone infection is characterized by edematous granulation tissue containing numerous plasma cells and necrotic bone.

Question 23

When possible, bone tumors are classified how?

Answer 23

When possible, bone tumors are classified according to the normal cell or matrix they produce.

Question 24

What are, in general, Osteoid Osteoma and Osteoblastomas?

Answer 24

Benign bone-producing tumors that have identical histologic features but differ in size, sites of origin, and symptoms.

Malignant transformation is rare

Question 25

How big are osteoid osteomas, and where do they normally present?

Answer 25

Osteoid osteomas are less than 2cm in diameter and usually occur in young men in their teens and 20s. Usually occur in cortex of bones in the appendicular skeleton (~50% in femur/tibia)

Question 26

What is the clinical presentation of osteoid osteoma? How is it usually treated?

Answer 26

Have severe nocturnal pain that is relieved by aspirin Usually treated by radiofrequency ablation

Question 27

How big is osteoblastoma, where does it normally occur?

Answer 27

Osteoblastomas are larger than 2cm in diameter and usually involve the posterior spine

Question 28

True/False: Osteoblastoma is manageable with pain meds like Aspirin

Answer 28

False

Question 29

What is an osteosarcoma?

Answer 29

Malignant tumor in which the cancerous cells produce osteoid matrix or mineralized bone. Most common primary malignant tumor of bone

Question 30

Any bone can be involved, but tumors usually arise typically where?

Answer 30

Any bone can be involved, but tumors usually arise in the metaphyseal region of the long bones of the extremities, and ~50% occur in the distal femur or proximal tibia (knee joint)

Question 31

Pathology of osteocarcoma and what do we see in radiology?

Answer 31

The tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation. The triangular shadow between the cortex and the raised ends of periosteum, known radiographically as Codman’s triangle, is indicative of an aggressive tumor - and is characteristic - but not diagnostic - of osteosarcoma; also has “sunburst” appearance on XRAY

Question 32

In osteo sarcoma, ~70% have acquired genetic abnormalities, including mutations to the following:

Answer 32

RB - negative regulator of the cell cycle TP53 - gene product promotes DNA repair and apoptosis INK4a - encodes two tumor suppressors (p16 and p14) MDM2 and CDK4 - cell cycle regulators that inhibit p53 and RB function

Question 33

What is achondroblastic osteosarcoma

Answer 33

When malignant cartilage is abundant, the tumor is called chondroblastic osteosarcoma.

Question 34

What accounts for the majority of primary bone tumors?

Answer 34

Cartilage tumors account for the majority of primary bone tumors (both benign and malignant)

Question 35

What cartilage types tend to be related to cartilage-forming tumors?

Answer 35

Characterized by the formation of hyaline or myxoid cartilage; fibrocartilage and elastic cartilage are rare components.

Question 36

What is Osteochondroma (aka exostosis)?

Answer 36

Benign cartilage-capped tumor that is attached to the underlying skeleton by a bony stalk

Question 37

Where is Osteochondroma (aka exostosis)?

Answer 37

Only develop in bones of endochondral origin and arise from the metaphysis near the growth plate of long tubular bones

Question 38

Genetic causes of Osteochondroma (aka exostosis)?

Answer 38

Hereditary exostoses are associated with germline loss-of-function mutations in either EXT1 or EXT2 gene. These genes encode enzymes that synthesize heparan sulfate glycosaminoglycans.

Question 39

Morphology of Osteochondroma (aka exostosis)?

Answer 39

1-20 cm in size. | The cap is composed of benign hyaline cartilage and is covered peripherally by perichondrium

Question 40

Clinical treatment/progression of Osteochondroma (aka exostosis)?

Answer 40

Usually stop growing at the time of growth plate closure. Symptomatic tumors are cured by excision. Osteochondromas rarely progress to chondrosarcoma, but it is possible.

Question 41

What are chondromas?

Answer 41

Benign Tumors of hyaline cartilage

Question 42

most common of intraosseous cartilage tumor

Answer 42

Enchondromas

Question 43

Morphology of Enchondromas

Answer 43

smaller than 3 cm, gray-blue, translucent; well-circumscribed nodules containing cytomorphologically benign chondrocytes; periphery my undergo enchondral ossification and center can calcify and infarct

Question 44

Diseases related to enchondromas?

Answer 44

Maffucci syndrome and Ollier disease are NON HEREDITARY disorders characterized by multiple enchondromas

Question 45

Where do we see Juxtacortical chondromas?

