Pathology Flashcards
(204 cards)
1
Q
What is the difference between hypertrophy and hyperplasia (including mechanism of action)?
A
Hypertrophy: ↑ size of cells via ↑ structural proteins and organelles
Hyperplasia: ↑ number of cells via proliferation of stem and differentiated cells
2
Q
What are examples of hypertrophy and hyperplasia?
A
Hypertrophy: Cardiac hypertrophy in respnose to chronic hypertension
Hyperplasia: Benign prostatic hyperplasia, endometrial hyperplasia (can become pathologic)
3
Q
What is the mechanism of atrophy?
A
↓ cell size via:
* Cytoskeleton degradation (ubiquitin-proteasome pathway)
* Autophagy (digestion of damaged/misfolded proteins)
Also involves ↓ protein synthesis and/or ↓ cell number (apoptosis)
4
Q
What are the causes of atrophy?
A
5
Q
What is the difference between metaplasia and dysplasia?
A
Metaplasia: Adaptive change — one mature cell type is replaced by another that can adapt to a new stressor
Dysplasia: Disordered, precancerous cell growth; not a true adaptive response
6
Q
What is the mechanism of metaplasia?
A
Reprogramming of stem cells → replacement of one cell type by another that can better adapt to a new stressor
7
Q
What are some examples of metaplasia?
A
Barrett esophagus (gastric reflux → intestinal epithelium in the esophagus)
Smoking (respiratory ciliated columnar epithelium → stratified squamous epithelium)
Myositis ossificans (formation of bone within muscle after trauma)
8
Q
Can dysplasia regress?
A
Yes — mild/moderate dysplasia may regress if the inciting cause is removed
9
Q
Which is considered a precancerous cell growth: metaplasia or dysplasia?
A
Dysplasia is considered a precancerous epithelial cell growth.
10
Q
What characterizes tissue dysplasia?
A
Disordered, precancerous epithelial cell growth
Loss of uniformity in cell size and shape (pleomorphism)
Loss of tissue orientation
Nuclear changes: ↑ nuclear:cytoplasmic ratio, clumped chromatin
11
Q
What does pleomorphism mean?
A
Pleomorphism refers to variation in size and shape of cells and their nuclei — a hallmark of dysplasia and malignancy.
12
Q
What may severe dysplasia progress into?
A
Severe dysplasia may become irreversible and progress to carcinoma in situ.
13
Q
What is dysplasia usually preceded by?
A
Dysplasia is usually preceded by persistent metaplasia or pathologic hyperplasia.
14
Q
What is the mechanism of reversible cellular injury?
A
↓ ATP → ↓ activity of ATP-dependent Ca²⁺ and Na⁺/K⁺-ATPase pumps → cellular swelling
15
Q
What is the earliest morphologic manifestation of reversible cellular injury?
A
Cellular swelling
16
Q
What swells in reversible cell injury?
A
Cytosol, mitochondria, endoplasmic reticulum, and Golgi
17
Q
What are plasma membrane changes in reversible injury?
A
Blebbing
18
Q
What happens to ribosomes in reversible injury?
A
Ribosomal/polysomal detachment → ↓ protein synthesis
19
Q
What is the significance of myelin figure aggregation in reversible cell injury?
A
Myelin figures are accumulations of peroxidized membrane lipids, indicating membrane damage. Their presence reflects ongoing oxidative stress and potential progression toward irreversible injury if the insult persists.
20
Q
What is the mechanism of irreversible cell injury?
A
Breakdown of plasma membrane → leakage of enzymes
Influx of Ca²⁺ → activation of degradative enzymes
21
Q
What happens to mitochondria in irreversible injury?
A
Damage/dysfunction → loss of electron transport chain → ↓ ATP
22
Q
How does autolysis occur in irreversible injury?
A
Rupture of lysosomes → release of enzymes → autolysis
23
Q
What is pyknosis?
A
Nuclear condensation (early stage of nuclear degradation)
24
Q
What is karyorrhexis?
A
Nuclear fragmentation caused by endonuclease-mediated cleavage
25
What is karyolysis?
Nuclear dissolution and complete disappearance of the nucleus
26
What is the second most important morphological correlate of reversible cell injury?
Fatty change: appearance of triglyceride containing lipid vacuoles in the cytoplasm. Mainly encountered in organs involved in lipid metabolisms (e.g. Liver).
27
3 characteristic phenomena of irreversible cell death
1. Inability to restore mitochondrial function (ATP) even after disappearance of noxious stimulus
2. Loss of structure and function of the plasma membrane
3. Loss of DNA and chromatin structural integrity
28
Mechanism of cell death in ischemia, toxin exposure, infections and trauma
Necrosis
29
Mechanism of cell death in less severe and non-accidental injury (e.g. during normal processes). Regulated cell death.
Apoptosis
30
What are the cytoplasmic changes in necrosis?
