Pathology

 Other feature of reversible cell injury: (+) disaggregation of granular

and fibrillar elements of the nucleus
 T in TNM staging for cancer refer to depth of invasion rather than absolute size
 Other chemotactic factors : (+) 5-HETE, N-formylated peptides
(formyl-methyl)
❖ Mention the markers used in identification of epithelium → keratin, cytokeratin
(they are protein present in stratified squamous )
❖ Mention the markers used in identification of muscle tissue → SM actin, caldesmon,
desmin
❖ Mention the markers used in identification of endothelium → CD34, VWF
❖ Physiological and pathological role of Metalloproteinase:
- Zinc containing enzymes that degrade components of ECM composed mainly of
laminin, collagen IV, VII
- Important in tissue remodeling, embryogenesis, BM penetration during tumor
invasion
- In neoplasia, tumor adhere to the BM (by ↑↑ laminin) then penetrate the BM by
↑inc metalloproteinase, Catheppsin D protease
❖ Additional infos about apoptosis :
1) Extrinsic apoptosis induced by TNF (when it is bound to TNFR-1), or Fas ligand
(when bound to the cell surface receptor Fas)
2) ↑↑ pro-apoptotic signals → formation of mitochondrial permeability transition &
releaseof of cytochrome C → activate caspases
3) Caspases are proteolytic enzymes that destroy cell components →contain cysteine
& able to cleave aspartic acid residuces (Cysteine –ASPartic acid- proteASES)
❖ Treatment of life threatening anaphylaxis:
• The 1st fdrug to be used is epinephrine → as it reverse all the manifestations of
anaphylaxis
• Steroids is not the 1st line as it don’t act acute like epinephrine
❖ Mention the intracellular enzyme responsible for carcinogenesis:
- Cytochrome P450 monooxygenase (present in hepatic micrososme &ER)
metabolise many things, but it is responsible for activation of most
proocarcionogens

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 - Most carcinogens are pro-carcinogen form → activated → DNA mutation and
cancer
❖ What is the physiological role of MDR1 gene:
- It produce P-glycoprotein which act as ATP dependant efflux pump
- Normally expressed in intestine and tuular cells > eliminate foreign compounds
form the body. It also prevent toxic compounds to enter the CNS by contributing
to the BBB
- In tumors; it affect mostly doxorubicin & daunurubicin
- Drugs as verapamil & diltiazem, ketoconazole reduce the action of MDR protein
in animal models
❖ What are the GF responsible for angiogenesis:
1) VEGF → stimulate angiogenesis in variety of tissues even normal tissues, but
usually prevented by the laminin act as physical barrier for vascular proliferation
2) FGF-2 → not only angiogenesis, wound healaing, it has important role in
embryogenesis
❖ What is the biochemical cause for autosomal recessive polycystic kidney disease.
It is due to mutation in PKHD1 gene → encode for fibrocystin which found in the
epithelium of bile ducts and renal tubules → polycystic changes in both
❖ Features of Osler Weber syndrome :
- AD congenital telengectasia of skin, mucous membranes
- Mostly affect lips, oropharynx, GIT, respiratory tact
- Rarely, affect brain, liver, spleen
 Rupture cause hematuria, GIT bleeding, epistaxis
❖ Cellular findings demonstrating anaplastic carcinoma:
The production of any cellular component (even if misplaced as keratin)is a sign off
differentiation.
1) Loss of polarity, complete disruption of normal tissue architecture, the cells are
organized into sheets or islands in infiltrative disorganized fashion

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2) Significant variation in the shape and size of cells & nuclei

3) Large nuclei (high nucleus to cytoplasmic ratio) with deep staining & large
nucleoli

4) Numerous abnormal mitotic figures

5) Giant multinucleate tumor cells

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❖ Chronic lead poisoning:
• Causes and risk factors for Chronic lead poisoning:
- Due to exposure & contct with dust, paint in homes built before 1978
- Risk factors include development of symptoms after new construction, living in
older homes.
• Diagnosis of Chronic lead poisoning:
- Screening should be done in children at high risk due to irreversible
neurological compromise.
- Measure blood lead level, urine δ amino-levulinic acid → both are elevated
• Mechanism & clinical picture of Chronic lead poisoning:
- Lead bind to sulfhydryl group on protein → replace calcium in cells → ↓↓
enzymes involve in heme synthesis.
- Neurological → cognitive impairment
- Gastrointestinal → constipation & pain
- Renal → interstitial nephritis
- Hematological → anemia
❖ Components of Lynsch syndrome: endometrial, ovarian colon
❖ Components of familial retinoblastoma: bilateral retinoblastoma + osteosarcoma
❖ Components of Li-Frumeni syndrome:
- consists of (sarcoma, Leukemia), (breast, brain) and adrenal cancer
- due to 2 hit hypothesis of TP53 tumor suppressor gene
❖ Mechanism of hereditary retinoblastoma:
- Rb gene (on chromosome 13) is tumor suppressor gene, one gene mutation is
inherited and the other allele must be mutated sporadically.
- 40% of retinoblastoma are hereditary (not always bilaterally)
- Osteosarcoma occur most commonly occur among the familial retinoblastoma

