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Uncontrolled, clonal proliferation of cells Neoplasia
What are hallmarks of cancer? 1. Evasion of apoptosis 2. Growth signal self-sufficiency, 3. Anti-growth signal insensitivity, 4. Warburg effect, 5. Sustained angiogénesis 6. Limitless replicate potential 7. Tissue evasion 8. Metastasis
What is Warburg effect? Shift of glucose metabolism away from mitochondria toward glycolysis.
What is the polarity of normal cells? Apical
What is carcinoma in situ? Irreversible severe dysplasia that involves the entire thickness of epithelium but does not penetrate the intact basement membrane.
What is another term of carcinoma in situ? Preinvasive
Definition of invasive carcinoma Cells have invaded basement membrane using collagenases and hydrolases
Cell-cell contacts lost by inactivation of E-cadherin Invasive carcinoma
What are the means of transport of metastasis? Lymphatics or blood
A carcinoma implies _______________ origin. Epithelial
A sarcoma denotes ______________ origin. Mesenchymal
Description of benign tumors: Well differentiated, well demarcated, low mitotic activity, no metastasis, and no necrosis.
Malignant tumors may show: Poor differentiation, erratic growth, local invasion, metastasi, and decreased apoptosis.
What are terms of non-neoplastic malformation? Hamartoma and choristoma
Disorganized overgrowth of tissues in their native location Hamartoma
What is Choristoma? Normal tissue in foreign location
What would be an example of choristoma? Gastric tissue in distal ileum in Meckel diverticulum
What is malignant tumor of blood cells? Leukemia, and lymphoma
What is benign tumor of smooth muscle? Leiomyoma
What is the common benign melanocytic tumor? Nevus/mole
What is differentiation? Degree to which a tumor resembles its tissue of origin
What is the definition of Anaplasia? Complete lack of differentiation of cells in a malignant neoplasm
Well-differentiated tumors are ________ aggressive. Less
What is meant with grande in respect to tumor classification? Degree of cellular differentiation and mitotic activity on histology.
Degree of localization/spread based on site and size of primary lesion, spread to regional lymph nodes, presence of metastases. Stage
TNM staging system T = Tumor size/invasiness N = Node involvement M = Metastases
Each TNM factor has ---> Independent prognostic value
What are musculoskeletal and cutaneous paraneoplastic syndrome? 1. Dermatomyositis 2. Acanthosis nigricans 3. Sign of Leser-Trélat 4. Hypertrophic osteoarthropathy
What are the associated tumors in Dermatomyositis? Adenocarcinomas, especially ovarian
What are the most common associated tumors of Acanthosis nigricans? Gastric adenocarcinoma and other visceral malignancies
Hypertrophic osteoarthropathy is seen with adenocarcinoma of the __________. Lung
What is the description Hypertrophic osteoarthropathy? Abnormal proliferation of skin and bone at distal extremities --> clubbing, arthralgia, joint effusions, periostosis of tubular bones.
Small cell lung cancer is associated with which Paraneoplastic syndromes? Cushing syndrome and Hyponatremia (SIADH)
What are some common hematologic paraneoplastic syndromes? Polycythemia, Pure red cell aplasia Good syndrome Trousseau syndrome Nonbacterial thrombotic (marantic) endocarditis
Thymoma is associated with which hematologic conditions? Pure red cell aplasia and Good syndrome
What is the "Good syndrome" most significant clinical feature? Hypogammaglobulinemia
Trousseau syndrome is most associated with ____________ (tumor). Pancreatic adenocarcinoma
Associated tumors that produce Polycythemia Pheochromocytoma, Renal cell carcinoma, HCC, Hemangioblastoma, and Leiomyoma.
List of Neuromuscular Paraneoplastic syndromes: 1. Anti-NMDA receptor encephalitis 2. Opsoclonus-myoclonus ataxia syndrome 3. Paraneoplastic cerebellar degeneration 4. Paraneoplastic encephalomyelitis 5. Lambert-Eaton myasthenic syndrome 6. Myasthenia gravis
What neuromuscular paraneoplastic syndrome is associated with Thymoma? Myasthenia gravis
Lambert-Eaton Myasthenic syndrome is associated with which tumor? Small cell lung cancer
Antibodies against presynaptic Ca2+ channels at NMJ. Dx? Lambert-Eaton Myasthenic syndrome
What is the cause of Myasthenia gravis? Antibodies against postsynaptic ACh receptors at NMJ
What condition affects the PREsynaptic calcium channels at NMJ? Lambert-Eaton Myasthenic syndrome
Which condition is seen with antibodies attacking the POSTsynaptic ACh receptors? Myasthenia gravis
"Dancing eyes, dancing feet". Dx? Opsoclonus-myoclonus ataxia syndrome
Which are the tumors associated with the development of Opsoclonus-myoclonus ataxia syndrome? Neuroblastoma in children and Small cell lung cancer in adults
Antibodies against antigens in Purkinje cells. Dx? Paraneoplastic cerebellar degeneration
What are the associated tumors of Paraneoplastic cerebellar degeneration? 1. Small cell lung cancer (anti-Hu) 2. Gynecologic and breast cancers (anti-Yo) 3. Hodgkin lymphoma (anti-Tr)
Anti-Hu, anti-Yo, and anti-Tr. Markers of tumors seen in the development of Paraneoplastic cerebellar degeneration
Ovarian teratoma often causes what neuromuscular paraneoplastic syndrome? Anti-NMDA receptor encephalitis
List of Paraneoplastic syndromes associated with Small cell lung cancer: 1. Hypertrophic osteoarthropathy 2. Cushing syndrome 3. SIADH 4. Opsonus-myoclonus ataxia syndrome 5. Paraneoplastic cerebellar degeneration 6. Paraneoplastic encephalomyelitis 7. Lambert-Eaton Myasthenic syndrome
Clinical signs include: Psychiatric disturbances, memory deficits, seizures, dyskinesias, autonomic instability, and language dysfunction. Associated with Ovarian tumor. Dx? Anti-NMDA receptor encephalitis
Which are some of the tumors or neoplasms that produce Hypercalcemia (due to increased PTHrP) as Paraneoplastic syndrome? 1. Squamous cell carcinoma of lung, head, and neck 2. Renal, bladder, breast, and ovarian carcinomas
EBV associated cancers: 1. Burkitt lymphoma 2. Hodgkin lymphoma 3. Nasopharyngeal carcinoma 4. Primary CNS lymphoma (immunocompromised)
Burkitt lymphoma is often see with what kind of infectious agent? EBV
What does Burkitt lymphoma, Nasopharyngeal carcinoma, and Primary CNS lymphoma have in common? Associated with EBV infection
Which hepatitis infections are associated with HCC? HBV and HCV
Associated cancer of HHV-8 infection? Kaposi sarcoma
HPV ----> associated cancers? Cervical and penile/anal cancers (types 16,18), head and neck cancer.