*Progressive **eosinophilia** (pinker cytoplasm) dye to increased RNA.
*Myelin figures
*Discontinuities in membranes
*Dilatation of mitochondria
31
3 types of nuclear changes in necrosis
1. Pyknosis = nuclear shrinkage and increased basophilia. The DNA condenses into a dark shrunken mass.
2. Karyorrhexis = pyknotic nucleus undergoing fragmentation.
3. Karyolysis = ultimately, basophilia fades due to digestion of DNA.
Within 1-2 days, the nucleus in a dead cell may completely disappear
32
What is the fate of necrotic cells?
a) persist for some time
b) digested by enzymes = disappear
c) replaced by myelin figures, which are either phagocytosed by other cells or further degraded in fatty acids, which bind calcium salts **resulting in calficiation of dead cells**
33
What are the 5 morphological patterns of necrosis?
1. Coagulative necrosis
2. Liquefactive necrosis
3. Caseous necrosis
4. Fat necrosis
5. Fibrinoid necrosis
34
Describe coagulative necrosis
Form of necrosis in which the underlying tissue architecture is preserved for at least several days after death of cells.
Affected tissue takes on a firm texture.
Necrosis denatures structural proteins AND enzymes = no degradation.
**Eosinophilic anucleate cells persist for days or weeks**.
35
How are dead cells ultimately cleared in coagulative necrosis
Leukocytes are recruited and ultimately digest the dead cells with lysosomal enzymes. Cellular debris is cleared by phagocytosis by macrophages and neutrophils.
36
In which diseases is there coagulative necrosis?
Infarcts of all solid organs except the brain.
37
What type of necrosis is seen in brain infarcts?
Liquefactive necrosis (poorly understood)
38
In which diseases is liquefactive necrosis typically seen?
bacterial and fungal infections
microbes stimulate rapid accumulation of inflammatory cells and the enzymes of these leukocytes digest (liquefy) the tissue
If initiated by infection = pus
39
What happens in gangrenous necrosis with no superimposed infection?
Coagulative necrosis of several tissue layers of a limb (generally lower) due to absent blood supply.
40
What happens in gangrenous necrosis with a superimposed infection?
The morphologic appearance changes from coagulative necrosis to liquefactive necrosis because of the destructive contents of the bacteria and the attracted leukocytes.
41
Describe caseous necrosis
Friable, yellow-white appearance (cheese-like) of the area of necrosis on gross examination.
Tissue architecture is completely obliterated, there are no cellular outlines.
42
Typical causative agent of caseous necrosis
Tuberculosis
43
Typical scenario causing fat necrosis
Typically due to release of pancreatic fat-digesting enzymes causing fat destruction in the peritoneal cavity. E.g. acute pancreatitis
44
Pathophysiology of fat necrosis
Pancreatic enzymes leaking out of acinar cells and ducts liquefy the membranes of fat cells in the peritoneum and fat is digested. Released fatty acids combine with calcium to produced grossly visible chalky white areas.
45
What is fat saponification?
Fat saponification is the process where free fatty acids released from fat cell breakdown combine with calcium to form chalky white calcium soaps.
It typically occurs in fat necrosis (e.g., pancreatitis or trauma to fat tissue).
46
Situations in which there is fibrinoid necrosis
Immune vascular reactions: Occurs in immune reactions in which Ab-Ag complexes are deposited in walls of vessels (type III HSTVT)
Non-immune vascular reactions: hypertensive emergency, preeclampsia.
47
Pathophysiology of fibrinoid necrosis
Immune complex deposition and/or plasma protein leakage from damaged vessel.
48
Characterize the plasma membrane of apoptotic cell
Remains intact (nothing leaks out of the cell), but becomes highly "edible" and reduced in size, such that they are very prone to phagocytosis.
49
Necrosis vs apoptosis in elliciting an inflammatory reaction
Necrosis = inflammation
Apoptosis = no inflammation
50
Give 5 examples of physiologic apoptosis
1. Embryogenesis
2. Turnover of proliferative tissues (intestinal epithelium, bone marrow, thymus)
3. Involution of hormone-dependent tissues (e.g. endometrium)
4. Decline of leukocyte numbers at the end of immune and inflammatory responses
5. Elimination of self-reactive lymphocytes
51
What two pathways of apoptosis converge into the pathway of caspase activation?
1) Mitonchondrial pathway (intrinsic)
2) Death receptor pathway (extrinsic)
52
Which pathway is responsible for most physiologic and pathologic apoptotic instances?
Mitochondrial pathway
53
Is apoptosis ATP-dependent?
Yes
54
What change in the DNA is a sensitive indicator of apoptosis?
DNA laddering (fragments in multiples of 180 base pairs)
55
Describe the mitochondrial pathway of apoptosis activation
1) DNA damage (ROS, toxins, radiation), misfolded proteins, hypoxia, or **deprived of growth factors**
2) p53 activation
3) p53 induces Bax/Bak
4) Bax/Bak induce Cytochrome C
5) Cytochrome C induces caspases
56
Which family of proteins regulate mitchondrial activation of apoptosis?
