Pathology Flashcards
What are the Transcription Factor Gene Mutations? What do they cause?
HOXD13- Brachydactyly syndrome
RUNX2- Cleidocranial dysphasia
FGFR3- Achondroplasia and thanatophoric dysphasia
What are Structural Protein disorders?
Osteogenesis imperfecta: skeletal fragility.
What are gene disorders influencing metabolic enzymes and transporters of the bone?
Osteopetrosis: Reduced resorption, no medullary canal
Treated with stem cell treatments.
Mucopolysaccharidoses: Lysomal storage, disorders. Can’t degrade some carbohydrates and it causes structural defects in cartilage by apoptosis.
Describe Osteoporosis. What is the difference between Osteoporosis and Osteopenia?
Osteopenia is bone loss from 1 to 2.5 standard deviations. Osteoporosis is more than 2.5 standard deviations.
Postmenopausal, senile, idiopathic are primary reasons. Osteoporosis is diagnosed by imaging only.
Paget Disease
Increased but disordered bone.
3 stages: osteolytic, mixed osteoclasts-osteoblastic, burned-out quiescent osteoscleric
Morphology: mosaic pattern of lamellae bone.
Usually radiologic diagnosis
Treated: calcitonin, bisphosphate.
Increased levels of serum alkaline phosphatase without an increase of Ca or Phosphate.*****
Rickets and Osteomalacia
Vitamin D and Calcium deficiency. Rickets: kids at growth plate
Osteomalacia: adult remodeling
Hyperparathyroidism
Increased osteoclast activity by PTH. Increase synthesis of vitamin D. Increase reopsorption of Ca in the kidneys.
Treated by reducing the PTH levels.
Renal Osteodystrophy
Increased resorption with not enough formation. (Too much clast, not enough blast)
Leads to renal failure, osteoporosis, osteomalacia, hyperparathyroidism (secondary), growth retardation.
What are the types of fractures
Simple Compound Comminuted-fragmented bone Displaced- ends aren’t aligned. Stress- slow developing Green stick- not all the way through Pathological- involving bone weakened by underlying disease.
Osteonecrosis
Infarction of the bone and marrow. Mostly happens in the medullary cavity.
Morphology: cortex usually not affected. Overlying cartilage lives. Usually wedge shaped.
Can heal if there isn’t disassociation from the cartilage.
Osteomyelitis. Differences between the two bacterial types?
Inflammation of bone and marrow
Pyogenic osteomyelitis: Hemagoenous spread or extension from a contiguous site (close by)
80-90% s. Aureous
Morphology: active neutrophil inflammation.
Mycobacteria Osteomyelitis: Most in underdeveloped countries. Can persist for years, is linked with tuberculosis and is very destructive.
Skeletal Syphilis
Syphilis and yaws
Can cause bone issues if syphilis isn’t treated. We may see more of these issues as syphilis is becoming more antibiotic resistant.
Cleidocranial Dysplasia
Birth defect that mostly affects bones and teeth. Collarbones are typically poorly developed or absent. Affected areas are shorter.
RUNX2 defect
Osterix or TF Sp7 causes what?
Osteogenesis imperfecta: blue tinge to white of eyes. Short height, loose joints, hearing loss, breathing problems.
Explain Osteogenesis Imperfecta
Mutation to COL1A1 and COL1A2
Causes deficiencies in the synthesis of type 1 collagen.
Most common inherited disorder of CT. Autosomal Dominant
Most mutations involve the substitution of glycine.
General: Too little bone, also blue sclerae, hearing loss, dental imperfections
4 types, but the most common is type 1 and is most mild. Most dangerous is type 2 and most people die in uterus.
Most dangerous types don’t allow helix to form. Most mild types are functional collagen with lower amounts
Explain Marian Syndrome
Mutations in FBN1 gene at chromosome 15q21. Very large gene, and all people with disease have mutations in this gene.
Defect in fibrillin-1 the scaffold for elastic CT.
Affects skeletal stature, long head, double joints, pectus excavatum or pigeon chest. Bilateral dislocation ocular change, Ectopia lentis
Most common cause of death is aortic rupture. No elastin.
Explain the secondary pathogens is of Marian syndrome
Loss of microfibrils leads to excess transforming growth factor-B TGF-B.
Usually gets stuck in the microfibrils, but the defect gives more free TGF-B to bind to receptors.
Explain Ehlers-Danilo’s Syndrome
Single gene disorders that are both autosomal dominant and recessive. 6 different variants
3 or more common variants:
- deficient type lll collagen from mutation in COL3A1 gene.