What infection is often associated to Gastric adenocarcinoma? H. pylori
H. pylori infection is associated with which tumors? Gastric adenocarcinoma and MALT lymphoma
HTLV-1 infections ----> Tumor? Adult T-cell leukemia/lymphoma
What microbe is associated with Cholangiocarcinoma? Liver fluke (Clonorchis sinensis)
Squamous bladder cancer is often described with preceding infection of: Schistosoma haematobium
Aflatoxin exposure examples: Stored in grains and nuts
What is the associated carcinoma of Aflatoxin exposure? Hepatocellular carcinoma
What are examples of aromatic amine exposure? 1. Textile industry (dyes) 2. Cigarette smoke (2-naphthylamine)
Aromatic amines cause ______________ cancer. Bladder cancer
What kind of bladder cancer is seen with exposure to industrial textile dyes? Transitional cell carcinoma of the bladder
Benzidine and 2-naphthylamine are examples of : Aromatic amines
What are common Arsenic exposures examples? Herbicides (vineyard workers), and metal smelting
Arsenic exposure causes damage to which organs? Liver, Lung, and Skin
Associated cancer of arsenic exposures and affection to the liver Angiosarcoma
Person with arsenic exposure. What is the cutaneous cancer association? Squamous cell carcinoma of the skin
Which jobs are often associated with Asbestos exposure? 1. Old roofing material 2. Shipyard workers
What organ is mostly affected by Asbestos exposure? Lung
Which cancer is most common in Asbestos exposures? Bronchogenic carcinoma
What are the two associated tumors/cancers with Asbestos exposure? Bronchogenic carcinoma>>>> Mesothelioma
What type of bladder cancer is due to cigarette smoking? Transitional cell carcinoma
Which are the associated cancers of the lung due to cigarette smoking? Squamous cell and Small cell carcinoma
Cigarette smoking may cause what kidney cancer? Renal cell carcinoma
What is the neoplastic manifestation of cigarette smoking and affection in the Esophagus? Squamous cell carcinoma/adenocarcinoma
What organs are most affected by excessive ethanol consumption? Esophagus and Liver
Ionization radiation to the Thyroid is associated with development of: Papillary thyroid cancer
What is an important risk factor for development of Papillary thyroid carcinoma? Ionizing radiation
What kind of toxin is presented with smoked foods? Nitrosamines
Nitrosamine consumption is associated with ____________ cancer. Gastric
What is the neoplastic relevant toxin found in material used to make PVC pipes? Vinyl chloride
What kind of worker/job is most likely to be in exposures with Vinyl chloride (toxin)? Plumber/plumbing
Vinyl chloride exposure affects the _____________ leading to development of __________________. Liver ----> angiosarcoma
What are Psammoma bodies? Laminated, concentric spherules with dystrophic calcification
What are conditions/cancers seen with Psammoma bodies? Papillary carcinoma of thyroid Serous papillary cystadenocarcinoma of ovary Meningioma Malignant Mesothelioma
Why type of thyroid cancer is seen with Psammoma bodies? Papillary carcinoma of thyroid
Which ovarian carcinoma is seen with Psammoma bodies? Serous cystadenocarcinoma of ovary
Which type of asbestos-related cancer is seen with Psammoma bodies? Malignant Mesothelioma
What is the most important/relevant histologic feature of Papillary thyroid carcinoma? Psammoma bodies
What histological finding can further distinguish between Bronchogenic carcinoma and Mesothelioma? Psammoma bodies in Mesothelioma
What should be the use of serum tumor markers? Monitor tumor recurrence and response to therapy
What is used to monitor tumor recurrence and response to therapy? Levels of serum tumor markers
What procedure should be the one used for definitive diagnosis of cancer? Biopsy
What the important associations of Alkaline Phosphatase? 1. Metastases to bone or liver, 2. Paget disease of the bone 3. Seminoma (placental ALP)
What is the common abbreviation for Alkaline Phosphatase? ALP
Elevated placental ALP is seen in __________________. Seminoma
Elevation in sumru tumor marker, ALP, is seen with metastases to ___________ or _________. Bone or liver
How can ALP be distinguished or separated from hepatic origin? Exclusion of hepatic origin by checking LFTs and GGT levels
Why are LFTs and GGTs levels often measured in cases of elevated ALP? To exclude is ALP is of liver origin.