Bcl-2 and Bcl-xL normally inhibit Bax and Bak as well as cytochrome C formation.
57
Describe instances in which the mitochondrial pathway is activated
1. When regulating factor is withdrawn from a proliferating cell population (e.g. no more IL-12 for inflammation)
2. After exposure to injurious stimuli
58
What does BCL-2 overexpression lead to?
It is the MoA of follicular lymphoma t(14,18) in which there is overexpression of BCL-2 = decreased caspase activation = tumorigenesis.
59
Describe the extrinsic pathway of apoptosis
Also called the death receptor pathway
Most cells express tumor necrosis factor (TNF-alpha). One subtype of TNF-alpha receptor is the Fas receptor.
Fas (CD95) interaction with FasL on cytotoxic T cells leads to activation of the death receptor pathway via caspase 8.
60
Common example of Fas-FasL mediated apoptosis
Negative selection of T lymphocytes in thymus medulla
61
What is autoimmune lypmhoproliferative syndrome?
Defective Fas-FasL interaction = failure of clonal deletion = increased numbers of self-reacting lymphocyes. Presents with lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias.
62
3 commonest mechanisms of ischemia
1. Decreased arterial perfusion
2. Decreased venous drainage
3. Shock
63
Examples of decreased venous drainage-induced ischemia
Budd-Chiari syndrome (hepatic venous outflow obstruction)
Testicular torsion
64
What are the two types of infarcts?
Red (hemorrhagic) infarct – occurs in dual blood supply organs or with reperfusion.
Pale (anemic) infarct – occurs in solid organs with single blood supply (e.g., heart, kidney, spleen)
65
What type of cell death does accumulation of reactive oxygen species lead to?
Necrosis
66
What is oxidative stress?
Cellular anomalies induced by ROS (free radicals).
67
Instances in which there is oxidative stress
1. Chemical and radiation injury
2. Hypoxia
3. Cellular aging
4. Tissue injury caused by inflammatory cells
5. Ischemia-reperfusion injury
68
What are free radicals and why are they noxious?
Chemical species with a single unpaired electron in their outer orbit. Such chemical states are extremely unstable, such that they readily interact with organic molecules: **attacking lipids, proteins, nucleic acids**.
Also, molecules with which free radicals interact are also themselves turned into other types of free radicals.
69
Are ROS normally produced?
Yes, in mitochondria when there is a redox reaction to turn O2 into H2O.
It produces short-lived toxic intermediates such as superoxide (O2-) which is rapidly converted to H2O2 and water.
70
When do ROS become toxic?
When there is increased production and decreased clearance.
E.g. Radiation, toxins, reperfusion increase ROS, which may overwhelm the removal mechanisms and cause accumulation.
71
What are the pathological effects of ROS accumulation in the cell?
1) Lipid peroxidation = membrane damage
2) Protein modifications = breakdown, misfolding
3) DNA damage = mutations
72
Explain how ROS are used in host defense against bacteria
ROS mainly produced in neutrophils, macrophages as a weapon for destruction of ingested microbes.
Generated in the phagosome and phagolysosomes of these cells in a process called the **respiratory/oxidative burst**.
73
What is the role of catalase in ROS?
Present in peroxisomes, catalyzes the decomposition of H2O2 into water and oxygen. One of the most active enzymes known.
74
What is the clinical relevance of catalase in immunology?
Catalase allows certain bacteria and fungi to break down hydrogen peroxide (H₂O₂), making them resistant to oxidative killing by phagocytes.
In chronic granulomatous disease (CGD), where the oxidative burst is defective, catalase-positive organisms (e.g., Staph aureus, Aspergillus) cause recurrent infections because they eliminate the little H₂O₂ available for microbial killing.
75
How do exogenous and endogenous anti-oxidants work?
By either blocking the formation of free radicals or scavenging them after htey have formed.
76
Examples of families of free radical injury
1) Oxygen toxicity (retinopathy of prematurity, bronchopulmonary dysplasia, reperfusion injury)
2) Drug/chemical toxicity: acetaminophen overdose
3) Metal storage diseases: hemochromatosis (iron) , Wilson disease (copper)
77
What are the two types of pathological calcifications? Describe them.
Dystrophic calcification – occurs in damaged or necrotic tissues with normal serum calcium levels. Calcium metabolism is normal.
Metastatic calcification – occurs in normal tissues due to elevated **due to hypercalcemia** (e.g., hyperparathyroidism, chronic kidney disease)
78
What are psammoma bodies?
Psammoma bodies are concentrically laminated, calcified spherules with basophilic calcium deposits seen on histology.
79
In which conditions are psammoma bodies seen?
