PATHOLOGY

Cystadenomas -Mass with multiple cysts -Seen in the ovary -Can have multiple finger-like projections Cancer counterpart for the CYSTADENOCARCINOMAS

-Large cystic masses (ovary) -Produce papillae protruding into cystic spaces -If it contains papillary protrusions in the tumor its called PAPILLARY CYSTADENOMAS

Lymphatic spread

-Most common pathway for dissemination of carcinomas -Exceptions *Renal adenocarcinoma and hepatocellular carcinoma-invade vessels -Pattern follows natural routes of drainage -Local LN may be bypassed-"skip metastasis" *Venous-lymphatic anastomoses *Inflammation / radiation obliterates lymphatic channels

The Genome -DNA gets its positive charge because of HISTONES (lysine, arginine), and negative charge due to phosphate group in the DNA

-NONCODING DNA -The human genome contains roughly 3.2 billion DNA -These proteins variously function as enzymes, structural components, and signaling molecules and are used to assemble and maintain all of the cells in the body

Dystrophic calcification

-Normal serum levels of calcium -Normal calcium metabolism -Deposition of calcium in dying tissues -Encountered in areas of necrosis -Seen in aging or damaged heart valves -Atheromas of advanced atherosclerosis -

Causes of Cell Injury

-Oxygen Deprivation -Physical Agents -Chemical Agents and Drugs -Infectious Agents -Immunologic Reactions -Genetic Derangements -Nutritional Imbalances

Ultra structural changes of reversible cell injury

-Plasma membrane- Blebbing Blunting Loss of microvilli -Mitochondria - Swelling Amorphous densities -ER - Dilatation Detachment of polysomes -Nucleus - Disaggregation of granular and fibrillar elements

Apoptosis

-Programmed cell death -Suicide program -Cells destined to die activate, activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins -Intact plasma membrane -Then the contents will be taken up by the macrophages -No inflammation in this process

Systemic effects of inflammation

-Pyrexia/ fever: due to endogenous pyogens (IL-1 and TNF induce the production of PGE2 in hypothalamus by activating cyclooxygenase) -Constitutional symptoms: malaise, chills, rigor, anorexia and nausea (due to action of cytokines on central nervous system) -Weight loss: due to negative nitrogen balance -Reactive hyperplasia of reticuloendothelial system: local or systemic lymph node enlargement in viral infections; splenomegaly in infections (malaria, infectious mononucleosis)

Keloid

-Raised scar (tumor like mass) due to excessive synthesis of type III collagen and maturation arrest. -Genetic predisposition. -More common in African Americans -Common sites: earlobes, face, neck, sternum. -Micro: composed of irregular thick collagen bundles extending beyond the original injury

Tissue repair an overview

-Repair: restoration of tissue architecture and function after an injury. -2 types of reaction: *Regeneration **Regeneration of surviving cells driven by growth factors *Repair by connective tissue deposition (scar formation) **Replacement of defect or dead cells by collagen and fibroblasts

Mechanism of Metaplasia -Key mechanism of metaplasia is stem cell reprogramming so the stem cells produce other type of epithelium

-Reprogramming of stem cells -Reprogramming signals reach stem cells from cytokines and growth factors -Other Aspects *Vit A deficiency (Retinoic Acid) causes squamous metaplasia of the Respiratory tract and urinary tract *Metaplasia leads to malignant transformation

Paraneoplastic syndromes

-Signs and symptoms that cannot be explained by the anatomic distribution of the tumor -They may be the earliest manifestations of an hidden malignancy -Some of them cause significant clinical problems, often fatal -They may mimic metastatic disease and therefore confound treatment -Endocrinal -Neuromuscular -Cutaneous -Hematologic

Liver regeneration

-hepatic injury or after partial hepatectomy. -Two main mechanism: *Proliferation of remaining hepatocyte *Liver regeneration from progenitor cells called oval cells (because of shape of nuclei). -If the connective tissue frame work get injured the healing occurs by fibrosis.

Type II collagen is predominantly found in ...?

1. Cartilage 2. Vitreous Humor 3. Nucleus Polposus

1. Human papilloma virus 2. HTLV causing T cell leukemia 3. H-pylori in the causation of adenocarcinoma of the stomach ____ 4. EBV viral gene responsible for Burkitt Lymphoma

1. E6, E7 2. Tax viral gene 3. Cag A gene 4. LMP-1

Insensitivity to growth inhibitory signals TUMOR SUPPRESSOR GENES REQUIRE A MUTATION IN TWO ALLELES IN ORDER TO CAUSE CANCER! - Therefore these are called LOSS OF FUNCTION mutation

- Abnormalities in these genes lead to failure of growth inhibition, another fundamental hallmark of carcinogenesis. *Thus, the protein products of tumor suppressor genes may function as *Transcription factors, *Cell cycle inhibitors, *Signal transduction molecules, *Cell surface receptors, *Regulators of cellular responses to DNA damage.

APC: Gatekeeper of Colonic Neoplasia. -APC usually binds the Beta Catenin and causes degradation of the Beta Catenin via the ubiquitin/proteosome pathway -If you have a survival signal for proliferation of enterocytes, you get wnt, once it receives the signals the APC releases the Beta Catenin and the Beta catenin goes into the nucleus and binds the transcription factor TCF -If you have a mutated APC, beta catenin is always made available, therefore it is always going to the nucleus for continuous proliferation

-APC is a component of WNT signaling pathway, which downregulates the growth of GI epithelium. -APC causes degradation of B-catenin in the proteasome. Otherwise B-catenin binds to TCF to form transcription factor complex -Familial adenomatous polyposis(FAP): Multiple colonic polyps 100-1000. Preneoplastic condition, there is 100% chance of turning into adenocarcinoma

Myeloperoxidase (MPO) deficiency

-AR inherited deficiency of myeloperoxidase (MPO). -Clinical feature: clinically silent (rarely systemic candidiasis or other fungal infection). -Diagnosis; Immunohistochemical staining for MPO: negative staining in affected leukocytes. -NBT test is positive.

Preferences of metastasis

-Breast cancer- bones -Neuroblastomas -liver and bones -Bronchogenic carcinoma- Adrenals -Exact pathogenesis is not known, probably tissue specific homing of the tumor cells

Autophagy

-Cell eats its own contents -Survival mechanism in times of nutrient deprivation. -Autophagolysosome = autophagic vacuole + lysosome -Mechanism of cell loss in : -Degenerative disorders of CNS(Alzheimer disease) -Cancer: Defense against cancers -Infections: Protection against certain viral infections(CMV).

Recognition of microbes and damaged cells

-Cellular receptor for microbes: Toll-like receptors (TLR), NOD like receptors (NLR) and other pattern recognition receptors expressed on epithelial cells, dendritic cells, macrophages and leucocytes -Sensors of cell damage: inflammosome -Other cellular receptors involved in inflammation: receptors for FC tail of antibody also recognize microbes -Circulating proteins: complement

Hallmarks of inflammation /cardinal signs/ Local effects of inflammation

-Celsus, a roman writer in 1st AD listed four cardinal signs of inflammation: *Rubor: redness *Tumor: swelling *Calor: heat *Dolor; pain -Rudolf Virchow in 19th century added; functio laesa - loss of function

Morphological features: Macroscopic features (gross features

-Chronic ulcer -Chronic abscess cavity -Thickening of wall of viscera (fibrosis/contracture) due to chronic inflammation -Granulomatous inflammation

5 Cardinal Signs of Inflammation

1. Heat 2. Redness 3. Swelling 4. Pain 5. Loss of Function

Atrophy

-Decrease in size leading to reduction in the size of an organ *Physiologic: -Notochord and thyroglossal duct undergo atrophy during fetal development *Pathologic types: -Decreased work load (disuse atrophy) -Loss of innervation (nerve damage) -Diminished blood supply (may eventually lead to apoptosis of the cells/organs) -Inadequate nutrition -Loss of endocrine stimulation -Pressure induced atrophy

PATHOGENESIS

"Sequence of events from the initial stimulus to the ultimate expression of the disease"

1. Factors that enhance metastasis? 2. Mechanism of carcinogenicity in UV-radiation 3. Mechanism of HPV viral carcinogenicity 4. EBV associated cancers:

1. Increased expression of MMP, loss of functino of E-cadherin 2. Pyrimidine dimers (nucleotide excision repair) 3. Loss of function tumor suppressor genes 4. Burkitt lymphoma, Nasopharyngeal carcinoma, Lymphoma in HIV

Metastasis -dissemination of the tumor into the vasculatures and where tumor prefers to go somewhere else where they can get maximum nutrition -SEED & SOIL THEORY

1. Loosening up tumor cell-cell interaction (Loss of adhesive proteins like E-Cadherin) THEN 2. Degradation of BM and interstitial tissue (Increased MMP) THEN 3. Attachment of tumor cells to ECM proteins (Increased Integrin) THEN 4. Locomotion of tumor cells in circulation (Actin and scatter factor)

Disorders of dysregulated apoptosis

-Defective apoptosis and increased cell survival. *Cancer *Autoimmune disorders -Increased apoptosis and excessive cell death. *Neurodegenerative diseases, *Death of virus-infected cells

Mechanism of intracellular accumulation

-Defects in protein folding and transport and an inability to degrade the abnormal protein efficiently ex: Accumulation of mutated alpha 1- antitrypsin in liver cells. -Inherited defects of enzymes required for metabolism of a particular substance ex: Lysosomal storage disorders -Exogenous substance ex: Carbon particles, Silica

Mechanism of Hypoxic Cell injury

-Depletion of ATP *Whenever there is an ischemia it leads to decreased ATP production, which affects ATP dependent cell membrane transport (Na+/K+ Pump) *Therefore there will be increased of Na+ in the cell which will lead to cellular swelling, mitochondrial swelling, and blebbing *Mechanisms of severe hypoxia include: 1. leakage of cellular contents 2. Shift of aerobic glycolysis to anaerobic glycolysis leading to increased lactic acid leading decreased pH, leading to picnosis and clumping of the chromatin 3. also detachtment of ribosomes from the ER leading to decreased protein synthesis -Mitochondrial Damage -Accumulation of Oxygen deried free radicals (Oxidative Stress) -Defects in the Membrane Permeability -Damage to DNA and other proteins

Metastatic calcification *Malignancy to the bone can also cause this

-Deranged calcium metabolism -Hypercalcemia -Deposition of calcium salts in normal tissues Causes of hypercalcemia: -Hyperparathyroidism -Destruction of bone tissue (Metastatic breast cancer) -Vitamin D-related disorders -Renal failure -Aluminium intoxication -Milk-alkali syndrome. -Principally affects the interstitial tissues of the *gastric mucosa *kidneys, *lungs, *systemic arteries, *and pulmonary veins -Noncrystalline amorphous deposits or as hydroxyapatite crystals

1. A 3 yo boy with abdominal mass. A diagnosis of Neuroblastoma is made. What's the mutated proto-oncogene? 2. A 55 yo male with progressiely increasing ulcer on the neck with blackish discoloration. Dx _____. Due to the mutated _____ oncogene 3. Identify the corresponding oncogenes with cancers Burkitt lymphoma 4. Pancreas and colon 5. Polycythemia Vera 6. CML

1. N myc 2. Melanoma, BRAF 3. Melanoma, BRAF 4. C-myc 5. K-RAS 6. Jak-2 7. BCR-ABL (Non-receptor tyrosine)

1. Psammoma bodies are seen in 2. 80 yo male presents with ha and cp. Autopsy reveals chalky white deposits on aortic cusps. Dx____ 3. The key histological feature of malignancy is

1. Papillary carcinoma of thyroid, serous papillary carcinoma of ovary, meningioma, mesothelioma *Remember the mnemonic PSaMM *A Psaommoma bodies are lamellated areas of calcificaiton 2. Dystrophic calcification - Senile aortic calcification 3. Invasion

Cell Signaling

-Extracellular cell-cell signaling pathways: *Autocrine signaling *Paracrine signaling *Endocrine signaling

Types of fluid accumulation in extra vascular space

-Exudation: Escape of fluid, proteins &/or blood cells from the vascular system into the interstitial tissue or body cavities. -Exudate -Transudate -Exudate: an inflammatory extravascular fluid with a high protein concentration & cellular debris. *Active: Seen in inflammation. *Altered vascular permeability due to cytokines and chemokines

Aplasia -NOT AN ADAPTATION! It is a developmental anomaly!

-Failure of an organ or tissue to develop during the embryogenesis -Example: Unilateral absence of a kidney

Sarcomas (Mesenchymal origin)

-Highly malignant -Usually arises from muscle, tendon, bone, cartilage, blood vessels -(sar = fleshy) -Less connective tissue stroma *LEIOMYOSARCOMA (smooth muscle) *RHABDOMYOSARCOMA (striated muscle)

Routes of metastasis Leiomyoma you will see a lot of well differentiated spindle cells Leiomyosarcoma you will see alot of atypical cells with areas of necrosis at the center, the route they prefer is the hematogenous route

1. Seeding of body cavities 2. Lymphatic spread 3. Hematogenous spread

Neoplasia Definition Ie. If a person smoked for 35 years but stopped, even after he has stopped smoking he is at risk of neoplasia

A neoplasm is an autonomous or relatively autonomous abnormal mass of tissue, the growth of which persists even after cessation of the initiating stimuli. -Willis A disorder of cell growth that is triggered by series of acquired genetic mutations affecting a single cell and its progeny

Which of the following is the correct sequence in causation of cancer? 1.Mild dysplasia 2. Metaplasia 3. Moderate dysplasia 4. Invasive carcinoma 5. Carcinoma insitu A. 2, 1, 3, 5, 4 B. 2, 3, 5, 4, 1 C. 2, 1, 5, 4, 3 D. 1, 2, 3, 4, 5

A. 2, 1, 3, 5, 4

A 30 yo male comes to you with hx of axillary swelling. A biopsy of the swelling reveals an encapsulating mass which is composed of sebaceous glands. Which of the following terms would best represent this lesion? A. Adenoma B. Carcinoma C. Sarcoma D. Harmatoma E. Choristoma

A. Adenoma -This is a benign tumor of the sebaceous glands

An experiment analyzes factors involved in the cell cycle. Cyc B binds and activates CDK-1. The active kinase produced by this process is most likely to control progression in which of the following phase of the cell cycle? A. G2-M B. G1-S C. M-G2 D. G0-G1

A. G2-M Phase G1-S - Cyclin D with CDK4/CDK6 & Cyclin E with CDK 2 with Rb-g

A 55-year-old man has had malaise and a 15lbs weight loss over the past 6 months. On physical examination his stool is positive for occult blood. An abdominal CT scan shows his liver contains multiple tumor masses from 2 to 5 cm in size with central necrosis. The surrounding hepatic parenchyma appears normal. Which of the following characteristics of neoplasia is best illustrated by these findings? A. Metastasis B. Primary HCC C. Anaplastic Tumro D. Exposure to Carcinogen E. Highly dysplastic

A. Metastasis

Intracellular killing or destruction of microbes and debris

A. Oxygen -dependent killing: -Rapid assembly of NADPH oxidase (phagocytic oxidase) and generation of superoxide anion. -H2O2 - MPO - halide system is most effective bactericidal system (neutrophils) B. Oxygen - independent killing: involved lysozymes, lactoferrin, acid hydrolase, and defensins.

Which of the following mediators is responsible for the patient's abdominal pain and fever in the case study? A. PGE2 B. Histamine C. PGD2 D. PGI2 E. TNF

A. PGE2

Triad deafness, blidness and hematuria are due to....

Alports Syndrome X-linked recessive

A junior pathologist examines a biopsy slide of an intestine. He notices increase in the eosinophilic cytoplasm and degradation of this cell into individual cells with intact membrane. What is the process?

Apoptosis

An autopsy image of the heart with reflected pericardium is attached. This patient died of severe sepsis and suffered from chronic renal failure. Which of the following best describes the nature of inflammation in the image? A. Serous B. Fibrinous C. Apoptotic D. Malignant E. Tubercular

B. Fibronous

A 38 yo male presents for a routine check up. On Ultrasound he is found to have a missing R kidney, however his kidney functions are preserved. What findings would you find in the Left kidney? A. Aplasia B. Hyperplasia C. Aplasia D. Dysplasia

B. Hyperplasia The kidney that did not form is considered aplasia. The kidney that did form undergoes hyperplasia to pick up the function

Which one of the following light microscopic features most ikely indicate chronic inflammation in this patient? A. Neutrophils, congested blood vessels, and necrosis B. Lymphocytes, plasma cells, macrophages and fibrosis C. Proliferating blood vessels and fibroblasts D. Liquefactive necrosis E. Fat necrosis

B. Lymphocyte,ss plasma cells, macrophages and fibrosis

Mediators of inflammation

Bradykinin: -Vasodilatation and increased venular permeability. -Activation of pain receptors. Interleukin - 6 (IL 6): -Cytokine responsible for increased levels of acute phase proteins from liver Nitric oxide: -Produced by endothelial cells -Stimulates relaxation of smooth muscle, -> vasodilation. -Inhibits platelet aggregation. -Important role in endotoxic shock (septic shock).

An 8 yo African immigrant comes to you with a hx of fever, malaise, and enlargement of the neck nodes. Biopsy is suggestive of Burkitt's Lymphoma. Which of the following is the mutated proto-oncogene in this condition? What type of translocation occurs in this condition? What is the common pathogen that leads to this type of malignancy?

C-myc 8:14 EBV -Cancers caused by EBV include Burkitts Lymphoma, Nasopharyngael carcinomas, & Lymphomas in a immunodeficient state

Which of the following is a second messenger in G-protein coupled receptor activation pathway? A. ATP B. Map Kinase C. cAMP D. GMP

C. cAMP Where do you get GMP? From NITRIC OXIDE and AMP which is mainly for vasodilation

Cholesterolosis

Collection of "foamy macrophages" -Due to problem with cholesterol and cholesterol Esters-2

E-cadherin E-cadherin -Cell adhesion molecule that holds the epithelial cells together -If there are any mutations or loss of functions of e-cadherin are mutated cells -These cells are usually prone for dissemination/malignancy -Since this gives the cells structural integrity

E-cadherin: cell adhesion molecule that plays an important role in contact-mediated growth inhibition of epithelial cells; Germline loss-of-function mutations in the E-cadherin gene (CDH1) associated with autosomal dominant familial gastric carcinoma

15 yo boy comes to you with severe HA, on exam he has hyperextensible joints on his fingers and hyperextensible skin and suddenly collapses in the ER. Spinal tap shows RBCs in the CSF. What is the diagnosis?