List of associations seen with elevated a-Fetoprotein: 1. Hepatocellular carcinoma 2. Endodermal sinus (yolk sac) tumor 3. Mixed germ cell tumor 4. Ataxia-telangiectasia 5. Neural tube defects
Low levels of AFP are seen with? Down syndrome
What kind of defects are seen with high levels of AFP? Neural tube and abdominal wall defects
Which endodermal sinus tumor is seen with elevated AFP? Yolk sac tumor
Elevated B-hCG is seen with: - Hydatiform moles -Choriocarcinomas - Testicular cancer - Mixed germ cell tumor
Which tissue normally produces B-hCG? Syncytiotrophoblasts of the placenta
Tumor markers for Breast cancer: CA 15-3/CA 27-29
Tumor marker of Pancreatic adenocarcinoma? CA 19-9
CA 125, is an _________________ cancer serum tumor marker. Ovarian
What serum marker is used in Ovarian cancer? CA 125
What is the most common serum marker used for Medullary thyroid cancer? Calcitonin
Which syndromes are seen with elevated Calcitonin? MEN2A and MEN2B
What are the two major associations of CEA? Colorectal and Pancreatic cancers
What are minor associations of CEA tumor marker? Gastric, breast, and medullary thyroid carcinomas
CEA is the abbreviation for: Carcinoembryonic antigen
What type of tumors use Chromogranin as a serum tumor marker? Neuroendocrine tumors
LDH is a serum tumor marker for which cancers? Testicular germ cell tumors Ovarian dysgerminoma
PSA is seen elevated in _____________ cancer. Prostate
LDH is elevated in which ovarian cancer? Ovarian dysgerminoma
Which testicular cancers result in elevated LDH leves? Testicular germ cell tumors
Prostate-specific antigen is abbreviated ___________. PSA
What other non-neoplastic conditions elevate PSA? BPH adn prostatitis
Why are immunohistochemical stains important in cancerous processes? 1. Determine primary site of origin for metastatic tumors 2. Characterize tumors that are difficult to classify
Immunohistochemical stains may have what important characteristic/ values? Prognostic and predictive values
What is Vimentin's (stain) target? Mesenchymal tissue
What stain is used to identify Mesenchymal tumors? Vimentin
List of important immunohistochemical stains: Vimentin, S-100 Desmin Cytokeratin GFAP Neurofilament PSA TRAP Chromogranin and synaptophysin
What is the target of S-100 stain? Neural crest cells
What stain is used to identify neural crest cells? S-100
What are common (+) S-100 tumors? Melanoma, Schwannoma, Langerhans cell histiocytosis
Melanoma and Schwannoma are both (+) for ___________. (stain) S-100
What is the most common immunohistochemical stain used for muscle tumors? Desmin
What is stain/targeted by desmin (immunohistochemical stain)? Muscle
What is Desmin? Important immunohistochemical stain of muscles
What are common cells identified as (+) GFAP? Astrocytes, Schwann cells, and Oligodendrocytes
What is the target of GFAP stain? Neuroglia
What are the two most important (+) GFAP tumors? Astrocytoma and Glioblastoma
What immunohistochemical stain can be used to ID Neurons and Neuronal tumors? Neurofilament
Neuroblastoma is (+) for what immunohistochemical stain? Neurofilament
What is the target for stain PSA? Prostatic epithelium
Prostatic epithelium is stain by ____________. PSA
Hairy cell leukemia is (+)___________. TRAP
(+) TRAP. Dx? Hairy cell leukemia
What are common tumors identified by (+) chromogranin and synaptophysin stains? 1. Small cell carcinoma of the lung 2. Carcinoid tumor
What is another name for P-glycoprotein? Multidrug resistance protein 1 (MDR1)
What is the function of P-glycoprotein? Pump out toxins, including chemotherapeutic agents
Why is P-glycoprotein considered a "resistance" factor to chemotherapy? It causes the pump-out of toxins, including those chemotherapeutic agents --> decreased response to therapy.
What is the most common cancer to show elevated levels of P-glycoprotein? Adrenocortical carcinoma
What is cachexia? Weight loss, muscle atrophy, and fatigue that occur in chronic disease.
What are the cytokines that mediate cachexia? TNF, IFN-gamma, IL-1, and IL-6.
What is the most common cancer? Skin cancer
What is the most common type of skin cancer? Basal >Squamous >> melanoma
What is the highest incidence cancer in men? Prostate
What is the top 3 cancer mortality in men? Lung > Prostate > Colon/ rectum
What is the number 1 cancer incidence in women? Breast
Leukemia is the cancer with highest incidence and mortality in ______________. Children (0-14 years)
What is the 2nd leading cause of death in the United States? Cancer
What is the leading cause of death in the USA? Heart disease
What is the leading cancer mortality in men and women? Lung
What are the top 3 cancer incidence and mortality in children? Leukemia > CNS > Neuroblastoma
What are 50% of brain tumors? Arise from metastases
What are the most common primary tumors that metastasizes to brain? Lung > breast > melanoma, colon, and kidney.
What type of primary tumor metastases to liver the most? Colon
What are the most common sites of metastasis after regional lymph nodes? Liver and lung
Gene prodcut of ALK Receptor tyrosine kinase
What are the associated neoplasms of ALK? Lung adenocarcinoma
What is the gen product of BCR-ABL? Tyrosine kinase
What are the associated neoplasms of BCR-ABL gene? CML, ALL
CML is due to which gene? BCR-ABL
What is the associated neoplasm of BCL-2? Follicular and diffuse large B cell lymphomas
What is the associated gene product of Follicular and diffuse large B cell lymphoma? Antiapoptotic molecule
What is the gene product of Bcl-2? Antiapoptotic molecule
What is the role or function of antiapoptotic molecule? Inhibits apoptosis
What gene is associated with Diffuse large B cell lymphoma? Bcl-2
Gain of function mutation converts proto-oncogene to oncogene. Oncogene function
Need damage to only one allele Oncogene
What is the gene product of BRAF? Serine/threonine kinase
What are the associated neoplasms of gene BRAF? Melanoma, non-Hodgkin lymphoma, papillary thryroid carcinoma
GIST associated gene? c-KIT
What is the gene product of c-KIT? Cytokine receptor
Cytokine receptor is the gene prodcut of which gene? c-KIT
What is the associated gene of Gastrointestinal stromal tumor? c-KIT
c-MYC produce asn ___________________ (gene product). Transcription factor
What is the associated neoplasm of c-MYC? Burkitt lymphoma
Burkitt lymphoma is due to a _____________ produced by c-MYC. Transcription factor
What is the HER2/neu (c-erbB2) gene product? Receptor tyrosine kinase
Which genes have Receptor tyrosine kinase as gene product? RET, HER2/neu , and ALK.