Papillary carcinoma (thyroid, kidney)
Somatostatinoma
Meningioma
Mesothelioma
Ovarian serous papillary cystadenocarcinoma
Milk (prolactinoma)
80
What is amyloidosis?
Amyloidosis is a condition caused by the extracellular deposition of misfolded proteins (amyloid) in β-pleated sheet form.
These deposits disrupt normal tissue structure and function, affecting organs such as the kidneys, heart, liver, and nerves.
81
With which stain are amyloid deposits visusalized?
Congo red stain and H&E stain
82
Examples of amyloidosis manifestations
83
What are the cardinal signs of inflammation? (5)
84
3 systemic manifestations of inflammation
1. Fever
2. Leukocytosis
3. Increased plasma acute phase reactants
85
What is the pathogenesis of fever?
Pyrogens (e.g., LPS) stimulate macrophages to release IL-1, IL-6, and TNF-α
These cytokines increase COX activity in anterior hypothalamus
**Prostaglandin E2 (PGE₂)** is produced
PGE₂ raises the hypothalamic set point → increased body temperature (fever)
86
Where are acute phase reactants produced?
Liver
87
Cytokine inducing acute phase reactants
IL-6
88
What is the role of telomeres in cell aging?
Telomeres are repetitive DNA sequences at chromosome ends that shorten with each cell division.
When telomeres become critically short, cells enter senescence or apoptosis, contributing to cellular aging.
In most somatic cells, telomerase is inactive, limiting regenerative capacity.
89
What is the role of ferritin in inflammation?
During inflammation, ferritin binds and sequesters free iron to reduce its availability to microbes, preventing microbial iron scavenging and growth.
**Ferritin increases with inflammation**
This is part of the body's nutritional immunity—limiting nutrients to pathogens during infection.
90
What is the role of haptoglobin in inflammation?
Haptoglobin binds free extracellular hemoglobin, preventing oxidative damage and limiting iron availability to microbes.
91
How is hepcidin useful during inflammation?
Hepcidin helps the body limit iron availability to pathogens by:
1. Blocking intestinal iron absorption
2. Trapping iron in macrophages
This is a protective response known as nutritional immunity, reducing iron needed for microbial growth — but it can also cause anemia of chronic disease.
92
What is the pattern of procalcitonin increase in inflammation?
Useful as a biomarker to distinguish bacterial vs viral infections.
93
What conditions increase ESR?
94
What conditions decrease ESR?
95
What does ESR (erythrocyte sedimentation rate) represent?
The rate at which RBCs aggregate.
RBCs normally remain separated via ⊖ charges. Products of inflammation (e.g., fibrinogen) coat RBCs → ↓ ⊖ charge → ↑ RBC aggregation. Denser RBC aggregates fall at a faster rate within a pipette tube → ↑ ESR.
96
What are common stimuli that trigger acute inflammation?
Infections, trauma, necrosis, and foreign bodies.
97
What are key mediators involved in acute inflammation?
Toll-like receptors, arachidonic acid metabolites, neutrophils, eosinophils, preformed antibodies, mast cells, basophils, complement, and Hageman factor (factor XII).
98
What is the role of the inflammasome in acute inflammation?
It detects dead cells, microbes, or crystals (e.g., uric acid), and activates IL-1 → inflammatory response.
99
What are the vascular changes during acute inflammation?
Vasodilation (↑ blood flow and stasis) and ↑ endothelial permeability via endothelial cell contraction which opens the interendothelial junctions.
100
What are the cellular changes during acute inflammation?
Extravasation of leukocytes (mainly neutrophils) from postcapillary venules → accumulation at the injury site → leukocyte activation.
101
What are the four steps of leukocyte extravasation?
Margination & rolling
Adhesion
Transmigration
Migration (via chemoattraction)
102
What cytokines mediate resolution of inflammation
IL-10, TGF-β
103
What cytokine mediates persistence of acute inflammation?
IL-8
104
When do macrophages predominate in acute inflammation, and what is their role?
Macrophages predominate in the late stages of acute inflammation (peak 2–3 days after onset) and influence the outcome by secreting cytokines.
105
What is PECAM-1 and what is its role in inflammation?
PECAM-1 (Platelet Endothelial Cell Adhesion Molecule-1) is a cell adhesion molecule involved in leukocyte transmigration across the endothelium.
It helps neutrophils pass through endothelial cell junctions during inflammation.
106
What is deficient in Leukocyte Adhesion Deficiency (LAD)?
LAD is caused by a deficiency in integrins (especially CD18, a β2 integrin subunit), impairing leukocyte adhesion and migration.
This leads to recurrent bacterial infections, delayed wound healing, and absence of pus despite high intravascular neutrophil counts.
107
What characterizes chronic inflammation?
Mononuclear infiltration (macrophages, lymphocytes, plasma cells) with simultaneous tissue destruction and repair, including angiogenesis and fibrosis.