- Deficiency of enzyme lysyl hydroxylase
- Deficient synthesis of type 5 collagen
Defects in collagen synthesis and structure. Stretchy skin, fragile skin, hyper mobilize joint, poor wound healing, Serious large artery or colon ruptures.
Overall explain Systemic Sclerosis
Excessive fibrosis in multiple tissues, obliterating vascular disease with cutaneous involvement.
Visceral involvement of GI, lungs, kidneys, heart, and skeletal muscle are more fatal
Etiology is unknown
What are the two groups of systemic sclerosis?
Diffuse: characterized by widespread skin involvement, rapid progression, and early visceral involvement.
Limited: Mild skin involvement of fingers and face, late viscera involvement, CREST syndrome.
Calcinosis Raynaud phenomenon Esophageal dismotility Scelrodactyly Telangiectasia
Explain the pathogenesis of Systemic Sclerosis
Unknown etiology
3 paths
Autoimmune responses: of CD4 T cells responding to unidentified antigen and releasing cytokines. Presence of ANA anti-nuclear antibodies
Vascular Damage: Microvascular disease may be initial lesion leading to fibrosis.
Fibrosis: May be from activated macrophages, fibrogenic cytokines, or scarring floolowing ischemic damage by vascular lesions (hybrid)
Explain the morphology of systemic sclerosis
Skin fibrosis that begins in fingers. Increase in fibrosis of epidermis and dermis.
Fingers are tapered and clawed may develop cutaneous ulceration
Face becomes drawn mask
GI: lower 2/3 of esophagus is immobile leads to gastric reflux
Kidneys: Renal hypertension
Lungs: Pulmonary hypertension
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Heart: Myocardial fibrosis, and RV hypertrophy
Joint problems
Explain Clinical Features of systemic sclerosis
3:1 female to male ratio, age 50-60
Skin thickening is the change that shows it isn’t arthritis
Raynaud’s phenomenon is vasoconstriction of fingers and extremities.
Dysphasia from esophagus fibrosis.
Malignant HTN leading to renal failure.
ANAs:
DNA topoisomerase l
Anticentromere antibody CREST syndrome
What are the malignant and benign tumors of bone and cartilage?
Bone:
Benign- Osteoid osteoma, osteoblastoma
Malignant: Osteosarcoma
Cartilage Forming:
Benign- Osteochondroma, Chondroma
Malignant: Chondrosarcoma
Unknown Origin:
Benign: Giant cell tumor, Aneurysmal bone cyst (ABC)
Malignant: Ewing Sarcoma
Which is more common, primary bone cancers or metastatic disease?
Metastatic disease. The spread of other cancers to the bone greatly outnumber the number of primary bone cancers. Come mostly from prostate, breast, kidney and lung cancers
Explain Non-Ossifying Fibroma
Benign mesenchymal proliferation most common in kids and young adults.
Very common almost 50% of that group.
Pinwheel like foamy cytoplasm with giant cells. Most of them undergo spontaneous resolution.
Radiography is sufficient to diagnose without a biopsy!***
How can you histologically differentiate the Tumors of Unknown Origin?
Ewing Sarcoma has very tight and uniform round cells that group together. They don’t produce bone or cartilage. In Diaphyses***
Giant-Cell Tumors are in the epiphyses of knee bones. Deal with RANKL and so will have lots of large Osteoclast cells with large nuclei
Aneurysmal Bone Cysts: in the metaphysis and vertebral bodies. Only tumor with no sex predilection. Has blood filled cysts***
Explain the differences between osteoid osteoma and osteoblastoma
Osteoid osteomas are small and in the knee. Pain is relieved by aspirin and NSAIDs
Osteoblastoma are large an din the vertebrae. They are unresponsive to aspirin.
Explain the differences between osteochondromas and chondromas?
Osteochondroma are in the metaphysis of long bones. Have a stalk and a head covered by cartilage.
Chondromas: Tumors of hyaline cartilage mostly on the hands and feet. C or O sign. Multiple chondromas can lead to chondrosarcomas. Usually small.
How much bone at any one time is normally being turned over?
Around 5%
What age do osteoclasts begin to outpace osteoblasts?
What changes at menopause to increase the osteoclasts?
Late 20s to early 30s
Estrogen declines and that increases RANK expression fueling a 90% increase in osteoclasts for the first few year after menopause.
What is the colloquial name for kyphosis scoliosis?
Dowegger’s Hump
What are is the prevalence of osteoporosis in women at:
70?
80?
90?
Number of women over 50 who will develop osteoporotic fracture? Men?
20%
40%
66%
1 in 2
1 in 5
Which hormones and minerals increase or decrease as a risk factor for osteoporosis?