Associated neoplasm of JAK2 gene? Chronic myeloproliferative disorders
What cancers are associated with gen KRAS? Colon, lung, and pancreatic cancers
Which transcription factor (gene) is associated with Lung tumor? MYCL1
N-myc gene makes a transcription factor and is associated with __________________. Neuroblastoma
RET gene is involved in which neoplasms? MEN 2A and 2B, and papillary thyroid carcinoma
Loss of function refers to tumor suppressor or oncogenes? Tumor suppressor genes
Both alleles of need to mutated for expressivity of disease Tumor suppressor gene
APC is a ____________________________ gene. Tumor suppressor
What is the associated condition of APC (gene)? Colorectal cancer
How does APC cause colorectal cancer? Negative regulator of B-catenin/WNT pathway
Which are two common DNA repair proteins associated with Breast, ovarian, and pancreatic cancer? BRCA1/BRCA2
What are the associated neoplasms of CDKN2A? Melanoma and Pancreatic cancer
Colon cancer is associated with which tumor suppressor gene? DCC
Gene APC refests to _______________________ cancer, and DCC is associated with ______________ cancer. APC ----> colorectal DCC ------> colon
Deleted in Colon Cancer DCC
Deleted n Pancreatic Cancer DCP
DCP is the gene product of which specific gene? SMAD4 (DPC4)
Gene product of MEN1? Menin
Gene product of NF2? Merlin (schwannomin) protein
Ras GTPase activating protein Neurofibromin
What is the role PTEN? Negatively regulates PI3K/AKT pathway
What are the associated neoplasm of PTEN? Breast, Prostate, and endometrial cancer
What is the product or function of Rb? Inhibits EF2; Blocks G1 ---> S phase transition
Retinoblastoma and Osteosarcoma are both associated with ____, a tumor suppressor gene. Rb
Which are the most important Rb-associated neoplasms? Retinoblastoma and Osteosarcoma
What is the role of TP53 gene? Its gene product is p53, which activates p21, and blocks G1 --S phase transition.
What tumor suppressor gene is often affected in most human cancers? TP53
What syndrome is due to mutated TP53 tumor suppressor gene? Li-Fraumeni syndrome
What malignancies are associated with Li-Fraumeni syndrome? Sarcoma, Breast, Leukemia, and adrenal gland
SBLA is another way to refer to: Li-Fraumeni syndrome
What is the the associated tumor suppressor gene and gene product of Tuberous sclerosis? TSC1; Hamartin protein
What are the two associated proteins in the development of Tuberous sclerosis? Tuberin and Hamartin proteins
What is the role of VHL? Inhibits hypoxia inducible factor 1a
What condition is associated with VHL? von Hippel-Lindau disease
Mutated tumor suppressor gene WT1 causes --> Wilms tumor (nephroblastoma)
What is the role of WT1 gene? Transcription factor that regulates urogenital development
What are cellular adaptations? Reversible changes that can be physiologic or pathologic
What is Hypertrophy? Increase structural proteins and organelles --> increase in size of cells
The cellular adaptation the causes increase in size of cells Hypertrophy
What type of cellular adaptation results in increase number of cells? Hyperplasia
What is hyperplasia? Controlled proliferation of stem cells and differentiated cells --> increase in number of cells
What can be complications of excessive cell stimulation? Pathological hyperplasia, which may progress to dysplasia and cancer
Definition of atrophy Controlled tissue mass due to decrease in size and/or number of cells
How is a decrease in tissue mass due to decrease size done? Increase cytoskeleton degradation via ubiquitin-proteasome pathway and autophagy.
What are some actions that lead to atrophy? Disuse, denervation, loss of blood supply, loss of hormonal stimulation, and poor nutrition
Reprogramming of stem cells --> replacement of one cell type by another that can adapt to a new stress. Metaplasia
What cellular adaptation occurs when one cell type is replaced by another? Metaplasia
What are some common causes of metaplasia? Cigarette smoking and irritation by gastric acid
What is dysplasia? Cellular adaptation consisting of disordered , precancerous epithelial cell growth.
Loss of uniformity of cell size and shape; loss of orientation; nuclear changes. Dysplasia
Precancerous epithelial uncontrolled growth. Dysplasia
Severe dysplasia: Usually becomes irreversible and progresses to carcinoma in situ.
Carcinoma in situ are commonly due to severe _______________. Dysplasia
What nuclear irreversible cell injury changes? 1. Pyknosis (condensation) 2. Karyorrhexis (fragmentation) 3. Karyolysis (fading)
What are clinical terms for Nuclear condensation, fragmentation, and fading? Pyknosis, Karyorrhexis, and Karyolysis
Cellular membrane blebbing and nuclear chromatin clumping are examples of: Reversible cell injury manifestations
Definition of Apoptosis: ATP-dependent programmed cell death
Does Apoptosis require ATP? Yes, it is a ATP-dependent activity
Apoptosis as ______________ and ______________ pathways. Intrinsic and Extrinsic
What are the shared features between the intrinsic and extrinsic pathways of apoptosis? Activate caspases --> cellular breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic bodies, which are then phagocytosed.
What cellular action is characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis, and karyorrhexis? Apoptosis
How does Karyorrhexis occurs in apoptosis? Fragmentation caused by endonuclease-mediated cleavage.
What is different in respect cell membrane between apoptosis and necrosis? In apoptosis the cell membrane remains intact without significant inflammation.