Ehlers Danlos - Vascular Type -Effect in type III collagen -All of these patients are at risk for RUPTURED aneurysm/berry aneurysm/subarachnoid hemorrhage due to WEAK BLOOD VESSELS

Hormonal carcinogenesis

Estrogen -Breast cancer -Squamous cell carcinoma of cervix -Leiomyoma of uterus Contraceptive hormones -Breast cancer -Hepatocellular carcinoma / Benign liver tumors Anabolic steroids -Liver- benign tumors

Pigments -We can't digest the pigments so they accumulate certain places

Exogenous - Carbon Tattooing Endogenous - Lipofuscin Melanin Hemosiderin Bilirubin

Factors influencing tissue repair

Extrinsic factors: *Infection: prolongs the inflammation and increases the tissue injury *Foreign bodies: fragments of glass, wood or bone *Mechanical factors: increased local pressure or even torsion may tear the wound apart *Glucocorticoids*: anti-inflammatory effect, weakness of scar due to its inhibitory effect on TGF-β. Intrinsic factors: *Diabetes mellitus: may be due to atherosclerosis, neuropathy or formation of advanced glycated end products which induce inflammation

A 65-year-old male presents with weakness, tinnitus and recurrent pruritis for the past month. A bone marrow biopsy reveals an increase in the number of erythroid precursors with rare blasts. A cytogenetic study confirms a diagnosis of chronic myeloproliferative disorder. A mutations in which of the following is most likely cause for this disorder? A. RET B. K RAS C. P53 D. RB E. C MYC F. JAK-2

F. JAK-2

Age and Sex Incidence

Female predominance - Breast and thyroid cancer Male predominance - Esophageal and pancreatic cancer Pediatric malignancies - Retinoblastoma - Wilms' tumor - Neuroblastoma - Leukemias, lymphomas - Sarcomas of bone and skeletal muscle Between 25-45 years -Testicular germ cell tumors -Hodgkin disease

Migragtion of cells in utero...?

HGF

HPV- Pathogenesis

Human papilloma virus (HPV) -Benign squamous papilloma (warts) -6 and 11 - "low risk" -Cervical cancer -16,18 - "high risk" Kaposi-sarcoma associated herpesvirus -Kaposi's sarcoma(HHV-8)

Triad of Sinusitis, bronchiectasis and situs inversus due to....?

Immotile Cilia Syndrome, Kartagener syndrome -Due to the defect in the DYNEIN

Vascular reaction in acute inflammation

Injury or Infection -> Vasodilation (Chemical mediator: Histamine) -> Increased vascular permeability/vascular leakage, in the postcapillary venules (Chemical mediator: Histamine, kinins) -> Stasis of blood cells due to slowing of blood flow -> Margination of leukocytes

Radiation exposure

Ionizing radiation -Direct effect -Indirect effect via free radicals -Affects G2-M transition of the cell cycle Radiation-induced neoplasms -Atomic bomb -Leukemia's (except CLL), thyroid cancer (papillary type) -Breast and lung cancers are less common -Skin, bone and gut are least susceptible

Ischemia reperfusion injury -Thrombolytics are used to lyse the thrombos *These drugs must be used at a particular time, or it is of no use and can potentially harm *After one hour of MI, it is no point in using thrombolytics OR you will worsen the size of the infarction called ISCHEMIA REPERFUSION INJURY -If you are on the verge on infarction and you suddenly relieve the block, the infarcted zone gets loads of hemoglobin and oxygen; because they are just recovering from the injury, they cant handle too much oxygen therefore they tend to make free radicals MAKING IT WORSE! -The main key event of ischemia reperfusion injury is the production of FREE OXYGEN RADICALS!

Ischemic tissues -> Restoration of blood flow -> Exacerbation of injury + Accelerated pace of destruction -> Loss of cells in addition to that suffered due to ischemia -> Contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow -Mechanism of reperfusion injury: -Increased generation of reactive oxygen and nitrogen species from parenchymal and endothelial cells and from infiltrating leukocytes. -Inflammation as a result of the production of cytokines and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells. -Activation of the complement system. Some of IgM antibodies bind to the ischemic cells due to unknown reason

Mediators of inflammation: Arachidonic acid metabolites

LEUKOTRIENE B4 (LTB4): -Chemotactic agent for neutrophil. -Adhesion molecule synthesis on neutrophils LEUKOTRIENE C4, D4, E4 : -Vasoconstriction and bronchoconstriction -Important in pathogenesis of asthma

Healing by secondary/ second intention

Large wounds, abscess, ulceration and ischemic necrosis (infarction) involving parenchymal organs: -Wound gap and tissue defect is larger and fibrin clot is larger. -More exudate and necrosis at the site of injury. -Much larger granulation tissue. Provisional matrix: fibrin, plasmanectin and type III collagen (type I). Wound contraction: large part of wound is closed by wound contraction -Reduce the surface area of the wound. -Achieved by myofibroblasts. -Within 6 weeks large skin defects are reduced to 5-10% of their original size.

81 yo male presents to ED with recent onset of aphasia and R sided weakness. Angiogram shows a block in the anterior cerebellar artery. What type of necrosis do you expect in this patient?

Liquefactive Necrosis

Gangrenous necrosis Common in diabetic patients -The moment you see gangrenous necrosis, check the pulses in that area -Limb is removed because keeping this the patient could end up in shock Caused by a combination of COAGULATIVE NECROSIS & LIQUEFACTIVE NECROSIS!

Loss of blood supply to a limb -> Coagulative necrosis(dry gangrene) -> Superimposed bacterial infection -> Degradative enzymes and leukocytes -> Liquefactive necrosis -> Wet gangrene

Which enzyme helps in cross linking of tripple helix collagen?

Lysyl oxidase which requires Copper Lysyl hydroxylase requires Vitamin C as cofactor. This adds hydroxyl groups to lysine residues of the developing collagen. Without this, you get SCURVY and related disease

Chronic Inflammatory cells

Macrophages: lifespan 60- 120 days. -Circulating blood monocytes and Tissue macrophages *Fixed tissue macrophages *Wandering macrophages: Alveolar Macrophages (lung) Lymphocytes: T and B cells. -Antigen-stimulated T and B cells produce cytokines (IL-17 , TNF) to recruit leukocytes at the site of inflammation. -Activation of macrophages by secretion of IFN-γ -Activated B lymphocytes and plasma cells produce immunoglobulins which helps in opsonization and removal of antigens. Eosinophils : in parasitic infections. Mast cells: both acute and chronic reaction.

35 yo female comes to you with history of hard lump in the right breast with nipple retraction. What could have caused her nipple retraction?

Mainly the stromal reaction or desmoplasia which is causing the nipple retraction

Seeding of body cavities

Malignant neoplasm penetrates into a natural "open field" -peritoneal cavity, pleural space, pericardial cavity Examples -Ovarian carcinoma -Mucin secreting ovarian and appendiceal carcinomas (pseudomyxoma peritonei)

Mediators of inflammation (continued)

Mediators cause : -Vasodilatation -Increased vascular permeability -Emigration of neutrophils -Chemotaxis -Itching and pain ( irritation of nerve endings) -Fever -Hypotension (shock) -Metabolic abnormalities Responsible for local and systemic effects in inflammation

Carcinogenesis

NON-LETHAL genetic/DNA damage -Inherited germ line mutations -Acquired mutations Tumors- Monoclonal expansion of a mutated cells Classes of normal regulatory genes 1. Growth promoting proto-oncogenes 2. Growth inhibiting tumor suppressor genes 3. Genes regulating apoptosis 4. Genes regulating DNA repair

Carcinogens

Naturally Occurring Carcinogens -Aflatoxin B1 -Potent hepatic carcinogen -Produced by fungus Aspergillus flavus -Improperly stored corn, rice, peanuts -Hepatocellular carcinoma Nitrosamines and Amides -Formed in GIT of humans -Gastric carcinoma -Origin *In stomach *From reaction of nitrostable amines and nitrates used as a preservative *Converted to nitrites by bacteria

Acute inflammatory cells

Neutrophil* (PMN/segmented neutrophil) -Nucleus; clumped, 3-4 segments connected by thin chromatin. -Primary (azurophilic) larger granules. Have Myeloperoxidases -Secondary (Specific) smaller granules. Have Lactoferrin -Life span in tissue : 1-2 days -Acute inflammation Macrophage: -Neutrophils are replaced by macrophages in 24-48 hrs. Macrophages survive in tissue longer ( 60-120 days). -Macrophages contain acid hydrolases, elastase, and collagenase. Secrete TNF, IL-1, IL-6, TGF and IL10. Eosinophils: -Recruited to the site of inflammation by IgE and in parasitic infection -Produce Major basic protein: toxic to parasites. *Mast cells: both acute and chronic inflammation.

10 yo boy comes to you with abd pain and massive hepatosplenomegaly. On examination everything is fine except for a pathological fracture of the right femur and the patient has mass in the right lower end of the femur. The physician suspects secondary in the liver because of primaries in the bone of the child. What is a bone tumor common in children? What kind of stains would we like to advise for this patient to confirm the diagnosis?

Osteosarcoma Vimentin!

ECM synthesis and platelet aggregation is done by...?

PDGF

Characteristics of malignant cells -Invasions is still the classical feature -You'll also see pleomorphism, along with hypochromatic nucleis, sometimes actively dividing cells

Pleomorphism: -Variation in size & shape of cells and nuclei Abnormal nuclear morphology: -Abundant DNA -Extremely dark staining (hyperchromatic) Nucleus-to-cytoplasm ratio: -Abnormal nuclear morphology: hyperchromatic (abundant DNA), increased N:C ratio (normal 1:4- 1:6) -In malignancy nucleus is much much bigger inside of the cell Mitoses -Malignant neoplasms possess large numbers of mitoses -Reflects higher proliferative activity of parenchymal cells

Wound healing by primary and secondary intention 1st day: Clot formation, production of cytokines, growth factors and chemokines. VEGF: increase permeability and edema 24-48 hours (day 2): migration of epithelial cells and deposition of BM Day 3: neutrophils replaced by macrophages and progressive formation of granulation tissue Day 5: Neovascularization reaches peak and edematous. TNF, PDGF, TGF, FGF, EGF, IL1

Primary intention / first intention: lacerated/ surgical wound. Cut edges are in close approximation Day 1: formation of blood clot on the surface of wound. Migration of neutrophils to wound margin and vasodilation of vessels (VEGF). Day 2: proliferation and migration of epithelial cells from both the edge of wound and form a thin continuous layer underneath the scab. Migration of monocytes to the site of injury.

A 35 yo male comes to you for a routine health check up. Xray reveals a nodule in the R lung parenchyma. Biopsy of the nodule shows cartilage and the pt is followed up for 3 years with xrays and the size has remained the same

Pulmonary Harmatoma

Growth Factor Receptors( oncogenes)

SEE PAPER NOTES

Oncogene Viruses

SEE PAPER NOTES

Oncogenes that are activated by translocations

SEE PAPER NOTES

Signal transduction pathway(Oncogenes)

SEE PAPER NOTES

Tumor suppressor genes

SEE PAPER NOTES

Molecular basis of multistep carcinogenesis

SEE PAPER NOTES -There are mutations/initiators. If you have these mutations in either one cell or all somatic cells, they may not turn into cancer because they require a series of accumulated mutations in order to get blown up into a full malignant cancer -IE. Adenoma carcinoma sequence *You will learn this in GI pathology -If a pt gets a germline mutation in the GI, they may not be malignancy but they are at risk of getting malignancy -Then there will be methylation abnormalities usually involving APC - Beta catenin -This will then turn into multiple polyps -Mutations in K-ras proto-oncogenes

Leukocyte (Neutrophil) recruitment to the site of inflammation -The most important leukocyte involved in any inflammatory response are NEUTROPHILS and MACROPHAGES -The steps of the neutrophils and macrophages getting to the site of injury starts with MARGINATION, then ROLLING, then ADHESION TO ENDOTHELIUM, then MARGINATION ACROSS ENDOTHELIUM and VESSEL WALL, and MIGRATION TOWARDS CHEMOTACTIC STIMULUS -This process is orchestrated by various proteins/cytokines

Sequence of events: -Margination -Rolling -Adhesion to endothelium The above is ACTIVATED ENDOTHELIUM BIND TO LEUKOCYTE AND HELP THEIR EXIT FROM BLOOD VESSELS -Migration across endothelium and vessel wall -Migration towards chemotactic stimulus

Small cell carcinoma vs Squamous Cell Carcinoma

Small cell carcinoma -Cushings -SIADH -Lambert Eaton Myesthenic Syndrome Squamous cell carcinoma of the lungs -Hypercalcemia -Hypertrophic Osteoarthropath

Hematopoietic stem cells Pt's who have undergone chemotherapy, OR immunocompromised (and ppl with low WBC count) are given hematopoietic stem cells to regenerate all of the hematopoietic lineages. This is used regularly. -They are obtained from the bone marrow, cultivated, stored in the right temp, and given to the pt after proper testing.

Sources: -Bone marrow -From umbilical cord blood -Peripheral blood of individuals receiving cytokines such as GM-CSF Applications: -Generate all of the blood cell lineages -Can reconstitute the bone marrow after depletion caused by disease or irradiation -Treatment of hematologic diseases

Repair by connective tissue deposition / scar formation

Steps in scar formation: 1. Neutrophil transmigration 2. Macrophage transmigration 3. Angiogenesis 4. Formation of granulation tissue. 5. Remodeling of connective tissue

TNM: Staging of tumor

T: Tumor size N: Regional lymph node involvement M: Metastasis

Anti-inflammatory effect and fibrogenesis is done by...?

TGF-beta

Mediators of inflammation

THROMBOXANE A2 (TXA2) -platelet aggregator -Vasoconstrictor and -Broncho-constrictor PROSTACYCLIN (PGI2) -PG H2 converted by endothelial cell derived prostacyclin synthase into PGI2 -Vasodilator -Inhibits platelet aggregation PROSTAGLANDIN E2: -Makes skin hypersensitive to pain -Vasodilator and increased vascular permeability -Imp in fever production (IL-1 stimulates PGE2 synthesis in hypothalamus)

Outcome of Acute Inflammation

Tissue destruction and persistent acute inflammation: Abscess formation -Is usually caused by pyogenic bacteria. -Results from tissue destruction by lysosomal products and other degradative enzymes. Progression to chronic inflammation -Occurs when acute inflammatory process cannot remove the noxious agent. -Nature of inflammatory infiltrate in inflammatory response Replacement of neutrophils with lymphocytes, macrophages and plasma cells. Angiogenesis and Healing by fibrosis

Additional characteristics of malignant cells -These features are nonspecific - for now just know that the main sign is INVASION, if you see invasion it is metastasis *If you see invasion and metastasis then it is malignant

Tumor giant cells: -Single huge polymorphic nucleus or ≥ 2 nuclei -Nuclei are hyperchromatic and large Central necrosis -Growing tumor cells require a blood supply, often vascular stroma is scanty -Large central areas undergo ischemic necrosis

Composition of Neoplasm Parenchyma - THE CELLS -Proliferating neoplastic cells Stroma - THE SUPPORTING TISSUE -Connective tissue and blood vessels

Two components in a tumor 1. Parenchyma -Proliferating transformed neoplastic cells -Determines its biologic behavior 2. Stroma -Non-transformed elements -Connective tissue/collagen and blood vessels

Proliferation of endothelial cells is done by..?

VEGF

Role of growth factors in angiogenesis and deposition of connective tissue

Vascular endothelial growth factor (VEGF) *Increases the vascular permeability *Stimulation of proliferation and migration of endothelial cells Fibroblast growth factor 2 (FGF-2) * Stimulation of proliferation of endothelial cells *Stimulation of proliferation of epithelial cells *promotes migration of macrophages and fibroblasts to the site of angiogenesis. Angiopoietin 1 &2 *Promotes structural maturation of vessels *Stabilization of newly formed blood vessels. Transforming growth factor - β (TGF-β) *Stabilization of newly formed vessel. *Suppression of endothelial proliferation and migration *Enhances the production of extracellular matrix proteins by recruiting and activating fibroblasts

Angiogenesis video

https://www.youtube.com/watch?v=Ep_nCSEDeAE

Steatosis ( Fatty change) -Seen a lot in alcoholics 2 types: 1. Micro Steatosis = when the vesicles within the hepatocytes are small 2. Macro Steatosis = when they become large cyst like

-Abnormal accumulation of triglycerides within parenchymal cells -Most common cause of fatty change in the liver in developed nations - alcohol abuse & non alcoholic fatty liver disease(NAFLD/NASH) is associated with malnutrition, obesity, diabetes. -Seen in liver and the heart commonly -Clear vacuoles within parenchymal cells -Stains: Sudan IV / Oil red O - Orange red color -Gross - enlarged bright yellow soft greasy -Histological features : -Liposomes closely applied to ER -Small vacuoles in the cytoplasm around the nucleus Vacuoles coalesce -Clear spaces with Nucleus displaced to periphery -Fatty cysts - enclosed fat globules coalesce after rupture of contiguous cells

Pathologic calcification

-Abnormal tissue deposition of calcium salts, smaller amounts of iron, magnesium & other mineral salts -2 types: 1. Dystrophic calcification 2. Metastatic calcification

Collagen Cross linking done by VITAMIN C dependent LYSYL HYDROXYLASE!

-Abundant extracellular matrix protein composed of three polypeptide chains in triple helix fashion -Cross linking of triple helix is done by VITAMIN C dependent LYSYL HYDROXYLASE (also needs COPPER) -Fibrillar collagens are abundant in bone, cartilage, blood vessels and skin -Type 1 - Bone, teeth - OSTEOGENESIS IMPERFECTA -Type 2 - Cartilage, Vitreous and nucleus pulposus -Type 3 - Blood vessels, uterus, granulation tissue - EHLERS-DANLOS (VASCULAR TYPE) -Type 4 - Basement Membrane - ALPORTS SYNDROME *Alport syndrome is X LINKED - and it affects the basement membrane of the GLOMERULUS leading to hematuria, and the LENS of the eye, and the COCHLEA (leads to deafness, blindness and hematuria)

Biochemical features of Apoptosis

-Activation of caspases -Caspases : Initiator and Executioner -Initiator caspases - caspase 8 and 9 -Executioner caspases - caspase 3 and 6 -DNA and Protein Breakdown -Membrane alteration to promote recognition by phagocytes : -Movement of some phospholipids (notably phosphatidylserine) from the inner leaflet to the outer leaflet of the membrane, *This gives a common "eat me" signal for the macorophages. The macrophages come attack the apoptotic body and it forms an apoptosome -Binding of a protein called annexin V -Annexin V staining is commonly used to identify apoptotic cells

Chemotaxis of leukocytes

-Activation of neutrophil by chemoattractant brings conformational changes in cell morphology -Polymerization of actin filaments at the edge of the cell and localization of myosin at the back (green arrow) -> Leukocyte migration Exogenous Chemoattractant -Bacterial products: *lipids *N-formyl methionine terminal amino acids Endogenous Chemoattractant -Cytokines: IL-8 -Complement products: C5a -Arachidonic acid (AA) metabolizes Leukotrines B4

Adaptations of cellular growth and differentiation

-Adaptations are REVERSIBLE CHANGES in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. -Hypertrophy -Hyperplasia -Atrophy -Metaplasia

Occupational Cancers SEE PAPER NOTES - MEMORIZE

-Agents: Asbestos -Cancers: Mesothelioma and lung cancers -Occupation: Fire resistant textiles, Shipyard -Agents: Arsenic -Cancers: Lung and skin cancers -Occupation: Byproduct of melting. E.g., electrical and semiconductor devices -Agents: Benzene -Cancers: Leukemia -Occupation: Paint, rubber industry -Agents: Vinyl chloride -Cancers: Hepatic Angiosarcoma -Occupation: Refrigerant, aerosol propellants -Agents: Β- Naphthylamine -Cancers: Urothelial cancer -Occupation: Dye industry -Agents: Aflatoxins -Cancers: Hepatocellular carcinoma -Occupation: Aspergillus( African)

Neoplasia "New Growth" -Abnormal proliferation of the cells -Even if you take away the stimulus, these still tend to grow

-An abnormal mass of tissue -Growth of which exceeds and is uncoordinated with that of normal tissue -Persists in the same excessive manner after cessation of stimuli which evoked the change

Connective Metaplasia -In connective tissue metaplasia, bone will be replaced in the skeletal muscle due to inflammation. I

-An example for Connective Tissue Metaplasia is a condition known as Myositis ossificans characterised by formation of bone - metaplastic bone formation e. If a pt had a fx 10 years back and now he comes to you with a mild discomfort in the site of the old fx. If you take the xray of the area, you will see separate foci of calcification within the muscle and a completely healed fracture. THis is called METAPLASTIC CALCIFICATION or MYOCITIS OSSIFICANS. The exact mechanism is not known, most common in arthritis. You might even see some of the bone in the soft tissue/muscle.

