USMLE-First Aid : Adaptations, Inflammation and Neoplasm Flashcards
Cellular Adaptations
Reversible changes that can be physiologic or pathologic. If stress is excessive or persistent, adaptations can progress to cell injury.
Hypertrophy
↑ structural proteins and organelles → ↑ in size of cells. Example: cardiac hypertrophy.
Hyperplasia
Controlled proliferation of stem cells and differentiated cells→ ↑ in number of cells.
Atrophy
↓ in tissue mass due to ↓ in size and/or number of cells (apoptosis).
Metaplasia
Reprogramming of stem cells → replacement of one cell type by another that can adapt to a new stress. Usually due to exposure to an irritant.
Dysplasia
Disordered, precancerous epithelial cell growth; not considered a true adaptive response. Characterized by loss of uniformity of cell size and shape (pleomorphism); loss of tissue orientation; nuclear changes
Coagulative Necrosis - Seen in :
Ischemia/infarcts in most tissues (except brain)
Coagulative Necrosis - Due to:
Ischemia or infarction; injury denatures enzymes → proteolysis blocked
Coagulative Necrosis - Histology:
Preserved cellular architecture (cell outlines seen), but nuclei disappear; ↑ cytoplasmic binding of eosin stain
Liquefactive Necrosis - Seen in :
Bacterial abscesses, brain infarcts
Liquefactive Necrosis - Due to:
Neutrophils/Microglia release lysosomal enzymes that
digest the tissue
Liquefactive Necrosis - Histology:
Early: cellular debris and macrophages
Late: cystic spaces and cavitation (brain)
Neutrophils and cell debris seen with
bacterial infection
Caseous Necrosis - Seen in :
TB, systemic fungi
Caseous Necrosis - Due to:
Macrophages wall off the infecting microorganism → granular debris
Caseous Necrosis - Histology:
Fragmented cells and debris surrounded
by lymphocytes and macrophages (granuloma)
Fat Necrosis - Seen in :
Enzymatic: acute pancreatitis (saponification of
peripancreatic fat)
Nonenzymatic: traumatic (eg, injury to breast tissue)
Fat Necrosis - Due to:
Damaged pancreatic cells release lipase,
which breaks down triglycerides; liberated fatty acids bind calcium → saponification (chalky white appearance)
Fat Necrosis - Histology:
Outlines of dead fat cells without peripheral nuclei; saponification of fat (combined with Ca2+) appears dark blue on H&E stain
Fibrinoid Necrosis - Seen in :
Immune vascular reactions (eg, Polyarteritis Nodosa)
Nonimmune vascular reactions
(eg, hypertensive emergency-Renal vessels, preeclampsia-Placenta)
Fibrinoid Necrosis - Due to:
Immune complex deposition (type III
hypersensitivity reaction) and/or plasma protein
(eg, fibrin) leakage from damaged vessel
Fibrinoid Necrosis - Histology:
Vessel walls are thick and pink
Gangrenous Necrosis - Seen in :
Distal extremity and GI tract, after chronic ischemia
Gangrenous Necrosis - Due to:
Dry: ischemia
Wet: superinfection
Gangrenous Necrosis - Histology:
Dry- Coagulative
Wet - Liquefactive superimposed on coagulative
Ischemia - Most Prone Regions: Heart
Subendocardium (LV)
Ischemia -Most Prone Regions: Brain - Watershed areas
Watershed areas (border zones) receive blood supply from most distal branches of 2 arteries with limited collateral vascularity. (From ACA,MCA,PCA) (This is also relevant for GI)
Ischemia -Most Prone Regions: Brain - Neurons most vulnerables
Purkinje cells of the cerebellum and pyramidal cells of the hippocampus and neocortex (zones 3, 5, 6).
Ischemia -Most Prone Regions: Kidney
Straight segment of proximal tubule (PT-medulla)
Thick ascending limb (TAL-medulla)
Ischemia -Most Prone Regions: Liver
Area around central vein (zone III)
Ischemia -Most Prone Regions: Colon
Splenic flexure (Griffith point),a rectosigmoid junction (Sudeck point)
Red infarct
Occurs in venous occlusion and tissues with
multiple blood supplies (eg, liver, lung , intestine, testes), and with reperfusion (eg, after angioplasty). Reperfusion injury is due to damage by free radicals.