What is an important and sensitive indicator of apoptosis? DNA laddering
What is DNA laddering? Fragments in multiples of 180 bp
The mitochondrial pathway refers to the ______________ pathway of apoptosis. Intrinsic
When does the intrinsic pathway of apoptosis occurs? As a regulating factor is withdrawn from a proliferating cell population.
What regulates the Intrinsic pathway of apoptosis? Regulated by Bcl-2 family of proteins
Two PRO-apoptotic proteins: BAX and BAK
Which Bcl-2 family proteins are anti-apoptotic? Bcl-2 and Bcl-xL
What is the function of BAX and BAK? Form pores in the mitochondrial membrane --> release of cytochrome C from inner mitochondrial membrane ito cytoplasm --> activation of caspases
Due to mitochondrial pore formation due to proapoptotic proteins what gets activated? Caspases
What are caspases? Cytosolic proteases
Caspase activation is associated with _______________. Apoptosis
How does Bcl-2 prevent apoptosis? Keeps mitochondrial membrane impermeable, thereby preventing cytochrome C release.
Bcl-2 overexpression ------->? Decrease caspase activation ---> tumorigenesis
What are the two pathways of the Extrinsic Pathway of apoptosis? 1. Ligand receptor interactions 2. Immune cell
What are the Ligand receptor interactions of the Extrinsic paths of apoptosis? 1. FasL binding to Fas, or, 2. TNF-alpha binding to its receptor
What is the Immune cell pathway of the extrinsic apoptotic pathway? Cytotoxic T-cell release of perforin and granzyme B
Fas-FasL interaction is necessary for: Thymic medullary negative selection
What is the result of mutations in Fas? Increased numbers of circulating self-reactive lymphocytes due to failure of clonal deletion
What is the result of defective Fas-FasL interactions? Autoimmune lymphoproliferative syndrome
Necrosis is an ________________ process unlike apoptosis. Inflammatory
What is the definition of Necrosis? Enzymatic degradation and protein denaturation of cell due to exogenous injury --> intracellular components leakage.
When is Coagulative necrosis seen? Ischemia/infarcts in most tissues (except brain)
Which is a tissue that does not show coagulative necrosis? Brain
Coagulative necrosis is due to: Ischemia or infarction; injury denatures enzymes ---> proteolysis blocked
Which type of necrosis is seen with Proteolysis blocked? Coagulative necrosis
Histology of Coagulative necrosis: Preceserved cellular architecture but nuclei disappear; Increased cytoplasmic binding of eosin stain
Histological view presents preserved cellular architecture, no nuclei, and increase cytoplasmic binding of eosin stain. Coagulative necrosis
Liquefactive necrosis is seen with: Bacterial abscesses and brain infarcts
What kind of necrosis is seen in brain infarcts? Liquefactive necrosis
Why does liquefactive necrosis occur? Neutrophils release lysosomal enzymes that digest the tissue
What are the main WBC type that carry out Liquefactive necrosis? Neutrophils
What is the late histological view of Liquefactive necrosis? Cystic spaces and cavitation (brain)
Which infections/conditions are seen with Caseous necrosis? TB, systemic fungi (histoplasma capsulatum), and Nocardia
Macrophages wall off infecting microorganism --> granular debris. Caseous necrosis pathogenesis
What is the histological features of Caseous necrosis? Fragmented cells and debris surrounded by lymphocytes and macrophages.
Which type of necrosis is seen with the formation of granulomas? Caseous necrosis
What are the main type of cells involved in Caseous necrosis? Macrophages
Fat Necrosis is seen with: 1. Enzymatic: acute pancreatitis 2. Nonenzymatic: Traumatic
Why does acute pancreatitis cause Fat necrosis? Saponification of peripancreatic fat
Fat necrosis is due to; Damaged cells release lipase, wich brask down triglycerides; liberated fatty acids bind calcium ---> SAPONIFICATION
Saponification is associated with _____________ necrosis. Fat
Fat necrosis histological features - Outlines of dead fat cells without peripheral nuclei - Saponification of fat appears dark blue on H&E stain
Vessel walls are thick and pink. Description of histological feature of ______________ necrosis. Fibrinoid
What conditions produce Fibrinoid necrosis? Immune reactions in vessels, preeclampsia, hypertensive emergency
How is fibrinoid necrosis produced? Immune complexes combine with fibrin leading to vessel wall damage
Fibrinoid necrosis is considered what kind of hypersensitivity reaction? Type 3
What type of necrosis is seen in distal extremity and GI tract, after chronic ischemia? Grangenous necrosis
Dry gangrenous necrosis is due to _________________. Ischemia
Wet gangrenous necrosis is due to ________________. Superinfection
Inadequate blood supply to meet demand. Ischemia
What are the mechanisms that involve ischemia? 1. Decreased arterial perfusion 2. Decreased venous drainage 3. Shock
What organ is the most vulnerable to hypoxia/ischemia? Brain
What areas are of the brain most susceptible to hypoxia/ischemia? ACA/MCA/PCA boundary areas
What are the most vulnerables regions to hypoxia? Brain> Heart> Kidney> Liver> Colon
What type of cells are most affected by hypoxia? Neurons, especially those include Purkinje cells of the cerebellum and pyramidal cells of the hippocampus and neocortex
What are two main types of infarcts? Red infarcts and Pale infacts
What is another name for red infarcts? Hemorrhagic infarcts
Red infarcts are due to: Venous occlusion and tissues with multiple blood supplies, such as liver, lung, intestine, testes
What is the main concept behind the development of a red infarct? Reperfusion
Damage or injury due to reperfusion is due to _________________. Free radicals
What is another name for Pale infarcts? Anemic
Which type of organs produce pale infarcts? Solid organs with a single blood supply, such as heart, kidney, and spleen.