Development of sustained angiogenesis Growing cancers need a lot of nutrients, there is always a battle between factors that promote angiogenesis and factors that inhibit angiogenesis -When theres a growth of tumor that exceeds the rate of angiogenesis, the center of the tumor will undergo a coagulative necrosis

-Angiogenesis is necessary for providing nutrients and to remove wastes ANGIOGENIC FACTORS -Endothelial growth proteins *VEGF, bFGF -Loss of angiogenesis inhibitors *Thrombospondin-I **If you get reduced throbospondin, you get more angiogenesis ANTI-ANGIOGENIC FACTORS -Angiostatin -Endostatin *these are cleavage products of plasmalogen and collagen

Angiogenesis

-Angiogenesis: process of new blood vessel development from existing vessel. -Steps involved: *Vasodilatation in response to: nitric oxide and VEGF. *Separation of pericytes from abluminal surface and breaking down of basement membrane. *Migration of endothelial cells towards the site of injury and proliferation of endothelial cells. *Remodeling in to capillary tube *Recruitment of periendothelial cells *Establishment of communication with target vessel.

Intrinsic Pathway of Apoptosis (Mitochondrial pathway) CHECK OLD NOTES TOO!

-Anti-apoptotic proteins - Bcl-2, Bcl-xl, and Mcl-1 -Proapoptotic effectors - Bax and Bak

Transudate

-Appearance: Clear -Cell count not increased in number. -Protein levels are less than that of serum protein levels (<0.5) or -LDH is < 2/3 of serum normal upper limit or -Effusion LDH to serum LDH ratio <0.6

Exudate

-Appearance: Cloudy -Increased leukocyte cell count in the fluid -Increase in protein levels more than serum protein levels (ratio >0.5) or -Increased effusion LDH > 2/3 of serum normal upper limit or Effusion LDH to serum LDH ratio >0.6

Environmental Factors

-Infectious agents: For example, human papilloma virus (HPV), -Smoking *Ie bladder cancer, Lung cancer -Alcohol consumption: larynx, and esophagus and, by the development of alcoholic cirrhosis, hepatocellular carcinoma. -Diet: colorectal carcinoma, prostate carcinoma *Vegans have high dietary fibers and are more protected against those who eat red meat in the case of colon cancers -Obesity -Reproductive history: cumulative exposure to estrogen stimulation, -Environmental carcinogens

Epstein Barr Virus

-Infects B cells using a complement receptor CD-21 -By activating LMP-1( Viral oncogene) -It activates Nfk-Beata pathway and promotes autonomous B-cell proliferation and -Infectious mononucleosis -Burkitt lymphoma -Nasopharyngeal carcinoma -CNS lymphoma in HIV

Morphological features: microscopic features

-Infiltration with mononuclear cells: Lymphocytes, Plasma cells, macrophages/histiocytes. -Specialized form of macrophages: Known as epithelioid cells -Giant cells: multinucleated cells -Few eosinophils and polymorphs may be present -Tissue destruction: necrosis (caseous/non-caseous) -Attempts at healing: angiogenesis, fibrosis

Introduction to Inflammation Inflammation and repair go hand in hand

-Inflammation is a response of vascularized tissue to infection and injury. -What are the agents involved in body defense? *White blood cells: Neutrophils, Monocytes, Macrophages, Lymphocytes, eosinophils. *Antibodies *Complement proteins. -During the process of defense against microbes or damage, the host body also bear the blunt of immune response.

Extrinsic pathway of Apoptosis ( Death receptor initiated) This mechanism is done particularly by Cytotoxic T Cells and natural killer cells CHECK OLD NOTES TOO!

-Initiated by engagement of plasma membrane death receptors -Death receptors - members of the TNF receptor family

Coagulative Necrosis -Preservation of the cell without the nucleus -You may find this within 3-4 hours, then later dead tissue will be degraded by neutrophils -You can get this in all parts of the body BUT THE BRAIN! GHOST APPEARING CELLS!!!

-It is caused by denaturation and coagulation of proteins within the cytoplasm *Infarct - Localized area of coagulative necrosis *Can occur due to ischemia, in all organs(common in Heart, kidney and spleen) except the brain. *Microscopy: Loss of the nucleus but preservation of cellular shape(Ghost appearing cells)

STROMA -Certain tumors produce a lot of stroma - very difficult to cut the tumor, ie SCIRRHOUS CARCINOMA OF THE BREAST -Certain tumors do NOT produce a lot of stroma - very soft, ie. MEDULLARY CARCINOMA OF THE BREAST -Has a lot of connective tissue and blood vessels -Growing tumors need this to grow and need a good support system

-It is the supporting connective tissue where neoplastic cells are embedded. -Provides nutrition (blood vessels) and mechanical support to the neoplastic cells -Composed of fibroblasts (secrete matrix). -Has contractile properties (retraction of skin in breast cancers) -Stroma is scant-> tumor is soft and fleshy e.g. medullary carcinoma of breast -Stroma is dense -> tumor is hard / scirrhous e.g. Invasive ductal carcinoma of breast.

Features of carcinomas All carcinomas metastasize to the LYMPH NODES EXCEPT: 1. BASAL CELL CARCINOMA (RODENT ULCERS) -Prefers lymphatic spread EXCEPT: 1. HEPATOCELLULAR CARCINOMAS 2. RENAL CELL CARCINOMA

-Lack capsules -Grow rapidly -Atypical mitotic spindles present *Tripolar mitoses -Show invasion -Can metastasize *Exception- Basal cell carcinoma (Also called RODENT ULCERS - penetrates to underlying structures/invades and can get to the bone) -Prefer lymphatic spread exceptions are *Renal cell carcinoma *Hepatocellular carcinoma

Features of sarcomas -Love to spread via the blood except: 1. RHABDOMYOSARCOMA

-Large, bulky, vascular, necrotic masses -highly malignant -No complete treatment for sarcomas -More dangerous than carcinomas -Need some sort of intervention (surgery, chemo, radiation) -Prefer hematogenous dissemination (spread through blood) *Exception RHABDOMYOSARCOMA -Arteries are thick, resistant for mestasis -Veins are thin, so they can easily spread to liver or lung

Cellular aging

-Progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences -Known changes that contribute to cellular aging: -Decreased cellular replication -Accumulation of metabolic and genetic damage -Senescence : terminal non dividing state seen in somatic cells after a fixed number of cell divisions -Werner's syndrome(premature aging) due to the deficiency of DNA helicase, a protein involved in DNA unwinding. -Progeria( Hutchison-Gliford Progeria) is a genetic condition due to LMNA gene mutation leading to an abnormal Lamin A(Intermediate filament) -Telomere shortening - incomplete replication of chromosome ends Ends of chromosomes viewed as broken DNA Activation of DNA damage response Cell cycle arrest

Accumulation of Proteins

-Protein droplets are found within the cytoplasm of Renal tubular cells *This is seen in conditions that cause Proteinuria *Nephrotic syndrome is a good example for a disease with massive proteinuria -Defective intracellular transport and secretion of critical proteins - emphysema due to alpha 1 antitrypsin deficiency *this can lead to cirrhosis in the liver and emphysema in the lungs due to degradation by the elastin -Aggregation of abnormal proteins- Amyloidosis -Russel bodies are found in all diseases affecting plasma cells. Russel bodies are abnormal immunoglobulins - Multiple myeloma is a good example -Accumulation of cytoskeletal proteins. *Mallory bodies are found in the hepatocytes- Keratin intermediate filaments seen in alcoholic liver disease *Neurofilaments - neurofibrillary tangle found in the brain in Alzheimer disease

Signal Transduction pathways -LOOK THIS UP FROM MED 2!

-Receptors with intrinsic tyrosine kinase activity *USE ATP -Receptors lacking intrinsic tyrosine kinase activity that recruit kinases -G protein-coupled receptors -Fizzled and Wnt receptors

Steps involved in inflammation

-Recognition of the injurious agent by defense system (leukocytes) *Via RECEPTORS -Recruitment of leukocytes to site of injury -Removal of the offending agent: phagocytosis, digestion and degradation. -Regulation (control) of the protective response *Review oxygen dependent killing and how the phagocytes come to these -Resolution: termination of inflammatory response and initiation of repair *Ie. For blood vessels to grow in this area and for repair of the area -Local and systemic consequences

Regeneration

-Replacement of damaged tissue/cells and return to a normal state -Occurs by two mechanisms: *Proliferation of surviving cells *Maturation of tissue stem cells. -According to the proliferative capacity of the cells *Labile tissue: hematopoietic stem cells, intestinal cells, skin. *Stable: liver, kidney and pancreas *Permanent: brain (microglial cell - gliosis) and myocardium (fibrosis).

Necrosis

-Result of denaturation of intracellular proteins and enzymatic digestion of lethally injured cells -Morphologic changes: -Increased eosinophilia -More glassy homogeneous appearance -Myelin figures - large, whorled phospholipid masses derived from damaged cell membranes. Karyorrhexis - Nuclear Fragmentation *Pyknotic nuclei membrane ruptures & nucleus undergoes fragmentation Pyknosis - Nuclear Shrinkage *DNA condenses into shrunken basophilic mass Karyolysis - Nuclear Fading *Chromatin dissolution due to action of DNAses & RNAses -All of these lead to nuclear dissolution which lead to ANUCLEAR NECROTIC CELL

Morphologic Alterations in Cell Injury

-Reversible Cell Damage - Decreased availability of ATP, leading to decreased oxidative phosphorylation. As a consequence, all the Na/K channels will have decreased function. The gradient is then ruined which effects many other things. -Irreversible Cell Damage - Loss of cell membrane integrity and cell membrane will be damaged, destroying the cell. -The moment the intracellular contents leak into the ECM, neutrophils come to respond giving a inflammatory response. This is another feature of Irreversible cell damage -Apoptosis is PROGRAMMED with no rupture of plasma membrane. The plasma membrane will be broken down /cell will be broken down and degraded without causing inflammation -Necrosis is a sign of irreversible cell damage

1. Proapoptotic factors 2. ANtiapoptotic facters 3. Leakage of Cyt C from the mitochondrial membrane and subsequent activation of caspases 4. Killing of virus infected cells by cototoxic T-Cells 5. Disappearance of the webs between fingers in-utero is an example of 6. Accumulation of misfolded proteins due to ER stress is an example of 7. Ink dot nucleus (pyknosis) and eosinophilic cytoplasm with intact cell membrane light microscopy, this feature suggest 8. Mutations of bcl-2 can lead to

1. Bax, Bad 2. Bcl2, Bcl1 3. Intrinsic 4. Granzyme 5. Physiological Apoptosis 6. Pathological Apoptosis 7. Apoptotitc Body 8. Follicular Lymphoma -There are 2 types of mutations in pathology (gain of function mutation and loss of function mutation)

1. Increased expression of telomeres are seen in 2. G1-S transition is mediated by 3. Signal transduction pathway for growth factors 4. Long term complication of Barretts Metaplasia 5. Long term complication of bronchial squamous metaplasia due to smoking 6. Intermediate Filaments IHC is used to identify skeletal muscle 7. Intermediate Filaments IHC is used to identify malignancy arising from blood vessels

1. Cancer cells, stem cells 2. Rb, p53 3. Tyrosine Kinase receptor Pathway 4. Adenocarcinoma of lower esophagus 5. Squamous Cell carcinoma 6. Desmin 7. Vimentin

1. What kind of necrosis would you see in pink fibrin like deposits in the walls of the blood vessels? (Seen in malignant hypertension and systemic vasculitis like SLE, scleroderma, polyarthritis nerdosa 2. What kind of necrosis would you see in ghost like appearance of a cell with loss of nuclei, eosinophilic cytoplasm 3. What kind of necrosis would you see in pink areas of necrosis + epithelioid cells + langhans giant cell? 4. What kind of necrosis would you see in areas of necrosis + calcium deposits + inflammation? 5. What kind of necrosis would you see in dead neutrophils with foci of fungal colonies?

1. Fibrinoid Necrosis 2. Coagulative Necrosis 3. Caseous Necrosis 4. Fat Necrosis 5. Liquefactive necrosis

A 70-year-old male presents with flank pain and painless hematuria for the past 15 days. A urinalysis shows hematuria. Cystoscopy is performed and there is a 3 cm mass in the dome of the bladder. Biopsies of the mass are taken and on microscopic examination show a urothelial carcinoma. Cells of this neoplasm demonstrate a single mutation causing cellular inability to hydrolyze GTP, thus resulting in cellular transformation. Which of the following oncogenes is most likely implicated in this case? 1. ABL 2. ERBB2 3. SIS 4. RAS 5. N-MYC

4. RAS -The diagnosis is UROTHELIAL CARCINOMA/TRANSITIONAL CARCINOMA -RAS is the best option here with this case, but NF1 is the tumor suppressor gene - whose main function is GTPase activating protein -AVL - oncogone -ERBB2 - oncogene -SIS - not learned this block, but it is something like a "ras" -N-MYC - Seen in neuroblastoma

A 45-year-old male presents with abdominal pain and loss of appetite for the past week. On physical examination there is jaundice. Rigidity is elicited in the right hypochondriac region with increased liver span. A liver biopsy is done to assess the severity of involvement of HepC virus. Biopsy image is attached. Which of the following pathological process best accounts for the presence of acidophilic bodies(Marked with an arrow) in the liver biopsy? A. Autophagy B. Apoptosis C. Necrosis D. Autodegredation E. Virus Particles

B. Apoptosis -Pink cytoplasm, dark nucleus -It is an apoptotic body -AUtophagy is difficult to appreciate on a stain -No signs of inflammation noted, if it were then it would be necrosis, also cell membrane still in tact

A 42-year-old female presents with a hard lump in the left breast along with nipple retraction. On examination mass measures 4cm and firm in consistency. Her mother died of breast cancer 5 years ago. The mass is excised and sent for histopathology. A diagnosis of infiltrating ductal carcinoma was made. Which of the following phenomenon is responsible for the nipple retraction? A. Metastasis B. Desmoplasia C. Angiogenesis D. Necrosis E. Invasion

B. Desmoplasia -Stromal

A 65-year-old male presented with complaints of headache and palpitations. On examination, his blood pressure is 190/100mm Hg, pulse is 100/min. If his blood pressure remains elevated for years, which of the following cellular adaptations would most likely be seen in the myocardium? A. Hyperplasia B. Hypertrophy C. Metaplasia D. Dysplasia E. Fatty change

B. Hypertrophy This is a classic case of CONCENTRIC hypertrophy

A 55-year-old female presents with unilateral headache and occasional vomiting for the past 15 days. MRI brain demonstrates a dural attached mass measuring 5cm with central areas of necrosis. A biopsy of the mass confirms a diagnosis of meningioma. In addition to the malignant menigothelial cells, which of the following changes can also be found on histology of this tumor? A. Apoptotic Bodies B. Laminated calcium spherules C. Amyloid protein D. Granuloma E. Macrophages with granulation tissue

B. Laminated calcium spherules (Aka Psammoma bodies)

A 79-year-old patient diagnosed with Alzheimer's disease dies due to sleep apnea. There was no history of DM/HTN. At autopsy, hepatocytes contain golden cytoplasmic perinuclear granules which are negative for Prussian blue. Which of the following pigment is most likely deposited in the liver? A. Calcium B. Lipofuscin C. Iron D. Amyloid E. Cholesterol

B. Lipofuscin -This is also seen in pts with severe cancer

A 27-year-old woman in excellent health has a routine health maintenance examination. A 2 cm firm, rounded mass is palpable beneath the skin of the left forearm. She has no difficulty using the arm and there is no associated pain with the mass, either in movement or on palpation. The overlying skin appears normal. The mass does not change in size over the next year. Which of the following neoplasms is she most likely to have? A. Rhabdomyosarcoma B. Lipoma C. Malignant Melanoma D. Leiomyoma E. Metastatic carcinoma

B. Lipoma -The most common benign tumor of the body

A 78-year-old man comes to the hospital with weakness of the right upper and lower extremity, and some difficulty with his speech as well. An MRI of the brain showed a ischemic infarct of the brain. A biopsy of the area if done would show which of the following findings? A. Coagulative necrosis B. Liquefactive necrosis C. Fat necrosis D. Fibrinoid necrosis E. Caseous necrosis

B. Liquefactive Necrosis

A 60-year-old man who has a 90 pack year history of cigarette smoking has had a chronic cough for the past 10 years. He has begun to lose weight (18lbs) during the past year. No abnormal findings are noted on physical examination. He has a chest radiograph that reveals a right hilar mass. A sputum cytology shows atypical, hyperchromatic squamous cells. What is the most common initial pathway for metastases from this lesion? A. Hematogenous B. Lymphatic C. Iatrogenic D. Transbranchial E. Trans-peritoneal

B. Lymphatic

A 55-year-old man is working in a textile industry for the past 30years. He knows that he has been exposed to aniline dyes and is concerned about how this may affect his health. He never smoked and deosnot consume alcohol. This occupational exposure increases the risk of development of which of the following malignancy? A. Gallbladder Adenocarcinoma B. Transitional Carcinoma C. Mesothelioma D. Pharyngeal carcinoma E. Thyroid Cancer

B. Transitional Carcinoma

A 26-year-old primi presents with a history of bleeding per vagina at 36weeks of gestation. On operating table she had profound bleeding, a Cesarean section with hysterectomy is performed to prevent the uterine rupture. A biopsy of the uterine muscle is shown in the image at the right side. This cellular adaptation is mediated by the increase in which of the following? A. DNA Polymerase B. mRNA C. Ubiquitin D. Telomerase E. Proteosome

B. mRNA The key mechanism in HYPERTROPHY is increase in mRNA by various signals, leading to increase in protein synthesis of various intracellular filaments as well as structural proteins. -In the picture you see elongated spindle cells of the uterus which indicates uterine hypertrophy -DNA Polymerase required for cellular division, HYPERPLASIA! -Proteosome and ubuquitin increase is best for ATROPHY!