Down: Vitamin D, Estrogen, Testosterone
Up: PTH, Thyroxine
How is a Frax Score best utilized? Explain what it is
Utilized as a screening tool to decrease the number or necessity of DEXA scans.
A UK test to view risk factors related to osteoporotic fractures risk over 10 years.
For each one SD drops in bone density what is the increase in fracture risk?
2.6x fracture risk increase.
When are medications recommended for Osteopenia or Osteoporosis?
Osteopenia: not recommended
Osteoporosis: DEXA -2.5 SD + osteoporotic fracture
Or FRAX score of greater than 3% hip fracture risk/10 yrs or greater than 20% other osteoporotic fracture risk/10 yrs
What are the 4 medication treatment options of osteoporosis?
Bisphosphonates:
Anti-restorative meds by prevent osteoclasts.
STOP after 3 years
Causes mod-severe GI, must be upright for 30-60 min. Osteonecrosis of the jaw
Selective Estrogen Receptor Modulators (SERMS)
Acts like estrogen on bone and anti-estrogen on uterine lining and breast tissue. For cancer.
Decreases SPINE fracture.
Tablet
Thromboembolism
Human Monoclonal Antibody: RANKL inhibitor prevents osteoclast activations. Injected 2x/yr Safe with impaired Renal function. Osteonecrosis of jaw.
Calcitonin: Inhibits osteoclasts Nasal Spray Lowers acute vertebral fracture pain. Hepatic Caner and other cancers.
Besides Duchenne and Becker Muscular Dystrophy what are 4 other kinds?
What is a serum level that is prevalent in childhood and slowly decreases in MD?
Myotonic Dystrophy: Autosomal dominant, hard to relax grip.
Limb-Girdle Muscular dystrophy: affects the proximal musculature of the trunk and limbs
Emery-Dreyfus Muscular Dystrophy: Heterogenous, affects protein in nucleus
Facioscapulohumeral Dystrophy: Autosomal Dominant, caused by change to DUX4 Transcription Factor. Normally repressed in mature tissues.
Creatine Kinase shows the atrophy of muscle, and goes away as they run out of muscle.
Explain Ion Channel myopathies
Group of ion channel inherited defects that are characterized by myotonia, relapsing episodes of hypotonic paralysis associated with abnormal serum potassium levels.
Explain Mitochondrial myopathies
Maternal inheritance.
Problem in mitochondrial or nuclear genomes.
Usually manifest in early adulthood with proximal muscle weakness, sometimes with severe involvement of the ocular musculature.
Can get lactic acidosis, cardiomyopathy, some show blotchy red ragged red fibers with aggregates of mitochondria. Sometimes with mitochondrial crystals.
Explain Dermatomyositis
Most common inflammatory myopathy in children.
In adults often manifests as paraneoplastic disorder.
Believed to have autoimmune basis that causes skin disease or interstitial lung disease.
Type 1 interferon gene products are unregulated in affected muscles. Other autoantibodies against Mi-2, p155, and p140
Morphology: Losts of cell infiltrates. Capillary dropout, myofiber damage
Clinical Features: proximal muscles first, getting up from chair or stairs are difficult. Will See high levels of Creatine Kinase in the serum. Skin manifestations are normal with red skin around eyes, dysphasia, and some interstitial lung disease. GOTTRON PAPULES ON HANDS
Explain Polymyositis
Adult onset inflammatory myopathy
Shares myalgia and weakness of dermatomyositis without the cutaneous features.
Similar autoantibodies, involvement of heart, and lungs, and proximal muscles.
Increased MHC class 1 molecules on myofibers that is attacked by CD8 cytotoxic T cells. Autoimmune attack leads to myofiber necrosis.
How would you treat inflammatory myopathies
Dermatomyositis and polymyositis are treated first with corticosteroids
If steroid-resistant disease is present you can use immunosuppressive drugs like azathioprine and methotrexate.
Intravenous immunoglobulin, and other antibodies that target B cells are third line therapies.
Explain Inclusion Body Myositis
Common inflammatory myopathy for patients older than 60.
May be a cause or effect of the inflammation in this disorder.
Presence of rimmed vacuoles that contain aggreagrates of proteins that accumulate in the brain. Possible degenerative disorder of aging.
Other features of chronic inflammatory myopathies are mononuclear cell infiltrates, endomysial fibrosis and fatty replacements.
What is the difference and prevalence of simple karyotype and complex karyotype soft tissue tumors?
Simple are euploid with limited chromosomal changes. 15-20%
Complex are aneuploid, or ploypoid with severe chromosomal changes. More common in adults.
80-85%
Explain Lipomas
Benign tumor of fat. Most common soft tissue tumor in adults.