Which are the most common organs that have red infarcts? Liver, lung, intestines, and testes
Heart, kidney, and spleen are often seen with __________ infarcts. Pale
An organ with an end-arterial blood supply will most likely suffer on what kind of infarct? Pale infarct
What is inflammation? Response to eliminate initial cause of cell injury, to remove necrotic cells resulting from the original insult, and to initiate tissue repair.
What are the two main divisions of the inflammatory process? Acute and chronic
What conditions lead to a harmful inflammatory response to itself (host)? If it is: 1. Excessive (septic shock) 2. Prolonged (TB) 3. Inappropriate (autoimmune disease such as SLE)
What are the cardinal signs of inflammation? 1. Rubor (redness), calor (warthm) 2. Tumor (swelling) 3. Dolor (pain) 4. Functio laesa (loss of function)
How is the rubor and calor developed in the inflammatory response? Vasodilation (relaxation of arteriolar smooth muscle) --> increased blood flow.
What are the mediators of redness and warmth in inflammation? Histamine, prostaglandins, and bradykinin.
What is the mechanism of action of Swelling caused by the inflammatory process? Endothelial contraction/disruption --> increased vascular permeability --> leakage of protein-rich fluid from postcapillary venules into interstitial space (exudate) --> incrase in oncotic pressure
What is the end result of the process of swelling caused by inflammation? Increased oncotic pressure due to increased level of proteins in the interstitial space.
What mediators cause or regulate endothelial contraction? Leukotrienes (C4, D4, E4), histamine, and serotonin.
Sensitization of sensory nerve endings Dolor (pain)
What are the mediators for dolor? Bradykinin and PGE2
What are the 3 systemic manifestations of inflammation? Fever, leukocytosis, and increased plasma acute-phase reactants
When is leukocytosis commonly seen? As a systemic manifestation of inflammation
What is leukocytosis? Elevation of WBC count
What is a leukemoid reaction? Severe elevation in WBC (> 40,000 cells) caused by some stressors or infections
What is the initial step in the pathogenesis of fever? Pyrogens (LPS) induced macrophages to release IL-1 and TNF
Fever causes an increase in ______ in perivascular cells of the _______________. COX activity ; Hypothalamus
What areas of the CNS is associated with the development of fever? Hypothalamus
Which interleukin is notably for inducing acute phase reactants? IL-6
Where are acute-phase reactants produced? Liver
Which are the POSITIVE acute phase reactants? Ferritin, Fibrinogen, Serum amyloid A, Hepcidin, and C-reactive protein
Positive acute phase reactants _____________________. Upregulate
What are the two most significant negative (downregulated) acute phase reactants in the process of inflammation? Albumin and Transferin
Albumin and Transferrin are important ___________________. Negative acute-phase reactants
What is the role of ferritin? Binds and sequesters iron to inhibit microbial iron scavenging
What protein is known to inhibit microbial iron scavenging? Ferritin
Ferritin binds to __________. Iron
What is a coagulation factor, that is also a positive acute phase reactant? Fibrinogen
Promotes endothelial repair; correlates with ESR; Coagulation factor involved in inflammatory process? Fibrinogen
The level of fibrinogen is correlated with the amount of _______. ESR
What are the two main roles of Hepcidin? 1. Decrease iron absorption 2. Decrease iron release from macrophages
How does hepcidin decrease the amount of iron absorption? Degrating ferroportin
What acute phase reactant is known to degrade ferroportin? Hepcidin
The actions (prolonged) of hepcidin will result in the development of ___________________________. Anemia of chronic disease (ACD)
C-reactive protein is an _________________________. Opsonin
What is the main action or role of C-reactive protein? Fixes complement and facilitates phagocytosis
Nonspecific sign of ongoing inflammation C-reactive protein
What is the role of Albumin as an negative acute phase reactant? Reduction conserves amino acids for positive reactants
Which two acute phase reactants are seen in lower levels during inflammation? Albumin and Transferrin
What is the main reason for the low levels of albumin during inflammation? Conservation of amino acids needed for positive reactants
What is the role of Transferrin (downregulated) during inflammation? Internalized by macrophages to sequester iron
What is the abbreviation for Erythrocyte Sedimentation Rate? ESR
What is ESR? Products of inflammation coat RBCs and cause aggregation
The denser RBC aggregates ----> Fall at a faster rate within a pipette tube --> Increase ESR
What is often co-tested with CRP levels? ESR
What are common conditions with elevated ESR? 1. Most anemias 2. Infections 3. Inflammation 4. Cancer 5. Renal disease (ESD or nephrotic syndrome) 6. Pregnancy
Which is the only anemia with a decreased ESR? Sickle cell anemia
What product of inflammation is downregulated or lower in Sickle cell anemia? ESR
Why is Sickle cell anemia manifested with a decreased ESR? Altered shape of the RBC
List of conditions with decreased levels of ESR 1. Sickle cell anemia 2. Polycythemia 3. Heart failure 4. Microcytosis 5. Hypofibrinogenemia
What is decreased in Polycythemia, heart failure, and microcytosis? ESR
What WBC characterize acute inflammation? Neutrophils in tissue
Acute inflammation is a manifestation of the ___________ immune system. Innate
What is the most common clinical manifestation of acute inflammation? Edema
Which are the MC mediators of acute inflammation? Toll-like receptors, arachidonic acid metabolites, neutrophils, eosinophils, antibodies, mast cells, basophils, complement, and Hageman factor
What is the name of Factor XII? Hageman factor
What is an inflammasome? Cytoplasmic protein complex that recognizes procedures of dead cells, microbial products, and crystals
What is the result of an inflammasome activity? Activation of IL-1 and inflammatory response
What is the vascular component of acute inflammation? Vasodilation and endothelial permeability
What is the cellular component of acute inflammation? Extravasation of leukocytes from postcapillary venules and accumulation in the focus of injury followed by leukocyte activation