Precancerous Lesions SEE PAPER NOTES - MEMORIZE

Barrett's Esophagus: Adenocarcinoma of the lower end of esophagus Leukoplakia: Squamous cell carcinoma Endometrial hyperplasia: Endometrial cancer Villous adenoma: Colorectal cancer Pernicious anemia ( Colonic metaplasia of stomach): Gastric adenocarcinoma

Tumors of smooth muscle

Benign - Leiomyoma (arising from the uterus) Malignant - Leiomyosarcoma

Tumors of mesenchymal origin

Benign - Lipoma Malignant - Liposarcoma

Tumors of blood vessel

Benign - Osteoma Malignant - Osteosarcoma

Tumors of Skeletal Muscle

Benign - Rhabdomyoma Malignant - Rhabdomyosarcoma

Types of Neoplasms

Benign Neoplasm: -A tumor is said to be benign when its gross and microscopic appearances are considered relatively innocent, implying that it will remain localized, will not spread to other sites, and is amenable to local surgical. *Benign are more localized, nonspreading, no invasion and no signs of metastasis *All benign malignancies resemble the parent tissue *Most benign tumors are encapsulated *These can be accessed easily and can be removed by surgical means Malignant Neoplasm: -Malignant tumors can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death. *Most malignant tumors will invated into the underlying structure so you don't really get the borders, the borders will be irregular *Invasion and metastasis are the key features that differentiate a malignant neoplasia from a benign neoplasia

Rate of growth

Benign and well-differentiated malignant tumors -Slower rate of growth Moderately-differentiated and poorly-differentiated malignant tumors -Faster rate of growth

Race, Ethnicity and Geography

Breast cancer -Incidence is low in Japanese women as compared with American women Gastric cancer -Incidence is higher in Japan and Iceland as compared with US *Because Japan eats alot of smoked meats/smoked fish Hepatic cancers -Incidence is higher in sub-Saharan African countries as compared with US *Commonly caused by aflatoxins/fungus for them Prostate cancer -In US, blacks are more affected than whites Skin cancers -More common in persons with fair skin, light hair, and blue or green eyes Bladder cancer -More often in patients who work in industries involving aniline dyes, textiles, or rubber Mesothelioma -In patients exposed asbestos (e.g., pipe fitters, ship builders)

A 60-year-old female has notices red-black discoloration of her right toe for the past month. On examination, there is reduced dorsalis pedis artery pulsations. These findings are typically noted in which of the following conditions? A. Sickle Cell Anemia B. Rheumatoid Arthritis C. Diabetes D. Gout E. Melanoma

C. Diabetes -Pay attention to age! -It is unlikely that a 60 yo man will come in with a sickle cell crisis -If the question were changed to a 16 yo male then maybe A would be the answer

A 42-year-old female presents with a history of hard lump in her left breast for the past 3-months. Both mammography and biopsy are suggestive of invasive ductal carcinoma. She also has involvement of left axillary nodes. Gain of mutations in which of the following proto-oncogene is most likely associated in this neoplasm? A. TP53 B. RB C. ERBB-2 D. RET E. BRAF

C. ERBB-2 There are drugss that act on this receptor and kills the malignancy -If you ask about oncogenes, you can't think of tumor suppressor genes as an option because they specifically asked for oncogenes

A52-year-man suffers a massive myocardial infarction due to complete occlusion of the LAD. The thrombus is destroyed by the infusion of streptokinase(Plasminogen activator) after 4hr of the diagnosis. However, despite of the treatment size of the infarction increases. Which of the following mechanism is most likely responsible for this injury? A. Release of Cytochrome C B. Ubiquitin - Proteosomal Degradation C. Free radical generation D. Endoplasmic Reticulum stress E. Accumulation of Cholesterol

C. Free Radical Generation

Blunt trauma to the abdomen of a 16 year old male occurred during a vehicular accident. He is found to have a hemoperitoneum, and at laparotomy, a small portion of the left lobe of the liver was resected because of the injury. After an year later CT-Abdomen shows the liver has regained its normal size. Which of the following cellular adaptations is most likely involved? A. Hypertrophy B. Atrophy C. Hyperplasia D. Aplasia E. Metaplasia

C. Hyperplasia The mechanism in Hyperplasia is CELLULAR DIVISION by the stem cells

A 45-year-old female presents with a history of headache and palpitations for the past few days. On detailed lab evaluations, she is found to have systemic lupus. On examination her blood pressure is 200/100mm Hg, pulse is 120/min. A representative biopsy of a small renal arteriole is attached. Which of the following mechanisms is most likely responsible for this histological change? A. Auto-digestion of cells B. Coagulation of proteins C. Immune complex deposition D. Tuberculosis infection E. Saponification of fat

C. Immune complex Deposition

A 35-year old male presents with a history of yellowish discoloration of sclerae and abdominal pain for the past three months. On physical exam, he is found to have jaundice and mild hepatomegaly. His Lab studies shows AST-800U/L(5-40), ALT-650U/L(6-56) and positive Hep B surface antigen. Which of the following is the cause of this patients elevated liver enzymes? A. Detachment of the ribosomes from RER B. Swelling of the hepatocytes C. Loss of plasma membrane integrity D. Swelling of the mitochondria E. Plasma Membrane Blebbing

C. Loss of plasma membrane integrity A, B, D, E - These are all nonspecific reversible changes

Microscopic sections of the lungs in a 70 yo patient with long standing congestive heart failure reveal yellow golden brown granules in the alveolar macrophages. Which of the following stains will be most helpful in demonstrating the substance accumulated in the macrophages? A. Congo Red B. Periodic Acid Schiff C. Prussian Blue D. Sudan Black E. Von Kossa

C. Prussian Blue -This is NOT Lipofuscin granules but they are not! Lipofuscin granules, as well as iron/Hemosiderin granules will have golden yellow discoloration in the macrophages. -In this particular example, because the pt is having heart failure (there is a pump failure/Left ventricular failure in this case that is pulling alot of RBCs into the lungs). Remember when you have RBCs alveolar macrophages go and attack these RBCs, you get hemosiderin from the heme. This would be seen through Prussian Blue -We actually don't have a stain for lipofuscin granules but we do have a stain (prussian blue) that can recognize iron granules

A 56-year-old female presents with a history of lump in the left breast for the past 5 months. Now she complaints of dyspnea and chest pain.On examination the mass is hard, 4x4cm and fixed to the adjacent structures. There are multiple palpable left axillary nodes. Biopsy of the mass is suggestive of poor is suggestive of poorly differentiated adenocarcinoma. Chest x-ray reveal multiple coin shaped shadows in both lung fields. Which of the following is consistent with her malignancy status? A. T1N0M0 B. T0N0M0 C. T1N2M1 D. T1N0M0 E. T1N0M1

C. T1N2M1 -Theres 1 tumor, 2 lymph nodes, and there is metastasis

A 20-year-old male presents with multiple lesions over the face and sun exposed areas along with few dark colored lesions on the back, the largest lesion is approximately 3cm in its greatest dimension. This patient most probably is suffering from an inherited cancer syndrome associated with unstable DNA repair and increased incidence of carcinomas. Which of the following is the most likely diagnosis? A. Multiple endocrine neoplasia B. Lynch syndrome C. Xeroderma pigmentosum D. Li Fraumeni syndrome E. Familial adenomatous polyp

C. Xeroderma pigmentosum

Mediators of inflammation: complement proteins

C5a -Neutrophil chemotactic factor -Stimulates adhesion molecule synthesis on neutrophils C3b -Opsonizing agent -C3b receptors on the surface of Neutrophils, monocytes and macrophages -> phagocytosis Regulators of complement pathway: -C1 inhibitor -Decay accelerating factor (DAF) and CD59: linked to plasma membrane by Glycosyl-phosphatidyl-inositol anchor (GPI) . DAF prevents formation of C3 convertase and CD59 prevents the formation of membrane attack complex. Deficiency of complement system regulators: -Paroxysmal nocturnal hemoglobinuria : *Recurrent bouts of hemolytic anemia due to complement mediated lysis of RBCs. *Due to lack of a proteins - decay accelerating factor (DAF) and CD59. -Hereditary angio-edema : *Inherited deficiency of C1 INH Angio- edema

What tumor markers do you use to identify surface epithelial ovarian tumors?

CA125 CA99 (from pancreas and colon)

Carcinoma in situ

Carcinoma in situ (CIS): -Full-thickness dysplasia extending from basement membrane to surface of epithelium -Applicable only to epithelial neoplasms Invasion: -Growth into surrounding tissue by direct expansion

Mediators of inflammation

Cell derived mediators: -Vasoactive amines: histamine and serotonin -Arachidonic acid (AA) metabolites: Prostaglandins, leukotrienes -Cytokines and chemokines: Tumor necrosis factor - α (TNF- α) Interleukin α (IL α), Monocyte chemoattractant protein 1 (MCP 1) . -Platelet activating factor (PAF) Plasma derived mediators: (produced in liver) -Complement proteins -Kinin: bradykinin. -Clotting factors (Hageman factor) -Fibrinolytic factors (plasmin)

Patterns of chronic inflammation

Chronic nonspecific inflammation: Characterized by -Infiltration by mononuclear cells e.g. lymphocytes, macrophages and plasma cells). -Inflammatory response not specific for any particular etiological agent. Granulomatous inflammation: -Characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis. -Two types (morphologically): 1. Caseating granulomas 2. Non- caseating granulomas

60 yo male presents to you with cough and hemoptysis and weight loss for the past 6 months. On examination, xray showed multiple coined shaped shadows (a characteristic feature of secondaries in the lungs). You believe that the primary is the GI epithelium, that has traveled to the lungs where it has manifested. Which of the markers would confirm this?

Cytokeratins! -Because it is expressed by epithelium of all tissues

Metastasis -Process where tumor leaves its original site and goes on to settle in a secondary site where they get maximum nutrients and blood supply -Mostly all carcinoma is spread by lymphatics -Mostly all sarcomas spread by hematogenesis -With testicular cancer, you never do biopsy because of the fear of metastasis by needle route

Exceptions -Gliomas in the central nervous system -Basal cell carcinomas of the skin (rodent ulcers) -Spread of a tumor to sites that are physically discontinuous with the primary tumor, as by definition benign tumors do not metastasize -Metastasis marks a tumor as malignant because benign neoplasms do not metastasize -Malignant cells penetrate into blood vessels, lymphatics, and body cavities for spread

Types of inflammation

Feature: Onset Acute Inflammation: Fast: min to hrs Chronic Inflammation: Slow: days Feature: Cellular Infiltrate Acute Inflammation: Mainly neutrophils Chronic Inflammation: Monocytes/macrophages and lymphocytes Feature: Tissue injury and fibrosis Acute Inflammation: Usually mild and self limited Chronic Inflammation: Often severe and progressive Feature: Local and systemic signs Acute Inflammation: Prominent Chronic Inflammation: Less

Example: Benign Vs Malignant

Fibroadenoma breast - benign tumor arising from the ductal epithelial cells -Completely encapsuated tumor vs Infiltrating ductal carcinoma of breast -Infiltrated into the fat -If studied under microscopy, the stroma will be normal appearing in the benign tumor but the stromar will be dense in the cases of malignancy

Systemic effects of inflammation

Hematological change: -Increased ESR : acute phase proteins (c reactive protein, fibrinogen and serum amyloid A protein) induced by IL-6, Il-1 and TNF, and immunoglobulins. -Leukocytosis: neutrophilia, lymphocytosis, eosinophilia. -Anemia: acute phase reactants; Hepcidin, bacterial toxins or bone marrow suppression in chronic inflammation Amyloidosis: Long standing chronic inflammation ( rheumatoid arthritis, tuberculosis etc) elevate serum amyloid A protein (SAA) and cause amyloid deposits in various tissue resulting in secondary amyloidosis. Severe bacterial infections (sepsis): enormous amount of TNF and IL1 leads to DIC and shock.

A 60 you pt comes to you with a recent onset of skin change and jaundice for the past 3 months. On genetic studies he is found to have a mutation in the iron absorption where there is increased iron absorption. If you are examine the biopsy of this pt, which of the following substances is most likely accumulated?

Hemocedirin pigments -Mainly because of the breakdown of the RBCs -You can use PRUSSIAN BLUE to identify this

Laboratory diagnosis

Histologic methods -Routine paraffin embedding -Frozen section for rapid diagnosis Cytologic methods -FNAC -Exfoliative cytology or PAP (Papanicolaou) smears Immuno-histochemistry -Diagnosis of undifferentiated tumors -Categorization of leukemias and lymphomas -To determine site of origin of metastasis -Detecting molecules having prognostic or therapeutic significance

RNA oncogenic virus

Human T-cell leukemia virus Type 1 (HTLV-1) -T-cell leukemia/lymphomas( Blood smear shows clover-leaf shaped T cells) endemic in parts of Japan and Caribbean basin -CD4 tropism -"Tax" gene is the responsible -Transmitted via intercourse, blood & breast feeding Helicobacter pylori infection -Peptic ulcer, gastric lymphoma, carcinoma -"Cag A"gene is responsible for carcinogenicity

Vascular reaction in acute inflammation

Immediate transient vascular response: -Short lived : 15-30 min -Induced by histamines, bradykinin, leukotrienes B4, platelet activating factor. -Example: on injecting small amount of histamine in to skin. Delayed prolonged leakage -Begins late (2-12 hour), but persist for long time (hours - days) -Due to direct damage to endothelial cells by microbial toxins, burns, UV radiation -Leukotrienes -Example: late appearing sun burn.

Abnormalities in tissue repair

Inadequate formation of granulation tissue or scar tissue: -wound dehiscence -Ulceration Excessive formation of scar tissue: -Hypertrophic scar -Keloid Exuberant granulation tissue formation (called as fervor, proud flesh). Desmoid or aggressive fibromatosis (rare low grade neoplasms). Contraction: Commonly seen after extensive burns. Compromise movements of joints.

Examples of granulomatous inflammation

Infectious: -Tuberculosis: with caseous necrosis -Leprosy -Cat-scratch disease Non- infectious: -Sarcoidosis -Crohn disease (inflammatory bowel disease) -Vasculitis: granulomatosis with polyangitis , Churg-strauss syndrome, giant cell arteritis -Chronic granulomatous disease -Foreign body substances: silica, talc powder, suture material, splinters, implants, keratin in ruptured dermoid cyst, etc.

Outcomes of Acute Inflammation

-Complete resolution: *Regeneration of damaged epithelium without scar tissue formation. -Healing by connective tissue replacement (scarring or fibrosis) *Occurs when there is more extensive damage to tissue.

Chronic inflammatory states and cancer SEE PAPER NOTES - MEMORIZE

-Condition: Asbestos -Associated Cancer: Mesothelioma and lung cancer -Etiologic agent: Asbestos Fibers -Condition: Chronic cystitis -Associated Cancer: Bladder cancer -Etiologic agent: Schistosomiasis -Condition: Lichen sclerosis -Associated Cancer: Vulvar cancer -Etiologic agent: - -Condition: Sjogerns and Hashimoto thyroiditis -Associated Cancer: MALT Lymphoma -Etiologic agent: - -Condition: Osteomyelitis -Associated Cancer: Draining sinuses cancer -Etiologic agent: Bacteria -Condition: Inflammatory bowel disease -Associated Cancer: Colorectal cancers -Etiologic agent: - -Condition: Gastritis -Associated Cancer: Gastric adenocarcinoma, MALT lymphoma -Etiologic agent: H. Pylori

Teratoma

-Contain derivatives of all 3 germ cell layers *From a single cell/totipotent cell which may be in the gonads (ie, testes or ovary) *Can give rise to all 3 germ layers like teeth, hair follicles, skin, thyroid tissue, etc. UGLY TUMOR *Has all the components of ectoderm, endoderm and mesoderm -Teratoma originates from totipotent germ cells that are normally present in testes and ovary -Example *Teratoma of ovary or testes *Most common germ cell tumors *Commonly have teeth and bone (visible on X-ray)

Hypoplasia -NOT AN ADAPTATION! It is a developmental anomaly!

-Decrease in cell production during embryogenesis -Relatively smaller organ -E.g.. Streak ovary in Turners syndrome -Rudimentary testis in Kinefelters syndrome

Composition of granuloma

-Epithelioid cells (E): hallmark cell of granuloma -Macrophages -Multinucleated giant cells (G) *Langhans giant cells (seen in tuberculosis) *Foreign body type of giant cells -Lymphocytes, Plasma cells -Central caseous necrosis (C) *Seen in granulomas due to tuberculosis, fungal infections.

Causes of inflammation

-Infections: *Bacterial, viral, fungal and parasitic infections. *Microbial toxins -Tissue necrosis: ischemia, physical injury, chemical injury. -Foreign bodies: splinters, implants, dirt, lipids, cholesterol crystals (atherosclerosis). -Immune reactions: Autoimmune disease.

Growth Factors and Receptors -Look up the growth factor pathway from cell signaling!

-A major role of growth factors is to stimulate the activity of genes that are required for cell growth and cell division -Promote entry of cells into the cell cycle -Relieve blocks on cell cycle progression (thus promoting replication) -Prevent apoptosis -Enhance biosynthesis of cellular components (nucleic acids, proteins, lipids, carbohydrates) required for a mother cell to give rise to two daughter cells.

Patterns of tissue necrosis

-Coagulative necrosis -Liquefactive necrosis -Gangrenous necrosis -Caseous necrosis -Fat necrosis -Fibrinoid necrosis

Local invasion

-Cohesive expansile masses that remain localized to their site of origin and lack the capacity to infiltrate or metastasize -Slowly developing tumor with a capsule, that separates it from the hosting tissue -It creates a plane, that makes it discrete, readily palpable and movable (non-fixed), amenable for the surgery -Malignant tumors invade and distorts the underlying structure

Sentinel lymph node Malenoma and Breast Malignancies are the most common

-1st node in a regional lymphatic basin that receives lymph flow from primary tumor -Detection *By radio labeled tracers or blue dyes -Use *Detects spread of breast cancer, melanomas, colon cancers, other tumors

Retinoblastoma -Majority of the Rbs are sporatic -In order to express the tumor suppressor genes in cancers you need to have 2 mutated alleles -As the definition of sporatic states, these 2 mutations you get after birth -Parents will say "my child eyes look like cat eyes/white/scary".

-40% of retinoblastomas are familial -Tumor is bilateral -Increased risk of osteogenic sarcoma -Here one mutation is in utero and the other immediately after birth -60% of retinoblastomas are sporadic: -Unilateral -No associated neoplasms -Here both mutations are after birth

Clinicopathologic correlations of Ischemia This is changes to the myocardium following ischemia -In the first few minutes within the cardiac cell, if the ATP is less than 10% of its availability, the particular cell will die by necrosis -In the first 40 minutes there are a few reversible changes - so if you give adequate oxygen and remove the block, you can save some cell death - REVERSIBLE *If you don't intervene at this stage then it will lead to Myocardial Infarction -After 40 minutes, you'll get IRREVERSIBLE cell injury where there will be release of troponins, creatin kinase MB -After 4 hours you will see under the microscope the patterns of necrosis -To save the muscle YOU MUST INTERVENE WITHIN THE FIRST HOUR OF HYPOXIA

-Approximate time events in ischemic cardiac myocytes -Onset of ATP depletion: seconds -Loss of contractility: <2 minutes -ATP reduced ,10% OF NORMAL: 40 minutes -Irreversible injury( Visible on Ultra microscopy): >40 minutes -Visible gross infarct under light microscopy: 4 hours

Cholesterol and Cholesterol Esters -1

-Atherosclerosis - cholesterol deposits in the tunica intima results in reduction of blood supply and later total obstruction - leading to ischemia and infarction respectively of the organ supplied by this vessel -Xanthomas - Yellow skin plaques, Which contain macrophages with Intracytoplasmic cholesterol

Chediak-Higashi Syndrome (CHS)

-Autosomal recessive condition, defective fusion of phagosome and lysosome -Nonsense mutation in the lysosomal trafficking regulator, CHS1/LYST protein. -Clinical feature: recurrent infections with bacteria, albinism, nerve defects, bleeding disorders. -Diagnosis: CBC; neutropenia and large abnormal (giant) granules on peripheral smear. Fluorescence cytometry studies. Definitive diagnosis by molecular genetic testing for CHS1 .