Pale infarct
Occurs in solid organs with a single (endarterial) blood supply (eg, heart, kidney)
Systemic Amyloidosis:
Primary amyloidosis - Fibril and When is it seen?
AL (from Ig Light chains). Seen in Plasma cell disorders
eg, multiple myeloma
Systemic Amyloidosis:
Secondary amyloidosis - Fibril and When is it seen?
Serum Amyloid A (AA). Seen in chronic inflammatory
conditions, (eg, rheumatoid arthritis, IBD, familial
Mediterranean fever, protracted infection)
Systemic Amyloidosis:
Dialysis-related amyloidosis- Fibril and When is it seen?
β2-microglobulin. ESRD and long term dialysis
Localized Amyloidosis:
Alzheimer disease - Fibril
β-amyloid protein
Localized Amyloidosis:
Type 2 diabetes mellitus - Fibril
Islet amyloid polypeptide
IAPP
Localized Amyloidosis:
Medullary thyroid cancer - Fibril
Calcitonin
Localized Amyloidosis:
Isolated atrial amyloidosis - Fibril
ANP
Localized Amyloidosis: Systemic senile (age related) amyloidosis
Normal (wild-type) transthyretin (TTR)
Familial amyloid cardiomyopathy or polyneuropathies - Fibril
Mutated transthyretin (ATTR)
Detection of Amyloidosis
Congo red stain, apple-green birefringence
Common systemic menifestations of Amyloidosis
Restrictive cardiomyopathy, Macroglossia, Nephrotic
syndrome, carpal tunnel syndrome and Neuropathy
Rubor (redness), calor (warmth) - Mechanism:
Vasodilation by Histamine, prostaglandins, bradykinin, NO
Tumor (swelling-Inflammatory cardinal sign) - Mechanism:
Endothelial contraction and Vascular Permeability: leukotrienes (C4, D4, E4), histamine, serotonin
Dolor (pain) - Mechanism:
Sensitization of sensory nerve endings - Bradykinin, PGE2, histamine
Ferritin - Is it a Positive or Negative Acute Phase Reactant?
Positive Acute Phase Reactant - More FFiSH in the C
Ferritin - Binds and sequesters iron to inhibit microbial iron scavenging.
Fibrinogen - Is it a Positive or Negative Acute Phase Reactant?
Positive Acute Phase Reactant - More FFiSH in the C
Fibrinogen - Coagulation factor; promotes endothelial repair; correlates with ESR.
Serum amyloid A - Is it a Positive or Negative Acute Phase Reactant?
Positive Acute Phase Reactant - More FFiSH in the C
Serum amyloid A - Prolonged elevation can lead to amyloidosis.
Hepcidin - Is it a Positive or Negative Acute Phase Reactant?
Positive Acute Phase Reactant - More FFiSH in the C
Hepcidin - ↓ iron absorption (by degrading ferroportin) and ↓ iron release (from macrophages) → anemia of
chronic disease.
CRP - Is it a Positive or Negative Acute Phase Reactant?
Positive Acute Phase Reactant - More FFiSH in the C
CRP - Opsonin; fixes complement and facilitates phagocytosis. Measured clinically as a nonspecific sign of ongoing inflammation.
Albumin - Is it a Positive or Negative Acute Phase Reactant?
Negative Acute Phase Reactant
Albumin - Reduction conserves amino acids for positive reactants.
Transferrin - Is it a Positive or Negative Acute Phase Reactant?
Negative Acute Phase Reactant
Transferrin - Internalized by macrophages to sequester iron.
When is ESR elevated?
Most anemias, Infections, Inflammation, Cancer, Renal disease and Pregnancy
When is ESR lowered?
Sickle cell anemia, Polycythemia, HF, Microcytosis
and Hypofibrinogenemia
When is Procalcitonin elevated?