108
What are the stimuli that lead to chronic inflammation?
Persistent infections (e.g., TB, T. pallidum, fungi, viruses), autoimmune diseases, toxic agents (e.g., silica), and foreign material.
109
What is the most important/dominant cell type in chronic inflammation?
Macrophages — they interact with T cells to sustain inflammation.
110
What do Th1 cells secrete and what is their effect in chronic inflammation?
Th1 cells secrete IFN-γ, leading to classical macrophage activation (pro-inflammatory).
111
What do Th2 cells secrete and what is their effect in chronic inflammation?
Th2 cells secrete IL-4 and IL-13, promoting alternative macrophage activation (anti-inflammatory and tissue repair).
112
What are the main mediators of tissue repair?
FGF (fibroblast growth factor)
TGF-β (transforming growth factor)
VEGF (vascular endothelial growth factor)
PDGF (platelet derived growth factor)
Metalloproteinases
EGF (endothelial growth factor)
113
How do FGF, TGF-β, VEGF, PDGF, and EGF differ in function?
FGF: Stimulates angiogenesis
TGF-β: Promotes angiogenesis and fibrosis
VEGF: Stimulates angiogenesis
PDGF: From platelets/macrophages; promotes vascular remodeling, smooth muscle migration, and fibroblast activation
EGF: Stimulates cell growth via tyrosine kinases (e.g., EGFR)
113
What is the relationship between fibroblasts and collagen?
Fibroblasts are the primary cells responsible for synthesizing collagen, which is a major component of the extracellular matrix essential for wound healing, tissue strength, and structural support.
113
What is the role of metalloproteases, and in which disease processes are they important?
Metalloproteases are enzymes that degrade components of the extracellular matrix, playing a key role in tissue remodeling during wound healing and inflammation.
They are crucial in:
Cancer invasion and metastasis (by breaking basement membranes)
Chronic inflammation and fibrosis
Atherosclerosis and aneurysm formation (via vessel wall degradation)
114
What are the main phases of wound healing and their timelines?
Inflammatory: up to 3 days
Proliferative: day 3 to weeks
Remodeling: 1 week to 6+ months
115
What happens during the proliferative phase of wound healing?
Deposition of granulation tissue
Type III collagen production
Angiogenesis, epithelial proliferation, wound contraction
Delayed if there's vitamin C or copper deficiency
116
What occurs during the remodeling phase of wound healing?
Type III collagen replaced by type I
Increased tensile strength
Collagenases (require zinc) break down type III collagen
Zinc deficiency delays healing
117
Which cells are involved in each phase of wound healing?
Inflammatory: platelets, neutrophils, macrophages
Proliferative: fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages
Remodeling: fibroblasts
118
Which nutritional deficiencies delay specific phases of tissue repair?
Vitamin C deficiency: Delays the proliferative phase (impaired collagen synthesis and angiogenesis)
Copper deficiency: Delays the proliferative phase (impaired cross-linking of collagen)
Zinc deficiency: Delays the remodeling phase (impaired collagenase function for collagen turnover)
119
What is the difference between type I and type III collagen in tissue repair?
120
What is the role of granulomatous inflammation?
It “walls off” resistant stimuli (e.g., microbes or foreign bodies) that cannot be fully eradicated, leading to persistent inflammation, fibrosis, and possible organ damage.
121
Why should patients be tested for TB before starting anti–TNF-α therapy?
TNF-α is crucial for maintaining granulomas that contain latent TB.
Blocking TNF-α (e.g., with infliximab or etanercept) can disrupt granulomas, leading to reactivation of latent tuberculosis.
122
What are the common etiologies of caseating granulomas?
Caseating granulomas are associated with central necrosis and are typically seen in infectious etiologies such as:
Tuberculosis (TB)
Fungal infections
123
What are the common etiologies of noncaseating granulomas?
Noncaseating granulomas have no central necrosis and are seen in noninfectious etiologies such as:
Sarcoidosis
Crohn disease
124
What causes scar formation instead of tissue regeneration?
Scar formation occurs when repair cannot be completed by cell regeneration alone. Non-regenerated cells are replaced by connective tissue, especially after severe acute or chronic injury.
125
What type of collagen and organization is seen in hypertrophic scars?
Collagen: ↑ type III collagen
Organization: Parallel
Confined to original wound borders
Infrequent recurrence
126
What type of collagen and organization is seen in keloid scars?
Collagen: ↑↑↑ types I and III collagen
Organization: Disorganized
Extends beyond original wound borders with clawlike projections
Frequent recurrence
127
What factors are associated with keloid formation?
Excess TGF-β (also in hypetrophic)
Increased incidence in individuals with darker skin
128
What percentage of tensile strength is regained after scar formation?
70–80% of tensile strength is regained by 3 months; little further gain occurs afterward.
129
What are the stages of neoplastic progression?