Nomenclature

-Benign Tumors -Designated by attaching suffix -oma to cell of origin Examples -Benign tumor arising from fibroblastic cells- Fibroma -Cartilaginous tumor- Chondroma -Tumor of osteoblasts- Osteoma -Tumor of adipocytes- Lipoma

Adenoma -Benign tumor of the glands -Ie. sweat glands -Malignant counterpart of adenoma: Adenocarcinoma -Adenoma is more microscopy, polyp is more gross

-Benign epithelial neoplasm derived from GLANDS, although they may from glandular structures You can see a very clear differentiation between the mucosa and submucosa

Papillomas -Any mass wtih finger like projections -Key feature is a fibrovascular cord within each finger, its like its feeding vessel -Common locations: Bladder papillomas, genital warts

-Benign tumor -Produces finger-like / warty projections from epithelial surfaces -Branching pattern -Squamous cell papilloma of squamous mucosa

Mechanisms involved in Hypertrophy

-By the actions of GROWTH FACTORS and VASOACTIVE AGENTS: increased production of cellular proteins *Examples of growth factors: FGF, TGF-Beta, IGF-I *Exaples of Vasoactive Agents are: Endothelin-1, Angiotensin II

The Warburg Effect(Aerobic glycolysis)- Metabolic alteration -In order for tumor cell division, you need energy, but you also need carbon elements like acetyl coa for the synthesis of membrane phospholipids, etc. All of these factors, its main thing is to divert this particular oxygen into a lesser ATP producing mechanism where they can get maximum out of the oxygen. It is an aerobic glycolysis. Here, they want multiple cytoskeletal proteins which will enhance multiple cell divisions and survival of the malignant tumors -Aerobic glycolysis is lesser energy and they yield more oxygen -Malignant tumors take up the dye and it shows as a "sweet spot"

-Cancer cells demonstrate distinctive increased glucose uptake -Increased conversion of glucose to lactose via glycolytic pathway -Clinically referred as glucose hunger -This phenomenon provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components. -This forms the principle of PET( positron emission tomography) scan for detection of cancers by injecting 18 Fluorodeoxyglucose -Sweet spot - Increased uptake

Exogenous pigments

-Carbon (coal dust) *Most common exogenous pigment *Anthracosis- blackening of the tissues of the lungs and the involved lymph nodes *Coal worker's pneumoconiosis -Tattooing: *Localized, exogenous pigmentation of the skin. *Pigments inoculated are phagocytosed by dermal macrophages

Pathologic Hyperplasia -In hyperplasia you require MITOSIS/DNA ESTROGEN STIMULATES CONTINUOUS PROLIFERATION OF THE ENDOMETRIUM, LEADING TO ENDOMETRIAL HYPERPLASIA and is a premalignant condition

-Caused by excessive or inappropriate actions of hormones or growth factors acting on target cells -Mechanisms: *Driven by growth factors/hormones for proliferation of mature cells and increased output of new cells from tissue stem cells -Eg.. -Endometrial hyperplasia - excessive estrogens *Estrogen stimulates continuous proliferation of the endometrium, leading to endometrial hyperplasia and is a premalignant condition . HIGH YIELD! -Prostatic hyperplasia - excessive androgens - benign -Viral infections - viral genes *Ie. Genital warts -Complications of hyperplasia: Hyperplastic conditions may lead to malignant transformation E.g.., Endometrial hyperplasia

Necroptosis

-Cell death is a hybrid of both necrosis and apoptosis -Because of duality of features termed as programmed necrosis -In contrast to apoptosis, necroptosis doesn't result in caspace activation( Caspase independent programmed cell death) -Receptor is similar to TNFR1, cascade involves receptor associated kinases(RIP1 & RIP3) -Terminal event include generation of ROS, permeabilisation of membrane and mitochondrial damage -Example: Bone remodeling in growth plate, cell death in hepatitis

Morphological changes in Apoptosis

-Cell shrinkage: dense cytoplasm, tightly packed organelles -Chromatin condensation -Cytoplasmic blebs and apoptotic bodies -Phagocytosis of apoptotic cell bodies by macrophages -Intact plasma membranes -Eosinophilic cytoplasm with DARK/dense cytoplasm

Morphologic alterations in reversible Cell Injury

-Cellular Swelling- first manifestation -Failure of energy dependent ion pumps in the plasma membrane *Light microscopic findings: -Swelling of cells -Small clear vacuoles in the cytoplasm -Increased eosinophilic staining

Liquefactive necrosis -Seen in the BRAIN due to ischemia. -Also seen in BACTERIAL INFECTIONS - due to pus showing up

-Cellular destruction by hydrolytic enzymes, leading to autolysis. - Digestion of the dead cells resulting in transformation of the tissue into a liquid viscous mass -Pus: Creamy yellow necrotic material due to the presence of dead leukocytes -Seen in: *Focal bacterial or rarely fungal infections *Hypoxic death of cells within the CNS Liquefactive necrosis. An infarct in the brain, showing dissolution of the tissue

Mechanisms of Atrophy 2 mechanisms: 1. Reduce the number of cells 2. Decrease proteins synthesis and increase protein lysis -It usually eats its own contents, autophagy -Protein is usually eliminated by ubiquitin pathway, and few by endosomes -Over activity of autophagy is mainly mediated by TNF-ALPHA, and can lead to cancer -If the cell can't digest all the proteins it leaves some residual bodies -LIPOFUSCIN GRANULE is a residual body due to the lipid peroxidation of the membrane resulting in incomplete digestion by endosomes or peroxisomes -Lipofuscin granule is a definite sign of free radical injury or cellular aging

-Decreased protein synthesis and increased protein degradation -Degradation takes place in the ubiquitin-proteasome pathway -Overactivity of this pathway by increased secretion of TNF-alpha leads to Cancer Cachexia -Atrophic cells show autophagic vacuoles -These vacuoles fuse with lysosomes -Lysosomal enzymes degrade cell products -Left over (not digested by enzymes) products in the cell are known as residual bodies -Lipofuscin granule( Wear and tear pigment) when found in the cytoplasm serves as example of Residual body due lipid peroxidation of membranes -"Brown Atrophy" of the heart is another example of accumulation of lipofuscin pigments in the cardiac muscles

Carcinogenesis (continued...) -Germline mutations - in utero -Sporadic mutations - usually occur after birth, Ie, caused by smoking, asbestos, etc -Usually individuals have a defective gene but it does not flare up until it is added or promoted by an accumulation of mutations - then it is expressed phenotypically as cancers - common with sporadic cancers

-Defects in DNA predispose to genomic mutations (mutator phenotype) -Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time *Accumulation of successive mutations *(E.g. Adenoma carcinoma sequence)

Tumor markers

-Diagnostic adjuncts detected by biochemical assays. -Carcino-embryonic antigen *CA colon, pancreas, stomach, breast -Prostate-specific antigen (PSA) *Prostate cancer -β-human chorionic gonadotropin *Trophoblastic tumors (choriocarcinoma) -CA-125 *Ovarian carcinoma α-fetoprotein (AFP) -Hepatocellular carcinomas -Germ cell tumors of testes or ovary

Dysplasia This is a cellular adaptation so if you take away the stimulus then it can be reversible. If it is a constant stimulus over the years it can however turn into a malignancy -If it affects 1/3 of epithelium - CIL-1 -If it affects 2/3 of epithelium - CIL-2 -If it affects the entire layer of epithelium including basement membrane it is CIL -3 or CARCINOMA IN SITU

-Disordered growth -Loss in uniformity of individual cells -Loss in their architectural orientation -Pleomorphism & mitoses are more prominent than in normal -Graded as -Mild, moderate and severe -Mild to moderate is potentially reversible -"Carcinoma in situ" *Full thickness dysplasia without the breach in basement membrane -Dysplasia may be a precursor to cancer, but does not invariably progress to cancer

Hamartoma -Normal tissue, normal sight BUT DISOARGANIZED ARCHITECTURE

-Disorganised but benign mass composed of cells indigenous to the involved particular site. -Developmental abnormality -Ie. During embrogenesis, formation of lungs and the thoracic cavity are simultaneous. Say during the process a part of the cartilage of the thoracic cavity goes into the lungs - this would be PULMONARY HARMATOMA *These are mostly found accidentally because the patient is asymptomatic

Fat Necrosis You get more fat in lesser and greater omentum, female breast, parenchymal something -Trauma to the breast can cause fat necrosis, then fibrosis, then a solid mass -You should also think of fat necrosis with acute pancreatisis *You get Liquefactive necrosis of the pancreas, but the peripancreatic tissue and omentum you get fat necrosis

-Doesnt denote a specific pattern of necrosis -Focal areas of fat destruction By the release of Pancreatic lipases -Foci of shadow outlines of necrotic fat cells with basophilic calcium deposits, surrounded by an inflammatory reaction -Seen in acute pancreatitis -Following blunt trauma to the breasts- Fat necrosis

Stem Cells -Has 2 important features: SELF RENEWAL CAPACITY and ASYMMETRIC DIVISION. With division, one daughter cell will keep its self renewal capacity while the other daughter cell will go on to maturation Zygote -> 2 stage -> 4 stage -> BLASTOCYST -The inner layer of the blastocyst has PLURIPOTENT CELLS (Can give rise to multiple cell types) or TOTIPOTENT CELLS (Can give rise to all cell types) For research we use pluripotent cells, the proper pH and the proper medium to grown them and create artificial cells or tissues. Adult stem cells are harbored in sites in various tissues for the proper signal and the cell type choice that they will become is limited. Ie. If you cut the liver, the Niches of the liver will activate and cell growth factors to other hepatocytes for continuous proliferation. They DO NOT have stem cell renewal capacity Once pluripotent stem cells commit, they lose their self-renewal capacity. This is the difference between adult stem cells and embryonic (pluripotent) stem cells For research, you must use pluripotent stem cells from the inner mass of the blastocyst

-During development, stem cells give rise to all the various differentiated tissues. -Stem cells replace damaged cells and maintain tissue populations as individual cells within them undergo replicative senescence due to attrition of telomeres -Characteristic properties of stem cells: -Self-renewal -Capacity to generate differentiated cell lineages -Embryonic stem cells are totipotent -Adult stem cells or tissue stem cells - more restricted capacity to generate different cell types -Niches: Special micro environment in which the somatic stem cells reside and which generate or transmit stimuli that regulate stem cell self-renewal and the generation of progeny cells.

Choristoma It has "stoma" in it but it is NOT A TUMOR! -This is due to some embryological defect unlike metaplasia were it develops because of some stimulus

-ECTOPIC REST OF NORMAL TISSUE -Here you are seeing a tissue that is not supposed to be present at that site -Ie. if you see a pancreas in the stomach - it is a choristoma -Ie. Meckel's diverticulum (a slight bulge in the small intestine present at birth and a vestigial remnant of the vitelline duct) -IT IS NORMAL TISSUE IN A FOREIGN LOCATION Examples: -Rest of adrenal cells under kidney capsule -Pancreatic tissue in mucosa of small intestine, stomach.

Nature of inflammatory infiltrate in inflammatory response -In cases like pseudomonas, even after 4 days you may still see neutrophils

-Early infiltrate: Neutrophils. Stay in tissue for 1-2 days and degenerate. -Late infiltrate: Monocyte, secrete TGF and IL 10 , stop signaling factors, and start regeneration/repair.

Carcinomas (Epithelial cell origin) Most tumors- Epithelial origin

-Ecto-, endo-, from any of the 2 germ layers -E.g., SQUAMOUS CELL CARCINOMA -ADENOCARCINOMA of the colon -UROTHELIAL CARCINOMA or TRANSITIONAL CELL CARCINOMA ( TCC of the bladder)

Anaplasia -It is a de-differentiation - or differentiation into a more immature form *Whenever you take a tissue, identify the tissue and its maturation. If you can't recognize the differentiation or the mother tissue, you would label it as Anaplastic Malignancy -The origin of the tumor can't be recognized. This is why cancers can be differentiated into: 1. Poorly Differentiated - Anaplasia is an example of this. No similarity from tumor and its origin 2. Moderately Differentiated - Tumor looks 25-50% like the parent site 3. Well Differentiated - tissue looks 100% like the tissue at its original site

-Extent to which neoplastic tissue resemble the corresponding normal parenchymal cells -Loss of differentiation( To form backward) -Cellular pleomorphism, hyperchromatic nuclei, high N:C ratio, giant cells, bizarre nuclei -Feature of malignant tumors -A good example of a tumor with this morphology is ANAPLASTIC CARCINOMA of the THYROID - very aggressive tumor and spreads fast to distant types. Multiple modalities needed to get this cancer under control

1. Self sufficient growth signals : Oncogene activation -PROTO-ONCOGENES - Normal function is to promote cell cycle and cell survival -If these proteins are mutated, they are called ONCOGENES *Oncogenes only need ONE mutated allele to cause cancer *We usually call this "Gain of Function" mutations, because you only need one allele to cause cancer

-Genes that promote autonomous cell proliferation in cancer are called oncogenes Unmutated versions of these proteins are called proto-oncogenes Two main categories of change exist: 1. Normal protein is overproduced 2. Mutant protein *Produced *Has aberrant function Receptor tyrosine kinase pathway: The most frequently mutated oncogenic pathway in human neoplasms.

Accumulation of Glycogen REVIEW GLYCOGEN STORAGE DISORDERS!

-Glycogen is found in renal epithelial cells, Beta cells of islets of Langerhans in diabetes mellitus -Glycogen also seen a lot in skeletal muscles -Another group is Glycogen storage diseases -Gauchers disease : Crumpled tissue paper appearance of histiocytes under light microscopy -Useful stain- PAS stain.

Clinicopathologic correlations of Apoptosis in Health and Disease Pathological - when there is a damage to the DNA (Ie. Radiation) -If you don't correct this, p53 comes and stops the cell cycle for a while so that the cell can get itself together -p53 sends signals of apoptosis and the cell undergoes its process

-Growth factor deprivation: *Hormone-sensitive cells deprived of the relevant hormone *Lymphocytes not stimulated by antigens and cytokines -DNA damage: due to radiation or chemotherapy p53 protein accumulates severe damage Apoptosis. *Pathological atrophy in parenchymal organs after duct obstruction(ex: pancreas, parotid gland) -Protein misfolding: Chaperones in the ER control proper folding of newly synthesized proteins, misfolded ones are ubiquinated and degraded by proteasomes. *Feature of a number of neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson diseases, and possibly type 2 diabetes -Apoptosis Induced By the TNF Receptor Family *FasL on T cells binds to Fas on the same or neighboring lymphocytes *Interaction plays a role in the elimination of lymphocytes that recognize self-antigens, and mutations affecting Fas or FasL result in autoimmune diseases in humans. -Cytotoxic T lymphocytes (CTLs) recognize foreign antigens presented on the surface of infected host cells

Proteoglycans and Hyaluronan -FIBRONECTIN- it binds cellular microfilaments to the collagen synthesized by variety of cells monocytes, fibroblasts and endothelial cells -LAMININ: Major component of basement membrane along with type IV collagen -INTEGRINS: through receptors can also trigger locomotion and proliferation of cells

-HYALURONIC ACID: Highly hydrated compressive gels that offers a protection against compressive forces -Provide lubrication to synovial joints( Knee Joints) *Acts shock absorber *You can get a deficiency in hyaluronic acid if you are overweight, IE heavy on the knee joints. You loose lubrication of the two bone surfaces in the knee causing more friction, degenerating the cartilage leading to arthritis -They serve as reservoirs of growth factors secreted into Extra cellular matrix -Adhesive glycoproteins: Involved in cell-cell adhesion, interaction with ECM components -FIBRONECTIN- it binds cellular microfilaments to the collagen synthesized by variety of cells monocytes, fibroblasts and endothelial cells -LAMININ: Major component of basement membrane along with type IV collagen -INTEGRINS: through receptors can also trigger locomotion and proliferation of cells

Hyaline change HYALINE means PINK in microscopy -Description of appearance of pink on slides -Proteins give a pink color, accumulation of water can also give pink color

-Hyaline - homogenous , glassy pink appearance in H & E sections -Intracellular hyaline deposits: *Reabsorption droplets *Russell bodies *Alcoholic hyaline -Extracellular hyaline deposits: *Hyalinization of walls of arterioles of kidney in longstanding hypertension and diabetes mellitus *Collagenous fibrous tissue in old scars

Desmoplasia -Increased stromal reaction by abundance of collagenous stroma and blood vessels -These tumors are VERY HARD TO CUT!

-Hyperplasia of activated fibroblasts -Abundant collagenous stroma around the tumor e.g. Tumors of female breast- stony hard or SCIRRHOUS

Hyperplasia Increase in cell NUMBER (which leads to increase in size)

-Increase in the number of cells that also cause increase in the mass of the organ in response to a stimulus. -Two types: Physiologic and Pathologic hyperplasia: *Physiologic hyperplasia is due to: (i) Hormone induced - growth of female breast during puberty (ii) Compensatory hyperplasia- best example is regeneration of liver after partial hepatectomy (iii) Marrow undergo marked hyperplasia up to 8 fold in response to a deficiency of terminally differentiated cells( Eg. Acute hemolysis)

Hypertrophy -Increase in cell SIZE, requires INCREASED PROTEIN SYNTHESIS -Happens only in permanent tissues where there is no chance of cell division like NEURONS, CARDIOMYOCYTES, SKELETAL MUSCLE! -Mainly due to the increase in intracellular proteins

-Increase in the size of the cells- Increased synthesis and assembly of additional intracellular structural components. -Leading to an increase in the size of the organ. An organ therefore is made up of larger cells -Two types 1. Physiologic - as seen during increased demand, hormonal activity or action of growth factors ex: skeletal muscle hypertrophy 2. Pathologic - Enlargement of heart - known as cardiomegaly

Leukocyte mediated tissue injury

-Infections which are difficult to eradicate prolonged host response contribute to more tissue injury than microbe itself. E.g.: viral infection, tuberculosis. -Inflammatory response inappropriately directed against host tissue: Autoimmune disease. -When host reacts excessively to harmless environmental substance; asthma.

Endogenous pigments Lipofuscin is a protein with a lipid attachted to it This is seen with patients with ADVANCED CANCER!

-Lipofuscin *Wear and tear pigment *Polymers of lipids and phospholipids in complex with proteins *Tell-tale sign of free radical injury and lipid peroxidation *Seen in Liver, heart of elderly, severe malnutrition and Cancer cachexia *Yellow brown, finely granular, cytoplasmic, often perinuclear pigment -Melanin: only endogenous brown black pigment *Melanin synthesized from Tyrosine, which is derived from phenylalanine -Ochronosis - Alkaptonuria - homogentisic acid Black pigmentation in skin, connective tissue and cartilage -Hemosiderin: golden yellow to brown granular or crystalline pigment *Major storage form of iron *Hemosiderin granules - aggregates of ferritin micelles - local or systemic iron excess *Local - bruise *Systemic - Hemosiderosis *Morphological features of hemosiderin accumulation: *Visualized by Prussian blue stain Coarse golden, granular pigment lying in the cell's cytoplasm *Hemochromatosis - increased absorption of dietary iron with subsequent deposition of so -Bilirubin: *Excess - jaundice

Cancer Cachexia

-Loss of body fat, and lean body mass accompanied by wasting and profound weakness -Increased BMR -Evidence of systemic inflammation -Pathogenesis: -Loss of appetite, metabolic changes are due to the release of TNF-α ( Cachectin) LIPOFUSCIN is the pigment that gets deposited in the cancer cachexia

Intracellular Accumulations

-Manifestation of metabolic derangement -Two categories: -Normal cellular constituent -Abnormal substance *Transient/ permanent *Cytoplasm/ nucleus -Mechanism of intracellular accumulation -A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it ex: Fatty change in the liver

Erythrocyte Sedimentation Rate - ESR

-Measures how fast red cells fall through a column of blood and an indirect measure of inflammation -Normal value: M-0-15 mm/hr and F- 0-20 mm/hr -The result of an ESR is reported as the millimeters of clear fluid (plasma) that are present at the top portion of the tube after one hour (mm/hr). -Elevated ESR seen in inflammation (autoimmune disease, infection, vasculitis, Inflammatory bowel disease etc.), Presence of paraproteins (Multiple Myeloma), malignancy, tissue injury (burns, MI, etc.), and transplant rejection .

