Thirty Three Flashcards
What are mucopolysaccharidoses? What is the pathogenesis? Pathology? Clinical features?
a) Lysosomal storage diseases
i) Mucopolysaccharidosis: Lysosomal storage diseases due to deficiency of acid hydrolase that degrades glycosaminoglycans (dermatan sulfate, heparan and
keratan sulfate).
Patients have short stature and bone dysplasia referred to as dysostosis multiplex.
(1) Pathogenesis: Chondrocytes normally metabolize extracellular matrix glycosaminoglycans. In MPS patients these cells are not capable of normal glycosaminoglycan metabolism.
(2) Pathology: Cartilage at the growth plate and articular surfaces is disorganized.
Describe the pathogenesis of gaucher disease? Pathology? Differentiate the 3 different clinical types. Treatment?
ii) Gaucher Disease: Most common lysosomal storage disease, AR mutation in gene that encodes for glucocerebrosidase, the enzyme that cleaves glucose
from ceramide. Patients accumulate glucocerebroside, a component of leukocyte and RBC membranes, in phagocytic cells. The pathologic changes in Gaucher’s disease are caused not just by the burden of storage material but also by activation of macrophages and the consequent secretion of cytokines such as IL-1, IL-6 and TNF.
(1) Three clinical types
(a) Type I: Chronic non-neuropathic form; storage limited to mononuclear phagocytes. Patients have HSM, pancytopenia and skeletal involvement with bone and joint pain but without CNS involvement. Can treat with enzyme infusion.
(b) Type II: Acute neuropathic form; HSM and progressive CNS disease, die in infancy or childhood.
(c) Type III: Intermediate form.
(2) Pathology: Phagocytic Gaucher cells accumulate in spleen, bone marrow, nodes, and thymus. Gaucher cells have crumpled tissue paper cytoplasm. In bone, Gaucher cells produce areas of erosion, pathologic fractures and
bone pain.
What is osteomyelitis? What is the pathogenesis? How is it different in children and adults? What are the most common causes and which pts do they occur in? What are the clinical features? What is the histology? Diagnosis?
A. Infection of marrow and bone
1 Usually occurs in children
B. Most commonly bacterial; arises via hematogenous spread
1 . Transient bacteremia (children) seeds metaphysis.
2, Open-wound bacteremia (adults) seeds epiphysis.
C. Causes include
1. Staphylococcus aureus—most common cause (90% of cases)
2. ^gonorrhoeae—sexually active young adults
3. Salmonella—sickle cell disease
4. Pseudomonas—diabetics or IV drug abusers
5. Pasteurella—associated with cat or dog bite/scratches
6. Mycobacterium tuberculosis—usually involves vertebrae (Pott disease)
D. Clinical features
1 . Bone pain with systemic signs of infection (e.g., fever and leukocytosis)
2, Lytic focus (abscess) surrounded by sclerosis of bone on x-ray; lytic focus is called sequestrum, and sclerosis is called involucrum.
E. Diagnosis is made by blood culture.
What is an osteochondroma? Pathology? pathogenesis? Gene involved? Risks?
A. Tumo r of bone with an overlying cartilage cap (Fig. 18,3); most commo n benign tumo r o f bone
B. Arises fro m a lateral projection of the growth plate (metaphvsis); bone is continuous with the marro w space.
C. Overlying cartilage can transform (rarely) to chondrosarcoma.
(1) Pathology: sessile or mushroom-shaped, benign 2 cm or less hyaline cartilage cap. The cortex of the stalk merges with the cortex of the host bone.
EXT1-makes proteins involved in the synth of heparan sulfate.
What is the histology of an osteoid osteoma? Epidemiology? Location? Presentation? What is seen on imaging?
II. O S T E O I D O S T E O M A
A. Benign tumo r of osteoblasts (that produc e osteoid) surrounde d by a rim of reactive bone
B. Occurs in young adults < 25 years of age (more commo n in males)
C. Arises in cortex of long bones (e.g., femur)
D. Presents as bone pain that resolves with aspirin
F„ imaging reveals a bony mas s (< 2 cm) with a radiolucent core (osteoid).
Constrast osteoblastoma with an osteoid osteoma.
E. Osteoblastoma is similar to osteoid osteoma hut is larger (> 2 cm), arises in
vertebrae, and presents as bone pain that does not respond to aspirin,
Describe a fibrous cortical defect. What is a non-ossifying fibroma? Pathology?
(a) Fibrous cortical defects are very common, in 30-50% of children older
than 2 years. Developmental defect, not a neoplasm. Eccentric, in
distal femur and proximal tibia metaphysis, half are bilateral or
multiple. 0.5 cm in diameter. Most spontaneously resolve.
(b) Non-ossifying fibroma (NOF): Those FCD that don’t regress but grow
to 5-6 cm, in adolescence. May present with pathologic fracture.
(2) Pathology similar with lucent lesion with cytologically bland fibroblasts
arranged in a storiform or pinwheel pattern and macrophages.
What is the pathogenesis of fibrous dysplasia? Treatment? Describe 3 clinical patterns. Pathology?
iv) Fibrous Dysplasia
(1) Clinical: Non-familial somatic gain of function oncogenic mutation in the GNAS1 gene occurs in all forms of fibrous dysplasia. The result of mutation is the same, the production of a hyperactive guanyl nucleotide binding protein encoded by the GNAS1 gene which promotes cellular proliferation.
Treatment may be observation if asymptomatic.