Normal cells
Dysplasia
Carcinoma in situ / preinvasive
Invasive carcinoma
Metastasis
130
What defines dysplasia?
Loss of uniformity in cell size and shape (pleomorphism), loss of tissue orientation, and nuclear abnormalities (↑ nuclear:cytoplasmic ratio); often reversible.
131
What differentiates dysplasia from carcinoma in situ?
Carcinoma in situ is **irreversible** and involves the **entire thickness of epithelium**, while dysplasia is often reversible and may be partial.
132
What must happen for carcinoma in situ to become invasive carcinoma?
The tumor cells must invade through the basement membrane, typically using collagenases and metalloproteinases.
133
What is the difference between a sarcoma and a carcinoma?
134
What is the relationship between E-cadherins and cancer?
E-cadherins are cell adhesion molecules that help maintain epithelial cell-cell adhesion.
Loss or inactivation of E-cadherins leads to reduced cell cohesion, enabling tumor cells to detach, invade, and metastasize.
135
What is differentiation and how is it linked to tumor malignancy?
Differentiation is the loss of normal cell features and function, seen in **poorly differentiated tumors**.
It is a hallmark of high malignancy.
136
What is tumor grade?
Tumor grade refers to the degree of cell differentiation and mitotic activity:
Low-grade: well differentiated
High-grade: poorly differentiated or undifferentiated (anaplastic)
Higher grade = more aggressive behavior.
137
What is tumor stage?
Tumor stage indicates the extent of invasion and spread from the original site.
Assessed by TNM system:
T = primary tumor size/invasion
N = lymph node involvement
M = metastasis (most important)
Stage is more predictive of prognosis than grade.
138
Which has more prognostic value: grade or stage?
Stage has greater prognostic value.
A high-stage, low-grade tumor often has a worse prognosis than a low-stage, high-grade tumor.
Stage = spread = survival impact.
139
What is growth signal self-sufficiency in cancer?
Cancer cells gain autonomy by mutations in proto-oncogenes or growth factor pathways (e.g., RAS, MYC, HER2, cyclins, CDKs), leading to autocrine signaling and uncontrolled proliferation.
140
What causes anti-growth signal insensitivity in cancer?
Loss of tumor suppressor genes (e.g., Rb) and E-cadherin function, leading to loss of contact inhibition and uncontrolled growth.
141
How do cancer cells evade apoptosis?
Through mutations in apoptosis-regulating genes like TP53 and BCL2, allowing survival despite DNA damage or stress.
142
What gives cancer cells limitless replicative potential?
Reactivation of telomerase, which prevents chromosome shortening and cell aging, allowing endless divisions.
143
How is sustained angiogenesis achieved in tumors?
↑ Pro-angiogenic factors (e.g., VEGF) or ↓ inhibitors.
Tumors grow blood vessels via angiogenesis (from extensions of existing capillaries) or recruit endothelial cells from bone marrow (vasculogenesis).
The vessels are less stable than regular vessels (leaky, dilated)
144
What is the Warburg effect?
Cancer cells shift from oxidative phosphorylation to aerobic glycolysis, producing lactic acid even in oxygen presence. It supports biosynthesis and fast proliferation.
145
How do tumor cells evade immune surveillance?
Normally, immune cells can recognize and attack tumor cells. For successful tumorigenesis, tumor cells must evade the immune system. Multiple escape mechanisms exist:
↓ MHC class I expression by tumor cells → cytotoxic T cells are unable to recognize tumor cells.
Tumor cells secrete immunosuppressive factors (eg, TGF-β) and recruit regulatory T cells to down regulate immune response.
Tumor cells up regulate immune checkpoint molecules, which inhibit immune response.
146
How do cancer cells invade tissues?
Loss of E-cadherin, degradation of ECM by metalloproteinases, and attachment to ECM proteins → locomotion and invasion.
147
What is the significance of the primary tumor site in metastasis?
It can predict the target organ of metastasis (e.g., lung → adrenal). Spread is often to the first encountered capillary bed.
148
What is the most common cancer overall ?
Skin cancer — in the order of basal > squamous >> melanoma — is the most common cancer.
149
What is the paraneoplastic cause of myasthenia gravis?
Autoantibodies against postsynaptic ACh receptors at the NMJ; associated with thymoma.
150
What is Lambert-Eaton myasthenic syndrome and its associated tumor?
Autoantibodies against presynaptic P/Q-type Ca²⁺ channels at the NMJ; associated with small cell lung cancer.
151
What causes paraneoplastic polycythemia?
↑ Erythropoietin production leads to high hematocrit; associated with pheochromocytoma, renal cell carcinoma, HCC, hemangioblastoma, and leiomyoma.
152
What is the paraneoplastic syndrome associated with acanthosis nigricans?
Hyperpigmented, velvety plaques in axilla and neck; seen in gastric adenocarcinoma and other visceral malignancies.