Interaction with the Extracellular Matrix

-Mechanical support -Control of cell proliferation -Scaffolding for tissue renewal -Establishment of tissue microenvironments.

Mediators of inflammation: Cytokines and chemokines

-Mediate and regulate immune and inflammatory reactions *IL-1 and TNF - Secreted by monocyte- macrophages -Effects: *Endothelial activation, *Activation of leukocytes and other cells (IL1 ->TH17 cells), **IL-1 also activates fibroblast to make collagen *Systemic acute-phase response. -Interleukin 1 (IL1): *Fever : stimulates synthesis of PG E2 in anterior hypothalamus. -Tumor necrosis factor (TNF): *Important mediator in inflammation: target for treatment in chronic inflammatory disease like rheumatoid arthritis, psoriasis, IBD.

Neutrophil Extracellular Traps (NETs) -This helps concentrate more antimocrobial proteins (cytokines, chemokines, complements) and prevents further spread of microbes by trapping them -This can be the source of nuclear antigens in systemic autoimmune diseases -This may be the possible cause of recurrent infections

-NETs : provide high concentration of antimicrobial substances at the sites of infection and prevent the spread of microbes by trapping them in the fibrils. -What these fibrillary network formed of ? *Mesh work of nuclear chromatin *This has been postulated to be source of nuclear antigens in systemic autoimmune disease

Factors influencing tissue repair

-Nutritional status: vitamin C deficiency can inhibit collagen synthesis. -Inherited defects in collagen synthesis or connective tissue: Ehlers-Danlos syndrome -Poor perfusion: either due to atherosclerosis or obstructed venous drainage (varicose veins) -Type and extent of tissue injury -Location of the injury: character of tissue involved is also important example: inflammation arising in tissue spaces like pleural cavity produce extensive exudates. Such cases resolution occurs by extensive fibrosis.

Morphologic features of dystrophic calcification PSAMM!!!

-Pathogenesis of dystrophic calcification: Crystalline Calcium phosphate mineral deposition in the form of an apatite similar to bone -Gross : Fine, white granules or clumps, felt as gritty stones -Histological appearance: basophilic amorphous, granular, sometimes clumped -Psammoma bodies ( Concentric lamellated calcified spherules seen in following cancers) -Papillary carcinoma of thyroid -Mesothelioma -Meningioma -Serous papillary ovarian cancer -Asbestosis - dumbbell forms

PATHOLOGY

-Pathos (suffering) -Logos *Study of structural, biochemical and functional changes in cells, tissues and organs that underlie disease -ETIOLOGY ("Cause") -PATHOGENESIS ("Insidious development") -MORPHOLOGY (ABNORMAL ANATOMY) -CLINICAL EXPRESSION *These are the four aspects about every disease you should keep in mind as a knee jerk reflex every time you hear the name of a disease.

Micro-RNA -Any mutations in this RNA will cause cancer. They are currently trying to find a drug that will counter this.

-Posttranscriptional silencing of gene expression by miRNA is a fundamental well-conserved mechanism of gene regulation present in all eukaryotes (plants and animals). -miRNAs do not encode proteins; instead, they function primarily to modulate the translation of target mRNAs into their corresponding proteins.

Histamine -First mediators to be released at the site of injury by the MAST CELLS -

-Produced by: Mast cells, basophils, platelets -Effect: vasodilatation, increased vascular permeability and endothelial activation -Responsible for the immediate response in acute inflammation -Triggers for release of histamine: *Binding of antibodies to mast cell *Binding of C3a and C5a (anaphylatoxins) *Cytokines (IL-1 & IL-8)

Physiologic Apoptosis Ie. Endometrial shedding Ie. Destruction of the lymphocytes we don't require Ie. Complete disappearance of the webs between the fingers during embryogenesis Ie. Elimination of certain potentially harming viruses or bacteria

-Programmed destruction of cells during embryogenesis -Involution of hormone dependent tissues upon hormone withdrawal Ex: Endometrial cell breakdown during menstrual cycle, Ovarian follicular atresia in menopause -Cell loss in proliferating cell populations to maintain homeostasis Ex: Immature lymphocytes in the bone marrow and thymus that fail to express useful antigen receptors -Elimination of potentially harmful self-reactive lymphocytes

Epithelial Metaplasia -Replacement of one type of epithelium/tissue by another type of tissue. -There is EPITHELIAL METAPLASIA vs CONNECTIVE METAPLASIA Chronic urinary irritation is another example -Usually the urinary system is lined by transitional epithelium. If there is any irritation *Ie. Chronic Schistosoma - Disease where helminth lays eggs on the urinary bladder so the bladder mucosa gets irritated over the years. In this case you may see squamous metaplasia of the urinary bladder. Youre typically not supposed to see squmous there until the terminal urethra. Seen typically from Egyptian or Iranian immigrants. Another alternative. THey could give a squamous columnar junction of the cervix. If women after 40 or 50 and have previously been exposed to HPV, the columnar cells will be replaced by squamous cells and then subsequent squamous cancer of the cervix will occur. All these adaptions are reversible however if the stimuli sustains, then it can ultimately turn into a pre-malignant condition

-Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type *Metaplasia occurs in epithelial and connective tissues *Two Examples for Epithelial Metaplasia -> In a smoker, ciliated columnar bronchial epithelium is replaced by squamous nonkeritanized epithelium *If the pt continues to smoke, it will ultimatel turn into DYSPLASIA and subsequent cancer (Squamous metaplasia of the bronchus) *Pt's can also get metaplasia of the bronchus with long term intubation -A risk of developing squamous cell carcinoma of bronchus ->In Barretts esophagus, Squamous epithelium at the lower end of esophagus is replaced by Intestinal epithelium with goblet cells - intestinal metaplasia - a risk of developing adenocarcinoma of the esophagus *In order to withstand chronic esophageal reflex disease

Hallmarks of inflammation /cardinal signs/ Local effects of inflammation

-Rubor: redness -Tumor: swelling -Calor: heat *For all the above: vasodilatation and increased vascular permeability (histamine, bradykinin, PG and Leukotrienes). Leakage of fluid through post capillary venules and formation of exudate. -Dolor; pain *Bradykinin and PGE2 -Functio laesa - loss of function *Limited mobility of affected part by pain and/or effusion (eg. Knee Joint infection)

Niemann-Pick Disease Type C

-Sea blue histocytes in the bone marrow are seen -Due to problem with cholesterol and cholesterl esters-2 -Due to defect in sphingomyelinase

Fibrinoid necrosis -Seen in malignant hypertension -Also seen in autoimmune diseases related to the blood vessels

-Seen in Immune reactions involving blood vessels -Deposition of immune complexes in arterial walls -Immune complexes+ leaking fibrin deposits = fibrinoid -Bright pink and amorphous appearance

Termination of Acute inflammatory response

-Short half life of neutrophils in the tissue (1-2days) -Triggering of stop signals by inflammatory mediators: switch in type of inflammatory mediators produced from pro inflammatory mediators to anti-inflammatory mediators like TGF-β and IL-10 from macrophages. -Production of anti-inflammatory mediators: lipoxins generated from arachidonic acid , it suppress inflammation by inhibiting the recruitment of leukocytes.

Caseous necrosis Check for 2 things here: Immigrants and immune status Because it is commonly seen in TUBERCULOSIS

-Soft friable cottage " Cheese like" -Friable white appearance of area of necrosis -Commonly seen in foci of Tuberculous infection -Collection of fragmented cells and amorphous granular debris enclosed within a distinctive inflammatory border - granuloma

A 58 yo male comes with a hx of smoking 300 pk/year for the past 20 years. He now presents to you with a hx of abd pain and jaundice. On exam, cerum calcium is 80mg per deciliter and CT test reveals a lesion in the hilum of the lung. What is the diagnosis? What type of manifestation is this?

-Squamous Cell Carcinoma -Paraneoplastic syndrome -Due to the smoking, the bronchus would have metaplasia, and the bronchus is in the CENTER of the lungs (not at the periphery).

Oncology -The most important change is DNA CHANGES!

-Study of tumors -Progressive, purposeless, pathological, proliferation of cells -Loss of control over cell division -DNA damage at growth control genes is central to development of neoplasm

Fibrosis in parenchymal organs

-TGF-β. -Myofibroblasts are the main source of collagen, but in liver stellate cells produce collagen. -Fibrotic disorders : *Cirrhosis of liver, *Systemic sclerosis, *Fibrosing diseases of lung, *End stage renal disease, *Constrictive pericarditis.

Flow cytometry

-Technology that is used to analyze the physical and chemical characteristics of particles in a fluid as it passes through at least one laser Applications: -Diagnosis of T cell/ B- cell leukemia -Cell sorting -Diagnosis of PNH -Measures DNA content of cells -Measures aneuploidy

Rudolph Virchow 1821-1902

-The Father of Modern Pathology -The second most profound thing ever said, in the 2nd millenium, after E=mc2, was by Rudolph Virchow. He said, "All diseases are the results of visible cell abnormalities", i.e., abnormal histology, i.e., histopathology. For this, he earned the undisputed title of "father of pathology."

Elastin, fibrillin, and elastic fibers:

-The ability of tissues to recoil and recover their shape after physical deformation is done by elastin -Elastic fibers = Central core of elastin + Fibrillin -Tissues that require elasticity for normal function: -Blood vessels, skin, uterus, and lung -MARFAN'S SYNDROME- Inherited defects in FIBRILLIN.

TP53

-The guardian of the genome -P53 regulates cell cycle progression, DNA repair, cell senescence and apoptosis -TP53 upregulates CDKIs such as p21, causing cell cycle arrest at G1—S *Inhibits the cell cycle progression through p21 if damage to the cell is severe -If DNA damage cannot be repaired, induces apoptosis by increasing the levels of BAX. -Li-Fraumeni syndrome: Multiple cancers due to the mutation of p53.

Chronic inflammation

-The tissue injury and attempts at repair coexist, in varying combinations. Causes: -Persistent infections -Prolonged exposure to toxic agents -Autoimmune diseases

The role of intermediate filaments in the diagnostic pathology Intermediate filaments: 7-10 nanometers The most common cancers in the brain, liver and in the lung are always SECONDARY. Secondary means that the primary tumor is harbored somewhere else. The manifestation is secondary VIMENTIN - Cancer arising from MESENCHYMAL CELLS - SARCOMA DESMIN - Cancer arising from MUSCLES - RHABDOMYOSARCOMAS CYTOKERATINS - Cancer arising from EPITHELIA - CARCINOMAS GFAP - Cancer arising from GLIAL CELLS/NEURONS - ASTROCYTOMA

-They have a characteristic tissue-specific patterns of expression -Useful in identifying tissue of origin in a poorly differentiated cancer Lamin A Source: Usually expressed in the nuclear lamina of all cells Vimentin Source: Expressed in all mesencymal cells *Mesenchymal cells are fibroblast, tendons, fascia, blood vessels Cancer: Malignant tumors that arise from mesenchymal cells/tissues are called SARCOMAS Desmin Source: Muscle (Skeletal and cardiac) Cancer: Rhabdomyosarcoma Cytokeratins Source: Epithelia (particularly desmosomes and hemidesmosomes) Cancer: Carcinomas GFAP (Glial fibrillary acidic protein) Source: Glial cells, Neurons Cancer: Astrocytoma *Here you would see a lot of GFAP+ malignant astrocytes in Astrocytoma

Acute inflammation

-Three major components: *Dilatation of blood vessels leading to increased blood flow *Increased vascular permeability: enables proteins and leucocytes to leave circulation ***All of the above is the VASCULAR RESPONSE! *Emigration of leucocytes to the microcirculation, accumulation at the site of injury and eliminate the offending agent by phagocytosis and intracellular destruction.

Polyp -Many students get confused between polyp and adenoma. Polyp is a mass which projects out of the mucosa to the hollow viscous (could be adenoma or it could be malignancy as well, its just a GROSS DESCRIPTION) -IE. GI Polyps into the lumen of the intestine, ethmoidal/nasal polyps from nasal mucousa projecting into the nasal sinus -If he says adenomatous polyp - it is a benign polyp with glands

-Tumor(Benign or malignant) projects from mucosal surface into the lumen of a hollow viscus -If the polyp has glandular elements its called as an ADENOMATOUS POLYP -2 types: 1. SESSILE - no stalk 2. STALKED or PEDUNCULATED

Hematogenous spread -Primary Hepatocellular Carcinoma would be one big focal mass -The liver would not have multiple masses unless it were secondary carcinoma

-Typical of sarcomas -Arteries are more difficult for tumor to penetrate than veins *With venous invasion, blood-borne cells follow venous flow draining tumor site *Cancers are in close proximity to the vertebral column can embolize via ( Paravertebral plexus of veins) i.e. Prostate cancer *Prostate plexus and vertebral plexus are in close proximity. Prostate cancer can easily spread to the back -Sites *Liver and lungs - frequently involved

Deposition and remodeling of connective tissue.

-Ultimately granulation tissue evolves in to a scar, largely composed of connective tissue and fibroblasts. -Scar undergo maturation by remodelling, progressive regression of vessels, and morphological transformation of fibroblasts in to myofibroblasts -Remodelling of connective tissue by matrix metalloproteinases (MMPs)

Morphology

-What it looks like -Gross Vs Microscopy

Chronic Granulomatous Disease (CGD)

-X-linked (70%) or AR (30%) inherited deficiency of NADPH oxidase: defect in production of reactive oxygen species. -Clinical features: children with recurrent deep tissue bacterial or fungal abscess with granuloma formation (LN, liver and lungs), recurrent folliculitis of skin. -Staphylococcus aureus, serratia marcesces, burkholderia cepacia, mycobacterial and aspergillus. -Diagnosis: Nitro blue Tetrazolium test - negative (normal neutrophil show positive NBT test), Florescent rhodamine test in neutrophils and monocytes.

2 Types of Hypertrophy in the Heart Heart muscle is a permanent muscle so it can't divide. How the heart combats is it arranges the sarcomeres in a certain way to combat the stress. CONCENTRIC: If the sarcomeres/heart muscle are arranged in PARALLEL the thickness of the ventricle increases so this can push the blood against the obstruction. DILITATION: If the heart is dealing with more of a aortic regurgitation, the myocytes lay down the sarcomeres side by side so that the room of the ventricle increases

1. Concentric Hypertrophy *Obstructions, increased in vascular resistance, changes in the valves, aortic stenosis *Results in the arrangement of cells parallel to each other 2. Dilitation *The deposition of sarocomeres in series, increasing the room of the ventricle *Aortic regurgitation, Heart

With reference to case study 1. Examination of pancreatic tissue under the light microscope will most likely reveal an abundance of which of the following inflammatory cells? Remember: Dx was ACUTE PANCREATITIS A. Lymphocytes B. Eosinophils C. Mast cells D. Neutrophils E. Plasma Cells 2. Identify the sequence of events occuring at the sit eof injury to recruit neutrophils and to clear the necrotic cells in the pancreas? 1. Rolling 2. Adhesion 3. Margination 4. Diapedesis 5. Phagocytosis 6. Intracellular Killing A. 3,1,2,4,5,6 B. 2,1,3,5,4,6 C. 3,2,1,5,6,4 D. 1,2,4,3,5,6 E. 2,4,3,6,5,4

1. D. Neutrophils 2. 3,1,2,4,5,6 3- Margination 1- Rolling 2- Adhesion 4- Dapedesis 5- Phagocytosis 6- Intracellular Killing

Growth Factors Involved in Regeneration & Repair

1. Epidermal growth factor(EGF) -Source: Activated macrophages, keratinocytes -Functions: Mitogenic for fibroblasts and fibroblasts 2. Transforming growth factor alpha(TGF-a) -Source: Activated macrophages and other cells -Functions: Proliferation of hepatocytes and other epithelial cells 3. Hepatocyte growth factor ( HGF) -Source: Stromal cells of liver, fibroblasts -Functions: Increases cell motility and proliferation of hepatocytes 4. Vascular endothelial growth factor (VEGF) -Source: Mesenchymal cells -Functions: Increases vascular permeability, proliferation of endothelial cells 5. Platelet derived growth factor(PDGF) -Source: Platelets, macrophages and endothelial cells -Functions: Stimulates fibro genesis and ECM protein synthesis 6. Fibroblast growth factor(FGF) -Source: Mast cells, endothelial cells -Functions: Stimulates angiogenesis and ECM protein synthesis 7. Transforming growth factor-Beta(TGF-B) -Source: Platelets, macrophages, fibroblasts, endothelial cells -Function: Suppress acute inflammation, stimulates ECM protein synthesis

1. Colonoscopic examination of a 35 yo man reveal multiple polyps. Dx _____. Due to mutaiton involving _____ gene 2. A 3 yo boy with flank pain, abdominal mass and hematuria -Dx___________. What's the underlying mutation ___________________ 3. Hereditary nonpolyposis colon cancer (HNPCC) is due to the defect in _______ mismatch repair genes

1. FAP, APC 2. Wilms tumor, WT-1 3. MLH1, MSH2

1. Tendinous xanthomas and xanthelasmas are seen in 2. Due to accumulation of 3. Fatty liver is seen in 4. Sea blue histiocytes (macrophages) in the bone marrow is suggestive of 5. Curmpled tissue paper appearance of histiocytes is a feature of _________ due to the deposition of _______

1. Familial Hypercholesterolemia Type II 2. Cholesterol 3. Alcoholics and Non-Alcoholics Stereatitis 4. Neamann Pick Disease - Due to deficiency of Sphingolomyelinase 5. Gauchers DIsease, deposition of glucocerebroside due to deficiency in glucocerebrosidase

1. What kind of necrosis would you see in a blunt injury of the breast? 2. What kind of necrosis would you see in thorn prick infection leading to pus? 3. What kind of necrosis would you see in acute pancreatic digestion after an episode of binge alcohol or due to blunt injury? 4. What kind of necrosis would you see in saponification of peripancreatic fat after pancreatitis? 5. What kind of necrosis would you see in splenic sequestration crisis? 6. What kind of necrosis would you see in a patient of SLE presenting with malignant hypertension? 7. What kind of necrosis would you see in a patient presenting with seizures on CT lab investigations, he is also found to have cerebral abscess. 8. What kind of necrosis would you see in a person with a diabetes ulcer?