What is the purpose of vasodilation in acute inflammation? Bring cells and proteins to site of injury or infection
What are the 4 steps in leukocyte extravasation? 1. Margination and rolling 2. Adhesión 3. Transmigration 4. Migration (chemoattraction)
What cells predominate in the late states of acute inflammation? Macrophages
Which Interleukin indicates persistent acute inflammation? IL-8
What is the result of acute inflammation progressing into chronic inflammation? Antigen presentation by macrophages and other APCs --> activation of CD4+ Th cells
Where does most of leukocyte extravasation occur? Postcapillary venules
What condition is associated with defective Margination and Rolling, step of extravasation? Leukocyte adhesion deficiency type 2
What leukocyte component is decreased /absent/nonfunctional in LAD type 2? Sialyl-Lewis x
Which proteins, serum markers are involved in Margination and rolling step of Leukocyte extravasation? E-selectin, P-selectin, and GlyCAM-1, CD34
What is another way to refer to adhesion step in Extravasation of leukocytes? Tight binding
Defective Adhesion step in Leukocyte extravasation process leads to development of ___________________. Leukocyte adhesion deficiency type 1
LAD 2 is due to defective step ___ in Leukocyte extravasation 1
LAD type 1 is due to defective step ___ in leukocyte extravasation. 2
Decreased CD18 integrin subunit is seen in : Leukocyte adhesion deficiency type 1
ICAM-1 and VCAM-1 are involved in: Tight binding (adhesion) step of Leukocyte extravasation
CD54 indicates? ICAM-1
CD106 indicates? VCAM-1
PECAM is represented by CD_. 31
What is another term used for transmigration? Diapedesis
Description of Diapedesis (step 3) in Leukocyte extravasation WBC travels between endothelial cells and exits blood vessel
What happens during migration (step 4) of WBC extravasation? WBC travels through interstitium to site of injury or infection guided by chemotactic signals
What are some chemotactic products released during Migration in response to bacteria? C5a, IL-8, LTB4, kallikrein, platelet-activating factor
Which are the main cells involved in chronic inflammation? Macrophages, lymphocytes, and plasma cells
What are the most common stimuli for chronic inflammation? Persistent infections --> Type IV hypersensitivity, autoimmune diseases, prolonged exposure to toxic agents, and foreign material
All the cells involved in chronic inflammation which are the most dominant? Macrophages
Chronic inflammation is the result of macrophage interaction with? T-lymphocytes
Which T helper cell is involved in the classical activation of inflammatory (proinflammatory)? TH1 cells
Th2 cells secrete IL 4 and IL-13 --> Macrophage alternative activation
What is the result of the macrophage alternative activation in the process of chronic inflammation? Repair and anti-inflammatory
What is the composition of granulomas? Composed of epithelioid cells with surrounding multinucleated giant cells and lymphocytes.
Granulomas are a pattern of chronic ____________. Inflammation
What are epithelioid cells in granulomas? Macrophages with abundant pink cytoplasm
What subtype helper T cells aid in the formation of granulomas? Th1 cells
What is secreted by Th1 cells that activates macrophages, in the process of making granulomas? INF-gamma
What cytokine is known to induce and maintain granuloma formation? TNF-alpha
What is a possible adverse consequence of using anti-TNF drugs in a patient with a granulomatous disease? Sequestering granulomas can break down leading to a disseminated disease
Why is a TB test always performed prior to starting anti-TNF therapy? To prevent the breakdown of from granulomas in latent TB, and thus, avoid development of disseminated disease.
What is electrolyte condition is strongly associated with granuloma formation? Hypercalcemia due to calcitriol production
What is needed on biopsy to diagnose Sarcoidosis? Non-caseating granulomas
What are the most common granulomatous disease of BACTERIAL origin? - Mycobacteria (TB, leprosy) - Bartonella henselae (cat scratch disease) - Listeria monocytogenes (granulomatosis infantiséptica) - Treponema pallidum (3 Syphylis)
Endemic mycoses are _____________________ diseases. Granulomatous
What is a granulomatous disease due to a parasitic infection? Schistosomiasis
Crohn disease si an autoinflammatory ___________________ disease. Granulomatous
What foreign material ingestion (inhaled) materials are granulomatous disease? Berylliosis, talcosis, hypersensitivity pneumonitis
Primary biliary cholangitis and Subacute (de Quervain) thyroiditis, are both _____________________ diseases. Granulomatous
What are the two types of calcification? Dystrophic and Metastatic calcification
Which type of calcification is seen in abnormal tissues? Dystrophic
Dystrophic calcification extend tends to be _________________. Localized
Metastatic calcification has an extend commonly described as _______________________. Widespread
What are some associated conditions that exhibit dystrophic calcification? TB (lung and pericardium) Granulomatous infections Liquefactive necrosis of chronic abscesses Fat necrosis Infarcts, thrombi, Schistosomiasis Congenital CMV, Toxoplasmosis, Rubella, Psammoma bodies CREST syndrome Atherosclerotic plaques
What areas are most commonly affected by metastatic calcification? Interstitial tissues of the kidney, lung, and gastric mucosa
Dystrophic calcification is most likely due to: Secondary to injury or necrosis
What is the etiology (reason of development) of Metastatic calcification? Secondary to hypercalcemia or high Calcium-Phosphate product levels
What are some examples of high calcium-phosphate product level conditions? CKD with secondary hyperparathyroidism, long-term dialysis, calciphylaxis, multiple myeloma
What is the serum calcium level of a person with evidence of dystrophic calcification? Normocalcemic
Which type of calcification is seen with abnormal serum Ca2+ levels? Metastatic calcification
A yellow-brown "wear and tear" pigment associated with normal aging. Lipofuscin
How is Lipofuscin formed? By oxidation and polymerization of autophagocytosed organellar membranes
Which organs usually show most Lipofuscin deposition upon autopsy of the elderly? Heart, colon, liver, kidney, and eye.