153
What cardiovascular changes occur with aging?
↓ Arterial compliance (↑ stiffness), ↓ aortic diameter, ↓ LV cavity size, ↑ myocardial hypertrophy, ↓ max HR, and valve calcification.
154
What GI changes are seen with aging?
↓ LES tone, ↓ gastric mucosal protection, and ↓ colonic motility.
155
How does aging affect the hematopoietic system?
↓ Bone marrow mass, ↓ bone marrow fat, and a less vigorous response to stressors (e.g., blood loss)
156
What is the effect of aging on the immune system?
Immunosenescence → ↓ naïve B and T cells, preserved memory B and T cells, and impaired response to new antigens (e.g., vaccines).
157
What musculoskeletal changes occur with aging?
↓ Skeletal muscle mass (sarcopenia), ↓ bone mass (osteopenia), and joint cartilage thinning.
158
What nervous system changes occur with aging?
↓ Brain volume (neuronal loss), ↓ cerebral blood flow, but cognitive function is mostly preserved normally.
159
How are special senses affected by aging?
↓ Accommodation (presbyopia), ↓ hearing (presbycusis), ↓ smell and taste.
160
What are the major skin changes with aging?
Atrophy with flattening of dermal-epidermal junction, ↓ collagen/elastin, ↓ sweat glands (↑ heat stroke), and ↓ sebaceous glands (xerosis cutis).
161
How does renal function change with aging?
↓ GFR (↓ nephrons), ↓ renal blood flow, ↓ hormonal function, and voiding dysfunction (e.g., urinary incontinence).
162
What happens to respiratory function with aging?
↑ Lung compliance (↓ elastic recoil), ↓ chest wall compliance (↑ stiffness), ↓ respiratory strength, and ↓ response to hypoxia/hypercapnia.
163
What is lipofuscin and where is it found?
Lipofuscin is a yellow-brown "wear and tear" pigment associated with normal aging.
It is composed of polymers of lipids and phospholipids complexed with protein, derived from lipid peroxidation.
Autopsy of older adults will reveal deposits in the heart, colon, liver, kidney, eye, and other organs.
164
What is the role of PD-L1 in cancer immune evasion?
Tumors overexpress PD-L1, which binds to PD-1 on activated T cells, NK cells, and B cells, converting T cells into exhausted T-cells that can’t kill cancer cells or secrete IL-2.
165
A 4-year-old boy has repeated ear and sinus infections, a wet cough, and breathing problems. He has crackles and wheezing in his lungs and his heart is located on the right side of his chest.
What part of his body is likely not working properly?
Dynein arms
- This is primary ciliary dyskenesia (Kartagener sydnrome = PCD + Situs Invertus)
166
Which cytokine is responsible for cachexia in cancer?
Tumor necrosis factor-α (TNF-α) is the main cytokine responsible for cachexia in cancer.
It is also known as cachectin and acts along with IL-1β and IL-6.
167
Which cytokine is primarily responsible for elevated ESR levels in cancer and chronic inflammation?
Interleukin-6 (IL-6) — it stimulates the liver to produce acute phase reactants like fibrinogen and globulins, which promote rouleaux formation and increase ESR.
168
What is the clinical relevance of HER2 in breast cancer?
HER2 is a tyrosine kinase receptor overexpressed in 20–30% of breast cancers. It promotes cell proliferation and is linked to poorly differentiated, rapidly growing tumors. HER2 status guides treatment with anti-HER2 monoclonal antibodies, such as trastuzumab.
169
What is the relevance of estrogen and progesterone receptors in breast cancer?
Breast cancers with high levels of estrogen and/or progesterone receptors have better outcomes. These receptors stimulate tumor growth, so anti-estrogen therapy (e.g., aromatase inhibitors, tamoxifen) is used to treat hormone receptor-positive breast cancer.
170
What is the most common cancer associated with osteoblastic bone metastases?
Prostate cancer.
171
What is a key cancer type that causes mixed osteolytic and osteoblastic bone metastases?
Breast cancer.
172
What is the primary cancer associated with osteolytic bone metastases?
Multiple myeloma.
173
What is the target and associated cancers of Chromogranin and Synaptophysin staining?
Target: Neuroendocrine cells
Tumors: Small cell carcinoma of the lung, carcinoid tumor, neuroblastoma
174
What does Cytokeratin stain identify and which tumors does it detect?
Target: Epithelial cells
Tumors: Epithelial tumors (e.g., squamous cell carcinoma)
175
Which tissue does Desmin staining identify, and which tumor does it indicate?
Target: Muscle
Tumors: Muscle tumors (e.g., rhabdomyosarcoma)
176
What is the target of Neurofilament staining and which tumor does it identify?
Target: Neurons
Tumors: Neuronal tumors (e.g., neuroblastoma)
177
What tissue does PSA staining detect and what cancer does it indicate?