Infections - especially of bacterial origin
Wound healing - Tissue mediators:
FGF - Role
Stimulates angiogenesis
Wound healing - Tissue mediators:
TGF-β - Role
Angiogenesis, fibrosis
Wound healing - Tissue mediators:
VEGF - Role
Stimulates angiogenesis
Wound healing - Tissue mediators:
PDGF - Role
Remodeling and smooth muscle cell migration.
Stimulates fibroblast growth for collagen synthesis.
Wound healing - Tissue mediators:
Metalloproteinases - Role
Tissue remodeling
Wound healing - Tissue mediators:
EGF - Role
Stimulates cell growth via tyrosine kinases
Bacterial causes of Granuloma:
Mycobacterium Tuberculosis, Mycobacterium Leprae, Bartonella Henselae, Listeria monocytogenes, Treponema pallidum.
Fungal causes of Granuloma:
Endemic mycoses (eg; Histoplasmosis)
Protozoa causes of Granuloma:
Schistosomiasis
Immune-mediated (Non-Vascular) Etiologies for Granuloma:
Sarcoidosis, Crohn’s disease, PBC , subacute Thyroiditis
Vasculitis - Etiologies for Granuloma:
Wegener’s Granulomatosis, Churg-Strauss, Giant cell arteritis, Takayasu arteritis
Foreign bodies - Etiologies for Granuloma:
Berylliosis, Talcosis, Hypersensitivity pneumonitis
Hereditary Etiology for Granuloma:
Chronic Granulomatous disease
Basic Scheme of Neoplastic Progression:
Normal cells/Adaptations → Dysplasia → Carcinoma in situ → Invasive carcinoma → Metastasis
Carcinoma in situ/ preinvasive
Irreversible severe dysplasia that involves the entire thickness of epithelium but does not penetrate the intact basement membrane
Invasive carcinoma
Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases).
Cell-cell contacts lost by inactivation of E-cadherin.
Anaplasia
complete lack of differentiation of cells in a malignant neoplasm.
Grade
Degree of cellular differentiation and mitotic
activity on histology.
Stage
T = Tumor size/invasiveness, N = Node
involvement, M = Metastases, eg, cT3N1M0. (more prognostic value than grade)
What allows tumors to have Growth signal
self-sufficiency?
Mutations in genes encoding:Proto-oncogenes, Growth factor receptors, Signaling molecules, Transcription factors and Cell cycle regulators
What allows tumors to have Anti-growth signal
insensitivity?
Mutations in tumor suppressor genes and Loss of E-cadherin function
What allows tumors to have Limitless replicative potential?
Reactivation of telomerase
What allows tumors to have Immune evasion?
1) ↓ MHC class I expression by tumor cells → cytotoxic T cells are unable to recognize tumor cells.
2) Tumor cells secrete immunosuppressive factors (eg, TGF-β) and recruit regulatory T cells to
down regulate immune response.
3) Tumor cells up regulate immune checkpoint molecules, which inhibit immune response.
What is the Warburg effect?
Shift of glucose metabolism away from mitochondrial oxidative phosphorylation toward glycolysis.
Which Type of Cancers metastasize hematogenously?
All Carcinomas and 4 specific Types of Sarcomas: Hepatocellular Carcinoma, Renal cell carcinoma, Follicular Thyroid Carcinoma and Choriocarcinoma.
Which Type of Cancers metastasize in lymphogenous manner ?
All Sarcomas
(EXCEPT FOR 4 specific Types: Hepatocellular Carcinoma, Renal cell carcinoma, Follicular Thyroid Carcinoma and Choriocarcinoma)
What are the 3 Immune-checkpoint proteins that are targeted by Immunotherapies?
PD-L1
PD-1
CTLA-4
What are the 3 Immune-checkpoint proteins that are possible to be overexpressed by tumor cells for evasion?