What is the pigment usually found in during the autopsy of an elderly patient around the heart and kidneys? Lipofuscin
How do free radicals cause damage to cell? By membrane lipid peroxidation, protein modification, and DNA breakage.
What are ways to eliminate free radicals? 1. Scavenging enzymes (catalase, superoxide dismutase, glutathione peroxidase) 2. Spontaneous decay 3. Antioxidants 4. Metal carrier proteins (transferrin, ceruloplasmin)
When does scar formation occurs? When repair cannot be accomplished by cell regeneration alone.
In scar formation, the nonregulated cells, are replaced by ________________. Connective tissue
What are the two types of scar formation? Hypertrophic and Keloid
What collagen synthesis is increased in hypertrophic scar formation? Type III collagen
Which collagen types are increased in synthesis in Keloid formation? Type I and III collagens
Which type of scar formation has a much higher or significant (increased) collagen formation? Keloid formation synthesis much more collagen
Hypertrophic scar has its collagen arrangement in _______________, which Keloid shows a ______________ collagen organization. Hypertrophic ----------- parallel Keloid -------- disorganized
Which type of scar is confined to borders of original wound? Hypertrophic
Description Of extent of keloid scar Beyond borders of original wound with "claw-like" projection typically on earlobes, face, and upper extremities
Keloid formation has an increased recurrence in ethnic groups with _____________________. Darker skin
What two tissue mediators solely stimulate angiogenesis? FGF and VEGF
What is the role of PDGF? 1. Induce vascular remodeling and smooth muscle migration 2. Stimulates fibroblast growth for collagen synthesis
What cells secrete PDGF? Activated platelets an macrophages
Which tissue mediator is in charge of tissue remodeling? Metalloproteinases
What is the specific role of EGF? Stimulates cell growth via tyrosine kinases
What are the characteristics of Inflammatory phase of wound healing? Clot formation, increased vessel permeability and neutrophil migration into tissue
What is the second phase of wound healing? Proliferative
What cells are involved in the proliferative phase of wound healing? Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, and macrophages
What are the effector cell of the Inflammatory phase of wound healing? Platelets, neutrophils , and macrophages
What are the effector cells of the Remodeling phase of wound healing? Fibroblasts
What are the features of Proliferative phase of wound healing? Deposition of granulation tissue and type III collagen, angiogenesis, epithelial cell proliferation, dissolution o clot, and wound contraction
What cells mediated wound contraction? Myofibroblasts
What two deficiencies can delay wound healing? Vitamin C deficiency and Copper deficiency
Which stage of wound healing is Type III collagen replaced by type I collagen, and incrase tensile strength of tissue? Remodeling
While Vit C and copper deficiency cause delay in wound healing during the Proliferative phase, the deficiency of Zinc causes same effect in the ______________ phase of wound healing. Remodeling
What enzymes break down type III collagen? Collagenases
What metal (mineral) is required by Collagenases to function? Zinc
Timeframe of proliferative phase of wound healing Day 3 - weeks after wound
What is the common time frame for remodeling phase of wound healing? 1 week --- 6+ months after wound
What is amyloidosis? Abnormal aggregation of proteins into B-pleated linear sheets
What is the end result of amyloidosis? Cellular damage and apoptosis caused by formation of insoluble fibrils
What is the composition of the insoluble fibrils in amyloidosis? Abnormal aggregation of protein into B-pleated linear sheets
What methods and/or procedures can be used to visualize Amyloidosis? 1. Congo red stain 2. Polarized light (apple green birefringence) 3. H&E stain
What is shown in a H&E stain of amyloidosis sample? Deposits in glomerular mesangial areas and tubular basement membranes
What are the systemic types of amyloidosis? Primary, Secondary, and Dialysis-related amyloidosis
What is the fibril protein involved in Primary amyloidosis? AL (form Ig Light chains)
Which disorders are seen with primary amyloidosis? Multiple myeloma and plasma cell disorders
What are the manifestations of systemic amyloidosis? 1. Cardiac (RCM, arrhythmia) 2. GI (macroglossia, hepatomegaly) 3. Renal (nephrotic syndrome) 4. Hematologic (easy bruising, splenomegaly) 5. Neurologic (neuropathy) 6. Musculoskeletal (carpal tunnel syndrome)
What is the most significant Musculoskeletal manifestation of systemic amyloidosis? Carpal Tunnel syndrome
What type of cardiomyopathy is seen with systemic amyloidosis? Restrictive
Is nephritic or nephrotic syndrome associated with amyloidosis? Nephrotic
What is defective protein in secondary amyloidosis? Serum Amyloid A (AA)
What type of conditions (examples) produce secondary amyloidosis? Rheumatoid arthritis, IBD, familial Mediterranean fever, protracted infection
B2-microglobulin protein defect is seen with _________________ amyloidosis. Dialysis-related
What type of patients develop Dialysis-related systemic amyloidosis? ESRD and/or long-term dialysis
What are examples of localized Amyloidosis? Alzheimer disease, Type 2 DM, Medullary thyroid cancer, Isolated atrial amyloidosis, and Systemic senile amyloidosis
B-amyloid protein is involved in _________________ disease. Alzheimer
What is the protein involved in amyloidosis in Type 2 DM? Islet amyloid polypeptide (IAPP)
What is the etiology of Type 2 DM amyloidosis? Deposition of amylin in pancreatic islets
What arrhythmia is more likely to develop in a patient with isolated atrial amyloidosis? Atrial fibrillation
Which part of the heart is most affected in systemic senile amyloidosis? Cardiac ventricles
What are the two types of hereditary amyloidosis? Familial amyloid cardiomyopathy and Familial amyloid polyneuropathies
Mutated transthyretin (ATTR) causes---> Familial amyloid cardiomyopathy and Familial amyloid polyneuropathies
Created by: rakomi
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