The fibrous dysplasia has been likened to a developmental arrest. All of the components of normal bone are present, but they do not differentiate into
normal mature structures.
(a) Three clinical patterns. The extent of the phenotype depends on thestage of embryogenesis when the mutation is acquired and the fate of the cell with the mutation.
(i) Monostotic 70% of cases, early adolescence, ribs, femur, tibia, jaw can be affected. Most often in the femoral neck. Often an incidental finding. May cause marked enlargement and distortion of bone so that if the craniofacial skeleton is involved, disfigurement can sometimes be severe. Monostotic disease does not evolve into the polyostotic form. Due to a mutation in an osteoblast precursor during or after formation of the skeleton.
(ii) Polyostotic without endocrine dysfunction (some but not all bones) presents at slightly earlier age than monostotic form, femur, craniofacial bones, shoulder and pelvic girdles are often involved with recurrent fractures, bone deformation, can transform into sarcoma. Approximately 27% of cases.
(iii)McCune-Albright syndrome: Only 3% of cases. Polyostotic with café au lait spots with irregular, serpiginous borders described as looking like the “coastline of Maine” and endocrine abnormalities
including precocious puberty. Bone and skin lesions are usually unilateral. Due to a mutation in an osteoblast precursor during embryogenesis.
(2) Pathology: benign tumor. Intramedullary, with bone trabeculae that mimic Chinese characters in background of fibrous tissue.
What are the genetics and pathogenesis of an aneurysmal bone cyst? Clinical presentation? pathology?
v) Aneurysmal Bone Cyst (ABC): Benign tumor of bone with multiloculated blood filled cystic spaces, expansile, rapidly growing. Distinctive 17p13 translocation that results in up-regulation of USP6, a deubiquitinating enzyme.
It encodes an ubiquitin specific protease that regulates the activity of the transcription factor NFκB. Increased NFκB activity appears to upregulate genes such as matrix metalloproteases that lead to cystic resorption of bone.
(1) Clinical: First two decades, in metaphyses of long bones, posterior vertebral body, pain and swelling. Treat with curettage or resection if lesion is large.
(2) Pathology: Multiple blood filled cysts. Fibrous tissue, multinucleated giant cells, benign bone formation.
What is an osteosarcoma? Epidemiology? Risk factors? Location? Presentation? What does imaging reveal? Biopsy? Treatment? Prognosis? Basic pathogenesis?
A, Malignant proliferation of osteoblasts
B. Peak incidence is seen in teenagers; less commonl y seen in the elderly
1 Risk factors include familial retinoblastoma, Paget disease, and radiation exposure.
- Arises in the metaphvsis of long bones, usually the distal femur or proximal tibia (region of the knee)
C. Presents as a pathologic fracture or bone pain with swelling
D, Imaging reveals a destructive mass with a ‘sunburs t ‘ appearanc e and lifting of theperiosteum (Codman triangle, Fig. 18.4A).
E, Biopsy reveals pleomorphic ceils lhat produc e osteoid (Fig, 18.4B).
(1) Pathogenesis: Genetic mutations common. Inactivation of tumor suppressor genes.
Treatment is
preoperative chemotherapy followed by surgery with or without postoperative
chemotherapy. Lung metastases are common and present in children who do
not survive.
(f) Five-year survival 60 % with aggressive chemotherapy/limb salvage. With metastasis or recurrent disease 20% survive
What is the pathology of a ewings sarcoma? Location? Epidemiology? Imaging? Biopsy? Genetics? Presentation? Treatment?
A. Malignant proliferation of poorly-differentiated cells derived from neuroectoderm
B. Arises in the diaphysis of long bones; usually in male children (< 1 5 years of age)
C. ‘Onion-skin’ appearanc e on x-ray
D. Biopsy reveals small, round blue cells that resemble lymphocytes (Fig, IS.5). in medullary cavity
1 . Can be confused with lymphoma or chronic osteomyelitis
2. (11;22) translocation is characteristic. c-myc
E. Often presents with metastasis; responsive to chemotherap y—PAIN
(c) Patients may have systemic symptoms, including fever, elevatedsedimentation rate, anemia and leukocytosis, which may mimic infection.
What are langerhans cells? What are some important diagnostic characteristics of langerhans cell histiocytosis? What is it?
L B A S I C P R I N C I P I . E S
A. Langerhans cells are specialized dendritic ceils found predominantly in the skin.
1 . Derived fro m bone marrow monocytes
2. Present antigen to naive T cells
B. Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells,
1 . Characteristic Birbeck (tennis racket) granules are seen on electron microscopy
(Fig. 6.21); cells are CDla* and Si00 ‘ by immunohistochemistry,
What is letterer siwe disease? How does it present? Age? Location? Prognosis?
II. L E T T E R E R S I W E DISEAS E
A. Malignant proliferation of Langerhans cells
B. Classic presentation is skin rash and cystic skeletal defects in an infant (< 2 years old).
C. Multiple organs may be involved; rapidly fatal
What is eosinophilic granuloma? Classic presentation? What is seen on biopsy?
III. EOSINOPHILI C G R A N U L O M A
A. Benign proliferation of Langerhans cells in hone
B. Classic presentation is pathologic fracture in an adolescent; skin is not involved.
C. Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous
eosinophils,
What is Hand-schuller-christian disease? What is the classic presentation?
I V h a n d - s c h O l l f r - c h r i s t i a n DISEASE
A. Malignant proliferation of Langerhans cells
B. Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child.