Target: Prostatic epithelium
Tumors: Prostate cancer
178
What cells does PECAM-1/CD31 staining detect, and what tumors is it used for?
Target: Endothelial cells
Tumors: Vascular tumors (e.g., angiosarcoma)
179
What cells does S-100 staining target and which cancers is it associated with?
Target: Neural crest cells
Tumors: Melanoma, schwannoma, Langerhans cell histiocytosis
180
What does Vimentin staining detect and which tumors does it identify?
Target: Mesenchymal tissue (e.g., fibroblasts, endothelial cells, macrophages)
Tumors: Mesenchymal tumors (e.g., sarcoma), and others like endometrial carcinoma, renal cell carcinoma, meningioma
181
What is the difference between proto-oncogene and tumor suppressor gene mutations in terms of "one-hit" vs "two-hit" hypothesis?
Proto-oncogene mutations follow a "one-hit" model: a single activating mutation is enough to promote uncontrolled cell growth.
Tumor suppressor gene mutations follow a "two-hit" model: both alleles must be inactivated (mutated) to lose growth inhibition.
182
What cancer is associated with mutation of the APC tumor suppressor gene?
Colorectal cancer (associated with familial adenomatous polyposis – FAP)
183
What cancers are associated with BRCA1/BRCA2 gene mutations?
Breast, ovarian, prostate, and pancreatic cancers
184
Mutation of NF1 or NF2 is associated with what condition?
Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2)
185
Mutation in the RB1 gene is associated with which cancers?
Retinoblastoma and osteosarcoma
186
What syndrome is associated with TP53 mutation?
Li-Fraumeni syndrome (increased risk for sarcoma, breast/brain cancer, leukemia, and adrenal gland tumors)
187
Mutation of the WT1 gene is associated with which tumor?
Wilms tumor (nephroblastoma)
188
What cancers are associated with mutation in the MEN1 tumor suppressor gene?
Multiple Endocrine Neoplasia type 1 (MEN1), which includes:
Parathyroid tumors (→ hyperparathyroidism)
Pancreatic neuroendocrine tumors (e.g., gastrinomas, insulinomas)
Pituitary tumors (e.g., prolactinomas)
189
A chef cuts her thumb deeply with a knife. Which of the following sequences best describes the normal order of wound healing?
Fibrin clot formation → cellular infiltration → angiogenesis
190
What tumor is associated with the ABL oncogene?
Chronic myeloid leukemia
191
What cancers are associated with the ALK oncogene?
Large cell lymphoma, non–small cell lung cancer
192
What tumor is associated with the BRAF oncogene?
Melanoma
193
What cancer is associated with the HER1 oncogene?
Squamous cell lung cancer
194
What cancers are associated with the HER2/neu oncogene?
Breast cancer, ovarian cancer
195
What cancers are associated with MYC oncogene variants?
Neuroblastoma (NMYC), Burkitt lymphoma (c-MYC)
196
What cancers are associated with the RET oncogene?
Medullary thyroid cancer, pheochromocytoma
MEN2A
MEN2B
197
What is the normal function of BRCA1 and BRCA2?
BRCA1 and BRCA2 are tumor suppressor genes involved in the repair of double-strand DNA breaks via homologous recombination. They help maintain genomic stability by ensuring accurate DNA repair and preventing mutations that could lead to cancer.
Mutations in these genes impair DNA repair, increasing the risk of cancers such as breast, ovarian, prostate, and pancreatic cancer.
198
What two substances are primarily responsible for driving angiogenesis?
Vascular endothelial growth factor (VEGF) – Stimulates angiogenesis by increasing endothelial cell motility and proliferation, leading to the formation of new capillaries.
Fibroblast growth factor (FGF) – Promotes endothelial cell proliferation, migration, and differentiation; also contributes to embryogenesis, hematopoiesis, and wound repair.
199
What are the first genetic changes that initiate the adenoma-carcinoma sequence in the colon?
Inactivation of the APC gene and accumulation of β-catenin, leading to hyperproliferative epithelium.
This is responsible for the initial appearance of adenomatous polyps.
200
Which mutation drives the progression from hyperproliferative epithelium to adenoma in the colon?
K-ras activation promotes further growth and formation of an adenoma.
201
Which genetic alteration is responsible for the transition from adenoma to adenocarcinoma in the colon?
p53 inactivation leads to the final transformation into carcinoma.
202
What is the role of Nuclear Factor-kappa B (NF-κB) in the immune response?
NF-κB is a transcription factor that plays a key role in the immune response to infection and inflammation. It is normally inactive, bound to its inhibitor IκB. Upon activation of IκB kinase (e.g., by bacterial antigen binding to TLRs), IκB is ubiquitinated and degraded, releasing NF-κB to enter the nucleus and promote transcription of inflammatory proteins like cytokines, acute phase reactants, and adhesion molecules. It also upregulates IκB to regulate its own activity.