Answer 45

Juxtacortical chondromas: arise on the surface of bones

Question 46

Genetic causes of chondromas?

Answer 46

Heterozygous mutations in the IDH1 and IDH2 genes of chondrocytes both cause the encoded proteins to acquire new enzymatic activity leading to the synthesis of 2-hydroxyglutarate (oncometabolite= interferes with regulation of DNA methylation); may diffuse into nearby cells and lead to epigenetic changes

Question 47

What do we worry about with patients that have Maffucci?

Answer 47

patients with Maffucci are at risk of developing other malignancies (e.g. ovarian carcinomas and brain gliomas)

Question 48

What is a chondrosarcoma?

Answer 48

Chondrosarcoma- malignant tumors that produce cartilage

Question 49

Genetic causes of chondrosarcomas?

Answer 49

Multiple chondrosarcoma: mutations in EXT genes chondrosarcomatosis-related & sporadochondrosarcomas: IDH1 & 2 mutations Sporadic: silencing of CDKN2A common

Question 50

Morphology of chondrosarcoma?

Answer 50

Conventional: large bulky tumors made up of nodules of glistening gray-white, translucent cartilage; matrix is often gelatinous or myxoid spotty calcifications present central necrosis that creates cystic spaces spreads to surrounding muscle or fat

Question 51

Histology of chondrosarcoma

Answer 51

histologically: cartilage infiltrates the marrow space and surrounds pre-existing bony trabeculae

Question 52

What is a dedifferentiated chondrosarcoma?

Answer 52

low grade chondrosarcoma with a 2nd, high-grade component that does not produce cartilage

Question 53

What is a clear cell chondrosarcoma?

Answer 53

sheets of large, malignant chondrocytes with abundant clear cytoplasm, numerous osteoclast-type giant cells, and intralesional reactive bone formation (confused with osteosarcoma)

Question 54

What is a mesenchymal chondrosarcoma?

Answer 54

islands of well-differentiated hyaline cartilage surrounded by sheets of small round cells; mimics Ewing Sarcoma

Question 55

How do chondrosarcomas present? Also compare Grade 1 to Grade 3.

Answer 55

Present as painful, progressively enlarging masses Grade 1 rarely metastasize; 70% Grade 3 spread hematogenously, especially to lungs

Question 56

What are Ewing Sarcoma Family Tumors?

Answer 56

Ewing Sarcoma Family Tumors: malignant bone tumors characterized by primitive round cells without obvious differentiation

Question 57

Genetic cause of Ewing Sarcoma?

Answer 57

t(11;22)(q24;q12): generating in-frame fusion of the EWS gene on chromosome 22 to the FLI1 gene

Question 58

Where does Ewing Sarcoma arise?

Answer 58

arises in medullary cavity: usually invades cortex, periosteum, and soft tissue

Question 59

Morphology clinically of Ewing sarcoma?

Answer 59

soft, tan-white tumor frequently containing areas of hemorrhage and necrosis

Question 60

Histology of Ewing Sarcoma?

Answer 60

sheets of uniform small, round cells that are slightly larger and more cohesive than lymphocytes; scant cytoplasm, may appear clear because of abundant cytoplasm dense cellularity, but relatively few mitotic figures

Question 61

Radiology of Ewing Sarcoma?

Answer 61

Plain radiographs show destructive lytic tumor with permeative margins that extends into the surrounding soft tissues; characteristic periosteal reaction produces layers of reactive bone deposited in an onion-skin fashion

Question 62

Treatment for Ewing Sarcoma?

Answer 62

Aggressive malignancies; treat with chemotherapy | Chemotherapy-induced necrosis is an important prognostic finding

Question 63

What causes Giant Cell Tumors?

Answer 63

neoplastic cells express high levels of RANKL (promotes proliferation of osteoclast precursors and diff. into mature osteoclasts via RANK expressed by these cells) → localized but highly destructive resorption of bone matrix by reactive osteoclasts

Question 64

Where do Giant Cell tumors arise?

Answer 64

Arise in epiphysis (may extend into metaphysis); knee (distal femur/proximal tibia) common, but can happen in any bone

Question 65

What is wrong with remodeling in Giant Cell Tumors?