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❖ Commonest sources of brain metastasis : lung, RCC, melanoma
❖ Metaplasia :
o Squamous metaplasia in the bronchi → replacement of goblet cells by stratified
epithelium → loss of muco-ciliary mechanism ➔ ↑↑ respiratory infection
o Coloumanr → squamous metaplasia (as in bronchi) is more common than
Squamous → coloumnar metaplasia (Barrett’s esophagus
❖ Meniere disease:
o Caused by endolymph hydrops > ↑↑ pressure & volume due to ↓↓ resorption
o Classic triad :
1) low frequency tinnitus + sensation of fullness
2) Vertigo
3) sensory neural hearing loss → worsen over time
• DD with BPPV → no hearing symptoms only vertigo

❖ Accumulation of misfolded Transtherytin protein (known as prealbumin) (due to

mutated TTR) → familial cardiac amyloidosis, polyneuropathy
Transthyretin → protein formed by the liver, carrier for thyroxine &
retinol
❖ Erythrocyte sedimentation rate (ESR)
• Chronic inflammation → persistent ↑↑ in inflammatory cytokines e.g. IL-1, IL-6,
TNF-α, IFN-γ
• Liver respond by these cytokines by producing acute phase reactant mostly
fibrinogen & globulin
• Acute phase reactant → make RBCs overcome zeta potential (negative charges
that separate them)→ rouleaux formation → ↑↑ ESR

❖ Keloid :

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 • Pathogenesis: normally, in proliferative phase, contraction of actin filaments in
myofibroblasts occurs to approximate wound edges. TGF-β help differentiation of
fibroblast into myofibroblasts & this process should diminish after healing
• In keloid, unregulated ↑↑ in TGF-β → extension beyond borders of scar
• It occur after minor trauma & major trauma, may be painful, pruritic, raised
• L/M of keloid show haphazardly arranged of thick, pink collagen bundles

❖ Bone metastasis :
• Cancers of the pelvis (including prostate) spread to the LSS via vertebral
venous plexus which run up the entire spinal column by valveless system → to
regulate Intra cranial pressure.
❖ Wound healing :
• Matrix metalloproteinase (MMP) → most important in wound healing lead
to myofibroblast accumulation & scar tissue remodeling
• Myofibroblast → initiate wound contraction during healing by secondary
intention
• Excessive MMPs activity & firoblast → lead to excessive wound contraction &
deformity ➔ most commonly at palms & sole, serious burn, anterior thorax
❖ Genes responsible for Lynch syndrome : MSH2, MLH1, MSH6, PMS2.
Inactivation of tumor suppressor gene with deletion of the remaining normal allele
→ loss of heterozygosity → malignancy (inherit one mutation & loss of the other
during adulthood)
❖ McCune Albright syndrome :
• Mosaic somatic mutation of GNAS gene → stimulate α subunit of G-protein →
persistant stimulation of Gs coupled receptors ….≫≫≫≫≫ uilateral
• Fibroblast → ↑↑ IL-6 → ↑↑ osteoclast → fibrous dysplasia
• Melanocyte → Café au lait patches large, irregular usually unilateral

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 • CRH & ACTH → Cushing syndrome
• TRH & TSH → thyrotoxicosis
• GHRH → acromegaly
• GnRH → precociuous puberty
❖ Cardiac ischemia :
o Ischemia of cardiac myocyte → STOP of Na/K ATPase, Sarcoplasmic reticulum
Ca+ ATPase → intra-cellular accumulation of Na, Ca+ & intra-mitochondrial
accumulation of Ca+ ➔➔➔ this leads to swelling of the myocyte & cessation of
muscle contraction.
❖ Giant cell arteritis:
• It is the most common systemic vasculitis in US
• Biopsy : intimal thickening, elastic lamina fragmentation, mutilnucleted giant
cells
• Optic complications: ischemic optic neuropathy → ophthalmic artery occlusion,
amaurosis fugax, CRA occlusion, cereberal infarction