1. Fat necrosis 2. Liquefactive Necrosis 3. Liquefactive Necrosis 4. Fat Necrosis 5. Coagulative necrosis 6. Fibrinoid Necrosis 7. Liquefactive Necrosis 8. Gangrenous Necrosis with Combination of both Coagulative as well as Liquefactive

1. Pleomorphic adenoma is a -Benign tumor of the parotid gland - when tampering with this be careful of the facial nerve 2. Normal tissue/normal site but disorganized architecture 3. Eptopic rest of normal tissue 4. Malignant tumor of the skeletal muscle 5. A tumor that involves all 3 germ layers

1. Mixed tumor 2. Hamartoma, peutz jegher polyps 3. Choristoma 4. Rhabdomyosarcoma 5. Teratoma

As pertaining to the previous case which of the following is the most likely cause and the clinical diagnoses in this case? 1. Pancreatic cancer, Trousseau syndrome 2. Small cell ca-lung, Cushing syndrome 3. Small cell ca-lung , SIADH 4. Squamous cell ca-lung, Hypertrophic osteoarthropathy 5. Sepsis, disseminated intravascular coagulation

1. Pancreatic cancer, Trosseau syndrome

Maintaining Cell Populations (Proliferation and the Cell Cycle) GO OVER -G1-S transition: CDK 4/CDK 6 & Cyclin D + CDK2 & Cycin E -S phase: CDK 1/CDK 2 & Cyclin A -G2-M transition: CDK 1 & Cyclin B -Any mutation in these Rb can lead to uncontrolled proliferation of cells due to loss of regulation of E2F -Rb mutated in RETINOBLASTOMA. Mother will bring child with leukokoria, the eyes will look like a cats eye at night because of the reflection and mutation of the retina -Rb also mutated in OSTEOSARCOMA (Rb mutaed in OSTEOSARCOMA & LEUKOKORIA)

1. Permanent Cells (G0 cells!) -These cells don't divide or enter into G1 -An example would be NEURONS, CARDIOMYOCYTES, SKELETAL MUSCLE *Once they are formed they never enter into G1 phase *If something happens to these tissues they don't divide, they just increase in size (Hypertrophy) -Hypertrophy is only seen in STABLE cells (G0) 2. Stand-by cells -Whenever these cells get stimulated they enter into G1 phase -LYMPHOCYTES, HEPATOCYTES 3. Labile cells -These cells have continuous division -Like BONE MARROW CELLS, GI EPITHELIAL CELLS -There are a few proteins in the cell cycle like CYCLINS & CYCLIN DEPENDANT KINASES (CDKs) -CDKs add a PHOSPHATE GROUP to the CYCLINS in order to promote the cell cyclin. -CDKs and Cyclins push the cell cycle passed the two checkpoints 2 check points in the cell cycle: G1-S & G2-M - G1-S (MOST IMPORTANT - primarily regulated by RETINOBLASTOMA-G & p53) -Typically when Rb-g is NOT phosphorylated, E2F is bound tight and will not promote transcription --Cyclin D/CDK4 + CDK6 phosphorylates Rb-g which will then release E2F allowing it to go to the nucleus for transcription -CDK-4, CDK-6 with Cyclin D and CDK 2 cyclin E regulate G1-S transition by phosphorylating Rb Protein -Cyclin A CDK1 &CDK-2 active during synthetic phase -Cyclin B CDK-1 essential for G2-M transition

1. A mass projects from the surface epithelium into a hollow viscus 2. Benign tumor involving glands 3. Malignant tumor of fibrous tissue 4. Malignant tumor of the uterine smooth muscle 5. Which component of the tumor helps in the desmoplasia 6. All carcinoma spread via lymphatics except

1. Polyp *Could be benign or malignant. For further detail you would have to seek microscopy to see if it is an adenomatous polyp (benign) or adenocarcinoma (malignant) 2. Adenoma 3. Fibrosarcoma 4. Leiomyosarcoma 5. Stroma 6. RCC (Renal Cell Carcinoma), HCC (Hepatocellular Carcinoma)

A 33-year-old female presents with a history of neck swelling and episodic headache for the past month. On examination, Pulse is 100/min, BP-180/100 mm Hg. The swelling in the thyroid gland, is not fixed to the adjacent structures. CT-Abdomen reveals an encapsulated mass in the left adrenal gland. A final diagnosis of Multiple endocrineneoplasia is made. Which of the following proto-oncogenes is most likely mutated in this disorder? 1. RET 2. RAS 3. ALK 4. KIT 5. P53

1. RET -RAS = Pancreas and colon cancer -KIT= GI and stromal tumors -ALK = Tyrosine Kinase, this is your Philadelphia Chromosome -p53 = almost all cancers

1. Cellular Swelling is due to? 2. What are Bax and Bak? 3. Leaking of intracellular enzymes? 4. Growth of a tissue by replicating cells 5. Coagulatie necrosis with cheese like material at the center 6. Tissues that can only hypertrophy (3) 7. Change of one epithelium to a different type of adaption 8. Whcih special stains is used to demonstrate -Iron ____ -

1. Reversible damage/inhibition of Na/K/ATPase 2. Proapoptotic factors 3. Membrane damage

1. Rolling is mediated by? 2. What is the complementary ligand on leukocyte for selectins? 3. Adhesion is mediated by activation of which molecule on the leukocyte cell surface? 4. Ligand for integrin on the endothelial surface is?

1. Selectins 2. Sialyl-lewis X protein 3. Integrin 4. ICAM1/VCAM1

Morphological patterns of acute inflammation There are specific morphological forms that are superimposed on normal morphological forms depending on 1. Site 2. Agent 3. Severity of reaction

1. Serous inflammation: -Exudation of cell poor, protein poor, watery fluid in to spaces due to increased vascular permeability. -Accumulation of serous fluid in body cavities (peritoneal, pericardial and pleural) is also called as effusion. 2. Fibrinous inflammation: -Pathogenesis: large vascular leak or when there is local procoagulant stimulus (ex: cancer cells). -It is characteristic of inflammation in the lining of body cavities; meninges, pericardium and pleura -Tissue section fibrin appear as eosinophilic meshwork of threads or amorphous coagulum. 3. Purulent (Suppurative) inflammation, Abscess: -Characterized by production of an exudate rich in neutrophils, liquefied debris of necrotic cells, and edema fluid (pus). -Cause: infection with pyogenic (pus forming) bacteria is most frequent cause. -Tissue section : central mass of necrosis surrounded by neutrophils *Infection with fungi and parasite also cause Suppurative inflammation. Carbuncle or boils is another example for Suppurative inflammation in skin. 4. Ulcers: -Defn: A local defect or excavation of the surface of an organ or tissue produced by the sloughing of inflamed necrotic tissue. -Most common sites: mucosa of oral cavity and gastrointestinal system, and skin. -Example: Peptic ulcer (both acute and chronic inflammation exist) *Acute: Marigins and base are formed by neutrophils and dilated capillaries *Chronic: Margins and base are covered by fibrous tissue (scar tissue), depositions of collagen. Along with chronic inflammatory cells like lymphocytes, macrophages, and plasma cells

Idenitfy the common chromosomal transolactions assocaited with cancers 1. Mantle cell lymphoma 2. Follicular Lymphoma 3. Burkitt Lymphoma 4. Ewing Sarcoma 5. Prot-oncogenes are normal components of cells (Yes or No)

1. T(11:14) 2. T(14:18) 3. T(8:14) 4. T(11:22) 5. Yes

1. Open needle biopsies are contraindacted in 2. Pseudomyxoma peritonei is an example of _______ route of metastasis and is seen in __________ 3. 78 yo presents with difficulty in passing urine and back pain. Xray shows blastic lesions on L3-L4. Dx_________ 4. Intraoperative sentinel lymph nodes biopsy are requested in 5. Rodent ulcer descriptively referred to which skin malignancy

1. Testicular tumors 2. Transcoelomic, Mucinous malignant tumors of ovary and appendix *Ie. Transcoelomic spread would be like a malignant tumor of the ovary or appendix spreading to the peritoneal cavity right next to it 3. Prostatic adenocarcinoma *Because of the communication of veins between the prevertebrae and the prostatic veins *NOTE: There are 2 types of vertebral metastasis manifestations in the bone - LYTIC LESIONS (When they metastasis to bone they cause destruction of the bone, seen in all cancers) & BLASTIC LESIONS (Lesions that produce unhealthy/weak/easily fractured bone, seen mostly in prostatic adenocarcinoma) 4. Breast, and Malignant melanoma 5. Basil Cell Carcinoma (BCC)

1. Factors that promote angiogenesis? 2. Factors that inhibit angiogenesis 3. Defect in the DNA repair induced by UV radiation 4. Familial retinoblastoma children are at increased risk of developing? 5. Pathologic mechanism of HPV in the causation of cancer

1. VEGF, FGF 2. Thrombospondin-1, Endostatin & angiostatin 3. Xeroderma pigmentosa 4.Osteosarcoma 5. E7 viral gene degrades RB

Genomic instability

1. Xeroderma Pigmentosa(XP): -Defective nucleotide excision repair to replace pyrimidine dimers resulting from UV radiation -Families are prone to SCC, BCC and Melanoma 2. Hereditary Nonpolyposis Colon Cancer (HNPCC or Lynch syndrome) -Defect in the family of genes( MSH2 and MLH1 ) required for the DNA mismatch repair -Errors accumulate in the DNA as "microsatellite instability" -Autosomal dominant condition characterized by cancers of the right colon and endometrium

A 32-year-old female complains of double vision and difficulty to read towards the end of the day for the past three months. On examination, the patient has left medial rectal palsy and squint. CT-Chest reveals a mass in the anterior part of the mediastinum, measuring10x5cm. Biopsy of the mass revealed a diagnosis of Thymoma. Which of the following pathogenic processes best describes her clinical manifestations? 1. Antibodies to presynaptic voltage gated Ca channels 2. Antibodies to postsynaptic cholinergic receptors 3. Antibodies to type IV collagen 4. Antibodies to ds DNA 5. Antibodies to self Citrullinated proteins

2. Antibodies to postsynaptic cholinergic receptors -The patient is having a thymoma -This is myestenia gravis where antibodies against post-synaptic acetylcholine receptors -Antibodies to presynaptic voltage gated CA channels = Lambert Eaton Myesthenic Syndrome -Antibodies to type IV collagen = Goodpasture syndrome -Antibodies to ds DNA = SLE -Antibodies to self citrullinated proteins = RA

A 32-year-old male presents with a history of an enlarging neck mass and malaise for the past 3 months. No history of smoking/alcohol/ weight loss. Biopsy of the mass show monoclonal population of abnormal B lymphocytes. A genetic analysis of these clonal cells revealed chromosomal t(14:18). This change would most likely up-regulates which of the following genes? 1. P53 inactivation 2. bcl-abr chimera 3. C myc 4. ERBB-2 4. BCL-2

2. BCL-2 -The diagnosis is FOLLICULAR LYMPHOMA -Due to mutation of BCL-2, there is upregulation of bcl-2 oncogene so therefore cells wont respond to the process of apoptosis. Continued survival of these abnormal atypical cells finally turning into follicular lymphoma What kind of translocations do you get in?.. -Burkitt's Lymphma - 8:14 -Mantle Cell Lymphoma - 11:14 -Ewing Sarcoma - 11:22

An 18-year-old boy presents with pain in his right leg for the past two months. There is no history of trauma. X-ray reveals an expansile mass in the diaphysial region of tibia with a characteristic onion skin appearance. A biopsy of the lesion is consistent with the Ewing sarcoma. Which of the following translocations is characteristic of this malignancy? 1. T(15;17) 2. T( 11;22) 3. T(14;18) 4. T( 11;14) 5. T(9;22)

2. T(11;22) -15:17 in APML (sometimes just called APL) -14:18 in Follicular -11:14 in Mantle -9:22 in Philadelphia Chromosome

A 60-year-old male presents with painless hematuria and right sided flank pain for the past week. On investigation he is found to have right renal mass and a biopsy of the mass is suggestive of a carcinoma. No significant family history. Cytogenetic study of the malignant mass cells reveals Ch 3p deletion. The deletion is most likely involve which of the following genes? 1. Rb 2. VHL 3. NF-1 4 WT-1 5 BRCA-1

2. VHL -This is definitely RENAL CELL CALCINOMA -Chr 3p deletion -RB: Chr 13 -p53: Chr 17 -WT-1: Chr 11 (not frequently asked) -VHL : Chr 3 *Other cancers involving VHL are CEREBELLAR HEMANGIOBLASTOMAS

A 60-year-old male presents with a history of dyspepsia and weight loss for the past 6-years. Gastroscopic biopsy is suggestive of well differentiated adenocarcinoma. Amongst the following, which is the most likely cause for the malignancy? 1. Benzene 2. Aniline 3. H-Pylori 4. Asbestos 5. Silica

3. H. Pylori -Benzene - leads to leukemias -Aniline dyes - Naphthylamine - lead to urothelial cancer/transitional carcinoma of the bladder -Asbestos - Mesothelioma -Silica (component of sandstones) - Skin & Lung cancers

A 35-year-old male presents with a history of painless hematuria and right flank pain for the past week. His sibling is diagnosed to have a cerebellar hemangioblastoma. CT- Abdomen reveals a mass in the hilum of the right kidney. A biopsy of the mass shows malignant clear cells with abundant watery cytoplasm. Which of the following genes is most likely mutated in this patient? 1. Ret 2. BRACA-1 3. VHL 4. APC 5. NF-2

3. VHL -Usually VHL will be associated with Renal Cell Carcinomas and Cerebellar Hemangioblastomas

A 6-year-old boy presents with a history of hematuria and renal colicky pain for the past week. USG-Abdomen reveals amass in the right kidney. A biopsy of the mass is consistent with the diagnosis of a Wilms tumor. Which of the following genes is most likely mutated in this patient? 1. Ret 2. NF-1 3. WT-1 4. APC 5. VHL

3. WT-1

A 60-year-old male presents with a history of abdominal pain and weight loss for the past three months. Now he complains of recurrent pain and swelling of both legs since a week. On examination, there is severe emaciation, loss of buccal pad of fat. USG-Abdomen reveals a mass in the head of the pancreas measuring 9x6cm. Biopsy of the mass reveal malignant glands surrounded by dense stroma. Which of the following pathologic processes best accounts for his clinical presentations? 1. Metastasis 2. Angiogenesis 3. Tumor homing 4. Paraneoplastic syndrome 5. Varicose veins

4. Paraneoplastic syndrome -Pancreatic Adenocarcinoma is the diagnosis -Most of these patients will die if you don't diagnose them -The patient is having manifestations/complaints of bilateral leg swelling which hints towards DVT so this is paraneoplastic syndrome -Not metastasis because it would not metastasize to the legs, maybe the liver, but not the legs -Even if the tumor has angiogenesis, this doesn't explain why the pt has leg pain and DVT -Tumor homing is consequence of metastasis, not happening in this case -Varicose veins are superficial and not deep

A 58 yo male presents with a history of chronic GERD for the past three years. Histologic examination of the lower end of the esophagus shows abnormal intestine-like epithelium composed of goblet cells. Which of the following is the most likely complication of this disorder? A. Adenocarcinoma B. Barrett metaplasia C. Connective tissue metaplasia D. Squamous cell carcinoma E. Squamous metaplasia

A. ADENOCARCINOMA Any long standing GERD can lead to Barretts Esophagus via metaplasia. Barrett's Esophagus is the diagnosis but the question is asking for the complication of that diagnosis. The complication of that Barrett's Esophagus is ADENOCARCINOMA

A 35-year-old man is presents with a history of altered bowel habits and weight loss for the past month. Colonoscopic examination shows a circumscribed, pedunculated mass with a short stalk is found on the rectal mucosa, measuring 2cm. Biopsy of this mass reveal intestinal glands without atypia. Which of the following terms best describes this lesion? A. Adenoma B. Carcinoma C. Cyst D. Hematoma E. Papilloma

A. Adenoma -The answer could also be an "adenomatous polyp" Here we have a microscopic description of the biopsy which reveals "Intestinal glands without atypia" Atypia = structural abnormality within a cell -If asked about a mass that was projecting out of the surface epithelium into the mucosa it would be a polyp

Which of the following substances produced during inflammation are responsible for the hematological manifestations (anemia and increased ESR) in this patient? A. Hepcidin and fibrinogen B. PG and LT C. IL-17 and IL-12 D> C5a and C3a

A. Hepcidin and fibrinogen

Which of the following mediator is responsible for patients hematological manifestation *WBC count and ESR) in the case study? A. IL-6 B. IL-1 C. IL-17 D. IL-12

A. IL-6 B. IL-1 BOTH ARE CORRECT

A 11-year-old girl presents with advanced features of aging such as wrinkles, cataract and osteoporosis. This child has inherited mutations in the gene that encodes which of the following types of intracellular proteins? A. Lamin B. Cytokeratin C. Fibrillin D. Elastin E. Helicase

A. Lamin -The diagnosis is PROGERIA due to a gene mutation to LAMIN -Cytokeratin is an IF that is more of use in detecting cancers - Fibrillin mutations = Marfans Syndrome -Elastin = Marfans Syndrome *Rupture of aortic aneurysm could cause immediate death in patients with Marfin's Syndrome -Helicase - Warnacke's can be associated with this

A 38-year-old man has a health screening examination. He has a routine chest x-ray that shows a 2 cm nodule in the right lower lobe. The nodule has focal calcification's. A wedge resection of the nodule is done. On microscopic examination the nodule shows caseous necrosis and calcification. Which of the following processes best explains the appearance of the calcium deposition? A. Metastatic Calcification B. Hypercalcemia C. Apoptosis D. Dystrophic Calcification E. Hemosiderin Deposition

A. Metastatic Calcification

An 18-year-old male concerned with a recent onset of multiple bumpy swellings on the back, arms and shoulders. On physical exam; these swellings are non-tender, non-mobile and firm on palpation. The physician also notes axillary and groin hyper pigmentation. A clinical diagnosis of neurofibromatosis is offered. A loss of function mutations in which of the following is associated with this malignancy? A. NF-1 B. NF-2 C. K RAS D. KIT E. RET

A. NF-1 -Tumor suppressor gene -If the mechanism were asked: GAP inactivated -If there were a question on NF-2, the clinical vignette would have acoustic neuroma or shwanomma -The NF's are tumor suppressor genes. The rest are oncogenes

What stain do you use to identify Leiomyosarcoma? A. Vimentin B. Desmin

A. Vimentin -Leiomyosarcoma is malignancy of the SMOOTH MUSCLE therefore we would look for vimentin -Desmin - for SKELETAL & CARDIAC muscle

Carcinomas

ADENOCARCINOMA -Glandular growth pattern microscopically SQUAMOUS CELL CARCINOMA -Producing recognizable squamous cells arising in any epithelium of the body (Skin, Gi, bladder mucosa, etc) TRANSITIONAL CELL CARCINOMA -Origin- Transitional epithelium in the urinary system

Cellular responses to stress and noxious Stimuli FLOW CHART of how normal cell maintains after exposure: -If the cell can handle the stress, it goes to ADAPTATION by increasing the number or size of the cell -If these cells cannot handle the stress, they die by cell necrosis or apoptosis ultimately