Answer 65

feedback btwn osteoblasts and osteoclasts that regulates this process during normal bone remodeling is absent

Question 66

Clinical morphology of Giant Cell Tumors

Answer 66

destroy overlying cortex → bulging soft tissue mass delineated by thin shell of reactive bone (red-brown masses freq. undergo cystic degeneration)

Question 67

Histology for Giant Cell Tumors?

Answer 67

histology dominated by multinucleated osteoclast-type giant cells, gives rise to synonym “osteoclastoma” and sheets of uniform, oval mononuclear cells (both cell types have ovoid nuclei with prominent nucleoli)

Question 68

Do Giant cells synthesize bone or cartilage?

Answer 68

Nope

Question 69

Radiology of giant cell

Answer 69

"Soap bubble" on x-ray

Question 70

What can Giant Cell Tumors look like on exam? How can we treat it?

Answer 70

location near joints can cause arthritis-like symptoms and pathologic fractures treated with curettage (removal with scraping or scooping using a curette) denosumab: RANKL inhibitor

Question 71

Genetic cause of Aneurysmal bone cyst

Answer 71

rearrangements of chromosome 17p13 resulting in fusion of USP6 to the promoters of genes that are highly expressed in osteoblasts (overexpression of USP6)

Question 72

What is biochemically wrong about aneurysmal bone cysts?

Answer 72

overexpression of USP6, encodes an ubiquitin specific protease that regulates the activity of transcription factor NFkappaB

Question 73

Morphology of aneurysmal bone cyst

Answer 73

multiloculated blood-filled cystic spaces, separated by tan-white septa (composed of plump uniform fibroblasts. multinucleated osteoclast-like giant cells, and reactive woven bone)

Question 74

Morphology of aneurysmal bone cyst

Answer 74

multiloculated blood-filled cystic spaces, separated by tan-white septa (composed of plump uniform fibroblasts. multinucleated osteoclast-like giant cells, and reactive woven bone) bone lined by osteoblasts; deposition follows the contours of the fibrous septa

Question 75

Treatment for aneurysmal bone cysts

Answer 75

treatment=surgery

Question 76

What are our two metaphyseal fibrous defects?

Answer 76

Fibrous Cortical Defect Nonossifying Fibroma

Question 77

How big are fibrous cortical defects?

Answer 77

about 0.5cm in diamter

Question 78

How big are nonossifying fibromas?

Answer 78

5-6cm

Question 79

Morphology typical of both metaphyseal fibrous defects

Answer 79

gray-yellow brown cellular lesions containing fibroblasts and macrophages fibroblasts arranged storiform (pin-wheel) pattern macrophages may take the form of clustered cells with foamy cytoplasm or multinucleated giant cells hemosiderin commonly present

Question 80

Clinical presentation of metaphyseal fibrous defects?

Answer 80

asymptomatic, are detected incidentally

Question 81

Genetic mutation for fibrous dysplasia and what is fibrous dysplasia?

Answer 81

somatic gain-of-function mutation during development in GNAS1 produce constituently active Gs-protein, promoting cellular proliferation This is just a benign tumor

Question 82

Morphologies of fibrous dysplasias on radiology

Answer 82

Radiologically: ground glass appearance with well-defined margination well-circumscribed, intramedullary and vary greatly in size large; expand and distort bone

Question 83

What type of macrophages are seen with fibrous dysplasias?

Answer 83

foamy macrophages

Question 84

Visual of fibrous dyslasia

Answer 84

tan-white, gritty and composed of curvilinear trabeculae (look like Chinese characters)

Question 85

Monostotic?

Answer 85

One bone

Question 86

Polyostotic?

Answer 86

Multiple bones

Question 87

What is Mazabraud syndrome?

Answer 87

usually polyostotic fib. dys. and soft tissue myxomas

Question 88

What is McCune-Albright Syndrome?

Answer 88

polyostotic disease, associated with cafe-au-lait spots and endocrine abnormalities (precocious puberty → earlier than normal)

Question 89

Where do most cancers that metastasize to skeleton come from?

Answer 89

prostate, breast, kidney, and lung

Question 90

What do tumor cells do when they reach native bone cells?

Answer 90

secrete substances like prostaglandins, cytokines, and PTHrP that upregulate RANKL on osteoblasts and stromal cells → stimulating osteoclast activity

Question 91

What matrix bound factors are released that stimulate tumor growth?

Answer 91

Tumor growth also supported by release of matrix-bound growth factors (TGF-beta, IGF-1, and FGF) as bone is resorbed