❖ Response to neuronal damage :

❖ TNF-α antagonists → ↑↑ susceptibility to TB, fungal , atypical mycobacteria

❖ Molecule important in diapedesis of the WBCs & its clinical significance: PECAM-1
“platelet endothelial cell adhesion molecule” (CD 31) which is expressed in cases of
hepatic angiosarcoma, arised from endothelium

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❖ PAS (periodic acid Schiff) staining:
• Mechanism of PAS (periodic acid Schiff) staining: oxidize carbo bonds →
brilliant magenta color upon reaction with fuschin-sulfurous acid
• Uses of PAS (periodic acid Schiff) staining: highlighting polysaccharides of
the fungal cell wall, muco-substances secreted by epithelia, BM (glycogen,
glycoprotein, glycolipid, mucin)
• Uses of Diastase with PAS staining: they are used together to determine
glycogen (diastase break glycogen → giving negative reaction), so in tissues with
glycogen → pink on PAS & negative in diastase
• Chracters of whipple disease staining: PAS positive (as they contain
glycoprotein present in cell wall of the bacteria), Diastase-resistance (to confirm
that the stain is not glycogen, but glycoprotein)
• How can demsontrate neutral lipid by histology: Nile red, sudan black (can be
used in frozen sections)
❖ Describe the liver biopsy findings in Sarcoidosis:
- Scattered granulomas affecting the portal triad is usually affected in 75% of cases

❖ Describe the pathogenesis of acute interstitial & necrotizing pancreatitis:

• Blockage of the pancreatic drainage → stasis of the secretions → lipase digest the
adipose cells → formation of fatty acid + Ca ≫ insoluble calcium salts → induce
inflammatory reaction → acute interstitial pancreatitis with edema & focal
fat necrosis.
• Continued inflammation → obstruction of the BV → acinar necrosis →
intracellular activation of trypsin → autodigestion of pancreatic tissue → acute
necrotizing pancreatitis with destruction of BV, hemorrhage, spread of
calcium deposits beyond the pancreas.
❖ Describe Trousseau syndrome :
• Migrator superficial thrombophlebitis due to hypercoagulable state associated
with paraneoplastic syndrome of pancreatic, lung & colon carcinoma
• Due to production of thromboplastin like substance form adenocarcinoma
• I usually affect one site, resolve an recur in another site
❖ Oncogenes:
• CCND1 TSG → breast, lung, esophageal carcinoma, certain lymphomas
• E6 → bind to P53: ubiquination & orotease degradation
• E7 → bind to Rb: promoting unregulated DNA proliferation, cyclin mediated cell
cycling
• ALK (anaplastic lymphoma kinase) → large cell lymphoma, lung cancer
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 • HER 1 → SCC of the lung
• Ras → pancreatic cancer
• BRAF → malignant melanoma
• EGFR → solid tumor
• PDGF → malignant transformation of glial cells in
glioblastoma
❖ Dystrophic calcification usually associated in cellular
necrosis, aortic valve in elderly undergo necrosis of
its epithelium & fibroblast → aortic sclerosis which
progress in the elderly to be obstructive aortic
stenosis. (if the calcification show outer lamellated
outline it is called Psammoma bodies) notice that
calcification appear in histology as deep blue
❖ Apoptosis ‫مراجعه كويس جدا‬:
• Intrinsic pathway (mitochondria): due to
inactivation of BcL-2, BcL-x, activation of BAX, BAK, Bim →activate
mitochondria to produce cytochrome C
• Extrinsic pathway:
- Death receptors on cells are of tumor necrosis factor receptor e.g. TNF receptor
1 (TNFR1), related protein Fas (CD 95)
- After activation of these death receptors → Fas molecules are accumulated to
form biding site for death domain containing adapter protein (FADD) which
activte caspases
❖ Atrophy on cellular level: ↓↓ mitochondria, RER, ↓↓ protein synthesis & ↓↓
myofibrils. In advanced atrophic changes → apoptosis may occur to ↓↓
cell number
❖ Clinical picture of hereditary angioedema ➔ painless, non-pitting, well
circumscribed edema at face, lips, tongue (AD disease)
❖ Hyperplastic arteriolosclerosis :
• Occur when the diastolic pressure > 120 – 130 bpm (hypertensive crisis)
• Laminated SM cells & BM proliferation → ↓↓ GFR → ↑↑ RAAS → more ↑↑ BP
• This viscious circle → cause malignant nephrosclerosis
• If associated with papilledema → accelerated malignant hypertension

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