Well encapsulated mass of mature adipocytes. Happen mostly in proximal extremities and trunk during middle adulthood.
Easily removed, painless, mobile and soft.
Explain Liposarcomas
They are malignant tumors and most common sarcomas of adulthood.
They occur in people in their 50s or 60s and happen in DEEP soft tissues of proximal extremities and retroperitoneum.
3 subtypes:
Well-differentiated: adipocytes with scattered atypical spindle cells. Includes gene MDM2 to inhibit p53. Not very malignant.
Myxoid liposarcoma: abundant extracellular matrix with capillaries and primitive cells. t(12;16). Intermediate malignancy.
Pleomorphic liposarcoma: consists of sheets of anaplastic cells, bizarre nuclei, and variable amounts of immature adipocytes. Complex karyotype. Metastasizes easily
Explain Nodular Fasciitis
Self-limited fibroblastic/myofibroblastic proliferation that occurs in young adults in upper extremity.
Grow rapidly to usually less than 5 cm. Has a fusion of MyH9-USP6 gene.
Arise in DHP dermis, subcutaneous or muscle. Highly cellular and contains p;lump immature fibroblasts.
Superficial Fibromatoses
Subtypes?
Infiltrative fibroblastic proliferation that cause local deformity but has an innocuous clinical course.
More in males than female. Poorly define proliferation’s in long sweeping fascicles. Abundant DENSE collagen
Palmar: Irregular thickening of palmar fascia. Implying, and affects the 4th and 5th fingers.
Plantar: Common in young patients. Unitlateral without contracture. Palmar and Plantar have 25% of cases that stabilize and don’t progress.
Penile: (peyronie disease) palpable induration or mass on the dorsolateral aspect of the penis.
Deep Fibromatosis
Desmond Tumors
Large infiltrative masses that frequently recur, but do not metastasize. Most frequent in teens to 30 and mostly in women.
Abdominal fibromatosis arise in the musculoaponeurotic structures of anterior abdominal wall. Excision is often difficult
Contain mutations in APC or B-catenin genes. Leads to increased Wnt signaling. (Those with Gardner syndrome can have hemline APC mutations)
Gray-white , firm, poorly demarcated masses from 1-15 cm. Have marked infiltration of surrounding muscle, nerve, and fat
Rhabdomyosarcoma
Malignant mesenchymal tumor with SKELETAL muscle
Subtypes: alveolar, Embryonal and pleomorphic.
Most common soft tissue sarcoma of childhood and adolescence. Often arise in sinuses, head, neck, and genitourinary tract.
Alveolar contains FOXO1 gene to the PAX 3 or 7 gene. Can fusion to FOXO1-PAX3
Embryonal present as soft gray infiltrative mass
Tumor cells mimic skeletal muscle.
Sarcoma botryoides is a VARIANT Embryonal cancer that develops in the bladder and vagina.
These are all aggressive neoplasms that are treated with surgery and chemotherapy, with or without radiation therapy. The Botryoid variant has the best prognosis (type of Embryonal). Pleomorphic is often fatal.
Leiomyoma
Benign tumor of smooth muscle often in the uterus. Most common neoplasm in women. They develop in 77% of women but can cause infertility.
Leiomyosarcoma
Account for 10-20% of soft tissue sarcomas. Mostly in adult women.
Develop in deep soft tissues of extremities, retroperitoneum, or arise from the great vessels. They are a painless firm mass.
Retroperitoneal tumors can be large and bulky and cause abdominal symptoms.
Superficial leiomyosarcomas are usually small and have good prognosis, the retroperitoneal are difficult to control. Can metastasis especially to the lungs.
Explain Synovial Sarcoma
Named for being found near knee joint. Can be in other locations.
More deep tissues for people in their 20s to 40s.
Translocation making fusion genes from portion of SS18 and one of three SSX genes. That have TF factors for the cell cycle.
Either Monophasic or Biphasic
Mono: uniform spindle cells with scant cytoplasm, and tight fascicles.
Biphasic: Gland like structure composed of cuboidal cells in addition to spindle.
Treated aggressively with limb-sparing surgery or chemo. 5yr survival is 25-62%
Mostly in the lung if metastasizes
Undifferentiated Pleomorphic Sarcoma
Includes malignant mesenchymnal tumors with high-grade, pleomorphic cells that cannot be classified into another category.
Arise in deep soft tissues of the extremity especially the thigh of middle-aged or older adults.
Most tumors are aneuploid with multiple chromosomal changes. Aggressive malignancies. Poor prognosis
Usually large, grey-white fleshy masses that can grow very large. Necrosis and hemorrhage are common because they can’t get vast allure through. Can have Large Bizarre nuclei