PD-L1
PD-1
CTLA-4
Top 3 Mortality rates for Cancer in Men:
Cancer mortality in Men
- Lung
- Prostate
- Colon/rectum
Top 3 Incidence rates for Cancer in Men:
Cancer Incidence in Men
- Prostate
- Lung
- Colon/rectum
Top 3 Incidence rates for Cancer in Women:
Cancer Incidence in Women
- Breast
- Lung
- Colon/rectum
Top 3 Mortality rates for Cancer in Women:
Cancer mortality in Men
- Lung
- Breast
- Colon/rectum
Top 3 Mortality and Incidence rates for Cancer in Children:
Cancer mortality and Incidence in Children:
- Leukemia
- CNS
- Neuroblastoma
Brain as a site of Metastasis - Primary Tumor origin of Metastasis:
Lung > Breast > Melanoma, Colon, Kidney
Liver as a site of Metastasis - Primary Tumor origin of Metastasis:
Colon»_space; Stomach > Pancreas
Cancer Sometimes Penetrates liver
Bone as a site of Metastasis - Primary Tumor origin of Metastasis:
Prostate, Breast > Kidney, Thyroid, Lung
Painful Bones Kill The Lungs
Oncogene:
ALK - Associated Neoplasm
Lung Adenocarcinoma
Oncogene:
BCR-ABL - Associated Neoplasm
CML, ALL
Oncogene:
BCL-2 - Associated Neoplasm
B-Lymphoma
Oncogene:
BRAF - Associated Neoplasm
Melanoma, non-Hodgkin lymphoma, papillary
thyroid carcinoma, hairy cell leukemia
Oncogene:
c-KIT- Associated Neoplasm
GIST
Oncogene:
c-MYC - Associated Neoplasm
Burkitt’s Lymphoma
Oncogene:
HER2/neu - Associated Neoplasm
Breast and gastric carcinomas
Oncogene:
JAK2 - Associated Neoplasm
Chronic myeloproliferative disorders
Oncogene:
KRAS - Associated Neoplasm
Colon cancer, lung cancer, pancreatic cancer
Oncogene:
MYCL1 - Associated Neoplasm
Lung tumor
Oncogene:
N-myc - Associated Neoplasm
Neuroblastoma
Oncogene:
RET - Associated Neoplasm
MEN 2A and 2B; papillary thyroid carcinoma,
pheochromocytoma
Tumor Suppressor Gene:
APC - Associated Neoplasm
Colorectal cancer (associated with FAP)
Tumor Suppressor Gene:
BRCA1/BRCA2- Associated Neoplasm
Breast, ovarian, and pancreatic cancers
Tumor Suppressor Gene:
CDKN2A- Associated Neoplasm
Melanoma, pancreatic cancer
Tumor Suppressor Gene:
MEN1- Associated Neoplasm
Multiple Endocrine Neoplasia type 1 - Prolactinoma, VIPoma and Parathyroid Adenoma
Tumor Suppressor Gene:
NF1/2- Associated Neoplasm
Neurofibromatosis 1 / 2 - Schwannoma, Pheochromocytoma, Meningiomas, Ependymomas
Tumor Suppressor Gene:
Rb- Associated Neoplasm
Retinoblastoma, Osteosarcoma
Tumor Suppressor Gene:
TP53- Associated Neoplasm
Most human cancers, Li-Fraumeni syndrome
(multiple malignancies at early age, aka, SBLA
cancer syndrome: Sarcoma, Breast, Leukemia,
Adrenal gland)
Tumor Suppressor Gene:
VHL- Associated Neoplasm
von Hippel-Lindau: Hemangioblastomas, Renal cell carcinomas, Pheochromocytomas
Tumor Suppressor Gene:
WT1- Associated Neoplasm
Wilms tumor (nephroblastoma)
Carcinogens - Aflatoxins (Aspergillus):
Exposure and Associated Cancer
Aflatoxins (Aspergillus) from Stored grains and nuts
Hepatocellular carcinoma
Carcinogens - Alkylating agents:
Exposure and Associated Cancer
Alkylating agents from Oncologic chemotherapy
Leukemia/lymphoma
Carcinogens - Arsenic:
Exposure and Associated Cancer
Arsenic from Herbicides and metal smelting
Angiosarcoma, Lung cancer, Squamous cell carcinoma
Carcinogens - Asbestos