ALTERED PHYSIOLOGICAL STIMULI; SOME NONLETHAL INJURIOUS STIMULI = CELLULAR ADAPTATION -Increased demand, increased stimulation (e.g., by growth factors, hormones) -> HYPERPLASIA, HYPERTROPHY -Decreased nutrients, decreased stimulation -> ATROPHY -Chronic irritation (physical or chemical) - METAPLASIA *Metaplasia is when their is a chronic site of injury the body will replace that tissue with a particular type of tissue that can stand the stress (replacement of one type of mature tissue by other to withstand the stress) *IE. Smoking. Usually bronchi covered by CILIATED COLUMNAR EPITHELIUM. In chronic smokers, the epithelium will be replaced by SQUAMOUS EPITHELIUM to withstand the stress. REDUCED OXYGEN SUPPLY; CHEMICAL INJURY; MICROBIAL INFECTION = CELL INJURY -Acute and transient -> Acute reversible injury->Cellular swelling fatty change -Progressive and severe (including DNA damage) -> Irreversible injury → cell death via Necrosis or Apoptosis METABOLIC ALTERATIONS, GENETIC OR ACQUIRED; CHRONIC INJURY = INTRACELLULAR ACCUMULATIONS/CALCIFICATIONS CUMULATIVE SUBLETHAL INJURY OVER LONG LIFE SPAN = CELLULAR AGING

A 55-year-old Mr. X arrives to emergency department with the complaints of Vomiting and abdominal pain for one day and sudden onset shortness of breath for the past few hours. Mr. X had sudden onset sharp abdominal pain with nausea and vomiting soon after attending the party where he ate heavy food and beer. Patient points to left upper quadrant as the center of pain that radiates to his back, with the intensity of the 8-9/10 (10 being the worst pain). He took aspirin soon after the pain started, but the vomiting started 30 min later. His past medical history obtained from his wife: Mr. X underwent successful alcohol rehabilitation, but started consuming alcohol about six months ago after the death of his father. He has hypertension. He does not have any history of food allergy or drug allergies. He denies of using tobacco or illegal substances. Vitals: HR- 114 bpm, RR-28, BP- 104/64 mm/hg, temperature- 101 F, SPo2 - 88% in room air. G/E: oriented to person, place and time. Obvious abdominal pain. Occasional grimacing and leaning over side of the wheel chair while clutching the pillow. Heart: regular rhythm. No gallops, murmur or rubs. Lung: breath sounds diminished in left lower lung field. Abdomen: distended, rigid with tenderness and pain in the left upper quadrant with light palpation. Liver is non-tender. No rebound tenderness. No abdominal bruit. Bowel sounds are hypoactive. CT scan: Pancreatic enlargement with lower-2/3rd border surrounded by fluid and necrosis. No tumor, or cysts noted in the pancreas. Complete blood count: RBC count- 3.5X106/cumm (4.3-5.9), WBC- 25X103/cumm (4.5-11), hemoglobin- 11g/dl (13.5-17.5), hematocrit- 33% (41-53), platelets- 475X103/cumm (150-400). Biochemistry: Random Glucose- 300 mg/dl (n- 80-140) , Na-130 meq/l (n-136-145), K-2.8 meq/l (n- 3.5-5), Ca-4 mg/dl (n- 8.4-10.2) BUN- 45 mg/dl (n- 7-18), serum creatinine- 1.3 mg/dl (0.6-1.2) Enzymes: Amylase- 600 U/dL (n- 25-125) and lipase - 400 U/dL (n- 23-85) 1. What is the expected WBC counts in the blood? A. Normal B. Low C. High 2. What is the term used for high WBC count in infections/inflammatory conditions? 3. What enzymes are expected to increase in this patient? 4. What type of fluid is most likely to be seen in the peritoneum of this patient? A. Exudate B. Transudate C. Chylous D. Serous 5. Which one of the following lab test of the patient indicate loss of function of the inflammed pancreas? B. Blood glucose!!!!

Acute Pancreatitis 1. C 2. Reactive Leukocytosis 3. Amylase and Lipase 4. Exudate -Why are platelet counts increased? This is a reactive increase Why is there a decrease in calcium levels? Amylase degrades the cell membrane, Lipase will go and combine with calcium leading toe deponization

Leukocyte recruitment to the site of inflammation

Adhesion to endothelium: Firm adhesion is achieved with the help of Integrin -Cytokines: TNF (tumor necrosis factor) and IL1 (interleukin 1) induce the expression of ligands VCAM/ICAM on endothelial cell surface . -Integrin on the surface of the leukocyte is upregulated by C5a and Leukotrienes -Firm adhesion and morphological changes *Cytoskeletal reorganization and change in shape of the cells. Integrin on Leukocyte : Ligand on endothelial cells VLA-4 (Beta 1 integrin): VCAM-1 LFA-1 (Beta 2 integrin): ICAM-1 MAC-1 (Beta 2 integrin): ICAM-1

A 68 yo male comes to you with fatigue and malaise for the past 15 months. Occupational history is that he worked in a PVC pipe industry for the past 20 years. CT abdomen shows an enhancing lesion in the R lobe of the liver and the biopsy showed malignant endothelial cells? Malignancy that arise from the blood vessels are called? What could be the occupational carcinogen?

Angiosarcomas, vinyl chloride

Mediators of inflammation: Arachidonic acid metabolites

Arachidonic acid metabolites (Prostaglandins and leukotrienes): -Arachidonic acid is a membrane phospholipid derived from diet or by conversion of linoleic acid. -AA released from the membrane by phospholipase A2. -Cyclooxygenase pathway thromboxane and prostaglandins -Lipoxygenase pathway leukotrienes

A 56-year-old male presents with a history of dyspepsia and indigestion for the past 6 months. Gastroscopy reveal an ulcer in the lower end of the esophagus. A representative gross and microscopic image is shown in the attached image. Which of the following is the most likely complication of this disorder? A. Squamous cell carcinoma B. Adenocarcinoma C. Hepatocellular carcinoma D. Angiosarcoma E. MALT lymphoma

B. Adenocarcinoma

A pathologist reviews the cervical biopsy slide of a 45-year-old female. He notices features of dysplasia, that are confined to the entire squamous epithelium with intact basement membrane. Which of the following pathological terms would best describes her cervical lesion? A. Carcinoma B. Metaplasia C. Choristoma D. Carcinoma in situ E. Hamartoma

D. Carcinoma in situ

A 45-year-old man hospitalized for acquired immunodeficiency syndrome (AIDS). Chest X-ray reveals a consolidation at the apex of the right lung. A PCR test for mycobacterium tuberculosis is positive. If a biopsy were done from this lesion. You would most likely see which of the following pathologic changes? A. Fat necrosis B. Fibrinoid necrosis C. Coagulative necrosis D. Caseous necrosis E. Gangrenous necrosis

D. Caseous Necrosis

IN reference to the CASE STUDY In this case the tissue injury, followed by acute inflammation and the persistence of the damaging agent is most likely to lead to.... A. Resolation B. Organization C. Suppuration D. Chronic Inflammation

D. Chronic Inflammation

A 45-year-old female presents with weight loss, fatigue and blood in stools for the past 4months. Colonoscopy reveals an ulceroproliferative mass in the right ascending colon. Genetic studies reveal mutations involving MSH2 and MLH1 in these malignant cells. This patient needs to be screened for which of the following additional cancers? A. Hepatocellular carcinoma B. Cervical carcinoma C. Burkitt lymphoma D. Endometrial carcinoma E. Transitional cell carcinoma

D. Endometrial Carcinoma

An epidemiologic study is performed to find risk factors for development of malignant neoplasms. A statistical analysis of pre-existing medical conditions is done. Some per-existing chronic medical conditions are observed to precede development of malignant neoplasms, while others do not. Which of the following conditions is most likely to be statistically related to development of a malignancy? A. Essential Hypertension B. Coronary Artery Disease C. Benign Prostatic Hypertrophy D. Endometrial Hyperplasia E. Chronic Bronchitis

D. Endometrial Hyperplasia -It is a premalignant condition that can lead to endometrial carcinoma

16-year-old male presents to the ER after an automobile accident. X-ray of the right leg reveals a compound fracture of the right tibia. The leg has been immobilized in a cast for 8 weeks. When the cast is removed, the patient notices that right leg is weak and smaller in circumference than the left. Which of the following pathologic mechanism is responsible for this morphological change? A. Increased DNA transcription B. Alteration of stem cell expression C. Increased secretion of growth factors D. Protein degradation by autophagolysosome E. Cell membrane rupture and inflammation

D. Protein degradation by autophagolysosome A = hypertrophy B = Metaplasia E = Irreversible cell damage

A 70-year-old man suffering from chronic knee pain for the past year. He has been evaluated. X-ray of the Knee joint shows decreased joints spaces with erosion and loss of articular cartilage. Destruction of which of the following matrix proteins is responsible for his disaese? A. Type IV B. Type I C. Type V D. Type II E. Type III

D. Type II Type II Collagen - Cartilage Type IV Collagen - Basement Membrane Type I Collagen - Bone Type III Collagen - Blood vessels, uterus & granulation tissue

A biopsy image of a chronic non healing ulcer on the cheek is attached. Pathologist describes this as malignant squamous epithelial cells with luminal keratin pearls surrounded by chronic inflammatory cells. Which of the following best describes the nature of this malignancy? A. Propensity to invade blood vessels B. Anaplastic carcinoma C. It indicates a poor prognosis D. Well differentiated carcinoma E. Well differentiated sarcoma

D. Well differentiated carcinoma

Primary intention / first intention

Day 3: neutrophils are largely replaced by macrophages. Formation of granulation tissue. Migration of fibroblasts. Day 4-5: Neovascularisation reaches its peak, granulation tissue fill the incision space and look oedematous (bec new vessels are leaky). Collagen bridges the incision site. One week: sutures are removed and tensile strength is ~ 10 % of unwounded skin. Second week: continues collagen accumulation and fibroblast proliferation and blanching. End of one month: connective tissue and devoid of inflammatory cells and covered by normal epidermis. By three months tensile strength of wound reaches to 70-80% of unwounded skin. Mostly composed of collagen type I.

Deposition and remodeling of connective tissue

Deposition of connective tissue : *Migration and proliferation of fibroblasts *Production of extracellular matrix Achieved and orchestrated by growth factors: PDGF, FGF-2 and TGF-β. Proliferating blood vessels, proliferating fibroblasts, neutrophils, monocytes and connective tissue (type III) form granulation tissue.

40 yo male comes to you with Chest pain, dyspnea and profuse sweating. His father died at the age of 36 due to MI. On examination he has yellowish deposits on the eye and hard masses on the tendon achiles. What is the diagnosis?

Diagnosis is Familial Hypercholesterolemia, due to defect in LDL receptor -You would get tendon xanthomas

A 60-year-old man presents with a history seizures and episodic syncope for the last 6-months. MRI-Brain reveals an enhancing hypodense area in the white matter of left parietal cortex. A representative biopsy of the lesion is diagnosed as a malignant glioma. Which of the following intermediate filament immunohistochemistry test, would help the Pathologist to confirm glial differentiation? A. Vimentin B. Desmin C. Cytokeratin D. Lamin E. GAFP

E. GAFP -GFAP is secreted by neuroglia such as astrocytes - the diagnosis is astrocytoma or glioma -Cytokeratin - Epithelium of various places (skin, GI, etc.) - CARCINOMAS -Desmin - Muscle -Vimentin - Mesenchymal Tissue (bone, cartilage, blood vessels, lipocytes)

Autopsy of a 67-year-old female with a past history of myocardial infarction revealed a cystic lesion in the left cortical white matter of the brain( Shown in the attached image). Which of the following best describes the morphology in the affected region? A. Caseous Necrosis B. Coagulative Necrosis C. Fat Necrosis D. Fibrinoid Necrosis E. Liquefactive Necrosis

E. Liquefactive Necrosis -MI pt's are more prone for thromboembolism. Some thrombos will embolyze from the heart to the brain leading to infarction of the brain leading to Liequefactive Necrosis -Coagulative necrosis you would get in all tissues except the brain

Proliferation of epithelial cells

EGF & TGF-alpha

Which hormones use nonreceptor Tyrosine Kinase Pathway?

EPO, Thrombopoetin, IL-2, IL-6

Grading and Staging

Grading -Based on microscopic features of cells which compose a tumor -Specific for tumor type -Done by the pathologist Staging -Based on clinical, radiological, and surgical criteria- tumor size, involvement of regional LN, & presence of metastases -Prognostic value -Done by the subject

A known hypertensive patient of 8 years comes to your office with palpitation and chest pain. You do an echo and see an ncreased L ventricle thickness and ECG shows tall QRS complex. What is the diagnosis?

Left Ventricular Hypertropy -Specifically CONCENTRIC hypertrophy *Don't get this confused with dilatation/essentric hypertrophy. These sarcomeres don't have the capacity to divide so they actually re-arrange

Defects in Leukocyte function: innate immune system -Here you will expect increased leukocytes in the circulation (leukocytosis)

Leukocyte adhesion deficiency (LAD) -Autosomal resistive conditions: LAD I, II and III -Most frequent is LAD I: Mutation involving β2 integrin gene (MAC-1 & LFA- 1) -Clinical features: recurrent bacterial and fungal infection which are pus free, skin infections, impaired wound healing, delayed falling of umbilical cord. -Diagnosis: CBC; leukocytosis (>30,000/μl) , Immunofluorescence and functional assays to detect β2 integrin defect.

Leukocyte recruitment to the site of inflammation (continued)

Leukocyte migration through endothelium: Transmigration or Diapedesis -Platelet endothelial cell adhesion molecule - PECAM-1 (CD31) helps in transmigration. -After traversing the endothelium leukocytes traverse basement membrane by secreting collagenases and other enzymes (stored in primary and secondary granules).

Leukocyte recruitment to the site of inflammation

Margination: -Accumulation of leukocytes along endothelial surface -Achieved by: mechanical factor (Vasodilatation and vascular stasis) and by chemical mediators ( Leukotrienes and complement products) *Normally the blood flows in the laminal fashion, in the central of the vessel you see cells and in the periphery you see the plasma. Because of changes in the vascular permeability and vasculostasis, laminar flow is destructed leading to margination -VASODILITATION and VASCULOSTASIS are the only factors that help with MARGINATION during inflammation, but later on leukotrines and complement proteins help with margination also Rolling: -Mediated by Selectins (CD 62) -Binding mediated by selectins is week and it easily disrupted by flow of blood -E-selectin (expression is induced by TNF and IL1) on endothelium bind to Sialyl-lewis X on Leukocytes -Expression of selectins and their ligands is regulated by TNF and IL1

Bone fractures with various phases of healing and blue sclerae ____________ due to the defect in the synthesis of ____________

Osteogenesis Imperfecta Due to the defect in COLLAGEN TYPE I -OI 1 is compatible with life -OI 2 is fatal

68 yo male comes to you with a history of hematuria for the past 10 days. Cystoscopy reveals an ulcer on the dome of the bladder and biopsy reveals a foci of squamous epithelium with adjacent inflammation. What is the diagnosis?

Metaplasia! -The normal lining of the urinary bladder is transitional epithelium. There should be no squamous epithelium there!

A 48 yo man comes to you with a hx of epigastric pain and a recent alteration in his mood. On exam his serum calcium levels are 18mg/dL. Endoscopy biopsy of the stomach shows calcified deposits within the GI epithelium. What type of calcification is it?

Metaplastic calcification -Epigastric pain and mood disorders are common with elevated serum calcium levels -You would see dystrophic calcification in the tissues such as necrosis, or dying tissues. Ie. senile aortic stenosis

Cancer incidence

Most common tumors In men PROSTATE, lung, colorectal cancers In women BREAST, lung, colon and rectum >50% of cancer diagnoses and cancer deaths in U.S. population -Lung, breast, prostate, colon/rectum *Remember LUNG CA has the HIGHEST MORTALITY

Necrosis Vs. Apoptosis

NECROSIS: -Enlarged cells (swelling) -Nucleus: Karyolysis -> Pyknosis -> Karyorrhexis -Plasma membrane: disrupted -Cellular contents: Enzymatic digestion, may leak out of cell -Adjacent Inflammation: Frequent -Physiological or pathologic role: Invariably pathalogic (culmination of irreversible cell injury) APOPTOSIS: -Reduced cells (shrinkage) -Nucleus: ragmentation into nucleosome-size fragments -Plasma Membrane: Intact; altered structure, especially orientation of lipids -Cellular Contents: Intact; may be released in apoptotic bodies -Adjacent Inflammation: No -Physiologic or pathologic role: Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage

Phagocytosis and clearance of offending agent

Phagocytosis 1. Recognition and attachment of particle to be ingested 2. Engulfment and formation of phagocytic vacuole 3. Killing or degradation of ingested material Phagocytic receptors: Recognition and attachment of particle to be ingested. -Mannose receptors: terminal mannose and fructose residues of GP & GL -Scavenger receptors: oxidized or acetylated LDL, -Specific receptors for IgG, C3b, and breakdown products of complements. Engulfment -Phagosome. -Lysosome and phagosome fuse together to form phagolysosome. -Killing of microbes occurs inside the phagolysosome.

Review of special histochemical stains used for identification of Pigments

Pigment: Iron Stain: Prussian Blue Pigment: Fat (triglycerides) Stain: Oil Red and Sudan Black Pigment: Glycogen Stain: PAS Pigment: Calcium Stain: Von Kossa Pigment: Melanin Stain: Masson-Fontana Pigment: Amyloid Stain: Congo Red

Middle aged female comes to you with history of abdominal distention so ultrasound reveals a cystic mass with teeth, hair, glands. What is the diagnosis?

Teratoma -Seen commonly in ovaries and testes

80 yo male comes to you with a history of difficulty of urination and back pain for the past 3 months. On scan, you found these metastasis as blastic. What is the diagnosis?

Prostatic cancer

A 30 yo female comes to you with seizures and HA for the past 10 days. CT of head shows a dural enhancing mass. If you do a biopsy, what changes are you most likely to see apart from the malignant cells?

Psammoma bodies -The diagnosis is MENINGIOMA (in block they will give the diagnosis) -This is HIGH yield -Remember PSMM *Papillary Carcinoma of the Thyroid *Serous Papillary Carcinoma of the Ovary *Meningioma *Mesothelioma

Mixed tumor -All malignant neoplasms have a single clonal abnormality, that is, they are MONOCLONAL (feature of malignancy) *Ie. If a cell has a bcl2 mutation. Ultimately, the lymph node will be filled with cells with that single abnormality. Just because of one cell, all cells will express that mutation in bcl2. -With mixed tumors, ONE SINGLE CELL CAN DIFFERENTIATE INTO TWO *Ie. It can differentiate into epithelial cell and mesenchymal cell *Common example is SALIVARY GLAND TUMORS (PLEOMORPHIC ADENOMA - common benign malignancy arising from the parotid gland - shows cartilagenous background and myoepithelial background)

Two morphological patterns -Derived from the same germ cell origin -Example *Mixed tumor of salivary gland *Origin- myoepithelial or Ductal reserve cells *Epithelial cells *Myxoid stroma and cartilage-like tissue

Radiation Carcinogenesis 3 types of UV radiation UVa, UVb, and UVc UVa has broad wavelength UVb is our interest of studies! 260-320! - known to causes multiple skin cells like BCC and squamous cell carcinanoma and malignant melanoma -Uses pyrimidine dimers in the same strand of DNA, if no dna repair mechanisms, the pyrimidine dimers will continue

UV radiation -Skin cancer *Basal cell carcinoma, squamous cell carcinoma, melanoma -Mechanism *Pyrimidine dimers → DNA damage -Individuals with defects in enzymes that mediate DNA repair are particularly susceptible