Exposure and Associated Cancer
Asbestos from Old roofing material, shipyard
Bronchogenic carcinoma > Mesothelioma
Carcinogens - Aflatoxins (Aspergillus):
Exposure and Associated Cancer
Aflatoxins (Aspergillus) from Stored grains and nuts
Hepatocellular carcinoma
Carcinogens - Alkylating agents:
Exposure and Associated Cancer
Alkylating agents from Oncologic chemotherapy
Leukemia/lymphoma
Carcinogens - Arsenic:
Exposure and Associated Cancer
Arsenic from Herbicides and metal smelting
Angiosarcoma, Lung cancer, Skin Squamous cell carcinoma
Carcinogens - Asbestos
Exposure and Associated Cancer
Asbestos from Old roofing material, shipyard
Bronchogenic carcinoma > Mesothelioma
Carcinogens - Nitrosamines
Exposure and Associated Cancer
Smoked foods - Nitrosamines
Intestinal Type Gastric Adenocarcinoma
Carcinogens - Radon
Exposure and Associated Cancer
Byproduct of uranium decay, accumulates in basements - Radon Lung cancer (2nd leading cause after cigarette smoke)
Carcinogens - Aflatoxins (Aspergillus):
Exposure and Associated Cancer
Aflatoxins (Aspergillus) from Stored grains and nuts
Hepatocellular carcinoma
Oncogenic microbes - EBV: Associated cancer
EBV:
Burkitt lymphoma, Hodgkin lymphoma,
nasopharyngeal carcinoma, 1° CNS lymphoma
Oncogenic microbes - HBV, HCV: Associated cancer
Hepatocellular carcinoma
Oncogenic microbes - HHV-8: Associated cancer
Kaposi sarcoma
Oncogenic microbes - HPV: Associated cancer
Cervical and penile/anal carcinoma (types 16,
18), Laryngeal Carcinoma (Other Head and Neck Cancers)
Oncogenic microbes - H pylori: Associated cancer
Gastric adenocarcinoma and MALT lymphoma
Oncogenic microbes - HTLV-1: Associated cancer
Adult T-cell Leukemia/Lymphoma
Oncogenic microbes - Liver fluke (Clonorchis sinensis): Associated cancer
Cholangiocarcinoma
Oncogenic microbes - Schistosoma haematobium: Associated cancer
Squamous cell bladder cancer
Serum tumor markers - Important Associations:
Alkaline phosphatase
Alkaline phosphatase: Metastases to bone or liver, Paget disease of bone, seminoma (Exclude hepatic origin by checking LFTs and GGT levels)
Serum tumor markers - Important Associations:
α-Fetoprotein
α-Fetoprotein: Hepatocellular carcinoma, Endodermal sinus tumor, Mixed germ cell tumor, Ataxia-telangiectasia, Neural tube defects.
Serum tumor markers - Important Associations:
hCG
hCG: Hydatidiform moles and Choriocarcinomas
(Gestational trophoblastic disease), testicular
cancer, mixed germ cell tumor.
Serum tumor markers - Important Associations:
CA 15-3/CA 27-29
CA 15-3/CA 27-29: Breast Cancer
Serum tumor markers - Important Associations:
CA 19-9
CA 19-9: Pancreatic Adenocarcinoma
Serum tumor markers - Important Associations:
CA 125
CA 125: Ovarian Cancer
Serum tumor markers - Important Associations:
Calcitonin
Calcitonin: Medullary Thyroid Carcinoma
Serum tumor markers - Important Associations:
CEA
CEA: Colorectal Carcinoma and Pancreatic cancers.
There are other minor associations
Serum tumor markers - Important Associations:
Chromogranin
Chromogranin: Neuroendocrine tumors
Serum tumor markers - Important Associations:
LDH
LDH: Testicular germ cell tumors, ovarian
dysgerminoma. Can be used as an indicator of tumor burden.
Serum tumor markers - Important Associations:
Neuron-specific enolase
Neuron-specific enolase: Neuroendocrine tumors (eg, small cell lung cancer, carcinoid tumor, neuroblastoma)
Serum tumor markers - Important Associations:
PSA
PSA: BPH, Prostatitis and Prostatic Adenocarcinoma
Important immunohistochemical stain:
For Neuroendocrine cells Tumors
Chromogranin and Synaptophysin
Important immunohistochemical stain:
For Epithelial cells Tumors
Cytokeratin
Important immunohistochemical stain:
For Muscle cells Tumors
Desmin
Important immunohistochemical stain:
For Neuroglial Tumors
GFAP
Important immunohistochemical stain:
For Neuronal Tumors
Neurofilament
Important immunohistochemical stain:
For Prostatic epithelium Tumors
PSA
Important immunohistochemical stain:
For Neural Crest Cells Tumors
S-100
Important immunohistochemical stain:
For Hairy Cell Leukemia
TRAP- Tartrate-resistant acid phosphatase
Important immunohistochemical stain:
For Mesenchymal Tissue Tumors
Vimentin
P-Glycoprotein (Aka MDR1) - In which tumors and what is the consequence?
Classically seen in adrenocortical carcinoma.
Pumps out toxins,including chemotherapeutic agents - Multidrug Resistant
What are the tumors that present Psammoma bodies on Histology?
PSAMMOMa Bodies : Papillary thyroid carcinoma, SSToma (Islets Carcinoma), Meningioma, Mesothelioma, Ovarian serous cystadenocarcinoma and prolactinoma(MILK).
Paraneoplastic syndromes - Most Commonly associated tumors with:
Dermatomyositis
Dermatomyositis - Adenocarcinomas, especially ovarian
Paraneoplastic syndromes - Most Commonly associated tumors with:
Acanthosis nigricans
Acanthosis nigricans - Gastric Adenocarcinoma (and DM)
Paraneoplastic syndromes - Most Commonly associated tumors with:
Sign of Leser-Trélat ( multiple seborrheic keratoses)
Sign of Leser-Trélat - GI adenocarcinomas
Paraneoplastic syndromes - Most Commonly associated tumors with:
Hypertrophic osteoarthropathy
Hypertrophic osteoarthropathy - Lung Adenocarcinoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Hypercalcemia←PTHrP
Hypercalcemia←PTHrP: Squamous cell carcinomas of lung, head, and neck; renal, bladder, breast, and ovarian carcinomas and Lymphoma.
Paraneoplastic syndromes - Most Commonly associated tumors with: Cushing syndrome←ACTH
Cushing syndrome←ACTH: Small cell Lung Carcinoma
Paraneoplastic syndromes - Most Commonly associated tumors with: SIADH
SIADH: Small cell Lung Carcinoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Polycythemia←EPO
Polycythemia←EPO:Pheochromocytoma, Renal cell carcinoma, Hepatocellular Carcinoma, hemangioblastoma, leiomyoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Good syndrome/Hypogammaglobulinemia
Hypogammaglobulinemia: Thymoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Anemia with low reticulocytes
Anemia with low reticulocytes: Thymoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Trousseau syndrome
Trousseau syndrome: Adenocarcinomas, especially pancreatic
Paraneoplastic syndromes - Most Commonly associated tumors with: Marantic Endocarditis
Marantic Endocarditis: Adenocarcinomas, especially pancreatic
Paraneoplastic syndromes - Most Commonly associated tumors with: Anti-NMDA receptor encephalitis
Anti-NMDA receptor encephalitis: Ovarian teratoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Opsoclonus-myoclonus ataxia
syndrome
Opsoclonus-myoclonus ataxia
syndrome: Neuroblastoma (children), small cell lung
cancer (adults)
Paraneoplastic syndromes - Most Commonly associated tumors with: Paraneoplastic cerebellar degeneration
Paraneoplastic cerebellar degeneration: Small cell lung cancer (anti-Hu), gynecologic and breast cancers (anti-Yo), and Hodgkin lymphoma (anti-Tr)
Paraneoplastic syndromes - Most Commonly associated tumors with: Paraneoplastic encephalomyelitis
Paraneoplastic encephalomyelitis: Small cell lung carcinoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Lambert-Eaton myasthenic syndrome
Lambert-Eaton myasthenic syndrome: Small cell lung carcinoma
Paraneoplastic syndromes - Most Commonly associated tumors with: Myasthenia gravis
Myasthenia gravis: Thymoma
Cachexia - What is it and What are the mediators?
Weight loss, muscle atrophy, and fatigue that occur in chronic disease - Mediated by TNF-α, IFN-γ, IL-1, and IL-6.